Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713. Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease (CVD) development during the disease course ,2. Up toHyperglycemia and insulin resistance contribute to enhanced oxidative stress, low-grade chronic inflammation, endothelial dysfunction, increase in advance glycation end-products and protein kinase C overactivation, and thus to increased atherogenesis and atherothrombosis . Other iThus, there is an absolute need for new, useful and easily measured prognostic markers, which can be utilized for the primary and secondary prevention of major adverse cardiovascular events (MACEs) and cardiovascular death in those patients .Arterial stiffness constitutes a prognostic marker of CVD, whereas pulse wave velocity (PWV) is the “gold-standard” for its quantification in daily clinical routine. Previous meta-analyses have shown the value of PWV for the prediction of future MACEs, cardiovascular and all-cause mortality, with a cut-off value of 10 m/s ,10,11. HSodium-glucose co-transporter-2 (SGLT-2) inhibitors have notable cardiovascular efficacy, as shown in the relevant cardiovascular outcome trials . Thus, tTherefore, we attempted to determine whether two different SGLT-2 inhibitors with established cardiovascular efficacy exert any effect on ambulatory PWV and other indices of arterial stiffness, by conducting a pilot, observational study in a real-world setting.This is a single-center, prospective, observational study, conducted in Greece, from January 2020 to August 2021. The study was registered at the International Standard Registered Clinical/soCial sTudy Number (ISRCTN) registry (ISRCTN88851713).The study design and protocol have already been described in detail in a previous publication by our research team .Enrolled patients were assigned dapagliflozin or empagliflozin, as described previously .We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Secondary efficacy outcomes of interest included: augmentation index (Aix); pulse pressure (PP); 24 h systolic and diastolic blood pressure ; central systolic and diastolic blood pressure ; 24 h heart rate (24-h HR). We also assessed several other markers of specific interest, including change in glycemic control [HbA1c and fasting plasma glucose (FPG)]; body weight and body mass index; office systolic and diastolic blood pressure; office heart rate; renal function [serum creatinine and estimated glomerular filtration rate as measured by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation]; 24 h urinary protein excretion and urine microalbumin in spot urine collection; hematocrit and hemoglobin; lipid profile parameters ; C-reactive protein (CRP) levels, from baseline to week 24.We also evaluated safety outcomes of interest throughout the study, including any and severe hypoglycemia; acute hyperglycemic crisis, mainly diabetic ketoacidosis; urinary and genital tract infection; lower limb amputation; orthostatic hypotension or volume depletion episode; acute kidney injury.Patients were initially evaluated regarding their potential inclusion in the study, according to the prespecified eligibility criteria. Eligible patients provided the investigators with a written informed consent, after a meticulous explanation of the study procedures.® 24 h PWA device (IEM GmbH). Blood pressure monitoring was performed every 20 min during the daytime (7:00 to 23:00) and every 30 min during the nighttime (23:00 to 7:00). Measurements were used for the analysis if >70% of the recordings were valid. Central hemodynamics and arterial stiffness indices were also recorded with the Mobil-O-Graph® 24 h PWA device, as previously described.These patients were instructed to visit the Diabetes Center on a scheduled morning after a 12 h period of fasting. A study investigator recorded baseline demographics, anthropometric parameters, medical history and concomitant medication. Blood samples were taken in order to determine glycated hemoglobin, hematocrit, hemoglobin, serum creatinine, estimated glomerular filtration rate, serum sodium, serum uric acid and CRP levels. All patients were instructed to perform a 24 h urine collection ending at the morning of the baseline evaluation to measure urine albumin. Office blood pressure was recorded with a validated oscillometric device and a cuff of appropriate size, with the patient sitting for at least 10 min and with three measurements per occasion