Inflammation, being a typical response to vascular tissue alterations, induces variations in tissue oxygen diffusion pressure. Diabetic microangiopathy, an inflammatory process, is characterized by an increase in vascular flow at rest, reduced venous and arteriolar responses, and increased capillary permeability, resulting in oedema development, decreased transcutaneous oxygen pressure, and increased transcutaneous carbon dioxide pressure. This phenomenon potentially hampers ulcer healing. Although the figure-of-eight method has proven to be a reliable, valid, quick, and efficient test for assessing foot and ankle measurements in patients with oedema and compromised skin integrity, it has not been studied in patients with diabetic foot. The aim of this study was to determine and compare the intra- and inter-observer variabilities of the figure-of-eight method in patients with diabetic foot. A prospective observational and cross-sectional study was undertaken, involving sixty-one subjects from a specialized Diabetic Foot Unit. Three investigators with varying levels of experience independently measured the subjects to assess both intra-observer and inter-observer variability. The evaluation was conducted using the Intraclass Correlation Coefficient (ICC). In the statistical analysis, an ICC of 0.93, adjusted using a 95% confidence interval (CI), was obtained for inter-observer reliability ICC, indicating excellent reliability among observers. Furthermore, an ICC of 0.98 with a 95% CI was obtained for the intra-observer reliability analysis, indicating excellent reliability. The results support using this test during the clinical management of oedema in patients with diabetic foot. The absence of an objective, fast, and readily available diagnostic method for oedema in diabetic foot patients in clinical practice might pose a limitation. Subsequent research should tackle this issue and explore the correlation between ankle perimeter measurements and other clinical outcomes in diabetic foot patients, including wound healing and quality of life. Oedema is the perceptible increase in fluid volume within the interstitial space. It can be localized to a specific area of the body or result in generalized swelling. This process can occur because of a single local trigger or manifest as a clinical sign of a systemic complication or disorder .Some of the most significant causes of oedema include several parameters: 1) increased capillary pressure, which can result from arteriolar vasodilation due to heat application or the presence of inflammation, or secondary to elevated venous pressure due to prolonged standing; (2) venous obstruction; (3) fluid retention during pregnancy or in premenstrual syndrome; (4) cardiac, renal, or hepatic insufficiency; (5) increased capillary permeability due to toxins, allergens, hypoxia, inflammation, or other causes; and (6) decreased plasma oncotic pressure due to nephrosis, starvation, or liver failure [ increaseAmong the previously mentioned risk factors for the development of oedema, heart failure and/or renal insufficiency (RI) are noteworthy. Diabetes mellitus (DM) stands out as the most prevalent cause of renal insufficiency globally. Cardiovascular disease (CVD) emerges as the leading cause of morbidity and mortality among individuals with DM, with RI significantly amplifying the risk of CVD . AbnormaDiabetic foot ulcers (DFUs) are often associated with infection and inflammation, acting as local triggers that give rise to foot oedema. Inflammation, as a ubiquitous response to vascular tissue alterations, exhibits a discernible pattern in terms of changes in tissue oxygen diffusion pressure. Particularly noteworthy is the vasodilation phase, during which oxygen pressure experiences a slight increase, followed by a subsequent decline correlated with the onset of oedema and the subsequent elevation in hydrostatic pressure. This intricate interplay has the potential to impede the healing process of DFUs, emphasizing the intricate dynamics underlying diabetic foot complications ,8.The proper supply and control of oxygen to a specific region depends on numerous factors, including capillary density, local flow rate, blood viscosity, and hemoglobin release pressure. The efficiency of oxygen diffusion through different tissues depends on the nature of the intercellular matrix, cellular density under physiological or pathological conditions, and whether the intercellular space is affected by oedema, the presence of microorganisms, and/or devitalized tissue. Hemostatic pressure (HP) in capillaries can be influenced by any external pressure above it, resulting in vessel compression. An increase in intrinsic pressure can occur due to the presence of oedema. If this pressure cannot be released, it will result in capillary collapse and tissue hypoxia ,8.Furthermore, additional diabetes-related processes play a pivotal role in the manifestation of this phenomenon. Diabetic microangiopathy, a distinctive feature of diabetes, is marked by increased vascular flow at rest, diminished responses in venous and arteriolar functions, and elevated capillary permeability. These intricate vascular changes collectively contribute to the onset of oedema, a decline in transcutaneous oxygen pressure, and an escalation in transcutaneous carbon dioxide pressure ,8. UnderThe comprehensive assessment of diabetic foot ulcers (DFUs) requires thorough examinations of vascular and neurological functions, coupled with a meticulous evaluation of ulcer characteristics. Successful treatment strategies predominantly include offloading utilizing suitable devices and prompt management of concurrent infections through procedures like debridement and, when warranted, revascularization ,8. DespiThe measurement of inflammation serves as a crucial tool for clinicians, enabling the evaluation of inflammation severity, formulation of treatment strategies, and assessment of treatment efficacy based on objective observations, rather than relying solely on subjective criteria. In this context, it becomes imperative to meticulously evaluate the accuracy and consistency of tests employed for determining foot and ankle measurements in patients with oedema ,10. ThisWater displacement volume, along with ankle circumference measurements using the Figure-of-Eight method, stand out as the most practical and reliable approaches for quantifying ankle oedema ,12. Whilp < 0.001), it stands as a swift and efficient alternative (p < 0.001) to volumetry for evaluating foot and ankle measurements in patients with oedema and compromised skin integrity [The figure-of-eight method, a non-invasive and cost-effective test, offers an objective quantification of ankle oedema through the utilization of a tape measure and specific bony landmarks around the ankle joint . Demonstntegrity . DespiteGiven the potential benefits of implementing a reliable, reproducible, non-invasive, and cost-effective method for objective oedema quantification in patients with DFUs—crucial for assessing severity and formulating treatment strategies in clinical practice—this study aimed to determine and compare intra- and inter-observer variabilities using the figure-of-eight method in individuals with diabetic foot.The study’s design involves observing and documenting individual measurements over time, without intervening in the natural progression of the pathology. A prospective observational and cross-sectional study was conducted following the guidelines outlined in Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) .During a single visit per patient between November 2022 and March 2023, measurements were conducted by three investigators in a specialized Diabetic Foot Unit. As a prospective observational and cross-sectional study, no follow-up was necessary. The investigators, with varying levels of experience, independently measured ankle circumferences. One investigator had five years of experience in ankle circumference measurement, another had one year of experience, and the third had no prior experience but was trained before the start of the study. To mitigate observer bias, the investigators measured ankle circumferences on the same subjects without knowledge of each other’s measurements.Reliability pertains to the reproducibility of results obtained through a measurement procedure. Intra-observer reliability gauges the agreement when a measurement is repeated by the same observer under identical conditions. Inter-observer reliability assesses the agreement when a measurement is repeated under identical conditions by different observers. Lack of reliability may stem from discrepancies in measurement instruments or the instability of the attribute being measured. Intra- and inter-observer variabilities were evaluated using the Intraclass Correlation Index (ICC) with a 95% confidence interval (CI).Study participants, aged 18 and above, were eligible if diagnosed with type 1 or type 2 diabetes mellitus, had a history of previous ulceration, and had signed the informed consent form. Exclusion criteria included patients with active ulcers and/or diagnosed with rheumatoid arthritis, as these may introduce potential bias due to non-diabetes-related ankle inflammation.The dependent variables of the study were the ankle circumference measurements taken by the three observers. The independent variables included demographic variables, such as age (years); gender ; weight (kg); height (cm); body mass index (BMI); DM diagnosis ; duration of DM (years); presence of peripheral vascular disease diagnosed via the presence or absence of distal pulses; ankle-brachial index (ABI) or toe-brachial index (TBI); presence of diabetic neuropathy diagnosed using the Semmes–Weinstein Monofilament (5.07 mm–10 g) for sensory testing and a biothesiometer (>25 mV) for vibratory sensibility assessment; and a personal medical history of smoking, hypercholesterolemia, diabetic nephropathy, cardiovascular conditions, venous insufficiency, Charcot neuroarthropathy, oedema, aetiology of oedema, and/or fractures.The ankle circumference measurement was carried out according to the original description of the test  using a The measurement was taken with subjects in a seated position with extended legs using a tape measure that was calibrated in centimeters. The ankle joint was held in a neutral position to eversion and inversion while maintaining a 90° ankle flexion position, if the subject’s range of motion allowed.The reference points considered for the measurement included several anatomical parameters: (1) tuberosity of the navicular bone, (2) base of the styloid process of the fifth metatarsal, (3) distal boundary of the medial malleolus, (4) distal boundary of the lateral malleolus, and (5) tendon of the anterior tibialis muscle.For the measurement of the subtalar joint, the starting point of the tape measure was placed at the midpoint between the tendon of the anterior tibialis muscle and the lateral malleolus. The tape