Patients with peripheral arterial disease (PAD) are generally less intensively managed than patients with coronary heart disease (CHD), despite that their risk of complications is believed to be equivalent. Identification of PAD patients at risk of poorly controlled blood pressure (BP) could lead to improved treatment, thus lowering the risk of cardiovascular (CV) complications. We aimed to describe the prevalence of poorly controlled cardiovascular (CV) risk factors, focusing on BP, in outpatients with PAD diagnosed in a vascular ultrasound laboratory.n = 402) and examined with blood sampling, clinical BP, and 24-h ambulatory BP measurements. A poorly controlled clinical BP was defined as ≥140/90 mmHg, ambulatory BP ≥130/80 mmHg, low-density lipoprotein (LDL)-cholesterol level ≥2.5 mmol/L, and glycated hemoglobin (HbA1c) level >53 mmol/mol in those with diabetes.Consecutive outpatients with carotid and/or lower extremity PAD were included  and ambulatory BP (51.7%) profiles. Antihypertensive medications were prescribed in 84% of the patients. However, >40% of them used only 0–1 medication, and <25% of them used three or more agents. Clinical BP, a low number of medications, body mass index, and the presence of diabetes independently predicted a poorly controlled ambulatory BP. Nearly one-third of the patients were smokers, and most of the cohort had an LDL-cholesterol level of ≥2.5 mmol/L. An HbA1c level of >53 mmol/mol was present in 55% of diabetic patients.Poorly controlled clinical and ambulatory systolic BP profiles were common. In addition, suboptimal control of other important CV risk factors was detected. The findings of this study highlight the need for better preventive efforts against CV risk factors in outpatients with PAD. Peripheral arterial disease (PAD) is a common clinical manifestation of systemic arterial atherosclerosis, affecting arteries other than the coronary arteries, intracranial arteries, and the aorta , 2. AtheThe overall prevalence of hypertension in adults is about 30–45%, and it becomes more common with advancing age . Among rAnalyses were based on patients included in the Peripheral Arterial Disease in Västmanland (PADVa) study . All patn = 15)  accepted the invitation to join the study. Everyone in the study was offered ABPM, of whom 35 individuals refused. We excluded patients with <10 daytime or <5 night-time ABPM readings (n = 15) , leavingThe study was approved by the Ethics Committee of Uppsala University, Sweden (Dnr 2005:382). All participants gave their written informed consent to participate. The study is registered with ClinicalTrials.gov number NCT01452165.All patients were invited to the Department of Clinical Physiology and were examined according to a standard examination protocol, comprising a questionnaire, including the number of persons in household , educational level (low level was defined as primary school or less), smoking status (smoking defined as regular smoking within the past year), medical history, medication, and physical activity . Self-reported diagnoses of CV disease and diabetes mellitus were confirmed from the medical records.Participants fasted overnight, and venous blood samples were taken by trained staff and immediately sent to the accredited Laboratory of Clinical Chemistry, Västmanland County Hospital, Västerås. The estimated glomerular filtration rate (eGFR) was calculated from creatinine levels standardized by isotope dilution mass spectrometry  using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula .Glycated hemoglobin (HbA1c) mono was determined using a TOSOH Glycohemoglobin Analyzer G7  and calibrated against the Swedish Mono-S method. The HbA1c was calculated from HbA1c mono using the formula: 10.45 × (HbA1c mono level) – 10.62 . The treatment target level for diabetics (≤53 mmol/mol) was based on the European Society of Cardiology (ESC) guidelines from 2003 .The serum total cholesterol (TC) concentration was determined using a UniCel DxC 800 or SYNCHRON LX20 Analyzer . Levels of low-density lipoprotein cholesterol (LDL-cholesterol) were calculated from those of TC, high-density lipoprotein cholesterol (HDL-cholesterol), and triglycerides using the Friedewald equation: (LDL-cholesterol = TC – HDL-cholesterol – Triglyceride levels × 0·45). The treatment target levels of LDL-cholesterol are based on the ESC guidelines from 2003 (<2.5 mmol/L) and 2019 (<1.4 mmol/L) , 30.Based on a standard 12-lead surface electrocardiography (ECG), left ventricular (LV) hypertrophy was defined as the Sokolow–Lyon voltage >35 mV or Cornell voltage >28 mV in men and >20 mV in women.Blood pressure in both arms and ankles was measured in all included participants in a supine position after at least 5 min rest. The ankle BP was measured in the bilateral dorsalis pedis and posterior tibial arteries using an inflatable leg-cuff, an aneroid sphygmomanometer, and a handheld Doppler instrument with a 5-MHz probe. The ABI was calculated by dividing the highest ankle pressure by the highest BP of both arms. An abnormal ABI was defined as ≤0.90 or ≥1.40 in either leg.Carotid artery ultrasonography has been described in detail . BrieflyClinical BP was measured manually by trained technicians and was obtained from the non-dominant arm or from the other arm if the systolic BP was >10 mmHg higher. The BP was measured from participants in the supine position after at least 5 min rest and was rounded up to the nearest 2 mmHg. Using the arm from which clinical BP was obtained, the ABPM 04 instrument  was applied for 24-h ABPM with readings taken every 20 min . Three dThe clinical BP was defined as poorly controlled if systolic BP was ≥140 mmHg or diastolic BP was ≥90 mmHg. The corresponding definition for ambulatory BP was a 24-h ambulatory systolic BP of ≥130 mmHg or diastolic BP ≥80 mmHg , 32. Whihttp://www.r-project.org). Two-sided P values <0.05 were considered to be statistically significantData are presented as mean ± standard deviation or frequency and (percentage). To investigate potential predictors of a poorly controlled ambulatory BP, we used logistic regression analysis. In a multivariable model, we included available variables that have been proposed or established in previous studies: age, sex, body mass index (BMI), smoking habit, educational level, living alone, physical activity, diabetes, eGFR, previous myocardial infarction (MI), stroke, heart failure, abnormal ABI, ICA stenosis, number of antihypertensive medications, LV hypertrophy, and clinical systolic and diastolic BP –18. StatNearly a third of the patients (28%) were smokers . Among pn = 283). Results of ABPM revealed that 120 (29.9%) patients exhibited white coat hypertension and 20 (5.0%) patients showed masked hypertension. An ambulatory 24-h systolic BP of ≥130 mmHg was detected in 207 (51.5%) patients and a 24-h diastolic BP of ≥80 mmHg observed in 40 (10.0%).Most of our patients with PAD had poorly controlled BPs, especially clinical BP (76.6%), but also ambulatory BP (51.7%) . A cliniAntihypertensive medications were prescribed in 84% of patients. The number of drugs was remarkably similar in patients with well-controlled and poorly controlled ambulatory BP . More thP = 0.604) but a higher ambulatory 24-h systolic BP .In a logistic regression analysis, higher clinical systolic BP, higher BMI, fewer antihypertensive medications, and diabetes mellitus were independent predictors of a poorly controlled ambulatory BP independently . ClinicaWe found that both clinical and ambulatory systolic BPs were poorly controlled in our outpatients with PAD, and that many of these patients appeared to have undergone suboptimal treatment with few antihypertensive medications. Patients with diabetes had an increased risk of poorly controlled ambulatory BP. Moreover, a high proportion of the patients were still smokers and with hyperlipidemia, further emphasizing that preventive care against CV risk factors could be improved in such patients. Among the patients with poorly controlled clinical BP, one-third had white coat hypertension, whereas only 5% of the patients exhibited masked hypertension. BMI, diabetes mellitus, number of medications, and clinical systolic BP were independent predictors of a poorly controlled ambulatory BP.The results of this study suggest that a substantial proportion of outpatients with PAD have undertreated systolic hypertension. In contrast, diastolic BPs were better controlled, which is in accordance with previous findings in patients with PAD and likely derives from the stiffness of arteries caused by atherosclerosis .Elevated BP is the most important risk factor for death and disability worldwide, accounting for almost 10 million deaths in 2015 . Only a Data on optimal BP treatment target levels in patients with PAD are conflicting. Possibly, lowering BP too far in these patients might reduce perfusion in lower limbs and increase the risk of PAD-related events. In a reanalysis of data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the association of clinical BPs with incident PAD events  was evaluated. The authors found a U-shaped association of systolic BP with PAD events. Higher rates of lower extremity PAD events were observed with high (>160 mmHg) as well as with low (<120 mmHg) systolic BP and with low diastolic BP (<70 mmHg) . In contA combination of drugs is recommended as first-line therapy against hypertension for most patients according to the latest guidelines . In a reIn the general population, white coat hypertension can be found in up to 30–40% of subjects with an elevated in-clinic BP level, and masked hypertension can be observed in around 15% of patients with a normal in-clinic BP level . AmbulatThe clinical features that predicted a high ambulatory BP were not surprising. The prevalence of hypertension is known to be increased in individuals with other CV risk factors, such as obesity and diabetes , 31. ThaIn parallel with poorly controlled BP profiles, it is obvious that the control of other important CV risk factors was weak in our population. Nearly 30% of our patients were smokers, which is markedly more common than in the general population, where the prevalence of smoking in Sweden has decreased from 14% to 7% between 2006 and 2018 according to the Public Health Agency of Sweden. Smoking is a particularly strong risk factor for PAD . SmokingThe latest European guidelines recommend lipid-lowering treatments in all patients with PAD, including a maximum tolerated dose of statins, plus ezetimibe or in combination with a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if needed. The use of statins and addition of a PCSK9 inhibitor to further lower the LDL-cholesterol level seem to provide a favorable effect on lower limb prognosis, in addition to further reduction of CV events , 39. A nDiabetes mellitus is strongly associated with an elevated risk of PAD and with worse outcomes , 10. HerThat many of our outpatients with PAD were still smokers and with LDL-cholesterol levels of ≥2.5 mmol/L, and that many with diabetes had HbA1c levels >53 mmol/mol, in addition to poorly controlled hypertension, suggests the need for improved preventive care in such individuals.n = 162) did not differ in age (P = 0.68) or sex (P = 0.93) compared with the participants. However, if more burdened with disease, these dropouts may have been a source of bias. The participants who declined ABPM (n = 35) or were excluded due to few ABPM readings (n = 15) did not differ significantly from the included participants regarding age, sex, BMI, smoking, diabetes, previous myocardial infarction, or stroke . Data on medication were based on self-reported information, which might be a cause of informational bias. However, good agreement between patient interview and computerized pharmacy records has been found in the elderly population (This research study was limited to consecutive outpatients of European origin who were found to have lower extremity and/or carotid artery disease in a visit to a vascular ultrasound laboratory. The invited patients who declined to join the study (pulation . The cliIn our outpatients with PAD, diagnosed in a vascular ultrasound laboratory, poorly controlled clinical and ambulatory systolic BP profiles were common. Those receiving a higher number of antihypertensive agents had a better BP control, thus suggesting room for improvement. In addition, we found a suboptimal control of other important CV risk factors in these patients, including smoking, HbA1c levels in those with diabetes mellitus, and LDL-cholesterol levels. This study will help in motivating intensified preventive efforts against CV complications in outpatients with PAD.