taken 2 min apart. Finally, all patients underwent ambulatory blood pressure monitoring (ABPM) with the Mobil-O-GraphThe augmentation index was calculated as the augmentation pressure, which is the pressure of the second systolic peak minus the pressure at the inflection point, expressed as the percentage of the pulse pressure and normalized for an HR of 75 bpm (Aix@HR75).p-values lower than 0.05 were considered statistically significant. R software environment has been used for statistical analysis.The statistical analysis has been described in detail elsewhere . The chaA total of 46 Caucasian subjects  were finally enrolled. Due to COVID-19 pandemic restrictive measures imposed by the Greek Ministry of Public Health during the study, the mean follow-up period was extended to 9.98 3.27) months. A detailed description of participants’ baseline characteristics is provided in a previous publication from this study  did not have a significant effect on the observed results both for empagliflozin and dapagliflozin.p = 0.008), office SBP , office DBP , 24 h SBP , 24 h DBP , cSBP , cDBP  and BMI . No correlation between the change in PWV and the change in glycemic control indices , in lipid profile parameters or in hematocrit/hemoglobin was demonstrated in our cohort.We finally assessed the correlation between PWV with other established cardiovascular risk factors. We demonstrated that PWV significantly correlates with body weight (r = 0.38, This is the first, real-world study available in the literature addressing the effect of two different SGLT-2 inhibitors on ambulatory PWV and other indices of arterial stiffness over a long follow-up period. We have shown that the SGLT-2 inhibitor treatment over almost 1 year of follow-up in a cohort of overweight or obese patients with long-standing T2DM, sub-optimal glycemic control and cardiovascular co-morbidities did not have a significant effect on any of the assessed indices of ambulatory arterial stiffness.Some of us have previously critically reviewed the studies assessing the effect of SGLT-2 inhibitors on arterial stiffness, reaching the conclusion that the current evidence is limited to provide definite answers, despite the fact that most of the studies demonstrated a beneficial effect of this drug class on PWV . More spOther trialists have previously found that 3- and 6-month treatment with empagliflozin led to a significant reduction in cPP , while oBased on the recent cardiovascular outcome trials proposing that SGLT-2 inhibitors might be crucial for the treatment of special patient sub-populations, such as those with concomitant HF with reduced or preserved ejection fraction ,22,23 orWe found a neutral effect of the SGLT-2 inhibitor treatment on ambulatory PWV in patients with T2DM and either established CVD or certain cardiovascular risk factors. Comparing with two previous trials evaluating the effect of empagliflozin  and dapaWe have to admit the presence of certain limitations. First, it is a preliminary study with an observational design and a small sample size. The number of enrolled participants is low to reach statistical significance and to draw certain conclusions. Second, we did not evaluate the effect of the SGLT-2 inhibitor on arterial stiffness parameters at shorter time intervals, in order to assess whether there was a short-term, beneficial effect. Third, the absence of a control group to assess the comparative effectiveness of SGLT-2 inhibitors on ambulatory arterial stiffness indices represents an additional limitation. Fourth, the present study took place within the COVID-19 pandemic, with an important adverse impact on patients’ quality of life, physical activity and access to national healthcare services . In addiIn conclusion, we have shown in this real-world study that an SGLT-2 inhibitor treatment did not improve ambulatory arterial stiffness measures over 10 months of follow-up. Based on the limited literature data regarding the effect of SGLT-2 inhibitors on ambulatory arterial stiffness, the promising role of ambulatory arterial stiffness in cardiovascular risk prediction or cardiovascular disease stratification and the established cardio-protective effect of this drug class, it seems that more data are needed. Large, well-designed, prospective studies, ideally randomized controlled trials, are required to shed further light on whether SGLT-2 inhibitors exert any effect on ambulatory arterial stiffness.