was then moved medially, until it reached the distal limit of the navicular tuberosity, continued along the medial arch, traversed the plantar surface towards the proximal limit of the base of the styloid process of the fifth metatarsal, and crossed over the anterior tibialis tendon. Subsequently, for the measurement of the talar joint, the tape measure continued around the ankle joint with the tape positioned distal to the apex of the medial malleolus so that it crossed the Achilles tendon on the posterior surface and traversed the lateral aspect of the limb through placing the tape below the apex of the lateral malleolus with the end of the measurement at the starting point of the tape.Consideration of potential biases inherent in observational studies is crucial, and the implementation of effective strategies to prevent these biases is equally important for ensuring the study’s integrity and reliability. Addressing these risks enhances the internal validity of the research, providing a more robust foundation for drawing meaningful conclusions from the observational data. Through acknowledging and managing potential biases, the study aims to uphold the highest standards of scientific rigor and contribute to the overall credibility of the findings.Concerning internal validity, a proactive approach was taken to mitigate potential selection bias through implementing a prospective study design. This strategic choice was made to ensure that the process of subject recruitment and selection occurred prior to the event of interest. Through adopting this method, the study aims to minimize the likelihood of obtaining inaccurate or skewed results related to the primary objectives. This careful consideration of study design enhances the internal validity, reinforcing the reliability and accuracy of the research outcomes.To minimize the risk of information or measurement bias, a standardized approach was employed. All observers consistently utilized the same measuring instrument throughout the study, effectively reducing the likelihood of differential error. This attention to maintaining uniformity in measurement tools contributes to ensuring a consistent and reliable methodology across all observations.To mitigate potential biases during the planning phase of the study, a comprehensive strategy was implemented. This involved thorough training for all observers, equipping them with the necessary skills and knowledge essential for precise measurements. Additionally, blinding procedures were rigorously enforced during the measurement process, ensuring that observers remained impartial and unbiased. This multifaceted approach to study planning safeguards against potential sources of bias, enhancing the credibility and reliability of the study’s outcomes.To minimize the potential impact of memory and data collection bias, a meticulous approach was employed. Information furnished by the participants underwent thorough cross-verification, aligning with the reports obtained under their prior consent. This dual-check mechanism ensured the accuracy and reliability of the collected data. Furthermore, the data collection instrument was deliberately designed with simplicity, featuring dichotomous response options and the recording of quantitative variables. This comprehensive strategy not only bolsters the integrity of the information gathered but also strengthens the study’s overall methodological robustness.Strategic measures were meticulously implemented to mitigate potential bias during the analysis and interpretation of results. To strengthen the methodological validity, the study adhered to the guidance provided by Portney and Watkins . This inNo specific interventions were considered imperative to address potential confounding bias, given its intrinsic control within the study’s case-control design. Correspondingly, preventive measures to avert loss to follow-up were deemed unnecessary, aligning with the study’s nature as a prospective cross-sectional observational inquiry that did not necessitate subsequent follow-up assessments. The study design inherently encapsulated elements to safeguard against confounding variables and precluded the need for additional strategies to mitigate loss to follow-up, reinforcing the study’s methodological coherence.To mitigate biases influencing external validity, careful consideration was given to the time necessary for measuring the outcome variable. This was achieved through employing a technique renowned for its ease of reproducibility in a clinical setting and its cost-effectiveness, ultimately enhancing the generalizability of the study’s findings.® Statistics 27 software . Categorical variables were analysed in terms of frequencies and percentages. The analysis of quantitative variables involved calculating the mean and standard deviation.Statistical analysis was performed using the IBM SPSSp < 0.05 with a 95% CI, and values of β were established to achieve a study power of 80%. Interpretation of the ICC values followed the guidelines of Portney and Watkins [Before conducting hypothesis tests, the normality of quantitative variables was assessed using the Kolmogorov–Smirnov test to verify their distribution. To measure overall agreement between two or more measurements involving quantitative variables, intra- and inter-observer variabilities were evaluated using the two-way random effects, absolute agreement, single rater/measurement ICC  with a 95% CI. Statistically significant values were considered for  Watkins  in whichThe study adhered to the ethical principles outlined in the Declaration of Helsinki  and compPrior to inclusion, participants received detailed information about the study and its procedures. Subsequently, they expressed voluntary agreement to participate through informed consent for the collection of data for scientific purposes.To uphold data confidentiality, the data collection notebook maintained anonymity and the study results were securely stored in dedicated files created specifically for this purpose, following the security measures mandated by current legislation in Spain.Sixty-one Caucasian subjects participated in the study  with forp < 0.0001), indicating excellent reliability among observers  with a 95% CI was obtained. The correlation between elements as 0.98 between the first measurement by the experienced investigator and the second measurement, 0.99 between the second observation and the third, and 0.98 between the first and third measurements, indicating excellent intra-observer reliability.In the intra-observer reliability analysis , an ICC The comprehensive evaluation of cases and continuous assessment of changes throughout the management of pathologies are essential to accurately gauge their severity and ascertain the effectiveness of the proposed treatment. In this context, maintaining a meticulous approach to minimize errors in the measurement of oedema becomes crucial. This meticulousness not only enhances the reliability of assessments but also ensures consistency, facilitating a more accurate interpretation of results over the course of the disease management process.While the figure-of-eight method has been acknowledged for its objectivity, reliability, validity, and efficiency, serving as a promising alternative to volumetry in assessing oedema in the foot and ankle, a notable research gap exists concerning its application in individuals with diabetic foot conditions. Despite its recognized utility, there is a scarcity of published studies examining its relevance in the context of diabetic foot cases. Thus, the primary aim of this study was to systematically investigate and compare both intra- and inter-observer variabilities of the figure-of-eight method specifically in patients with diabetic foot.p < 0.0001) with a 95% CI, signifying excellent consistency among the observers. Furthermore, the intra-observer reliability exhibited an ICC value of 0.98  with a 95% CI, affirming excellent reliability within each observer’s measurements.The measurement technique was systematically implemented by three distinct observers on individuals with diabetic foot conditions, followed by rigorous statistical analysis. As per the result analysis guidelines outlined by Portney and Watkins , the intp < 0.001). Similarly, Devoogdt et al. [p < 0.001).The findings of the current study align with outcomes reported in investigations conducted by Rohner-Spengler et al. , whereint et al.  observedThe measurement of ankle circumference has been previously employed as a tool in other research and for monitoring in clinical practice related to various medical conditions. For instance, Guex et al.  utilizedThe guidelines for diagnosing and treating active Charcot neuro-osteoarthropathy (CN) in individuals with diabetes, as proposed by the International Working Group on the Diabetic Foot, designate unilateral oedema as a clinical indicator of active CN. They propose that monitoring the oedema could aid in identifying the remission phase of the condition. However, there is insufficient evidence to substantiate the use of reliable techniques for such monitoring or to establish a correlation between their results and radiological findings. Consequently, the management of CN is currently restricted to the subjective quantification and diagnosis of oedema .Our findings, indicating favorable intra- and inter-observer reliability, support the use of this assessment test in clinically managing oedema in diabetic foot patients. This test could aid clinicians in detecting and managing complications like Charcot neuro-osteoarthropathy and serve as a valuable tool for future investigations. Notably, it is an easily applicable, cost-effective, and reproducible test, requiring only basic knowledge of lower limb anatomy and a short training period in the measurement technique.Strengths of this study include being the first to correlate ankle perimeter measurements with oedema in diabetic foot patients. However, limitations exist as no studies explaining the pathophysiology or prevalence of oedema specifically in diabetic foot patients were found. This limitation affects sample size calculations, leading to sampling bias and affecting the generalizability of results. The absence of a quick and accessible diagnostic method for oedema in diabetic foot patients complicates clinical practice, which relies on subjective clinical signs ,12,24. TFuture research should address these gaps, exploring the relationship between ankle perimeter measurements and various clinical outcomes in diabetic foot patients, such as wound healing and quality of life.In summary, the figure-of-eight method exhibited excellent inter- and intra-observer reliability in patients with diabetic foot. Integrating this assessment test into clinical practice for oedema management in diabetic foot patients could aid clinicians in detecting and addressing complications, while also providing a valuable tool for future research endeavors.