De novo thrombotic microangiopathy accounts for the majority of cases. Distinguishing between the 2 conditions can be difficult, given there is an overlap between them. Complement overactivation is the cornerstone of all post-transplant thrombotic microangiopathies, and has been demonstrated in the context of organ procurement, ischemia-reperfusion phenomena, immunosuppressive drugs, antibody-mediated rejection, viral infections, and post-transplant relapse of antiphospholipid antibody syndrome. Although treatment of the causative agents is usually the first line of treatment, this approach might not be sufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve renal function. Complement blockade with eculizumab has been shown to be an effective therapy in post-transplant thrombotic microangiopathy, but it is necessary to define which patients can benefit from this therapy and when and how eculizumab should be used.Thrombotic microangiopathy is a rare but serious complication that affects kidney transplant recipients. It appears in 0.8–14% of transplanted patients and negatively affects graft and patient survival. It can appear in a systemic form, with hemolytic microangiopathic anemia, thrombocytopenia, and renal failure, or in a localized form, with progressive renal failure, proteinuria, or arterial hypertension. Post-transplant thrombotic microangiopathy is classified as recurrent atypical hemolytic uremic syndrome or  Thrombotic microangiopathy (TMA) is a life-threatening disease, characterized by endothelial dysfunction and the presence of thrombi in small blood vessels. As the thrombus forms, there is platelet consumption and mechanical disturbance of red blood cells, leading to thrombocytopenia and microangiopathic hemolytic anemia. Vessel occlusion results in tissue ischemia and organ damage, primarily affecting the kidneys, although other organs can be involved –4.Escherichia coli . De novo PT-TMA is caused by various pathogenic mechanisms, whereas aHUS recurrence is a consequence of complement system deregulation triggered by several activating conditions (Post-transplant thrombotic microangiopathy (PT-TMA) is a rare but devastating condition that can lead to poor patient and graft outcomes. It can occur as a nditions . The prinditions .de novo PT-TMA is much more frequent than recurrent aHUS , but the risk associated with the development of PT-TMA is much higher  in patients with a history of aHUS . In the chronic phase, the characteristic lesions are double contour formation in peripheral walls with hyaline deposits in arterioles and fibrous intimal thickening with concentric lamination (onion skin). By electron microscopy, new subendothelial basement membrane and widening of the subendothelial zone can be observed , 25, 38.After the diagnosis of TMA, the etiology of the native kidney ESRD should be investigated to rule out previously missed aHUS .The overall prognosis for PT-TMA is quite poor for the allograft and for the patient, resulting in a graft loss rate of 33–40% in the first 2 years , 21, 23,de novo PT-TMA.At the time of kidney transplantation, the coincidence of several mechanisms that activate the complement system can trigger the recurrence of aHUS in patients with a genetic background or the development of In aHUS, the recurrence risk is determined by a genetic mutation in complement proteins –41, 48. De novo aHUS has also been described in patients with C3 glomerulopathy in the native kidneys  is suspected when there is a sudden onset acute kidney injury, usually within hours or a few days after drug exposure, and resolution can be observed when the drug is stopped or reduced , 89, 113de novo PT-TMA has been well documented in the literature, with the risk higher with cyclosporine than with tacrolimus , with or without IVIg and additional immunosuppression –68. DespPT-TMA that is unresponsive to the previous measures has typically been treated with PE. PE has been shown to reduce mortality in TTP patients , 94, andEculizumab, a recombinant, fully humanized monoclonal antibody targeted against human complement protein C5, blocks generation of the lytic C5b-9 MAC. It has been shown to be effective in the treatment and prevention of recurrent aHUS after transplantation –103. In Neisseria meningitidis serogroups B, A, C, W135, and Y is mandatory. Vaccination should be administered 2 weeks before initiation of eculizumab treatment. But in PT TMA, usually it is not possible to delay eculizumab treatment two weeks, and prophylactic antibiotic should be used in the meantime. Given neither vaccines nor prophylaxis guarantee full protection against meningitis, patients and their families should be taught to recognize the alarm signs and symptoms of the infection ; in secondary TMA, however, it is not clearly addressed. In previous reports, a short course of eculizumab was shown to be an efficient therapy to control TMA and to reduce the risk of graft loss due to this disease. Discontinuation of the therapy can be considered when complications of TMA have completely resolved, and on a case-by-case basis. It can also be considered when the kidney function has not improved after 3 to 6 months or when a lack of viability of the kidney graft is documented by means of a kidney biopsy or imaging tests .The current data are not strong enough to expand the recommendation for the use of eculizumab in all patients with PT-TMA, but in cases resistant to treatment of the offending event, eculizumab is a good therapeutic option. Although PE has been used, its efficacy is limited and it is important to note that in patients with PT-TMA, the sooner eculizumab starts, the better the renal function will be at the end of the follow-up , 98.de novo or recurrent, on allograft survival is underestimated. Several factors related to the donor and procurement process and to the recipient and events during the post-transplant period , trigger the development of this disease. The treatment of PT-TMA includes management of the offending event, PE, and recently, eculizumab, with promising results. However, further studies are needed to establish which PT-TMA kidney transplant recipients are most likely to benefit from eculizumab therapy, including when and how to use it given the high economic burden associated with this approach.The incidence and the impact of PT-TMA, either All authors contributed to the article and approved the submitted version.AA have received fees for conferences from Alexion pharmaceutical. 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.


Previous studies found visit-to-visit heart rate variability (VVHRV) may be positively associated with risks of several cardiovascular events, but whether VVHRV affected the benefit of intensive blood pressure control remained unknown. In this study, we assessed the risk of the composite cardiovascular outcomes associated with VVHRV among the older patients with hypertension and evaluated whether the benefit of intensive blood pressure control in the prevention of the composite cardiovascular outcomes was consistent in the context of elevated VVHRV.post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). We explored the relationship between VVHRV and the composite cardiovascular outcomes by multivariate Cox proportional hazard regressions. The primary endpoint was the composite cardiovascular outcomes, same as SPRINT, defined as a composite of myocardial infarction, stroke, heart failure, and/or death from cardiovascular causes. We used multiple adjustment models for all regressions.This was a Nine thousand two hundred and fourty-seven patients from the SPRINT were included in our analysis. We found a positive association between VVHRV and the risk of composite cardiovascular outcomes among the elderly with hypertension. Per 1 CV increment in HRCV, the hazard ratio of the risk of composite cardiovascular outcomes was 1.04  in the fully adjusted Model. The benefit of intensive blood pressure control in managing cardiovascular events was consistent in different VVHRV subgroups. There was no significant interaction in other confounders.We found the VVHRV was associated with the composite cardiovascular outcomes among the elderly with hypertension, intensive blood pressure control did not change the above association, and the benefits of intensive blood pressure management were consistent across different VVHRV groups. High resting heart rate (RHR) was reported as a predictor of cardiovascular diseases and cardiovascular mortality in the general population as well as in the elderly according to several epidemiology studies . In patiIn order to solve the measurement error of RHR, the coefficient of variation of heart rate (HRCV) was often calculated to represent the visit-to-visit heart rate variability (VVHRV), which became an emerging risk indicator for cardiovascular diseases. Accumulating evidence proved that VVHRV may be positively associated with risks of several cardiovascular events, such as myocardial infarction, heart failure, atrial fibrillation, and cardiovascular mortality –7. The Shttps://biolincc.nhlbi.nih.gov/studies/sprint/). The rationale, protocols, and main results of the SPRINT have been published previously  to assess the visit-to-visit heart rate variability (VVHRV). HRCV was calculated using the following formula: HRSD = The primary outcome of this study was the composite cardiovascular outcomes. The composite cardiovascular outcomes were the first occurrence of cardiovascular events after randomization, including myocardial infarction (MI), non-MI acute coronary syndrome (non-MI ACS), new-onset stroke, heart failure, and death attributable to CVD. The definition of clinical outcomes was previously published in the SPRINT protocol .t-test  or Mann-Whitney U test (skewed distribution) were used to determine any significant differences between the means or medians of the groups. The normal distribution of data was assessed by Kolmogorov-Smirnov test.We assessed baseline characteristics and crude outcomes stratified by the tertiles of HRCV: T1: the low tertile; T2: the middle tertile; T3: the high tertile. Categorical variables were expressed as frequencies and percentages. Means ± standard deviations or medians (interquartile ranges) were used for continuous variables based on the distribution of data. Differences in categorical variables were evaluated using the Chi-square analysis. The two-tailed According to the recommendation of the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement . we conshttp://www.R-project.org). Statistical significance was set at P < 0.05.All analyses were performed using the statistical software packages R , P = 0.25] was not significantly different from that in the low HRCV tertile in Model 3. We also used HRCV as a continuous variable to investigate the relationship between HRCV and outcomes (The association between visit-to-visit HRCV and composite cardiovascular outcomes was shown in outcomes . HRCV waoutcomes .P for interaction = 0.013) or systolic blood pressure categories  and HRCV on composite cardiovascular outcomes. The effect of HRCV on the risk of composite cardiovascular outcomes was smaller in participants aged 75 years or older  than in those aged <75 years . HRCV remained significantly associated with increased risk of outcome in patients with baseline systolic blood pressure ≤ 132 mmHg or between 133 and 144 mmHg, but not in patients with baseline systolic blood pressure ≥145 mmHg . The results in other subgroups were shown in The restricted cubic splines in