Controlled clinical intervention studies have demonstrated that cocoa flavanols (CF) can decrease blood pressure and arterial stiffness in healthy humans, although a large variability in the effect size across trials has been reported. In this study, we evaluated the intra- and inter-individual variability of responses to CF in everyday life using a series of n-of-1 trials in healthy free-living individuals with normal blood pressure carrying personal devices. In total, eleven healthy young humans participated in a repeated crossover randomized controlled double-blind n-of-1 trial. On 8 consecutive days, each volunteer consumed on alternating days 6 CF capsules (862 mg CF) on 4 days and 6 matched placebo capsules  on another 4 days in one of the two randomized sequences (CF-P-CF-P-CF-P-CF-P or P-CF-P-CF-P-CF-P-CF). On each day, the capsules were taken at the same time in the morning with breakfast after baseline measurements. Each subject was provided with an upper arm blood pressure monitor and a finger clip that measures pulse wave velocity (PWV). Measurements of blood pressure, heart rate, and PWV were taken at least hourly over 12 h during the day by the participants. On the first 2 days, measurements were performed under supervision to provide training. The overall mixed model analysis showed that CF significantly decreased 12-h systolic blood pressure and PWV by −1.4 ± 0.3 mmHg and −0.11 ± 0.03 m/s, respectively. Peak effects were observed within the first 3 h  and again after 8 h post-ingestion. Large inter-individual variation in responses was found . When analyzing single individuals’ datasets, there was also considerable between-day variation in individual responses that varied greatly between subjects . Effect sizes inversely correlated with baseline blood pressure values both between- and within-subjects. The data confirm that cocoa can decrease blood pressure and arterial stiffness in everyday life when elevated within the normal range. The large inter- and intra-individual variation in responses calls for more personalized nutritional intervention strategies. Epidemiological data suggest that there is an inverse relationship between the consumption of flavonoid-rich diets and the risk for cardiovascular disease –6. SigniIn the so-called n-of-1 study design, individuals are exposed to interventions and control multiple times , 12. It n = 11) were healthy male and female adult subjects (<45 years) with normal blood pressure and without history, signs, or symptoms indicative of cardiovascular disease, including previous myocardial infarction, stroke, and peripheral artery disease or current or previous medication.The study participants , the study participants self-monitored blood pressure, heart rate, and pulse wave velocity (PWV) over 12 h during the day on 8 days . MeasureOn each of the 8 study days, participants consumed either 6 cocoa flavanol capsules  or 6 placebo (empty 00 capsules filled with brown sugar). All participants were randomized to one of the two different sequences of treatment periods. The alternating treatment allocations were either flavanol-placebo-flavanol-placebo-flavanol-placebo-flavanol-placebo or placebo-flavanol-placebo-flavanol-placebo-flavanol-placebo-flavanol. All capsules were provided in black opaque zip-lock bags labeled with an alphanumeric code, and capsules were supposed to be directly tipped into the mouth and swallowed with water together with breakfast.On the first 2 days of the study, measurements were performed under supervision at the universities research facility to provide training to participants. On the following days, the measurements were performed during the normal life of the participants. The participants were instructed to sit down for 10 min before measurements and take measurements of blood pressure, heart rate, and PWV on the left arm with the arm resting on a table in front of them. They were also taught how to use the software to operate the devices on a provided small tablet device  and introduced to an electronic case report file to which participants transferred their data.1. The study protocol was reviewed and approved by the University of Surrey Ethics Committee with the registration number FER-1819-040, and written informed consent was obtained from all participants.On the training days of 8 subjects, we also performed measurements of flow-mediated dilation (FMD) at baseline before (0 h), at 2 h, and at 8 h after the first intervention to ensure the biological activity of test materials. The allocation was double-blinded and randomized, and the randomization sequence was generated using an online calculatorThe cocoa supplement and placebo capsules were purchased from Amazon.co.uk. According to the provided supplement facts, 6 capsules of CocoaVia supplement  contained 862 mg  CFs. CFs as defined here correspond to the sum of flavanol monomers and procyanidins with a degree of polymerization up to 7, according to the AOAC 2020.05 method . While cStandard upper arm systolic and diastolic blood pressure and heart rate  and finger PWV  were measured in 30 min intervals for the first 3 h after the morning intake of the capsules and at hourly intervals over a total of 