To investigate the effect of dapagliflozin therapy on the clinical outcome of drug-eluting stent (DES) implantation in elderly patients with type 2 diabetes mellitus (T2DM).  We retrospectively studied the real-world data of patients with coronary heart disease who received DES implantation in our hospital from May 2019 to May 2021. Baseline general data and laboratory results of patients were collected. All patients were followed up for two years after PCI, and the follow-up endpoints included in-stent restenosis, major adverse cardiovascular events (MACE), revascularization, rehospitalization, and all-cause mortality. P < 0.05). There were significant differences in BMI, systolic blood pressure, diastolic blood pressure, FBG, and HbA1c between the two groups before and after treatment. At the end of follow-up, the incidence of in-stent restenosis and MACE in the dapagliflozin group was lower than that in the nondapagliflozin group. K-M curve analysis showed a significant difference in in-stent restenosis and MACE after DES implantation between the dapagliflozin group and the nondapagliflozin group .  Compared with those before treatment, body mass index, systolic blood pressure, diastolic blood pressure, TG, TC, LDL-C, FBG, and HbA1c were decreased in both groups after treatment, while HDL-C was increased after treatment ( In accurate clinical data, dapagliflozin could significantly improve the postoperative BMI, blood pressure, and blood glucose outcome of patients with T2DM complicated with coronary heart disease and positively impact in-stent restenosis and MACE. Epidemiological surveys show that the global prevalence of diabetes is as high as 9.3% and is expected to rise to 10.2% by 2030. Diabetes is a significant public health problem that has burdened the global economy and medical resources  show than = 131) and the nondapagliflozin group (n = 106) according to whether they took dapagliflozin or not. The study design followed the Declaration of Helsinki and was approved by the hospital's medical ethics committee.T2DM patients complicated with coronary heart disease who received DES implantation from May 2019 to May 2021 in the Department of Cardiology of our hospital were selected as subjects. Inclusion criteria are as follows: (1) meeting the relevant diagnostic criteria for T2DM and coronary heart disease , 15; (2)μg nitroglycerin were given. Judkins method was used for body position projection, and the interventional physician judged the responsible blood vessel and the vascular status quo. PCI was performed after patients or their family members signed informed consent, and stent dilation surface and adhesion degree were evaluated. All patients received dual antiplatelet therapy for more than 12 months after PCI.All patients were treated with a standardized PCI strategy. Under lidocaine local anesthesia, the puncture sheath was inserted into the radial or femoral artery using the Seldinger method, and 3000 IU heparin and 200 All patient data were obtained from our hospital's follow-up database, and patients' baseline clinical data were obtained through electronic medical records and archived paper medical records. After collecting and processing the original data of the patients, all the enrolled patients were coded twice after their personal information was hidden. Two physicians performed relevant data entry and verification, and cardiology and imaging physicians were invited to review the results.The following data of the patients were collected: (1) baseline general data, including gender, age, body mass index (BMI), hypertension, dyslipidemia, smoking, drinking, systolic blood pressure, diastolic blood pressure, type of coronary heart disease, number of lesions, number of stents implanted, the total length of stents implanted, the minimum diameter of stents, and insulin use; (2) laboratory indicators, including triglyceride (TC), total cholesterol (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), and glomerular filtration rate (eGFR); and (3) clinical outcomes, all patients were followed up for two years after PCI. The follow-up endpoints included in-stent restenosis, major adverse cardiovascular events (MACE), revascularization, rehospitalization, and all-cause mortality.t-test was used for comparison. The count data were expressed as the number of cases or rate, and the χ2 test or Fisher's exact method was used for comparison. Cox proportional hazards model was used to evaluate the effect of dapagliflozin on prognosis during follow-up, and hazard ratio (HR) and 95% confidence interval (95% CI) were calculated. Kaplan-Meier survival curve was used to observe and compare the clinical outcomes between the two groups, and the Log-rank method was used to compare the differences. All statistical tests were conducted by bilateral test, and P < 0.05 was considered statistically significant.The collected experimental data were analyzed using SPSS 21.0. The measurement data in the experimental data that conformed to the normal distribution were expressed by P > 0.05), and it was comparable, as shown in There were no significant differences in gender, age, hypertension, dyslipidemia, smoking, drinking, type of coronary heart disease, number of lesions, number of stents implanted, the total length of stent implanted, the minimum diameter of the stent, and insulin use between the dapagliflozin group and the nondapagliflozin group (P > 0.05). The BMI, systolic blood pressure, diastolic blood pressure, TG, TC, LDL-C, FBG, and HbA1c in the two groups decreased after treatment, while HDL-C increased with statistical significance . The differences in BMI, systolic blood pressure, diastolic blood pressure, FBG, and HbA1c before and after treatment were significantly different between the two groups (P < 0.05), while there was no significant difference in the differences in TG, TC, HDL-C, and LDL-C before and after treatment between the two groups (P > 0.05), as shown in There were no significant differences in BMI, systolic blood pressure, diastolic blood pressure, TG, TC, HDL-C, LDL-C, FBG, and HbA1c between the two groups before treatment (P < 0.05). At the same time, there were no statistically significant differences in revascularization, rehospitalization, and all-cause mortality between the two groups (P > 0.05), as shown in By the end of follow-up, the incidence of in-stent restenosis and MACE in the dapagliflozin group was lower than that in the nondapagliflozin group, with statistically significant differences , as shown in The K-M curve analysis results showed a statistically significant difference in in-stent restenosis and MACE after DES implantation in elderly T2DM patients between the dapagliflozin group and nondapagliflozin group (logrankP < 0.05), while there was no significant difference in the differences in TG, TC, HDL-C, and LDL-C before and after treatment between the two groups. This result shows that dapagliflozin treatment has obvious clinical benefits in BMI, lowering blood pressure, and controlling blood sugar, but there is no apparent advantage in blood lipids. In previous foreign studies [Currently, STLT2 inhibitors listed in China include dapagliflozin, canagliflozin, and empagliflozin, among which dapagliflozin is the most widely used , 17. SGL studies , 21, som studies . SGLT2 i studies . HoweverIn terms of improving clinical outcomes, this study showed that the incidence of in-stent restenosis and MACE in the dapagliflozin group was significantly lower than in the nondapagliflozin group. At the same time, there was no difference in revascularization, rehospitalization, and all-cause mortality between the two groups, and further, K-M curve analysis also showed the same results. In previous studies , 25, theAs a retrospective real-world study, this study showed that dapagliflozin treatment could significantly improve postoperative BMI, blood pressure, and blood glucose outcomes in patients with T2DM complicated with coronary heart disease in real-world clinical data and had a positive effect on in-stent restenosis and MACE. However, this study has certain limitations. For example, this study is a single-center study, and it is difficult to control the main clinical variables of patients, which may cause certain selection biases. This study only evaluated the benefits of BMI, blood pressure, blood glucose, and blood lipids and had less evaluation of other possible benefits. It is necessary to expand the sample size and follow-up time further to improve and supplement the conclusions.


Orthostatic intolerance commonly occurs following immobilization or space flight. We hypothesized that daily artificial gravity training through short-arm centrifugation could help to maintain orthostatic tolerance following head-down tilt bedrest, which is an established terrestrial model for weightlessness.2) who participated in the 60-days head-down tilt bedrest (AGBRESA) study. They were assigned to 30 min/day continuous or 6 × 5 min intermittent short-arm centrifugation with 1Gz at the center of mass or a control group. We performed head-up tilt testing with incremental lower-body negative pressure until presyncope before and after bedrest. We recorded an electrocardiogram, beat-to-beat finger blood pressure, and brachial blood pressure and obtained blood samples from an antecubital venous catheter. Orthostatic tolerance was defined as time to presyncope. We related changes in orthostatic tolerance to changes in plasma volume determined by carbon dioxide rebreathing.We studied 24 healthy persons . The change in orthostatic tolerance was not correlated with changes in plasma volume.Compared with baseline measurements, supine and upright heart rate increased in all three groups following head-down tilt bedrest. Compared with baseline measurements, time to presyncope decreased by 323 ± 235 s with continuous centrifugation, by 296 ± 508 s with intermittent centrifugation, and by 801 ± 354 s in the control group (Daily artificial gravity training on a short-arm centrifuge attenuated the reduction in orthostatic tolerance after 60 days of head-down tilt bedrest.The online version contains supplementary material available at 10.1007/s10286-023-00959-5. Orthostatic intolerance commonly occurs in astronauts returning from space missions . While e2, and non-smokers were potentially eligible. Key exclusion criteria comprised requirements for prescription medications including contraceptives, health conditions that would preclude participation, such as history of cardiovascular disorders including syncope, musculoskeletal, neurological, metabolic or endocrine disturbances, or increased thrombosis risk, among others. Women were required to have a menstrual cycle lasting between 26 and 32 days. We enrolled 24 healthy persons . All subjects provided written informed consent prior to study entry. The study was approved by the North Rhine Medical Association Ethics Committee and prospectively registered on DRKS .Our study is part of the NASA/ESA/DLR 60-day − 6° head-down-tilt bed rest study AGBRESA, which was conducted at the DLR:envihab research facility. Detailed inclusion and exclusion criteria and psychological and medical screening procedures have been described elsewhere . BrieflyStudy design and standardization measures have been described elsewhere . BrieflyDuring the bedrest period, participants were randomly assigned to a control group without countermeasures, daily artificial gravity training through continuous centrifugation over 30 min, or daily artificial gravity training through intermittent centrifugation for six times 5 min with 3-min breaks. Centrifugation induced gravitational forces of 1Gz at the center of mass and 2Gz at the feet. For safety reasons, heart rate was measured continuously by a three-lead electrocardiogram and blood pressure was assessed intermittently with an oscillometric brachial cuff during centrifugation . A contrWe conducted orthostatic tolerance testing 5 days before the bedrest phase and immediately after 60 days of bedrest in the morning hours after an overnight fast. Every subject was familiarized with the experiment 1 day before we obtained the first measurements. At baseline, subjects walked to the examination room and remained in the supine position for 15 min before the protocol was started. Following the bedrest phase, patients were taken on a stretcher in the head-down position to the tilt table such that orthostatic tolerance testing was the first time participants assumed an upright position. We obtained heart rate through three-lead electrocardiogram and finger blood pressure  continuously. We measured oscillometric brachial blood pressure every 2 min. We inserted an antecubital venous catheter for blood sampling. We placed a lower-body negative pressure chamber at the level of the iliac crest. Following instrumentation, participants remained in the supine position for 15 min. We obtained baseline measurements and blood samples in the last 2 min of this period. Then, we tilted the table to 80° head up. After 15 min of head-up tilt, we added incremental lower-body negative pressure of − 10 mmHg every 3 min. We terminated orthostatic tolerance testing when participants wished to abort the test or when presyncope occurred. We defined presyncope as a sudden onset of pallor, blurred vision, lightheadedness, sweating, or nausea, accompanied by a greater than 40% heart rate reduction and/or greater than 40% systolic blood pressure reduction compared to the first 5 min of asymptomatic standing. After the occurrence of presyncope, subjects were tilted back to the supine position and another blood sample was collected. We defined orthostatic tolerance as the time from head-up tilt onset to presyncope. We determined heart rate, systolic blood pressure, and diastolic blood pressure in the supine position, during 15 min of 80° head-up tilt, and with stepwise increase of lower-body negative pressure (LBNP) every 3 min until pre-syncope occurred. At baseline, and immediately after HUT, we averaged 5 min of continuous finger blood pressure and heart rate recordings. We determined finger blood pressure and heart rate during presyncope by averaging up to 60 seconds (if available) before tilting back.After drawing blood, we stored samples on ice until plasma was separated by centrifugation and frozen to − 80° Celsius. Norepinephrine, epinephrine, dopamine, aldosterone, renin, and copeptin were analyzed by an in-house essay developed at Radboud University Nijmegen and validated the method by LC–MS/MS after derivatization with propionic anhydride and subsequent solid-phase extraction (SPE) .p < 0.05 indicated statistical significance. The data supporting the reported results are available from the corresponding author upon reasonable request.Results are reported as mean ± standard deviation. Based on the prospective study design, we used a survival analysis with log-rank (Mantel–Cox) test to assess changes in orthostatic tolerance, the primary objective of this investigation, during head-down tilt bedrest in the centrifugation and control groups. Furthermore, we used an ordinary one-way ANOVA with Tukey's multiple comparisons test to detect possible group differences before and after bed rest. We conducted a mixed-effects analysis with Šidák's multiple comparisons test to analyze hemodynamic and neurohumoral response before and after bedrest. p = 0.047). Following 60 days of bedrest, the time to presyncope decreased by 801 ± 354 s in the control group, by 323 ± 235 s in the continuous centrifugation group, and by 296 ± 508 s in the intermittent centrifugation group .Subjects’ characteristics, plasma volume, and changes in hemodynamics from supine to HUT and at presyncope are listed in Tables 1, 2, and 3 in the supplement. Figure p < 0.0001; Fig. p < 0.0001; Fig. p = 0.0367) Below is the link to the electronic supplementary material.