P for interaction = 0.111) and intensive blood pressure control.In this study, we found a positive association between VVHRV and the risk of composite cardiovascular outcomes among the elderly with hypertension. Increased VVHRV was an independent predictor of a higher risk of cardiovascular events. The benefit of intensive blood pressure control in managing cardiovascular events was consistent in different VVHRV subgroups. In clinical work, long-term heart rate variability should be paid more attention rather than one-time measurement. VVHRV should be paid attention to in the management of elderly patients with hypertension, whether using standard or intensive blood pressure treatment.The effect of long-term HR variability on health outcomes was studied in several epidemiology research. A population-based prospective cohort study in the Kailuan Chinese community found long-term RHR variability to be positively associated with all-cause mortality . ResultsThe causal mechanism of long-term variation of RHR leading to cardiovascular outcomes remained unclear. It was hypothesized that VVHRV reflects sympathetic overactivity, which may induce myocardial work and activate platelet, leading to several cardiovascular outcomes including thrombosis and arrhythmia . VVHRV wBoth RHR and VVHRV were proven to be positively associated with the risk of cardiovascular outcomes. A sub-study of the SPRINT randomized controlled trial found that the increase in the risk of composite cardiovascular events toward elevated baseline RHR was more potent in hypertensive subjects received intensive blood pressure treatment, compared to those with standard blood pressure treatment . Howeverpost-hoc analysis of SPRINT trial found that long-term HR variability was positively associated with the risk of composite cardiovascular outcomes among older patients with hypertension. Intensive blood pressure control did not change the above association, and the benefits of intensive blood pressure management were consistent across different VVHRV groups. In clinical settings, less attention need be paid on VVHRV when treating hypertensive patients with intensive blood pressure regimen. Further studies were needed to extrapolate these results to the general population.In conclusion, this https://biolincc.nhlbi.nih.gov/studies/sprint/.Publicly available datasets were analyzed in this study. This data can be found here: RZ and ZW completed the writing of the paper. KY applied for the database and made statistical analysis. WC was responsible for the revision of the paper. All authors confirmed the final version of the paper, contributed to the article, and approved the submitted version.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.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. 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Multivariate regression analysis confirmed that age  and LBMI  independently influenced the tacrolimus C/D ratio. A LBMI assessed by BIA may influence the tacrolimus metabolism in the early post-transplant period and can be a useful in the optimization of initial tacrolimus dosing.There are several premises that the body composition of kidney transplant recipients may play a role in tacrolimus metabolism early after transplantation. The present study aimed at analyzing the relationship between the body composition parameters assessed by bioimpedance analysis (BIA) and initial tacrolimus metabolism. Immediately prior to transplantation, BIA using InBody 770 device was performed in 122 subjects. Tacrolimus concentration-to-dose (C/D) ratio was calculated based on the first blood trough level measurement. There was no difference in phase angle, visceral fat area, lean body mass index (LBMI) and the proportion of lean mass as a percentage of total body mass between the subgroups of slow and fast metabolizers. However, subjects with LBMI ≥ median value of 18.7 kg/m Nowadays, the calcineurin inhibitor tacrolimus is the primary therapeutic option for patients after kidney transplantation. However, due to its substantial intra- and inter-patient variability in metabolism rate the accurate dosing is still challenging ,2,3. MorTo date, several different approaches were proposed in order to optimize the initial tacrolimus dosing, including clinical factors and CYP3A5 genotyping ,12,13 asThus, the aim of our prospective study was to investigate the relationship between several recipient’s body composition parameters acquired by bioimpedance analysis (BIA) and the tacrolimus metabolism rate in the first days after kidney transplantation.We prospectively analyzed all 153 consecutive patients who received their kidney transplant in our center between August 2019 and June 2021. After the exclusion of patients using tacrolimus prior to the most recent transplantation, those with insufficient data and those who withdraw consent to participate, 122 subjects were included in the final analysis . The stuIn each patient, the bioimpedance analysis of body composition was performed immediately prior to kidney transplantation procedure. The first tacrolimus blood trough level was determined within first day’s post-transplantation.2), lean body mass (LBM) and lean body mass index  were calculated. Additionally, the proportion of LBM as a percentage of total body mass was also calculated and analyzed. We also performed the segmental lean analysis in 5 different body sectors: both arms, trunk and both legs.The body composition analysis was performed within few hours before transplantation procedure using BIA device  with a multifrequency analyzer . All measurements were performed according to the manufacturer’s instructions. Patients refrained from eating for minimum 5 h. During examination, patients stepped barefoot on the footplate containing separate foot electrodes and additionally held the right- and left-hand electrodes. Based on the measurements and BIA software program equations, intracellular water (ICW), extracellular water (ECW), total body water (TBW), ECW/TBW ratio, phase angle, visceral fat area , mycophenolate mofetil and steroids, with an induction therapy using basiliximab or rabbit antithymocyte globulin (rATG). First doses of tacrolimus and mycophenolate were given pre-operatively. Mycophenolate mofetil was started from 750 mg BID. Steroids were given intravenously during operation (500 mg), then 125 mg i.v. the next day and subsequently 20 mg of oral prednisolone daily. Patient receiving rATG was given 125 mg of methylprednisolone instead of prednisolone before each dose.All patients received routine immunosuppression regimen, consisted of twice daily tacrolimus . Based on the first tacrolimus blood trough level measurement, the tacrolimus C/D ratio was calculated.According to the center protocol, the tacrolimus dose was prescribed based on patients’ body weight. In order to avoid tacrolimus levels exceeding 15 ng/mL, the initial tacrolimus dose was decreased  in patients older than 55 years, with BMI >25 kg/mDelayed graft function (DGF) was defined as a need for dialysis therapy in the first post-transplant week. Acute rejection (AR) was diagnosed based on the results of protocol biopsy performed at a median 8th post-transplant day.2 test . Variables with skewed distribution were compared using the Mann-Whitney U test. The second analysis compared patients with LBMI equal and above or lower than median value, using similar tests. Stepwise multiple regression analysis was performed for the tacrolimus C/D ratio as a dependent variable and age, BMI, the amount of residual diuresis, and LBMI as potential independent variables. For all analyses, a p value below 0.05 was considered statistically significant.Statistical analyses were performed using Statistica 13.3 PL for Windows  and MedCalc v19.2.1 . Values are presented as means with 95% confidence interval, medians with interquartile ranges or frequencies. The main study comparison was performed between groups of patients allocated based on the initially calculated tacrolimus C/D ratio, using the Student t-test (for quantitative variables) or the χp < 0.01). There was a tendency to more frequent re-transplants and lower HLA class II mismatch in the fast metabolizers group . As expected, despite the substantially lower initial tacrolimus dosing, slow metabolizers presented significantly higher tacrolimus level and almost 4-fold more subjects reached the supratherapeutic drug level  vs. 9.1 (7.1–10.8) ng/mL; p = 0.88, at discharge: 9.4 (7.2–10.9) vs. 8.7 (7.6–9.7) ng/mL; p = 0.33, respectively).There was no difference between the groups in the time from transplantation to the day of the first tacrolimus blood trough level measurement (median 2 (2–3) vs. 2 (2–3) days; ug level . Neverthp = 0.07). However, the median serum creatinine concentrations during the hospital stay (3rd post-transplant day: 5.0 (2.8–8.1) vs. 3.5 (2.2–7.9) mg/dL; p = 0.29, 7th day: 2.3 (1.3–5.8) vs. 1.9 (1.2–5.5) mg/dL; p = 0.33, respectively) and at discharge (1.5 (1.1–2.1) vs. 1.5 (1.1–1.8) mg/dL; p = 0.68) were similar. Of note, the frequency of early AR episodes was also similar in both groups  vs. 14 (13–19) in fast metabolizers, respectively; h groups .p = 0.90), with comparable values of systolic and diastolic blood pressure measured at 7th post-operative day 9SBP: 135 (130–150) vs. 140 (130–160); p = 0.18, DBP: 80 (80–90) vs. 85 (80–90); p = 0.55) and at discharge from the hospital (SBP: 130 (120–140) vs. 130 (125–140); p = 0.38, DBP: 80 (75–90) vs. 80 (78–85); p = 0.49).The BIA parameters describing the pre-transplant hydration status were also comparable between study groups, including the detailed lean mass analysis in 5 individual segments of the body. In line, the median post-transplant weight loss during the hospital stay was similar in both groups (3.1 (2.2–4.1) vs. 3.2 (2.3–4.1) kg in slow and fast metabolism groups, respectively; p = 0.01). On the other hand, we also noted a weak reverse association between the residual diuresis and tacrolimus C/D ratio .Interestingly, we found a significant positive association between the post-transplant weight loss and the amount of pre-transplant residual diuresis  and LBMI , whereas the correlations with LBM  and phase angle  were less pronounced. Of note, we found a weak reverse correlation between LBMI and tacrolimus C/D ratio . None of the remaining above analyzed parameters correlated significantly with tacrolimus C/D ratio.There were no significant differences between both analyzed groups in BIA parameters which reflect the proportion of fat and lean body mass  . In the p = 0.50), but the subjects with LBMI ≥ 18.7 kg/m2 had significantly greater BMI (27.4 (26.5–28.4) vs. 23.7 (22.6–24.8) kg/m2; p < 0.001) and residual diuresis (median 600 (250–1500) vs. 175 (0–1000) mL; p < 0.01) than subjects with LBMI below median value. They also presented significantly greater phase angle (5.4 (4.8–5.9) vs. 4.7 (4.2–5.3); p < 0.001), greater percentage of pre-transplant hydration measured in 5 different body compartments and greater median body weight reduction during the first post-transplant hospitalization (5.3 (2.8–6.3) vs. 1.9 (0.5–3.3) kg; p < 0.001).In additional analysis, in which all study patients were assigned into two groups based on the value of BIA-derived LBMI equal and above or lower than median value, both groups were comparable in recipient age (49.0 (45.8–52.2) vs. 47.4 (44.1–50.8) years, respectively; p = 0.94), the group of patients with LBMI ≥ 18.7 kg/m2 had a significantly lower tacrolimus C/D ratio (median 