12 h see . The cufAll of our previous studies have confirmed positive responses to cocoa flavanols on FMD as primary end point, while only some but not others showed significant effects on blood pressure , 9, 17. max-diameterbaseline)/diameterbaseline × 100.The FMD was measured as previously described . Brieflyn = 1). A random subject effect accommodates the correlation between the repeated measurements in day/time within-subjects and is substituted by a random day effect in the individual models. By using the intraclass correlation coefficient (ICC), a ratio of the within-individual variance to the total, the inter-individual reliability of a measure can be indicated. High ICCs indicate that variation in measures is attributable to differences between individuals and is not dominated by day-to-day variation within individuals , a fitted model was applied that adjusts for the baseline measure of the parameters on each study day and includes an intervention effect, time, and an interaction between time and intervention to allow for the effect to change with time. The analysis was performed first with all values over 12 h included and then repeated on a restricted dataset only including baseline and 1.5 h values. The statistical models were separately fitted for the group and for individuals  in a way that would allow comparison with other conventional studies in which participants’ measurements are taken only at selected timepoints in each study arm once for each intervention and placebo.interventionp < 0.0001, timep < 0.001, interaction intervention*timep = 0.268) and −0.11 ± 0.03 m/s , respectively. There was also a decrease in diastolic blood pressure that depended on time (−0.5 ± 0.3 mmHg) . The heart rate significantly increased by 0.9 ± 0.4/min . The responses greatly varied between participants as indicated by intra-cluster correlation coefficients (ICC) . The variation in responses did not differ between the first 2 supervised and the remaining 6 home-based unsupervised measurements. Using the consecutive study days as a continuous covariate, we found no evidence that over the course of 8 days, there was a cumulative effect of CF despite interspersed placebo days.The time courses  were quainterventionp = 0.032, dayp = 0.645, interactionp = 0.702). In this restricted dataset, the decrease in PWV did not reach statistical significance . A numerical decrease in DBP was observed that was not significant . There was a significant time-dependent decrease in heart rate −0.5 ± 1.5/min . The responses on the level of SBP, DBP, and PWV at 1.5 h much less varied between participants as compared with 12 h effects as indicated by low ICC , while ICC of heart rate was 0.59 rather indicating large between-subject variation.We then evaluated the magnitude and inter-individual variation of peak effects at 1.5 h after ingestion. This analysis showed greater effects as compared with the overall 12 h effects. SBP and PWV decreased by −4.9 ± 2.5 mmHg .n = 10 and 3 data points from n = 1). Note that all 11 show a linear fit line with negative slopes and that several participants showed both positive and negative responses depending on the baseline value in the morning before CF ingestion. This indicates that CF did not lower blood pressure when values were already low (approximately below 115/75 mmHg).To illustrate this, This study shows for the first time a significant real-life biphasic response in terms of blood pressure and arterial stiffness lowering with maximal effects within 3 h and later at approximately 8 h. This was paralleled by increases in FMD at 2 and 8 h. The improvement of FMD by approximately 2% at 2 h was similar to what was obtained in other previous studies in healthy volunteers using slightly different cocoa flavanol interventions , 20, 21.Alongside the overall analysis of the results, this study investigates for the first time intra- and inter-individual responses to cocoa flavanols using the n-of-1 study design. It shows that a large proportion of intra- and inter-individual variation effects were related to baseline blood pressure values. Not all participants responded and not all responded all the time. Specifically, if the blood pressure was low in a person on a certain day, the cocoa flavanols decreased blood pressure and arterial stiffness less. This has important safety and mechanistic implications. In particular, in primary prevention, safety is a major issue, and excessive blood pressure lowering may pose a safety risk as described for antihypertensive medication  for the The variability of responses highlights the importance of personal devices that can monitor biomarkers of biological effects frequently as therapeutic targets for personalized medicine. For instance, home blood pressure monitoring is now recommended in clinical practice guidelines . Our datThe effective exploitation of n-of-1 trials for personalized medicine requires standardized statistical models to analyze the results, and there is currently no standard approach. In this study, we adopted mixed model approaches that allow adjustments for baseline measures of the parameters on each day and include an intervention effect, time, and an interaction between