Males had a significantly higher level of Hb (p = 0.019) and UA (p = 0.001), and a lower level of platelets (p = 0.004) and Ca (p = 0.003), and used more tobacco (p = 0.046) and alcohol (p = 0.024) than females. Comparing patients < 80 and ≥80 years, we found differences in frequency of vascular risk factors among men (p = 0.027). In total, 102 patients were treated for psychosis . Conclusions: The results of this study could be useful for a progressive demonstration of the causal relationship between cardiac and cerebral vascular events and VLOSLP.Background: The aims of this study were to analyze prevalence and severity of vascular risk factors in older patients referred to our clinic due to onset of Very Late-Onset Schizophrenia-Like Psychosis (VLOSLP) and to create a specific phenotype based on pathophysiological insight rather than age of onset. Methods: In a longitudinal study, 103  patients were evaluated with cognitive, neuropsychiatric, and functional assessment scales. Blood concentration of hemoglobin (Hb), mean corpuscular volume (MCV), platelets, total protein test (TPT), creatinine, azotemia, glycemia, total cholesterol (TC), triglycerides (TG), uric acid (UA), sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), folate, vitamin B12 (Vit-B12), and homocysteine were measured. Presence/absence of tobacco use, alcohol consumption, psychoactive substance use, hypertension, hyperlipidemia, diabetes mellitus, and history of vascular disease were collected. Results: Females were more apathetic than males (NPI-Apathy:  Schizophrenia (SZ) is a severe psychopathological syndrome characterized by delusions, hallucinations, and impaired skills and social relationships ,2. Usual-to analyze the prevalence and severity of vascular risk factors in a population of older patients referred to our clinic due to the onset of VLOSLP;-to create a specific phenotype based on pathophysiological insight rather than age of onset.From January 2015 to December 2022, we screened older subjects who had consecutively attended the Cognitive Impairment Evaluation Unit of the Complex Unit of Geriatrics of Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) “Casa Sollievo della Sofferenza” for possible study enrollment. We obtained written informed consent for research from each patient, or from relatives or a legal guardian. All subjects were Caucasian, not including people of Jewish, Eastern European, or North African descent, with most individuals having Southern Italian ancestry, living in Southern Italy for at least three generations.Inclusion criteria were (1) age ≥ 65 years; (2) diagnosis of Late-Onset Schizophrenia and Very-Late-Onset Schizophrenia-Like Psychosis according to International Late-Onset Schizophrenia Group (LOSG) criteria ; (3) absThe present study was conducted according to the Declaration of Helsinki, the Guidelines for Good Clinical Practice and the guidelines for Strengthening the Reporting of Observational Studies in Epidemiology, and it was approved by the local ethics committee for human experimentation (Prot. N. 3877/DS). This study was a longitudinal study, in which the assignment of an intervention to the participants, its effect assessment, and health-related biomedical or behavioral outcomes were not considered.In all patients, cognitive status was defined with the Mini-Mental State Examination (MMSE) , after aThe neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory (NPI) , which cIn all patients, functional status was assessed by activities of daily living (ADL)  and instGenotyping was conducted on blood samples. Apolipoprotein E (ApoE) alleles  +3937/rs429358 and SNP + 4075/rs7412) were genotyped using the ABI 7900 Taqman  system. The two ApoE single nucleotide polymorphisms exist at amino acids 112 and 158, which were targeted by the Taqman probes. The individual genotypes at the two sites were then combined to create a single standard ApoE genotype.The blood samples (3–5 mL of blood) were collected intravenously from an upper limb of each patient in the morning. Then, blood samples were stored in Vacutainer tubes containing citrate; within not more than 30 min, the samples were transferred to the department of biochemistry and analyzed in a full autoanalyzer. The blood concentration of hemoglobin (Hb), mean corpuscular volume (MCV), platelets, total protein test (TPT), creatinine, azotemia, glycemia, total cholesterol (TC), triglycerides (TG), uric acid (UA), sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), folate, vitamin B12 (Vit-B12), and homocysteine were measured in all patients.Through a semi-structured interview, medical history and milestones from the patient’s life were assessed as shown below: (1) lifetime tobacco use, (2) alcohol consumption, (3) psychoactive substance use and abuse, (4) history of vascular disease , and (5) anti-smooth muscle antibody (ASMA). Following the guidelines for the diagnosis and management of hypertension in adults, hypertension was defined as systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg, or as currently receiving antihypertensive treatment . Hyperlipidemia was defined according to the guidelines for management of dyslipidemia and prevention of cardiovascular disease . All recDiabetes mellitus was defined according to the Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm . At the time of the medical visit, all patients were in treatment with acetylsalicylic acid; the patients with atrial fibrillation were in oral anticoagulant therapy.All patients had performed a neuroimaging examination (CT scan) in order to highlight the presence of white matter hyperintensity. The focal cortical–subcortical outcomes were reported in patients with previous stroke.t-test or analysis of variance (ANOVA) under a general linear model. For non-normally distributed variables, hypotheses regarding differences among the groups were compared by means of the Wilcoxon rank sum test with continuity correction or by means of the Kruskal–Wallis rank sum test. Risks (adjusted by cognitive impairment presence/absence and severity) are reported as odds ratios (OR) along with their 95% confidence interval (CI). All the statistical analyses were made with the R Ver. 2.8.1 statistical software package . Tests in which the p value was smaller than the type I error rate α = 0.05 were declared significant.For dichotomous variables, hypotheses regarding differences between the groups were tested using chi-square test. This analysis was made using the 2-Way Contingency Table Analysis. For continuous variables, normal distribution was verified by the Shapiro–Wilk normality test and the one-sample Kolmogorov–Smirnov test. For normally distributed variables, hypotheses regarding differences among the groups were compared by means of Welch’s two-sample During the enrollment period, 181 older patients were screened for inclusion in the study. Of these, 12 patients were excluded because they were younger than 60 years, 58 had a diagnosis of dementia, 6 had not run a CT scan, and 2 had an incomplete examination. Thus, the final population included 103 patients, comprising 39 men (37.86%) and 64 women (62.14%) with a mean age of 80.32 ± 7.65 years and a range from 65 to 95 years. p = 0.040).As shown in p = 0.019) and UA (p = 0.001), and a lower level of platelets (p = 0.004) and Ca (p = 0.003), than females; in terms of vascular risks, males used more tobacco (p = 0.046) and alcohol (p = 0.024) than females.As shown in p = 0.027).As the data in Regarding psychiatric and clinical treatment , 102 patIn this study, we explored the neuropsychiatric profile of older people with psychotic symptoms arising in a state of normal cognitive function, paying close attention to vascular risk factors. We studied our patients, first of all, divided by gender and noting that most are female as in previous studies ,45,46. IWe analyzed homocysteine levels and the presence of the ɜ4 allele of the ApoE gene ,48 consiIn addition, we focused on the prevalence of vascular risk factors and previous acute cardiac and cerebral vascular events. We also considered previous Acute Myocardial Infarctions (AMI) as an expression of systemic ED , which mFinally, regarding the role of ED in neurobiology of schizophrenia, we share the recent theory of Neurovascular Unit (NU) dysfunction . NU consWe therefore deem it necessary, with regard to “vascular depression”, which is known as a specific subtype distinct from nonvascular forms , and wit


Even on postoperative day (POD) 28, the patient had repeated deviations from the blood pressure limit (systolic pressure 90-140 mmHg) during a 200-m walk. Therefore, leg bathing (42°C for 20 minutes) before walking for three days was started on POD 38. No changes in medications or other medical interventions from POD 28 until discharge from the hospital were made. Mean blood pressure values during the seven days before leg bathing were 151/94 mmHg at rest and 168/107 mmHg after walking, with a maximum value of 180/113 mmHg. After leg bathing, blood pressure after walking was 147/96 mmHg on day 1, 149/96 mmHg on day 2, and 127/82 mmHg on day 3. The mean blood pressure values during the seven days after three days of leg bathing were 137/81 mmHg at rest, 147/89 mmHg after walking, and 167/97 mmHg at maximum, with no more deviations from the blood pressure limit at rest and a slight increase with exercise. Three days of leg bathing produced sufficient antihypertensive effects for this patient. The findings in this case indicate the need for comparative studies with a control group in the future.Thermal therapy is expected to have an antihypertensive effect associated with increased blood flow and vasodilation. Here, we report a case of postoperative aortic dissection in which leg bathing was effective for treating hypertension. A 50-year-old female (body mass index: 25.3 kg/m Cardiovascular rehabilitation is an essential disease management program for cardiovascular diseases, and standard programs have been developed for both acute myocardial infarction and heart failure. Another cardiovascular disease targeted by the Japanese Cardiovascular Society is acute aortic dissection (AAD). However, the prognosis of AAD differs according to disease type, false lumen status, and the presence of complications . TherefoEven after surgery, patients with AAD are at increased risk of re-dissection and rupture of the false lumen, so antihypertensive treatment is considered important . As antiIn physical therapy, whole-body thermotherapy  is known to exert an