1.39 (0.94–1.79) vs. 1.67 (1.00–2.28), respectively; p < 0.05) in comparison with the other group. As a consequence, regardless of the significantly higher initial tacrolimus dosing in subjects with the LBMI ≥ 18.7 kg/m2 (median 12.0 (7.0–13.0) vs. 8.0 (4.0–10.0) mg/day; p < 0.001), the first tacrolimus blood trough level was similar in both groups (median 11.8 (7.8–18.5) vs. 10.4 (7.4–15.8) ng/mL, respectively; p = 0.32). Multiple regression analysis revealed that age  and LBMI  independently influence the tacrolimus C/D ratio.At baseline, there were no differences in dialysis vintage, CIT, ECW/TBW, and visceral fat area between those groups. However, despite similar initial tacrolimus dose per kg of body weight (median 0.13 (0.09–0.15) vs. 0.14 (0.07–0.15) mg/kg/day; To our best knowledge, this is the first study which analyze the association between various parameters of body composition and the early post-transplant tacrolimus metabolism in kidney transplant patients. Hereby, we showed the independent association between the lean body mass index, calculated based on the bioimpedance measurement and the first post-transplant C/D ratio. This finding is of potential importance as it may be useful for the more precise tacrolimus dose determination immediately prior to kidney transplantation.It is worth to noticing that tacrolimus C/D ratio calculated at 3-month or 6-month post-transplant time-point was previously shown to be a risk factor for significantly worse patient survival, worse kidney graft function and survival, higher rejection rate and the development of calcineurin inhibitor nephrotoxicity and BK nephropathy ,20,21. ORecently, an increasing interest is observed in the literature in the role of body composition-based pharmacokinetic analyses in an effort to reduce severe drug toxicity. Particularly sarcopenia and body composition in cancer is being studied extensively, resulting in the emergence of body composition-tailored drug administration schemes . As it wIn our transplant center, based on clinical observations and previous reports, we started to reduce the initial tacrolimus dose from 0.2 to 0.1–0.15 mg/kg/day in older and overweight/obese patients since 2011. However, as we summarized our experience, we found that such a policy did not decrease the percentage of subjects with supratherapeutic first tacrolimus level substantially . The preAmong the study limitations it should be noticed that the bioimpedance measurements were performed around the clock, when the potential recipients of a kidney from deceased donors were arriving to the transplant center. However, they abstained from eating for a minimum of 5–6 h prior to the examination, as they were aware of the planned transplantation and the pre-transplant dialysis session was performed. Another limitation is the lack of CYP3A5 genotyping in our patients. However, Polish Caucasian population is rather homogenic, with the vast majority of subjects (approximately 90%) being slow calcineurin inhibitor metabolizers . MoreoveTo conclude, in our present study we found the independent influence of LBMI on the very early tacrolimus C/D ratio post kidney transplantation. Thus, one could expect that based on this immediately assessed, non-invasive body composition parameter it will be possible to more precisely adjust the initial tacrolimus dose in order to minimize its potential toxicity. However, the clinical utility of this novel covariate for the optimization of tacrolimus dosing is still to be proven and needs the prospective validation in the randomized study.


Background and objective: Nephrolithiasis (NL) is a public health problem in the population of Southeast Mexico because of its high prevalence and recurrence. The evolution of this pathology can result in renal damage and may even cause chronic kidney disease (CKD), leading to a reduced glomerular filtration rate (GFR), decreased kidney function, and kidney loss in advanced stages. However, few studies support this evidence in the population. The present study aimed to determine risk factors associated with CKD in adult patients in an endemic population of Mexico. Materials and methods: A case-control study was carried out with patients diagnosed with NL. Additionally, the clinical information of patients , characteristics of the stones , and biochemical parameters were collected. Results: The recurrence of NL was associated with CKD . In addition, male sex (p = 0.016), surgical history (p = 0.011), bilateral kidney stones (p < 0.001), and urinary tract infections (p = 0.004) were other factors associated with CKD. Interestingly, thirty-two patients younger than 50 years old with >2 surgical events presented a significant decrease in GFR (p < 0.001). Conclusions: The recurrence of NL and the number of surgical events were risk factors associated with CKD in patients with NL treated in our population. Nephrolithiasis (NL) is a disease characterized by a saturation of crystals in the nephrons that can generate kidney stones and damage renal tissue and function . GeneticThe worldwide prevalence of NL ranges from 1% to 20%, varying according to age, sex, race, geographic location, and environmental factors. For example, a higher incidence has been reported in men 40–60 years old compared with women .Patients with NL have a 51–68% chance of developing chronic kidney disease (CKD) ,8.The Centers for Disease Control and Prevention estimated that 15% of the adult population (37 million people) in the USA presented CKD in 2019, being more common in people aged 65 and older (38%) and less prevalent in people 54–65 (13%) and 18–44 (7%) .On the other hand, there is an increased prevalence of non-communicable diseases (NCDs) in the Mexican population. According to the National Health and Nutrition Survey, 2018(ENSANUT), type-2 diabetes mellitus (T2DM) is present in 15.3%, hypertension represents 12.9%, and obesity is prevalent in 35.3% of the population over 20 years old. In the same survey, Southeast Mexico had a prevalence of 15.4% for T2DM, 32.7% for hypertension, and 36.1% for obesity . In thisDue to the lack of evidence of risk factors associated with CKD in patients with NL in the Mexican population and the high prevalence and recurrence of this pathology, we conducted the present study to identify the risk factors associated with CKD in an endemic population Mexico.The study design was case-control and cross-sectional. Patients over 18 years old with NL diagnoses verified by computed tomography scan and treated at the Urology Department of the Regional High Specialty Hospital of the Yucatan Peninsula (HRAEPY in the Spanish acronym) between January 2018 and June 2020 were included. Patients with acute kidney injury (AKI) and prostatic hypertrophy diagnoses were excluded. 2). The case group comprised patients with NL and CKD (GFR < 60 mL/min/1.73 m2). In both groups, GFR was calculated using the CKD-EPI formula. The sample size was calculated using OpenEpi software  for an unmatched case-control study . Subjects were divided into two groups according to their GFR values. The control group consisted of patients with NL without CKD , recurrence of NL, presence of CKD, history of recurrent urinary infection, and general urine test and urine culture results. Additionally, the nutritional status of the patients was assessed using the body mass index (BMI).According to the surgical procedures, all patients who underwent kidney stone extraction at the host hospital underwent endourological procedures. Thus, the main surgical procedures performed were percutaneous nephrolithotomy and laparoscopic nephrectomy in patients with irreversible kidney damage. Nephrostomy and abscess drainage were carried out to improve kidney function. The hospital also received patients from other hospitals with a diagnosis of NL and a history of previous surgeries. The urology department evaluated these patients, and the previous diagnosis was confirmed. They were scheduled for surgical intervention when required. From all cases, surgical history was obtained  for NL and the number and type of surgical procedures.Radiological characteristics of the stones, such as the number, size (length and width), location , radiodensity (expressed in Hounsfield units), and the presence of staghorn stones, were documented. In addition, biochemical parameters  were also recorded.t-test or Mann–Whitney U-test were performed to compare the mean or median. Data were expressed as the mean ± standard deviation or median and quartiles. Frequencies were expressed in percentages. Differences between proportions were analysed using the Mantel–Haenszel chi-square test. Correlations between two variables were evaluated using the Pearson test. Multivariable logistic regression tests were used to explore NL risk factors. The variables were calculated using Jamovi software, computer software version 1.6, . Values of p < 0.05 were considered statistically significant.Continuous variables were evaluated using the Kolmogorov–Smirnov test to analyse the type of distribution. Student’s In this study, a total of 204 patients with NL were included: 79 patients with CKD  and 125 patients without CKD . p = 0.001) and systolic blood pressure (p = 0.004) when patients with and without CKD were compared. As expected, haemoglobin, uric acid, urea, serum creatinine, and GFR showed statistically significant differences when patients with and without CKD were compared (p < 0.001)  . Only onp = 0.742), the number of stones , presence of staghorn stones , and Hounsfield units (HU)  between patients with and without CKD . Additionally, T2DM was statistically significant in the adjusted analysis.p = 0.078) and left kidney  did not show significant differences between patients with and without CKD. Only having stones in both kidneys  was statistically significant in patients with CKD compared with patients without CKD .Regarding the location of the kidney stones, the right kidney  to control the impact of age on GFR and by the number of surgical events . These results are expressed in p = 0.954) and frequency of CKD (p = 0.783).Patients 50 years old or younger had more surgical events than older patients, which resulted in a decrease in GFR values and more cases of CKD . In patip = 0.037) and urinary tract infections . However, when hypertension and urinary tract infections were considered in conjunction, the significance was lost .A multivariable logistic regression of CKD patients was performed to determine whether the recurrence of NL is a risk factor for CKD, independent of hypertension and urinary tract infections. The results showed that recurrence of NL remained statistically significant independent of hypertension , thus promoting renal impairment.Although women were the majority in this study, the male sex was a risk factor in patients with CKD, also representing the older population. In contrast, a study by Shoag et al., found that a history of kidney stones was associated with a statistically significant increased risk of CKD among women. Nonetheless, no significant association was evident in men. Shoag et al., proposed a characteristic pathophysiology process in each gender . While iUnadjusted results indicated that hypertension is a risk factor associated with CKD, but the significance was lost when the results were adjusted, although it should be noted that there was still a trend, which could be due to the number of participants. In this context, many studies have confirmed the role of hypertension in the development of CKD thus, we