time and intervention, as well as random subject or day effects to appropriately capture the between- and within-subject variation. The ability to compare the pooled analysis over subjects and study individual effects demonstrates the importance of further investigation of individualized approaches over simple population-based methods.ca. 2 mg/kg (Several limitations not previously mentioned apply to this study. The small sample size limits generalizability to the wider population. Furthermore, the effect of CFs may be influenced by the diet and, in particular, the breakfast with which it was consumed. Unfortunately, we did not collect data related to the diet consumed throughout the study or take blood samples to evaluate biomarkers of polyphenol intake to investigate this. Another limitation relates to the fact that the cocoa supplement did not only contain cocoa flavanols but also significant amounts of methylxanthines, primarily theobromine. It is now appreciated that methylxanthines can have health effects on their own . The pla 2 mg/kg , 40. The 2 mg/kg . Therefo 2 mg/kg .In conclusion, our data confirm that cocoa can improve vascular function and decrease blood pressure and arterial stiffness not only within the first 3 h after ingestion but also later at 8 h in healthy normotensive people. Our study uncovers considerable intra- and inter-individual variation in responses using an innovative n-of-1 study design with personal devices. With this approach, we uncovered baseline blood pressure as a major determinant of response in healthy young people. Our data highlight the need for personal health monitors to develop and implement effective personalized nutritional intervention strategies in the future.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the University of Surrey Ethics Committee. The patients/participants provided their written informed consent to participate in this study.MB: project administration and preparation, investigation, analysis, and writing – review and editing. PC: supervision and review and editing. AR-M: review and editing. SS: statistical analysis and review and editing. CH: conceptualization, project administration, supervision, investigation, analysis, and writing – review and editing. All authors 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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A total of 55% of patients lost ≥7% in GMV compared to 11% of patients in IMV (p ≤ 0.001). Individuals who lost >5% of their baseline weight had a higher reduction in overall blood pressure. For systolic and diastolic blood pressure, the differences between baseline and three months for GMV and IMV were −7.4 vs. 4.1 mm of Hg (p = 0.002) and −4.6 vs. 4.2 mm of Hg (p = 0.003), respectively. Results from this study demonstrate that GMV may be a potentially useful modality for addressing weight and blood pressure in an underserved population.The effect of group medical visits (GMV) compared to individual medical visits (IMV), on weight and blood pressure in a large primary care practice serving a predominantly underserved population, was assessed. The records of 304 patients attending a weight-loss program were analyzed using mixed-effects regression models. Patients in GMV lost an average of 11.63 lbs, whereas patients in IMV lost an average of 3.99 lbs ( The underserved population is disproportionately affected by obesity . ObesityGroup medical visits (GMV) are healthcare visits shared alongside similar patients that are conducted by transdisciplinary healthcare teams to increase the time spent with healthcare providers, address physiological and psychological issues, and provide group social support . GMV areIn this paper, we investigated the role of GMV compared to IMV in reducing weight and blood pressure using a retrospective cohort analysis. We hypothesized that when compared to IMV, GMV will demonstrate improved weight loss and blood pressure control.Data were abstracted from electronic medical records of patients attending the Clinical Weight Loss (CWL) program at Banner University Medical Center—South Campus in Tucson, Arizona, USA, during 2017–2018. The program is housed within a family medicine clinic located in South Tucson, a federally designated medically underserved area where 49.4% of patients treated in the clinic identify as Hispanic or Latino. The median household income is $21,160 with 57.7% households reporting an income less than $25,000 .The CWL program is a physician-led medical weight-loss program that offers both GMV and IMV appointment options. The initial visit was a one-on-one medical visit led by a physician consisting of a detailed patient history, full physical examination, and orders for laboratory tests (if indicated). After the initial visit, patients were given the option to schedule their follow-up appointments as GMV or IMV and were scheduled every 2–3 weeks. Patients could schedule the frequency and timing of their visits at their convenience and could participate in the program as long as desired. GMV were conducted by a physician and a health coach. The group included 2–8 patients scheduled during the same 60 min. Patients would rotate one at a time with a private check-in