antihypertensive effect by dilating blood vessels throughout the body ,3. FurthHere, we report a case with AAD in which lower leg bathing reduced pressure and allowed the patient to start exercise therapy. Leg bathing increases whole-body skin blood flow as heat dissipation takes place in nonthermal areas. We expected the antihypertensive effect due to increased peripheral vascular blood flow associated with the warmth. The patient provided written informed consent after receiving explanations of both the purpose of this report and compliance with the protection of personal data.2) was admitted to our emergency department with sudden back pain, dysesthesia, and weakness in the left lower limb. A computed tomography scan revealed type A aortic dissection with occlusion of the left common iliac artery. Therefore, she underwent emergency surgery for ascending arch aortic replacement and thoracic endovascular aortic repair (TEVAR) [A 50-year-old female  . Leg batThe patient’s mean body weight during hospitalization was 63.8 ± 0.5 kg (range: 63-64.5 kg), and no significant changes in fluid volume were observed. The patient’s blood pressure and pulse before and after walking from 29 days postoperatively until discharge are shown in Figures In session 3 day 42), blood pressure after walking was within the blood pressure limit, and EBF increased  during leg bathing . On postoperative day 56, the patient was discharged home with postoperative exercise tolerance of 352.6 m in a 6-minute walk test. At that time, her physical function scores were as follows: grip strength (right/left): 19.3/14.0 kg, 10-m walk test (seconds/steps): 8.8/18, and SPPB: 12 points. At 6 months after discharge from the hospital, she is still able to maintain a home systolic blood pressure of less than 130 mmHg.In the present report, we described a case with postoperative AAD who showed an antihypertensive effect resulting from leg bathing. The patient was unable to tolerate antihypertensive medication because of suspected drug fever, which made her blood pressure difficult to control and delayed the introduction of exercise therapy. However, leg bathing at 42°C for 20 minutes for three days provided sufficient antihypertensive effects and eventually led to the introduction of exercise therapy. The safety of lower leg bathing has been confirmed in patients with acute coronary syndrome in the coronary care unit . InitialFirst, we discussed the direct antihypertensive effect of leg bathing. We considered two factors to be involved in the direct antihypertensive effect: vascular endothelial function and autonomic nervous system function. Waon therapy, also known as thermotherapy for cardiovascular diseases, has an immediate effect on peripheral vasodilatation , and repIn the present case, EBF during walking was measured on a separate day from the leg bathing as an indicator of peripheral circulation. Goma et al. (2015)  and GomaNext, we discussed the indirect antihypertensive effects of leg bathing. A previous study reported that at least five sessions are required to obtain an antihypertensive effect with repeated Waon therapy . In the Here, we reported the case of a female patient who experienced a reduction in blood pressure that allowed the start of postoperative exercise after only three sessions of leg bathing. As this was an observational study of a single case, future comparative studies with a control group are needed.


Anorexia nervosa (AN) is associated with maladaptive cardiovascular changes. This study investigated whether individuals who recovered from AN during adolescence experience long-term cardiovascular risk in early adulthood.Former AN patients discharged from the Royal Children’s and Monash Children’s Hospital Eating Disorder Services in Melbourne, Australia underwent cardiovascular testing. Measurements were performed using an oscillometric device for blood pressure and pulse wave velocity, ultrasound for carotid wall structure/function, resting electrocardiogram for heart-rate variability, and the EndoPat 2000 (Itamar) system for endothelial function. Patient measures were compared to healthy controls and/or normal thresholds.N = 22) and controls (N = 66) were female, aged approximately 25 years, with a healthy body mass index. The mean time interval from AN recovery to participation was 7.4 years. Pulse wave velocity was lower in the former AN patients than controls. Carotid intima–media thickness was not different; however, carotid distensibility and compliance were lower, and the elastic modulus higher in the former AN patients. Greater vagal tone was observed and endothelial dysfunction was evident in 46% of the former patients.Ninety-one percent of the former AN patients  and population studies have revealed that developmental adaptations in response to undernutrition have long-term consequences for cardiovascular health.In this study of young adults treated for AN during adolescence, there was evidence of increased carotid artery stiffness, reduced aortic stiffness, vagal hyperactivity, and endothelial dysfunction in early adulthood when compared to healthy controls.It is important to consider the cardiovascular health of patients with AN beyond achieving medical stability.Interventions that monitor cardiovascular health could minimise the burden of future cardiovascular disease. These adaptations have been associated with sudden cardiac death.7 Functional impairment of the cardiovascular system occurs due to the structural and electrophysiological adaptations. Orthostatic hypotension and a lack of normal circadian variations in blood pressure are common, along with impaired endothelial function.9 Many of these cardiac complications are thought to resolve with refeeding and weight gain. Whether the myocardial fibrosis in patients with AN will resolve over time is less clear.10 This affects contractility and may contribute to increased cardiovascular mortality.Changes in cardiac size and function during the acute phase of illness are well described.12 An increased incidence of atherosclerosis and ischaemic heart disease has been observed among former prisoners of war.14 Adult survivors of severe acute malnutrition in infancy have also exhibited altered cardiac structure accompanied by elevated peripheral resistance.15 Although the types of malnutrition in this study population were varied, there were reductions in cardiac output, stroke volume, and outflow tract diameter. Such studies indicate that periods of significant malnutrition in early life have long-term consequences for cardiovascular health.Furthermore, changes in vascular properties in patients with AN after weight restoration have not been reported in detail. Studies of populations exposed to malnutrition have revealed alterations in cardiovascular structure and function in later life. For example, early onset of coronary artery disease has been reported among survivors of famine.16 the present study aimed to determine the presence of long-term cardiovascular changes in individuals who were malnourished during adolescence due to an eating disorder.To date, most studies assessing cardiovascular risk factors in AN have been conducted in patients currently undergoing treatment. The long-term cardiovascular prognosis post-recovery is unknown and indeed most patients are discharged from clinical services. Using well-established assessment techniques employed widely in children and adults,17This study took place at the specialist Eating Disorder programmes operating at the Royal Children’s Hospital (RCH) Melbourne and Monash Children’s Hospital. These multidisciplinary services provide inpatient and outpatient care to patients under 18 years of age who are diagnosed with an eating disorder according to the Diagnostic and Statistical Manual of Mental Disorders.18 and expressed interest in the cardiovascular component of the research. Patient commitment to exercise was comparable to the general population according to the Commitment to Exercise Scale. Twenty-two participants were successfully recruited from the potential pool of 36 former AN patients. Nine patients could not be contacted and the remaining five declined participation due to other time commitments or no longer residing in Melbourne. To be included, participants had been discharged (discharge requires an Eating Disorder Examination (EDE) Global Score within 1 SD of community norms and a body mass index (BMI) ≥ 95% of the median for age and sex) from the Eating Disorder Service ≥5 years ago, were aged >18 years, exhibited a current EDE Global Sore within 1 SD of community norms, and possessed a BMI ≥ 18.5 kg/m2. Additional historical information was obtained from patients’ medical records, including the duration, severity, and age at AN presentation, as well as the presence of any physical or mental health comorbidities.The study population comprised of a sample of former patients who were treated for AN and clinically discharged from the Eating Disorder Services between June 2008 and July 2016. Of these patients, 36 had previously undergone psychological assessment19 a longitudinal study of extremely preterm infants that included a term-born control group. Controls were matched to former AN patients by age and sex with a ratio of 3:1. Cardiovascular data in the AN group was obtained prospectively and employed the same protocols for collection of data as the VICS control group.Healthy controls did not have a previous diagnosis of an eating disorder themselves or among their first-degree relatives and did not have any known chronic disease. Controls were drawn from the Victorian Infants Collaborative Study (VICS),A sample size of 88 participants (22 former AN and 66 control) would enable differences of at least 0.7 SD to be detected with 80% power using a two-sided type I error of 5%.20 Maximal and minimal vessel diameters were measured to examine vessel distensibility. Brachial blood pressure was used to calculate vessel compliance and the incremental elastic modulus. These measures indicate carotid arterial stiffness, and thereby the extent of vascular aging or atherosclerosis.20Participants underwent non-invasive cardiovascular assessment by a trained researcher at the RCH vascular research laboratory. Testing was conducted in the morning, in the absence of caffeine intake and after fasting for at least 3 h. While lying in the supine position with the head turned 45° to the left, ultrasound of the right carotid artery was performed with a GE Vivid ultrasound machine . Image analysis was performed