do not rule out the impact of hypertension, and this effect was attributed to the sample size .The increase in prevalence of CKD in our population may be due to the coexistence of several clinical associations that accelerate renal function damage. Although T2DM was a statistically significant factor in the adjusted analysis by BMI, sex, and age, it was more frequent in patients without CKD, suggesting that T2DM is not an exclusive risk factor for CKD. Moreover, it is important to mention that factors such as the disease course and age of diagnosis were not considered. In this regard, studies suggest that T2DM and factors such as NL, urinary infections, and obesity can increase the risk of irreversible kidney damage, but further studies with an increased sample size that include data on disease course and age of diagnosis are needed ,20. Previous studies have shown an association between staghorn stones and CKD . Interesp = 0.032). Infectious processes are usually frequent in patients with NL hence, these infections could be due to an obstructive process that can damage the kidney parenchyma, leading to increased morbidity and a high risk of mortality [Urinary tract infections were risk factors for CKD in female patients  . In addip = 0.001), and age was a risk factor. Likewise, the percentage of patients with an invasive surgical history also significantly differed between those with and without CKD , suggesting a relationship between both parameters. Glassock et al., in their reports, suggested that GFR decreases with age, even in healthy older patients [p < 0.001)  . In suppOn the other hand, no statistically significant differences were observed when comparing patients older than 50 years with more than two surgical events versus patients younger than 50 years old. Therefore, the high risk conferred by number of surgical events was independent of age. It is important to mention that significance remained when analysing whether recurrence of NL was a risk factor for CKD independent of hypertension and urinary tract infections.The study showed some biases (Berkson bias): (a) all patients were selected from the High Specialty Hospital, who were referred from other medical units; (b) most of them had comorbidities ; (c) as the present study was cross-sectional, it was not possible to know the GFR of patients prior to each surgical event. In addition, some of them lived in a rural area without enough resources to cover the cost of traveling and attending all medical appointments, leading to an incorrect medical control of the disease progression.Regarding urine supersaturation, this was not evaluated because the excretion of urinary components are modified once the GFR is impaired. Hence, we considered that it was not appropriate to include this comparison with patients with CKD.The recurrence of NL and the number of surgical events were risk factors associated with CKD in patients with NL in our population. Additionally, male sex, bilateral kidney stones, and urinary tract infections were also risk factors for CKD in patients with NL. These findings indicated that independent of the type of surgical procedure, recurrence of NL increases the risk of irreversible kidney damage, and many patients may lose a kidney and require substitutive therapy, which increases mortality in the population.


The AUROC after combination of VD and DTABR was 0.896 and showed better predictive accuracy than the Glasgow Coma Scale score (0.75), VD (0.76), and DTABR . TCD-QEEG provides a good understanding of the coupling mechanisms in the brain and can improve our ability to predict the prognosis of patients with PCCI.Posterior circulation cerebral infarction (PCCI) can lead to deceased infratentorial cerebral blood flow (CBF) and metabolism. Neural activity is closely related to regional cerebral blood flow both spatially and temporally. Transcranial Doppler (TCD) combined with quantitative electroencephalography (QEEG) is a technique that evaluates neurovascular coupling and involves synergy between the metabolic and vascular systems. This study aimed to monitor brain function using TCD-QEEG and estimate the efficacy of TCD-QEEG for predicting the prognosis of patients with PCCI. We used a TCD-QEEG recording system to perform quantitative brain function monitoring; we recorded the related clinical variables simultaneously. The data were analyzed using a Cox proportional hazards regression model. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the cut-off for the diastolic flow velocity (VD) and (delta + theta)/ ratio (DTABR). The area under the ROC curve (AUROC) was calculated to assess the predictive validity of the study variables. Forty patients  were assessed. Mortality at 90 days was 40%. The TCD indicators of VD [hazard ratio (HR) 0.168, confidence interval (CI) 0.047–0.597,  Stroke is a leading cause of mortality and disability . CerebraThe flow dynamics of intracranial arterial blood are assessed by transcranial Doppler (TCD) and the physiological parameters of blood flow by the ultrasonic Doppler effect , 10. DisA study by Chen et al. reported that the prognostic accuracy of TCD-QEEG was statistically superior to that of any single clinical or neurophysiological assessment in patients with intracerebral hemorrhage . HoweverThe study protocol was approved by the Ethics Committee of the First Hospital of Jilin University, China and was conducted in accordance with the tenets of the Declaration of Helsinki. Consecutive patients with PCCI who were admitted to the Neurological Intensive Care Unit (NICU) between July 2018 and July 2019 were prospectively enrolled. Written informed consent was obtained from the immediate family members before inclusion in the study. The inclusion criteria were admission within ≤72 h of onset, PCCI diagnosed on clinical examination, magnetic resonance imaging (MRI), and age ≥18 years. The exclusion criteria were as follows: presence of cerebral hemorrhage; stroke induced by a brain tumor, moyamoya disease, or hematological disease; previous ischemic or hemorrhagic cerebrovascular disease; marked environmental disturbance, such as severe hypoxia (<50 mg/dL) or hyperglycemia (>400 mg/dL); recanalization therapy; and use of a central nervous system depressant, such as a sedative, antipsychotic, or antiepileptic drug. Twenty healthy controls matched for age and sex  were also enrolled.We recorded and analyzed the following variables: demographic characteristics (patient age and sex); risk factors  using the definitions of hypertension and diabetes mellitus reported by Song et al. ; GlasgowTCD combined with QEEG monitoring  was performed with the patient in the supine position. TCD was performed using 2-MHz pulsed-wave Doppler probes fixed to each temporal window with a helmet. We measured bilateral posterior cerebral arteries and optimal posterior cerebral artery signals were acquired at a depth of 60–75 mm bilaterally. When the temporal acoustic bone window in TCD was inadequate, we took the probe off the helmet and manually fixed it to a pillow window and measured the velocity of the ipsilateral vertebral blood flow (at a depth of 50–80 mm) because both the posterior cerebral artery and vertebral artery reflect the hemodynamics of the posterior circulation. QEEG was recorded according to the 16-electrode system installed in the international 10-20 system using bipolar longitudinal Fp1-F3, Fp2-F4, F3-C3, F4-C4, C3-P3, C4-P4, P3-O1, P4-O2, F7-T3, F8-T4, T3-T5, and T4-T6 with 0.5-Hz low frequency and 35-Hz high frequency filters. The band resolution was 0.25 Hz and the sampling frequency was 500 Hz. The impedance of each lead and electrode was maintained at <5 kΩ. Patients in the healthy control group remained awake with eyes closed during the procedure. The specific monitoring time took place at 9:00 A.M. or 2:00 P.M. on the second day after admission. Each patient was monitored only once. The data were recorded for over 30 min until a stable recording was established; the recorded data were stored for further analysis.The data for each patient were analyzed in a blinded manner. The systolic flow velocity (VS), diastolic flow velocity (VD), mean velocity (VM), and pulsatility index (PI) from the left and right hemispheres were recorded with TCD. VM was calculated as (VS–VD)/3 + VD and PI as (VS–VD)/VM. Considering that the lesions in the vessels of the posterior circulation are mostly bilateral, we averaged the TCD data between the two hemispheres. All segments of artifact-free EEG were selected and quantitatively analyzed offline to compute the relative power using Fast Fourier transform for each electrode over the 1–35 Hz range, as follows: relative delta power (0.5–4 Hz), relative theta power (4–8 Hz), relative alpha power (8–13 Hz), and relative beta power (13–35 Hz). We recorded the following QEEG parameters: delta/alpha ratio (DAR), (delta + theta)/ ratio (DTABR), alpha/beta ratio, brain symmetry index (BSI), alpha variability, spectral entropy, 95% spectral edge frequency, gross energy, median frequency, peak frequency, ambulatory EEG, envelope analysis, and delta ratio.t-test and median two-sample test were used to examine normally distributed variables, and non-parametric Wilcoxon  analysis of variance was used for non-normally distributed variables. Categorical variables were compared using the chi-squared test. Risk factors with a p-value < 0.05 in univariate analysis were included in a multivariate Cox proportional hazards regression forward model to analyze the hazard ratio (HR) for mortality. The survival rates were assessed by Kaplan-Meier analysis using log-rank tests to evaluate the significance of the multivariate models and compare the survival curves. Receiver-operating characteristic (ROC) curve analysis was used to evaluate the cut-off values for VD and DTABR, and the area under the ROC curve (AUROC) was used to assess the predictive ability of the variables. The ROC curves were compared using DeLong's test. All statistical tests were two-tailed, and a p-value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 17.0 , GraphPad Prism 8.0 , and MedCalc 19.0.7 .The data for the univariate analysis are reported as the mean ± standard deviation for normally distributed variables and as the median (interquartile range) for non-normally distributed variables. Categorical variables are presented as percentages. The Student's Forty-six patients with PCCI were enrolled. Three patients were excluded because of signal artifacts and three patients because of lack of follow-up. Finally, we enrolled 40 patients, 16 (40%) of whom died during the 90-day follow-up period. The median age was 63.7 ± 9.9 years and 30 (75%) of the patients were male.n = 5), unilateral vertebral artery stenosis or occlusion (n = 12), and bilateral vertebral and/or basilar artery occlusion (n = 23). As TOAS types of occlusion, 35 patients (87.5%) with PCCI showed an atherosclerotic occlusion of the great arteries and five patients (12.5%) with PCCI showed a cardiogenic occlusion. The only variables associated with mortality were the GCS (p = 0.001) and FOUR scores (p = 0.008). There was no statistically significant between-group difference in patient demographics, risk factors, vital signs, laboratory findings, or ejection fraction , VD (p = 0.001), and VM (p = 0.012) were associated with mortality. There was no significant difference in VS, VD, or VM between survivors and healthy controls or in PI among any of the groups , higher DAR (p = 0.027), higher DTABR (p < 0.0001), lower alpha variability (p = 0.043), lower relative alpha power (p = 0.027), lower delta ratio (p = 0.02), lower spectral entropy (p = 0.042), lower median frequency (p = 0.015), and lower peak frequency (p = 0.022) were associated with mortality. There were significant differences in QEEG, relative theta and beta power, spectral entropy, 95% spectral edge frequency, DTABR, gross energy, and median frequency  between the patients with PCCI and healthy controls. There was no significant difference in the BSI or alpha/beta ratio  among any of the groups  and VD  were independent predictors of mortality at 90 days.All variables with p = 0.001). Median survival in patients with a VD ≤ 14.5 cm/s was 20 days. The optimal DTABR cut-off for predicting the mortality risk was 2. The 90-day survival rate was 60% (95% CI 49.05–72.45) for all patients but was lower in patients with a DTABR > 2 than in those with a DTABR ≤ 2 . Median survival in those with a DTABR > 2 was 28.5 days . Therefore, the contribution of the final model was significant , VD (AUROC 0.76), or DTABR . The patients/participants provided their written informed consent to participate in this study.YCa contributed to the study conception and design, data collection, analysis and interpretation, and drafting of the manuscript. YCh and YX contributed to the study conception and design, analysis and interpretation of the data, and revision of the final manuscript. XS contributed to the study conception and design, analysis and interpretation of the data, and revision of the manuscript. LW and YQ contributed to the data collection and revision of the manuscript. All authors gave final approval of the version to be published.