with the physician while the rest of the group met with the health coach. Once all 1:1 check ins were complete, the physician would join the group. In addition to the medical supervision of the physician, patients received lifestyle modification education and support during the group setting. The lifestyle modification was encouraged through increasing self-efficacy using tools such as S.M.A.R.T.  goals, nutrition, and physical activity education and general social support as patients discussed their challenges and successes toward achieving their weekly weight-loss goals. Most of the visits were bi-weekly, 60 min in duration, and with a maximum group size of eight patients. IMV were conducted by a physician only  in a one-on-one 15 min visit. t-tests were used to describe continuous variables and chi-square tests were used for categorical variables at baseline. Since data were conducted over multiple time points without fixed intervals, mixed-effects regression models were conducted to determine the impact of GMV and IMV on overall weight loss in patients over time. Analyses were adjusted for age, race, and the presence of co-morbidities. Subset analysis was conducted to determine the effect of group medical visits on blood pressure. Analyses was performed using STATA14 statistical software . Weight and blood pressure data were collected during each visit conducted every 2–3 weeks. Analyses were restricted to patients who had made three or more visits in the CWL program and weight was included in the visit record. Blood pressure readings, diabetic status, and other diagnoses were extracted if present. The data from 304 patients who attended the clinical weight-loss clinic for this retrospective cohort study are demonstrated in p = 0.45) at the initial visit. Co-morbidities were extracted from the initial visit of the patient chart using diagnosis codes and included, but were not limited to, insulin resistance, hypertension, and obstructive sleep apnea. There were no differences between the IMV and GMV on diabetic status ; however, the total number of co-morbidities was slightly higher in the GMV group (p < 0.001) after adjusting for age, number of co-morbidities, start weight, and sex, as described in Mixed-effects regression models indicated that patients in the IMV group lost an average of 3.99 lbs, whereas patients in the GMV settings lost an average of 11.63 lbs. This result remained statistically significant (p ≤ 0.001), as shown in Patients’ total weight loss  was categorized by whether they achieved 7% or more weight loss. Attaining a 7% weight loss is related to a reduction of diabetes risk or transitioning pre-diabetes to diabetes . Among pp = 0.002), respectively. The difference for diastolic blood pressure between GMV and IMV, for baseline and three months, was −4.6 vs. 4.2 mm of Hg (p = 0.003), as shown in Data for blood pressure were available from 81 patients. There were 22 subjects in the IMV and 59 subjects in the GMV. As shown in This retrospective cohort study demonstrates that GMV may be an effective modality for lowering weight and blood pressure in a population of underserved patients. Patients attending GMV tended to stay in the program longer than those who attended IMV. Patients losing more than 5% of their body weight demonstrated greater reduction in blood pressure, with more patients in the GMV group achieving a >7% weight loss than those in the IMV group. These findings are in line with those described by Trento et al., who demonstrated a significant greater weight loss in diabetic patients in GMV (2.6 kg or 5.73 lbs) compared to IMV (0.9 kg or 1.98 lbs) . The curThe non-randomized nature of group category assignments in this real-world intervention is both a strength and a limitation of the study. The patients chose their preference of continuing with GMV or IMV after their initial visit and there were no restrictions on the number of sessions that they could attend, thus creating a risk of selection bias, but at the same time increasing the generalizability of the results in a real-world clinic setting. Patients attended as many visits as they felt comfortable, giving them greater control in customizing care to meet their needs. Analyses were adjusted for the number of visits to address this potential bias.The novelty of this study lies in the setting in which it was conducted. The CWL program is embedded in a busy full-spectrum family medicine practice and a residency training program, serving a predominantly underserved racially and ethnically diverse population. As a result, the CWL program needed to adapt operations to fit within the workflow of the existing full-spectrum family medicine clinic, utilizing existing clinic staff, and adjusting the intervention to multiple parent clinic operational requirements. Although validation of these findings through appropriate designed prospective studies are needed, results from this study indicate that the medical group therapy model is a promising strategy for increasing the efficacy and efficiency of clinical weight-loss interventions and blood pressure control, especially among the high-volume resource-lacking practices that serve the underserved populations.