offline using the Carotid Analyser Software for Research . Digital callipers were subsequently used to measure carotid intima–media thickness (IMT) of the far wall of the common carotid artery 5–10 mm from the carotid bulb at end-diastole (R-wave of ECG); with intima–media thickening a proven pre-clinical marker of atherosclerotic risk.21 Measurements were also made of the carotid–femoral pulse wave velocity as a surrogate of aortic stiffness. This was performed with a hand-held tonometer at the carotid pulse and a proximal thigh cuff. The distance from the carotid pulse to the suprasternal notch, from the suprasternal notch to the right femoral pulse, and from the femoral pulse to the top of the thigh cuff were measured with a tape measure to record the distance travelled by the waveforms.22 The time difference between the foot of the two waveforms was used for pulse wave velocity calculation. All blood pressure and pulse wave velocity measurements were performed in triplicate and the average calculated for each participant.Central and peripheral blood pressure were measured on the non-dominant arm using a SphygmoCor XCEL oscillometric device . The peripheral measurement was taken directly and central pressure estimated from this using in-built functions. While more difficult to measure, there is increasing evidence of the strength of this parameter as a measure of cardiovascular risk due to varied augmentation of blood pressure in peripheral vessels.23A three-lead electrocardiogram was recorded for 15 min using a PowerLab system operating with the LabChart 8 software . Resting heart rate and heart rate variation during normal breathing were measured at a sampling rate of 1 k/s. As a measure of autonomic nervous system function, short-term HRV analysis was conducted in the LabChart HRV add-on version 2.0 using the Lomb Periodogram nonparametric method for power spectral density estimation. Analysis parameters included a window size of 200 sampling points with 50% overlap, a model order of 18, percentage of successive RR intervals (pRR) threshold of 50 ms, and standard deviation of the set of averaged RR intervals averaging over 300 s. Time and frequency domain measures were obtained in accordance with guidelines developed by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.25 In this study, we captured a beat-to-beat plethysmographic recording of the finger arterial pulse wave amplitude in response to reactive hyperaemia using the EndoPAT 2000  system. Pneumatic finger probes were placed on the index fingers of each hand and a brachial blood pressure cuff was placed on the dominant arm. A baseline recording was obtained for 5 min at rest followed by arterial occlusion of the dominant arm via cuff inflation to supra-systolic pressure for 5 min. A 5 min recording measured reactive hyperaemia following blood pressure cuff deflation. The magnitude of flow-mediated hyperaemia was calculated as the ratio between baseline and post-occlusion pulse wave amplitude (reactive hyperaemic index (RHI)), corrected for systemic changes measured in the non-occluded arm. The VICS cohort did not undergo this assessment of endothelial function.19 A threshold RHI <1.67 is considered abnormal in adults.26Assessment of the endothelial-dependent flow-mediated vasodilation of arteries is a well-established measure of arterial vessel health.p ≤ 0.005 to indicate strong evidence of a difference and 0.005 < p < 0.05 to indicate moderate evidence of a difference. All statistical analyses were performed using the R software .General descriptive statistics of the former AN and control samples were calculated. Clinical characteristics of the former AN patients at the time of their diagnosis were also summarised. The mean and standard deviation (SD) were reported for physically obtained cardiovascular data that were normally distributed. For data that were not normally distributed, median and interquartile range (IQR) were reported. The mean difference and corresponding 95% confidence interval (CI) between the controls and former AN patients with respect to each of the measures of carotid IMT, blood pressure, pulse wave velocity, and HRV were estimated using multivariable linear regression with group as the variable of interest, adjusted for age and sex. Quantile regression was similarly used to estimate median differences and corresponding 95% CIs for skewed variables. In addition, the RHI of former AN patients was compared to normal reference values and the percentage of the sample with abnormal readings reported. Given the number of comparisons performed in our study, we considered N = 22) and the control group (N = 66) were aged approximately 25 years (24.5 (2.7) and 24.9 (0.91), for former AN patients and controls, respectively) and had a BMI within the healthy range (22.36 (2.61) and 23.76 (2.24), p = 0.017, for former AN patients and controls, respectively). The majority (91%) of former AN patients were female. The time since discharge from their respective Eating Disorder Services to study participation ranged from 5 to 10 years with a mean (SD) interval of 7.4 (2.1) years. Two (9%) of the former AN patients smoked and 15% of the female patients reported the presence of amenorrhoea.The former AN patients  of their body weight over a period of 4–24 months. Medical instability was prevalent, with more than half the patients experiencing bradycardia, and more than a third experiencing postural hypotension. Anxiety affected approximately one quarter of the patients; while other mental health and medical comorbidities were less frequently reported.Table p = 0.029)  Fig. . Measurep = 0.006), lower compliance   than controls.There was no evidence of a difference in the carotid IMT or carotid artery diameters between former AN patients and controls Table . There w01) Fig. , and a hp = 0.043). There was stronger evidence of greater beat-to-beat variance in heart rate  among the former AN patients than the controls . Frequency domain measures also differed between the two groups. There was moderate evidence of a difference in total power with former AN patients exhibiting higher total power than the control group ; indicating higher overall autonomic activity. In addition, lower LF power  and higher HF power  resulted in a lower LF-to-HF (sympathetic–parasympathetic) ratio among the former AN patients compared to the controls   Fig. .Table 4H26 The average RHI for the former AN patients was 1.59.Lastly, 46% of the former AN patients exhibited reduced endothelial function with a RHI less than the normal threshold of 1.67.In this first study of the cardiovascular function of former AN patients, we have observed no difference in carotid IMT, but increased carotid artery stiffness, as young adults. Conversely, decreased aortic stiffness was observed. Moreover, there was persistence of high vagal tone at this early stage of adulthood, although blood pressure was normal. The former AN patients also exhibited a high prevalence of endothelial dysfunction.12 Alternatively, individuals exposed to the Dutch Famine while in utero exhibited reduced carotid IMT27 but no difference in compliance.28 It must be noted that these famines at the time of war were different in terms of duration with the former lasting several years and the latter considered to have lasted about 6 months. Furthermore these reports are of male and female survivors, while AN predominately occurs in females.There are varied reports of the effects of malnutrition on carotid IMT and stiffness. Increased carotid IMT with no difference in arterial stiffness has been observed in survivors of the Leningrad Siege seventy years on.29 This was a study of 7845 women from the Prospect-EPIC cohort who experienced various degrees of starvation during the Dutch famine. The risk of cardiovascular disease was stratified based on severity of exposure as well as the age of the women at the time of exposure. Overall, more extreme levels of starvation were associated with higher risk of coronary heart disease. Interestingly, this risk was highest in those women who experienced the famine between 10 and 17 years of age (corresponding with the age of eating disorder onset in our cohort). Conversely, the risk of stroke was lower in women who were exposed to famine compared to unexposed women. The authors do caution, however, that the stroke data were relatively scarce in the cohort. It is possible that stiffer carotid arteries seen in our population in the presence of a more compliant aorta may paradoxically protect against pulse propagation into the cerebral circulation and reduce the incidence of cerebrovascular accidents.Perhaps of more relevance to our findings are the data reported by van Abeelen and colleagues.15 This group of survivors was a similar age to our cohort with an average age of 29 years and exhibited markedly elevated systemic vascular resistance with only slight elevation of diastolic blood pressure. The authors postulated that the higher systemic vascular resistance might be due to higher sympathetic drive and arteriolar constriction. Our population would appear to differ in having greater vagal tone but does demonstrate a high prevalence of endothelial dysfunction.Reduced aortic stiffness, as shown by reduced pulse wave velocity, has similarly been reported in adult survivors of severe acute malnutrition in infancy.29 Lower RHI has been correlated with cardiovascular risk factors including obesity, dyslipidaemia, diabetes, and smoking.32 It is also an independent predictor of cardiovascular risk in patients with peripheral artery disease.34 Therefore, this finding may represent an underlying level of vascular dysfunction among the former AN patients.Endothelial dysfunction is a well-accepted early indicator of arterial disease and may correspond with extreme levels of starvation in the Prospect-EPIC cohort being associated with higher coronary risk.35 A significant decrease in the ratio of elastin–collagen was observed in both the carotid arteries and aorta, leading to stiffer vessels. Similar mechanisms could be contributing to the stiffer carotid vessels in the former AN patients, although a more compliant aorta is contradictory. While the effects of foetal malnutrition on the developing cardiovascular system are of potential interest, induced changes are unlikely to be the same as undernutrition at the stage of adolescent development. There are no histological data for arterial structure following malnutrition in childhood. Furthermore, the changes in rat offspring are