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.


Optic nerve sheath diameters (ONSD) have been validated as an accurate screening tool to detect elevated intracranial pressure in hypertensive encephalopathy. The neurologic manifestations of preeclampsia and/or eclampsia mimic those of hypertensive encephalopathy. This study was performed to assess the incidence of elevated optic nerve sheath diameters of patients with severe preeclampsia and neurologic criteria compared to non-preeclamptic patients. The secondary objective was to determine baseline optic nerve sheath diameters in patients with severe preeclampsia without neurologic criteria and preeclampsia without severe features.2 test. Continuous variables were presented as mean ± standard deviation, and discrete variables were presented as medians and compared by Kruskal–Wallis testing. Normality was confirmed by Shapiro–Wilk testing. Linear and logistic regression were used to test the association between the preeclampsia groups and optic nerve sheath diameters. Models were presented as unadjusted and adjusted for BMI, gestation, hypertension, diabetes, parity, and gravidity.Single site cohort study including 62 pregnant women 18 years or older and 20 weeks or further gestation. Patients with preeclampsia without severe features, preeclampsia with severe features by non-neurologic criteria, preeclampsia with severe features with neurologic criteria, and patients without preeclampsia were enrolled via convenience sampling. One blinded reviewer measured sheath diameters; baseline demographics and pregnancy data were collected by chart review. Statistical analysis was completed with STATA/IC 16. Categorical variables were compared by the χThe incidence of optic nerve sheath diameters > 5.8 mm was 43.8% in the severe preeclampsia with neurologic features cohort, and 42.1% in the control cohort, with a relative risk of 1.04. Patients with severe preeclampsia without neurologic features had sheath diameters of 5.75 mm ± 1.09 mm; non-severe preeclampsia patients had sheath diameters of 5.54 mm ± 1.26 mm.We did not find a significant elevated optic nerve sheath diameter relative risk between severe preeclampsia patients with neurologic features and non-preeclampsia control patients. This is the first study to assess a North American population utilizing ACOG criteria for severe and non-severe preeclampsia, with severe cohorts additionally stratified by neurologic criteria. Preeclampsia (PE) is an obstetrical complication characterized by new-onset hypertension or super-imposed hypertension with or without one systemic condition including proteinuria, hepatic dysfunction, neurologic symptoms, renal insufficiency, pulmonary edema, or thrombocytopenia during the second half of pregnancy.The clinical manifestations of severe preeclampsia can be confusing for the clinician, as several subjective symptoms such as headache, epigastric pain, or right upper quadrant pain can be benign findings in pregnancy. Although hypertension in pregnancy is acknowledged to be a continuum of risk, and early delivery is indicated for many women, identifying an objective measure of lower risk could be useful in stratifying the need for early term delivery to avoid complications of premature delivery, and subsequent maternal management.The clinical neurologic manifestations of preeclampsia and/or eclampsia have multiple theories about pathogenesis. One theory is that hyper perfusion of the brain due to decreased cerebrovascular resistance leads to vasogenic edema, similar to hypertensive encephalopathy , 2. HypeCerebral edema is believed to cause this increase in intracranial pressure. The subarachnoid spaces surrounding the optic nerve communicate with the intracranial cavity, and changes in cerebrospinal fluid pressure are transmitted along the distensible optic nerve sheath to increase sheath diameter , 9. Two n = 7) and non-severe preeclamptic (n = 1) patients. The sample included preeclampsia patients predominantly diagnosed (54%) with severe features by renal dysfunction, which is reported only in approximately 1% of women with severe preeclampsia [To date, there have been four studies evaluating ONSD in preeclampsia and eclampsia. Dubost et al. evaluated a total of 51 women: 26 preeclamptic patients, of which 13 had severe preeclampsia, and 13 had preeclampsia without severe features. A self-reported weakness of the Dubost study was the small percentage of severe preeclampsia patients with neurologic symptoms, limiting the ability to determine a relationship with ONSD enlargement [clampsia . They foSimenc et al. assessed 30 severe preeclampsia patients and compared their ONSD and optic disc height (ODH) measurements to control patients . They diThis aim of this study was to estimate the incidence of elevated ONSD in severe preeclampsia patients with neurologic features compared to non preeclamptic patients. The secondary objective was to determine baseline optic nerve sheath diameters in patients with severe preeclampsia with and without neurologic criteria and preeclampsia without severe features. We anticipated correlation of clinical features of severe preeclampsia to elevated ONSD representing vasogenic edema.This was a prospective study including four pregnant cohorts: patients without preeclampsia (“controls”); patients with PE without severe features; patients with severe PE (sPE) but no neurologic findings, and patients with sPE and neurologic findings. Recruitment began in November 2018 and continued until January 2020, when access to the study-specific ultrasound was expected to cease. Participants were recruited from the inpatient or antepartum unit of Labor and Delivery at a major university hospital in a southern state.Patients were enrolled by convenience sampling. Inclusion criteria included women with a singleton, nonanomalous pregnancy, participants > 20 weeks gestation, and 18 years old or older at the time of recruitment. Exclusion criteria included patients with preexisting eye conditions or ocular surgeries as well as any woman with pseudotumor, intracranial hypertension, seizure disorder, or known intracranial pathology.Preeclampsia by ACOG criteria is traditionally defined by a patient having two elevated blood pressures of 140/90 four hours apart with a urine protein to creatinine ratio of 0.3 or higher. If the patient did not meet urinary protein criteria, they could also be diagnosed by severe features, including elevated liver enzymes to twice the upper limit of normal, elevated creatinine of greater than 1.1 mg/dL, pulmonary edema, new-onset headache unresponsive to acetaminophen, visual disturbances, severe persistent right upper quadrant or epigastric pain, a platelet count less than 100 × 109 /L, or severe range blood pressures of 160 mm Hg or higher, diastolic blood pressure of 110 mm Hg or higher.We powered this study by assuming a relative risk of 8.6 , expectePatients were interviewed at the time of enrollment and asked their age, ethnicity, and history of intracranial pathology. BMI, blood pressures, gravidity and parity, and gestational age were recorded from their medical record. Subjects were asked about symptoms of severe preeclampsia, including persistent headaches, visual scotomata or changes, right upper quadrant or epigastric pain, and shortness of breath that would indicate pulmonary edema. Informed consent was obtained in writing with an IRB-approved form.Subjects were placed in a semi-recumbent position with the upper part of the body and head at 30–45 degrees from the vertical position for three minutes or less to obtain ultrasound data. A thick layer of water-soluble gel was applied to the orbital fossa with the eye closed, in accordance with prior published protocols –22. A siAn attending emergency room physician (R.B.) trained in ocular ultrasound performed a blinded assessment of de-identified images to obtain ONSD measurements. This was done in a post hoc fashion directly on the ultrasound machine. ONSD was measured 3 mm behind the globe using an electronic caliper at an axis perpendicular to the optic nerve. Two ONSD measurements were taken in each eye, and the mean of the measurements was used. If the two measurements could not be taken, then one data point was used instead of a mean. A maximum of four values were taken, and the mean values for each eye, or one value if only one clear image was obtained, was stored for data analysis.Statistical analysis was completed with STATA/IC 16 . We powered our study using the elevated ONSD incidence of 43% from Simenc et al. , and an 2 test. Continuous variables of gestational age and BMI were presented as mean ± standard deviation, and discrete variables of gravidity and parity were presented as medians and compared by Kruskal–Wallis testing. The normality of the ONSD data was confirmed by Shapiro–Wilk testing.Categorical variables of chronic hypertension (cHTN) and preexisting diabetes (DM) were presented as total numbers and compared by the χLinear and logistic regression was used to test the association between the preeclampsia groups and ONSD. Models were presented as unadjusted and adjusted for BMI, gestation, hypertension, diabetes, parity, and gravidity. The incidence of elevated ONSD in each group was calculated, and the relative risk of elevated ONSD was assessed. Statistical analysis was completed with STATA/IC 16  = 3.56, The ONSD has been validated as an accurate screening tool to detect elevated intracranial pressure in patients with idiopathic intracranial hypertension, traumatic brain injury, and spontaneous intracranial hemorrhage , 27.This study’s lack of a significant increase in ONSD measurements in the severe preeclampsia cohorts was an unexpected outcome, as Simenc et al.’s study noted a significant increase in the percentage of ONSD measurements > 5.8 mm in severe preeclampsia