dependent on sex, with males exhibiting worse adaptations.36 Indeed most AN patients are female. One study observed decreased aortic stiffness, but no changes in the carotid artery, in oestorgen-deficient female rats.37 Oestrogen deficiency is a known consequence of AN and regional differences in its modulation of vascular function could explain the contrasting carotid and aortic stiffness observed in our patients. A full metabolic workup would be required to examine this thoroughly.The mechanisms leading to altered arterial wall properties in AN specifically are unknown. There are however studies in other populations which lend some insight. Changes in expression of multiple proteins in the extracellular matrix of the arterial wall of rat offspring after maternal undernutrition have been demonstrated.23 Vagal hyperactivity contributes to bradycardia and hypotension in patients with AN.38 In contrast to our findings, another study in weight-recovered patients with AN reported HRV had normalised.39 This study was performed at early follow-up, however, with a range of 3–18 months after acute refeeding. It is possible that while BMI has returned to normal range that our patient cohort in early adulthood continues to have relatively higher levels of exercise to explain this increased vagal tone.The abnormal HRV among the former AN patient group demonstrates persisting changes in autonomic regulation. Parasympathetic activity (HF) was significantly greater among the former AN patients. Moreover, the low LF-to-HF ratio indicates persistence of deficient vagal inhibition when compared to the normal range of 1.5–2.0 stipulated in the HRV guidelines.40 There is a predominance of women in our former AN patient cohort but this reflects the sex distribution of the condition, although the number of young males affected is increasing.41 It is possible that males may be affected differently. In addition, there is a myriad of variables that affect cardiovascular health, such as smoking, diabetes, and hypercortisolaemia, but analysis of these was beyond the scope of this study.There were several limitations to the current study. The menstrual cycle has been shown to influence HRV and this could be particularly pertinent to our sample given the disproportionate sex distribution.The exercise history of our cohort was not clearly documented besides completion of a Commitment to Exercise Scale and a more rigorous assessment would be needed to explain our findings of increased vagal tone. It is difficult to assess whether the former AN patients were completely recovered without a detailed clinical psychological assessment. More information on the current nutritional intake of the former patients and controls, as well as fat mass and modes of exercise, would be beneficial for determining whether differences arise from persisting behaviours or a history of AN. Pre-morbid health status and any family history of cardiovascular disease would also be useful.In addition, the former AN patients were tested after 3 h of fasting as a longer period was unethical given the high-risk participant history. This affects the accuracy of comparisons with the VICS cohort who fasted for at least 6 h prior to testing. Moreover, EndoPAT measures were unable to be compared to sex- and age-matched controls from the VICS cohort since these were not an outcome measure for that study. While this is the nature of using historical population data for comparison, it limits the significance of our findings for endothelial function.42 also indicates lesser condition severity among our sample. It is possible that patients who fared better than others were more likely to agree to participate in research relating to their illness. Investigating the relationship between AN severity and cardiovascular impact is a potential future research direction. Furthermore, even though patients may have been recovered at the time we conducted cardiovascular assessments, any relapses in recovery or additional treatment sought could have affected our results. Inclusion of the remainder of the 36 patients who originally expressed interest could also affect the results; although chart review indicates historical characteristics  to be similar to the current sample.Lastly, all patients were ascertained through specialist Eating Disorder Services and thus our findings cannot be readily generalised to populations with milder disease or those who never sought treatment. Patient historical information indicates our study sample had not experienced the greatest degree of illness chronicity or severity. A moderately, as opposed to severely or extremely, malnourished cohort and an illness duration of <1.5 years may have led to more favourable long-term outcomes. The lower prevalence of bradycardia (55%) and postural hypotension (32%) in this study population compared to data for cardiovascular complications in other AN studiesIn conclusion, this is the first study to conduct a long-term follow-up assessment of cardiovascular health in patients who formerly had AN during adolescence. Our findings show increased carotid artery stiffness, endothelial dysfunction, reduced aortic stiffness, and altered autonomic regulation in early adulthood. This study is preliminary in nature given the discussed limitations and further cardiovascular follow-up studies of AN, with continued monitoring into later life, should be conducted to corroborate our findings and investigate potential disease progression. Nonetheless, the persistent cardiovascular adaptations identified in our findings highlight the need for greater attention to the cardiovascular complications that occur in AN. Clinics should consider routine monitoring of AN patient’s cardiovascular health so treatments can be adapted to minimise disease risk.


Diabetic kidney disease (DKD) is a complication of diabetes that can lead to kidney failure. Over the years, several drugs have been developed to combat this disease. In the early 90s, angiotensin blockade (ACEi and ARBs) was introduced, which revolutionized the treatment of DKD. In recent years, newer drugs such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, endothelin antagonists, and mineralocorticoid receptor antagonists (MRA) have shown great promise in reducing albuminuria and protecting the kidneys. These drugs are being used in combination with lifestyle modifications, patient education, and risk factor modification to effectively manage DKD. In this review, we will explore the latest pharmacological options, their efficacy, and their potential to revolutionize the management of this debilitating disease. It is a progressive condition that can ultimately lead to kidney failure, requiring dialysis or transplantation. Despite advances in monitoring and treating diabetes, it remains the most common cause of end-stage kidney disease. According to the 2022 United States Renal Data System (USRDS), 14.0% of adults have a low estimated glomerular filtration rate (eGFR), albuminuria, or both. The data also showed that the prevalence of diabetes has increased in the most recent years, reaching 9.5% in those without chronic kidney disease (CKD) and 35.6% in those with CKD as of March 2020  infers an increased risk of cardiovascular disease which is the leading cause of death in people with diabetes and CKD. The management of DKD is multifaceted and it typically involves a combination of lifestyle modifications, patient education, and pharmacotherapy. Over the years, a variety of medications have emerged to combat DKD and its associated complications. These drugs work in different ways to protect the kidneys, mitigate disease progression, and reduce the risk of cardiovascular disease. The first class of medications to revolutionize the management paradigm of DKD are angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB). By blocking the renin-angiotensin aldosterone system (RAAS), these medications can reduce glomerular hypertension, reduce proteinuria, and slow the progression of DKD.In recent years, newer classes of medications emerged such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonist, endothelin antagonists, and mineralocorticoid receptor antagonists (MRAs) are all showing great promise in the battle against DKD and its cardiovascular morbidity. Despite the availability of these medications, the management of DKD remains a challenge with a significant residual risk remaining even with optimal medical therapy.22.1For more than 3 decades, RAAS blockade agents have been the mainstay of treatment in DKD . The mai2.2Trials have shown that these agents slow the progression of moderately increased albuminuria to overt proteinuria and even prevent the development of albuminuria in normotensive patients with no albuminuria . Hence, However, as with all effective medications, RAAS inhibitors come with a range of side effects. The initiation of ACEi and ARBs may result in elevated levels of serum potassium and creatinine. The reversible drop in eGFR is expected knowing the mechanism of action of these medications and their benefit in reducing single-nephron hyperfiltration. For the majority of patients, these changes are not worrisome. However, in patients with advanced chronic kidney disease who are at risk of volume depletion, acute or chronic kidney injury, and hyperkalemia, it is advisable to monitor kidney function and electrolyte levels approximately 2–4 weeks after starting the medication . It is sCough and angioedema are also important barriers seen mainly with ACEi. Switching patients who exhibit these side effects to an ARB has been subject to debate. According to the American Heart Association, it is reasonable to switch to an ARB in patients developing ACEi-provoked cough or angioedema. It is preferred that patients undergo a 6-week washout period between stopping the ACEi and starting the ARB (Class 1 recommendation with level A evidence) .It is important to note that women of childbearing age should be on contraception while on ACEi or ARBs and guidelines recommend stopping these agents if pregnancy were to occur due to their teratogenic effects , 18.2 of body-surface area) were randomized into either to discontinue or continue the therapy with RAAS inhibition. This multi-centered, open-label study showed no significant difference in the long-term rate of eGFR decline between the two arms. It is thus recommended not to discontinue RAAS inhibition unless treatment is complicated by side effects such as refractory hyperkalemia. This is of particular importance in