groups compared to controls . LimitatBelfort et al. have studied the use of transcranial Doppler and shown that a majority of women with preeclampsia have altered cerebral perfusion pressure (CPP)  althoughThis is the first study to assess a North American population utilizing ACOG criteria for non-severe and severe preeclampsia stratified by neurologic criteria. Prior studies used inclusion criteria  that is not endorsed by ACOG for defining severe versus non-severe preeclampsia , varyingAs preeclampsia has similar imaging findings as hypertensive encephalopathy, utilizing ONSD as a marker of severity for preeclampsia as for hypertensive encephalopathy is biologically plausible. The physiology of raised intracranial pressure with vasogenic edema from preeclampsia would logically apply to the use of ocular ultrasound as an objective measure of severity. All images were obtained by a single sonographer, removing inter-observer variability.The limitations of this research include being a single site study. Additionally, a cut-off value for ONSD, such as above 5.8 mm, has not been validated in an obstetric cohort to predict increased ICP. Assessing ONSD prior to the initiation of antihypertensive medications and magnesium or assessing pre- and post-magnesium values would control for a common intervention which could have impacted measurements. It has been found in prior studies on non-pregnant adults that there are rapid changes in ONSD with changing cerebrospinal fluid pressure . HoweverUnfortunately, as we enrolled by convenience sampling, self-selection bias is a possible confounder, and chronic hypertension was not controlled for during enrollment. It is known that the background rate of intracranial hypertension is higher in women with chronic hypertension and obesity . AlthougThe use of the linear probe may not be available in all labor and delivery units, and evaluation with use of the more common curvilinear probe would be of interest. However, studies comparing measurements made in the visual axis versus the coronal axis have shown significant differences when using a curvilinear probe  and decrObtaining larger sample sizes would improve the ability to control for potential confounders, such as timing of antihypertensive medications or use of magnesium, chronic hypertension , class IOptic nerve sheath diameters were not found to be significantly different between severe preeclampsia patients with neurologic features and healthy control patients, nor was there a significant difference between any of the cohorts’ ONSD means.This study does not support that ONSD is associated with hypertensive disease severity. Continuing to search for an objective measure to differentiate severe preeclampsia from a chronic hypertension exacerbation would be clinically advantageous, as several subjective symptoms such as headache, visual changes, or right upper quadrant pain can be benign findings in pregnancy. Hypertension in pregnancy is acknowledged to carry a spectrum of risk, and early delivery is indicated for many women. However, identifying an objective measure of risk could be useful in stratifying the need for early term delivery to avoid complications of premature delivery and for maternal management.


To investigate the relationship between quantitative parameters of echocardiography and vascular endothelial function in patients with chronic heart failure (CHF) and the predictive value of short-term major adverse cardiovascular events (MACE).  From February 2018 to February 2020, 86 CHF patients in our hospital were selected as the observation group, and 46 healthy subjects were selected as the control group during the same period. Quantitative parameters of echocardiography (left ventricular ejection fraction (LVEF), left ventricular short-axis shortening rate (FS), and ratio of peak flow velocity between early and late mitral valve diastole (E/A)) and endothelial function indexes (endothelin-1 (ET-1)/nitric oxide (NO)) were compared between the two groups. The correlation between quantitative parameters of echocardiography and vascular endothelial function in patients with CHF was analyzed. A logistic regression equation was used to analyze the risk factors of MACE in patients with CHF. The receiver operating characteristic curve (ROC) was used to analyze the predictive value of quantitative parameters of echocardiography and NO/ET-1 for the risk of MACE in patients with CHF. P < 0.05). In CHF patients, LVEF and FS were positively correlated with NO/ET-1, while E/A was negatively correlated with NO/ET-1 (P < 0.05). Logistic regression analysis showed that the decrease of LVEF, FS, NO/ET-1, and E/A were risk factors for MACE (P < 0.05) after adjusting for age, body mass index, and cardiac function grading. The AUC value of short-term MACE predicted by quantitative parameters of echocardiography and NO/ET-1 combined was 0.883, with a corresponding sensitivity of 86.21% and specificity of 73.13%.  LVEF, FS, and NO/ET-1 in the observation group were lower than those in the control group, while E/A was higher than that in the control group ( Quantitative parameters of echocardiography in CHF patients are related to vascular endothelial function, and their combination can effectively predict the risk of MACE in the near future, providing reference for clinical treatment. Chronic heart failure (CHF) is the final stage of the development of various cardiovascular diseases, characterized by high morbidity and mortality, and its prevention and treatment is an important public health issue , 2. TherFrom February 2018 to February 2020, 86 CHF patients in our hospital were selected as the observation group, and 46 healthy subjects were selected as the control group during the same period. Inclusion criteria: (1) the observation group all met the diagnostic criteria of CHF in the guidelines for the diagnosis and treatment of acute and chronic myocardial failure issued by the European Society of Cardiology  and had Quantitative parameters of echocardiography: the Vivid E95 color Doppler ultrasound diagnostic instrument of GE company was applied. M5Sc probe parameters mainly included left ventricular ejection fraction (LVEF), fraction shortening rate of left ventricle (FS), and E peak of early diastole/A peak of late diastole (E/A).NO/ET-1 detection: 3 ml of fasting peripheral venous blood was collected and centrifuged . Serum was taken, and enzyme-linked immunosorbent assay was used to detect ET-1 and NO using a Wuhan Huamei Bioengineering Co., LTD., kit.β-blocker, angiotensin-converting enzyme inhibitor or angiotensin ii receptor antagonist, aldosterone receptor antagonist, and digoxin and diuretics when necessary.Treatment methods: the observation group received conventional anti-heart failure drugs, including General data, quantitative parameters of echocardiography, and vascular endothelial function indexes of the two groupsCorrelation between quantitative parameters of echocardiography and vascular endothelial function in CHF patientsUnivariate analysis of recent MACE risk in CHF patientsMultivariate analysis of recent MACE risk in CHF patientsThe predictive value of quantitative parameters of echocardiography and NO/ET-1 for the risk of MACE in the near futureS). An independent-sample T-test was used for comparison between groups. Count data were expressed by n (%) and the χ2 test. Correlation was analyzed by Pearson. The influencing factors were analyzed by logistic regression. The predictive value was analyzed by the receiver operating characteristic curve (ROC) to obtain AUC, confidence interval, sensitivity, specificity, and cutoff values. The combined prediction was performed by logistic binary regression fitting. The prediction probability logit (p) is returned as the independent test variable. A bilateral test was used for all cases, and P < 0.05 was considered statistically significant.Statistical software SPSS22.0 was used to process the data. The Bartlett variance homogeneity test and Shapiro–Wilk normality test were used for measurement data, which were confirmed to have variance homogeneity and approximately conform to normal distribution, described by (±P < 0.05), as shown in There were 28 patients in grade II, 37 patients in grade III, and 21 patients in grade IV cardiac function in the observation group. LVEF, FS, and NO/ET-1 were lower than those in the control group, while E/A was higher than that in the control group, with statistically significant differences  and FS  were positively correlated with NO/ET-1, while E/A was negatively correlated with NO/ET-1 , as shown in In CHF patients, LVEF (P > 0.05). Age, body mass index, cardiac function grading, quantitative parameters of echocardiography , and NO/ET-1 were all influential factors for the recent risk of MACE in CHF patients (P < 0.05), as shown in MACE occurred in 19 patients  6 months after treatment. Gender, smoking history, and LDL-C and HDL-C levels were not associated with recent MACE risk in CHF patients (P < 0.05), see Taking the occurrence of MACE as the dependent variable , the factors with statistically significant differences in Using quantitative echocardiographic parameters  and NO/ET-1 of patients with MACE as positive samples and quantitative echocardiographic parameters  and NO/ET-1 of patients without MACE as negative samples, ROC curves for predicting the risk of MACE were drawn. The results showed that the AUC of LVEF-, FS-, E/A-, and NO/ET-1-predicted MACE was 0.740, 0.719, 0.797, and 0.691, respectively. The joint application ROC theoretical model of SPSS software was used to construct the joint prediction ROC model of each indicator. The results showed that the joint prediction AUC was the largest, which was 0.883, as shown in CHF is a complex syndrome in which myocardial injury induces abnormal activation of the neuroendocrine regulatory system, resulting in sodium and water retention, circulating congestion, heart and vascular remodeling, etc , 11. Theβ-adrenaline effect of cardiomyocytes, directly leading to the weakening of myocardial contractility [β-receptor, promote NO synthesis in endothelial cells, activate the protein kinase G signal transduction pathway, reduce intracellular calcium ion concentration, increase matrix metalloproteinase synthesis, and accelerate ventricular remodeling by mediating negative myocardial muscle strength and vasodilation [CHF patients have poor quality of life, and the 5-year survival rate is similar to that of malignant tumors. About 40% of patients will be readmitted to hospital within 12 months due to deterioration of disease . At presactility . This stactility . (2) ET-dilation . (3) Chadilation . VEGF prdilation . TherefoCHF is a long-term progressive disease, and genetic and environmental factors can affect the prognosis of patients . EvidencIn conclusion, vascular endothelial function injury in CHF patients may be an important factor in the deterioration of cardiac function, and both of them can effectively predict the risk of MACE in the near future. Therefore, vascular endothelial cell function is expected to become a target to improve the cardiac prognosis of patients. The shortcoming in this study is the research related to the MACE of the measured value of the variable is a single point in time, did not investigate the changes of these variables in a period of time influence on prognosis, is only a single-center study, prone to selection bias, and has yet to be further continued as a multicenter study with in-depth exploration and large sample size.