patients with additional indications for RAAS inhibition  (According to the American Diabetes Association (ADA) and Kidney Disease Improving Global Outcomes (KDIGO) guidelines, SGLT2 inhibitors are now recommended first-line agents for patients with type 2 diabetes, CKD, and eGFR ≥20 mL/min/1.73 mndation) , 39. In ndation) .2) in the first 2 weeks of initiation, which is explained by the hemodynamic effect of this medication in reducing glomerular hyperfiltration  can cause medullary hypoxic injury and vasoconstriction of the afferent renal arteriole, reducing the kidney’s ability to regulate glomerular blood flow . TherefoFinally, it is important to mention that in all landmark trials involving kidney outcomes using SGLT2 inhibitors, patients were on a maximally tolerated RAAS inhibition medication (in the form of ACEi or ARB) before starting SGLT2 inhibitors. Therefore, optimizing RAAS inhibition is important prior to SGLT2 inhibitor initiation .3.32 and albuminuria of 200–5,000 mg/g (2) with and without albuminuria. The primary outcome of kidney disease progression or death from cardiovascular causes was reduced by 28% in the empagliflozin group compared to the placebo group  which improves insulin sensitivity and secretion in a way similar to GLP-1 . Kidney 4.2It is important that clinicians familiarize themselves with the different medications in this class, since not all of them share the same degree of benefits. When looking at their utilities from a kidney standpoint, only liraglutide, dulaglutide, and subcutaneous semaglutide have demonstrated kidney benefits and effects on major cardiovascular events . ImportaWhen patients on insulin treatment begin taking a GLP-1 receptor agonist, it is crucial to monitor their insulin dosage closely. Increasing the dose of the GLP-1 receptor agonist may require a decrease in insulin dosage and adjustment or discontinuation of insulin secretagogues if hypoglycemia is a concern.Glucagon-like peptide-1 receptor agonists can be used as a combination therapy with insulin and other oral medications except for other incretin therapies such as DPP-4 inhibitors; this combination is unlikely to provide additional benefits on glycemic targets.Clinicians must counsel patients on potential side effects, particularly gastrointestinal effects which tend to be temporary and can be mitigated by starting with a low dose and up-titration every 2–4 weeks. Providing patients with dietary consultation, including eating small meals with low-fat content and avoiding spicy food, might help reduce their symptoms. Patients with underlying gastroparesis might benefit from a slower titration. In patients with severe forms of gastroparesis, GLP-1 receptor agonist should be avoided.Another consideration is to evaluate patients for gallbladder disease before initiating the medication in patients with symptoms suggestive of cholelithiasis. Pancreatitis has been reported in association with GLP-1 receptor agonist use; however, causality has not been established. If patients develop symptoms suggestive of pancreatitis, the medication should be discontinued.Medications of this class are contraindicated in patients with a personal or family history of medullary thyroid cancer (c-cell tumors). Although the risk was only seen in animal models, human prevalence is not determined. None of the other more common thyroid cancers have been associated with an increased risk. Clinicians should reassure patients with a personal or family history of non-c-cell thyroid tumors.Glucagon-like peptide-1 receptor agonists’ effect on retinopathy has been debated for the past years. Studies using data from cardiovascular outcome trials suggested an association between retinopathy progression and GLP-1 receptor agonist use. However, one could argue that retinopathy can worsen with any treatment that causes rapid hemoglobin A1c reduction. Furthermore, an analysis of the FDA Adverse Event Reporting System showed no evidence that GLP-1 receptor agonists are associated with adverse effects related to retinopathy progression. More studies showed no effect of GLP-1 receptor agonists on angiogenesis and no association between GLP-1 agonist exposure and severe diabetic retinopathy. In clinical practice, we suggest close follow-up in patients with a history of moderate to severe retinopathy, particularly in patients who experience a rapid reduction of hemoglobin A1c levels with GLP-1 receptor agonist treatment .4.3post hoc analysis of EXSCEL trial data compared exenatide to placebo which showed decreased onset of severe albuminuria in the exenatide group, but the difference was not statistically significant   and it was only statistically significant in participants with stage A3 albuminuria  , 62. A pto −6.0) , 64.The LEADER trial, which studied liraglutide vs. placebo, showed renal benefit in patients with type 2 diabetes as lower rates of nephropathy events were seen in the liraglutide group (13%) compared to placebo group (14.9%) . SUSTAINThe AWARD-7 trial compared dulaglutide to insulin glargine in patients with moderate to severe kidney disease and type 2 diabetes; a decrease in UACR was seen in patients receiving dulaglutide 1.5 mg weekly . The REWpost hoc analysis of data from the tirzepatide trial (SURPASS-4) showed a slower rate of eGFR decline (−1·4 mL/min per 1·73 m2 per year) in the tirzepatide group compared to the insulin glargine group (−3·6 mL/min per 1·73 m2 per year); UACR increased from baseline in the insulin-treated group, whereas there was no significant increase observed in the group receiving tirzepatide  were on SGLT2 inhibitors during these trials. Currently, it is recommended that providers initiate and prioritize maximally tolerated RAAS and SGLT2 inhibition as the standard of care before considering additional treatment like finerenone, despite limited data on the efficacy of ns-MRA in patients receiving both RAAS and SGLT2 inhibition.2 and 10 mg in patients with eGFR 25–60 mL/min/1.73 m2 then up titrated to 20 mg as tolerated.Finerenone should be started at 20 mg in patients with eGFR ≥ 60 mL/min/1.73 mDespite being used to address concerns around hyperkalemia, it is worth noting that ns-MRAs can still result in the elevation of potassium levels in a notable percentage of patients, with rates ranging from 11 to 16% based on data from the FIDELIO and FIGARO clinical trials . The conDuring treatment, potassium levels should be followed regularly. It is safe to increase the dose from 10 to 20 mg for patients with potassium <4.8 mmoL/L and recheck levels in 4 weeks post-dose up-titration. Finererone should be withheld if potassium increases to >5.5 mmoL/L. If hyperkalemia was the limiting factor preventing dose up-titration, it is recommended to resume the medication at a lower dose after the achievement of normokalaemia on follow-up labs.n = 27), −11.2 mmHg  for finerenone 15 mg (n = 34), and − 9.9 mmHg  for finerenone 20 mg (n = 31)  for finerenone 10 mg ((n = 31) , 74.Lastly, it should be noted that concomitant use of both steroidal and ns-MRAs is not recommended .5.3p = 0.007) in the spironolactone group and by 16.8%  in the losartan group.Spironolactone has demonstrated promising efficacy in managing DKD, particularly in reducing proteinuria and slowing the progression of kidney damage. Several reviews including a Chocrane systematic review confirmed the additional benefit of steroidal MRAs for kidney and cardiac protection when used with an ACEior ARB , 76. AddMultiple phase II randomized clinical trials investigated the efficacy and safety of finerenone. Fewer side effects were seen with the ns-MRA as highlighted in the Mineralocorticoid Receptor Agonist Tolerability Trial (ARTS) showing significantly less hyperkalemia compared to spironolactone . A dose-In more recent years, phase III trials namely the finerenone in reducing kidney failure and decreasing progression of diabetic kidney disease (FIDELIO-DKD) and the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease (FIGARO-DKD) provided the biggest evidence of cardiorenal protection. The composite kidney outcome occurred in 5.5% of patients receiving finerenone and 7.1% receiving placebo . Once ag66.1Endothelins were first discovered in 1985 with the first endothelin aptly named endothelin 1. Endothelin 1 has simultaneously been implicated in inflammation, vasoconstriction, and mesangial proliferative effects mediated by endothelin receptor A. These derangements are implicated in the underlying pathophysiology, both initial insult and ongoing injury/progression of DKD, hypertension, and glomerulonephritis . There i6.2Volume overload and heart failure exacerbations remain a concern when for treatments using endothelin receptor antagonists. Combining endothelin receptor antagonists with SGLT2 inhibitors may reduce fluid retention similar to thiazides or loop diuretics . This caWhen prescribing endothelin antagonist, other effects should be considered beyond the medication’s effect on volume overload. First, it is key to exclude pregnancy before starting treatment and 1 month after stopping the medication. This recommendation is mainly due to the teratogenic effect of these drugs seen in previous endothelin receptor agonist’s studies for pulmonary arterial hypertension . It is a6.32 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)   . Patientfailure) .7New alternative treatment options encompass antifibrotic interventions utilizing pirferidone or pentoxifylline , Nox1/4 8Several new agents have made a significant impact in the field of DKD with clear protective advantages not only in terms of kidney disease progression but also in cardiovascular risk mitigation. While RAAS inhibitors continue to be essential for managing these patients, we now have the option of offering additional medications that can complement the benefit of blocking RAAS including SGLT2 inhibitors, GLP-1 receptor agonists, and MRA.In summary, borrowing the terminology from our heart failure colleagues, the guideline-directed medical therapy for DKD is here and for the time being includes ACEi or ARB, SGLT2 inhibitors, GLP-1 receptor agonist, and an MRA. The expansion of therapeutic options has marked the beginning of a new era in DKD management where we can hopefully be more impactful in the care of these patients .YB: Writing – original draft. AA: Writing – original draft. KA: Writing – original draft. OO: Writing – original draft. AM: Conceptualization, Supervision, Writing – review & editing. HS: Conceptualization, Supervision, Writing – review & editing.