In the uncomplicated T2D population, however, the prevalence of effort intolerance and the underpinning mechanistic bases are uncertain. Leveraging the multiparametric characterization allowed by imaging-cardiopulmonary exercise testing (iCPET), the aim of this study is to quantify effort intolerance in T2D and to dissect the associated cardiopulmonary alterations.Type 2 diabetes mellitus (T2D) increases the risk of incident heart failure (HF), whose earliest fingerprint is effort intolerance . Despite a comparable cardiac output, patients with effort intolerance showed reduced peak peripheral oxygen extraction , lower VO2/work slope , impaired left ventricle systolic reserve  and global longitudinal strain  than subjects with VO2peak above 80%. Diastolic function, vascular resistance, endothelial function, biohumoral exams, right heart and pulmonary function indices did not differ between the two groups.Forty-eight patients (55%) had effort intolerance reaching a lower VO2peak is a severe and highly prevalent condition in uncomplicated, otherwise asymptomatic T2D. It results from a major defect in skeletal muscle oxygen extraction coupled with a subtle myocardial systolic dysfunction.Effort intolerance and reduced VOThe online version contains supplementary material available at 10.1186/s12933-021-01314-6. Effort intolerance is the hallmark of heart failure (HF), is part of the definition of the HF syndrome and is intimately linked to its pathophysiology  at peak. These results are reported in Table All patients performed a maximal exercise test, as defined by the maximal respiratory exchange ratio steadily greater than 1.05 at peak exercise according to guidelines [i.e. an increase in LVEF > 7.5%), reduced ΔS’ (peak vs baseline), as well as in reduced early (4 min of exercise) GLS and GLS change from baseline (ΔGLS). LV diastolic indices, stroke volume, and cardiac output did not differ between the two groups throughout the iCPET test, as well as the right heart indices did not change throughout the test  , LVEF, S’, GLS, and E/e’ all increased linearly with the workload. A reduced systolic reserve was observed in the group with effort intolerance in the form of: lower prevalence of subjects with a normal contractility reserve (O) Table .2. In the whole population, univariate determinants of Δ(a-v)O2 at peak were: sex, hemoglobin levels, peak CO, peak systemic vascular resistance, peak mean arterial pressure, GLS at 4 min and ΔGLS. In a multiple regression model, only male sex , hemoglobin levels , and ΔGLS  were independent predictors of peak Δ(a-v)O2 , as well as between ΔS’ and VO2peak (panel B), between GLS at 4 min and VO2peak (panel C) and ΔGLS and VO2peak (panel D). Also, we observed a significant correlations between Δ(a-v)O2 and GLS at 4 min (panel E) and change in GLS (Panel F).To gain insight on the link between reduced peak oxygen utilization and systolic dysfunction, linear regression analyses were performed on the two corresponding sets of variables in the whole population Fig. . Signifi2peak in the whole population (18 mL/kg/min) falls far below the reference values for the general population of this age group  [2peak (18.0 ± 6.6 mL/min/kg) has been recently reported in a larger and even younger (by 10 years) cohort of 224 asymptomatic subjects with T2D, falling into the lower 10% of the age-matched male general population distribution and the lower 20% of female general population [2peak below 80% of the predicted value according to Wasserman equation, is widely used to define negative prognosis in subjects suffering from heart disease [2peak values that are commonly found in patients with overt HF, a population wherein such a reduced VO2peak portends a rather poor prognosis [We examined 88 older adults with well-controlled and uncomplicated T2D undergoing a maximal iCPET. The observed value of VO/kg/min) , confirm/kg/min) . An idenpulation . Exercisrognosis .2peak. This, together with the presence of a small difference in age, prompted the decision to verify the differences in iCPET data after adjusting for age, sex and BMI  or peripheral  impairment [2 that was reduced by 20% compared to the control group and that correlated with the reduced VO2peak. Notably, in line with our findings, the Authors conclude that a reduced peripheral oxygen extraction might be regarded as a limitation to whole-body oxygen uptake. The older study showing normal Δ(a-v)O2 was conducted in a very small group of female adolescents [Our first finding is that effort intolerance is not due to a defect in mechanical efficiency , gince Fig.  and thatpairment . We exclpairment , 34. Notpairment  and the pairment  performeThe two groups of our study did not differ in biohumoral values, endothelial function, indices of pulmonary function, diastolic function indices, right heart indices, mean arterial pressure, and systemic vascular resistances throughout the entire iCPET. The subjects with effort intolerance showed higher prevalence of chronotropic incompetence. The large difference, however, is driven by the fact the patients of our study group fall close to the 80% threshold (mean HR peak%: 86.1%) thus a small difference in peak HR generates a major recruitment of subject with a diagnosis of chronotropic incompetence. In quantitative terms, the difference between the groups was small; subjects with effort intolerance exploited their HR reserve only 8% less than the others (82.6 vs 90.2%) with a difference in peak HR of just 8 beats/minute (129 vs 137 bpm). If we also consider that no subject had evidence of CAN at conventional tests and, more importantly, that HR kinetics and peak CO were superimposable in the two groups throughout the whole iCPET, it is unlikely that chronotropic incompetence is the cause of effort intolerance in our patient; it might rather be the consequence of their lower fitness.2peak. Based on our data, diastolic dysfunction is not relevant for explaining effort intolerance in T2D.Whilst crude indices of systolic performance such as SV, CO and LVEF were not different between the two study groups, less load-dependent indices (S’ and GLS) showed a gradient that was evident both in resting conditions and in exercise-induced changes. It is widely known that a reduced baseline GLS is an early marker of LV subclinical systolic dysfunction, being present both in HFpEF patients irrespective of the diabetic state  and in T2—the main factor explaining the reduced VO2peak in our population—were sex, hemoglobin levels, and ΔGLS O2 and VO2peak is a novel finding suggesting a strong link between skeletal and cardiac muscle pathology in T2D. This relationship was previously demonstrated in animal models of T2D [2 in T2D subjects with effort intolerance [In multivariate analysis, the determinants of Δ(a-v)OLS Table . This cos of T2D , while is of T2D , reduceds of T2D , or reduolerance , but non2peak, indicates a reduced aerobic capacity and strongly supports the hypothesis of a mitochondrial defect either in number or in function, as previously observed in this population [Taken together, the results of the present study suggest a myogenic limitation of whole-body oxygen uptake in T2D limiting exercise tolerance, with a tight interplay between myocardial and skeletal muscles. Whether this is secondary to a reduced number of mitochondria, a mitochondrial functional impairment, altered myofibrillar structure and/or composition, muscle microvasculature, or to systemic regulators of muscle perfusion  goes beypulation , 53. Thepulation , 55.2peak, Δ(a-v)O2, and GLS of the subjects with T2D and effort intolerance observed in the present study represents a phenotype which is also shared by the patients with HFpEF wherein reduced peripheral oxygen extraction and/or GLS appear as the major determinants of effort intolerance [e.g. exercise) is possible to prevent the development of HFpEF in T2D patients.The combination of reduced VOolerance , 56, 57.olerance . LongituEffort intolerance is severe and highly prevalent in uncomplicated, otherwise asymptomatic T2D, and is mainly driven by a primitive muscular impairment involving both skeletal and myocardial muscle in the form of impaired peripheral oxygen extraction and a reduced systolic reserve, despite preserved LVEF and cardiac output. These alterations closely resemble the major clinical features of HFpEF and could represent an intermediate pathological condition.One strength of the present study is the sample size (greater than previous reports), the multi-parametric analysis performed , the careful exclusion of micro- and macrovascular complications (previous works frequently included complicated patients and highlighted the contribution of specific complications to reduced aerobic capacity), and the study of effort intolerance within the diabetic population .2 was not directly measured, however our method has been extensively validated, used by several investigators [We recognize some limitations of the present work. This is a single-centre, cross-sectional study with a relatively small sample size. We only focused on asymptomatic, uncomplicated T2D; therefore, the results should not be applied to different cohorts. We acknowledge that the technical challenge of acquiring echocardiography images during exercise may affect SV and CO measurements, despite the technique has been extensively validated and used by different groups . Also Δ(tigators , 25; andtigators , 59. Ourtigators ; cautionAdditional file 1: Table S4. Sensitivity analysis performed after having excluded all subjects taking beta-blockers. And repeating the statistical analysis as described for the whole population.