Excess cardiovascular burden in patients with chronic kidney disease (CKD) has been attributed to the occurrence of CKD-Mineral Bone Disease (CKD – MBD). This study aimed to determine the spectrum of CKD-MBD among Nigerians with CKD using Fibroblast Growth Factor 23 (FGF 23) and intact Parathyroid Hormone (iPTH).Cross sectional survey of 105 patients with non-diabetic CKD and 104 controls. Information obtained were demographics, aetiology of CKD, features of CKD-MBD. Serum iPTH and FGF 23 were assayed.The mean ages were 48.7±15.3 vs 48.6±17.4 years while 54.7% and 45.2% were males for cases and controls, respectively. The mean plasma FGF 23  and abnormal iPTH  were higher in cases. The prevalence of MBD were  in cases and controls while dialysis status OR 2.94, 95% CI (1.2803–5.3645), and elevated FGF 23 OR, 1.87, 95% CI (1.1782–5.4291) were associated with CKD-MBD.The study demonstrated high prevalence of CKD-MBD among patients with non-diabetic CKD while FGF23 and iPTH were useful assays in the diagnosis of CKD-MBD among Nigerians with CKD. Chronic kidney disease (CKD) is a major contributor of disease burden among the sub-Saharan African population, it is associated with rising prevalence, poor awareness, excess cardiovascular disease (CVD) burden and high morbidity and mortality.10The gold standard for assessment of CKD-MBD is bone biopsy and histology, which is invasive and not commonly used in routine clinical practice.16In most of the sub-Saharan Africa, patients with CKD are either minimally or not evaluated for CKD-MBD at all, as majority of the patients pay out of pocket and thus add to the cost of care which is already not affordable by a large proportion of patients with CKD.th August 2019 and 28th February 2020. To be eligible participants must be 18 years and above, have diagnosis of CKD from non – diabetic kidney disease. Excluded from the study were individuals with Diabetes mellitus, kidney transplantation and those with history of parathyroidectomy.A cross sectional study of non – diabetic kidney disease patients who were attending the Medical Outpatient Clinic of the University College Hospital, Ibadan and apparently healthy controls who were age and gender matched volunteers. Non-diabetic kidney disease was defined as participant with estimated Glomerular Filtration Rate (eGFR) less than 60mls/min/1.73mAll participants gave written informed consent and ethical approval was obtained from the Joint University of Ibadan and University College Hospital institutional review board with the approval number UI/EC/19/0113.Relevant information was obtained using standard case report forms. All participants provided information on demographics, age of diagnosis, etiology and stage of CKD, symptoms and signs of CKD-MBD , history of co-morbidity, dialysis, dialysis vintage and medication history. Physical measurements obtained were weight, height and blood pressure.All participants gave 20ml of blood, plasma intact parathyroid hormone (iPTH) was assayed in all participants using Enzyme Linked Immunosorbent Assay with ELISA kits . The manufacturer's range was 12.35–1,000pg/mL while the intra and inter-assay coefficients were <10% and < 12%, respectively. The plasma c-terminal FGF 23 (cFGF-23) was analyzed using ELISA assay kits . The manufacturer's range was 7.8 – 500RU/ml  while the intra and inter-assay coefficients were <10% and < 12%, respectively. Both assays were analyzed using Emax ELISA Reader . Serum electrolytes, calcium and phosphate were determined using spectrophotometric method with a semi-autoanalyzer . eGFR was estimated from the serum creatinine using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.Data obtained was entered into Microsoft Excel and was subsequently transferred to the Statistical Package for Social Science version 23 for analysis. Baseline descriptions of socio-demographic and clinical variables were reported as proportions for categorical variables and mean (standard deviation) for continuous variables. The association between categorical variables was tested using chi-square analysis while Student's T - test was used to test association between continuous variables. A logistic regression analysis was employed to determine factors independently associated with CKD-MBD. Statistical significance was set as p-value <0.05.Elevated cFGF 23 was defined as FGF 23 above 104RU/ml 21 while elevated iPTH was defined as iPTH above 65ng/L.22 Hypocalcaemia was defined as serum calcium < 2.1mMol/L23 and hypercalcaemia was defined as serum calcium > 2.5mMol/L.24. Hyperphosphatemia was defined as serum phosphate > 1.45mMol/L.25 High turn over mineral bone disease was defined as elevated iPTH > 65ng/L while low turn over mineral bone disease was defined as iPTH < 10ng/L.26 CKD-MBD was defined as abnormality in one or more of serum iPTH, calcium and phosphate.272) while the mean DBP (84.1 vs 79.8 12.3mmHg) and SBP (140.1±22.8 vs 130.1±19.6mmHg) were higher among cases, A total of 209 participants were enrolled for the study, 105 were individuals with non-diabetic kidney disease while 104 were healthy controls. The mean ages for cases and controls were 48.7±15.3 vs 48.6±17.4 years, respectively. The males accounted for 54.7% of cases and 45.2% of controls, The mean serum creatinine (632 ± 34.2 vs 106 ± 15.8µmol/L)), plama FGF23 (392.8 ± 35.3 vs 133.8 ± 22.7 RU/mL), plasma iPTH (289 ± 25.6 vs 118 ± 10.8 ng/L), while the median urinary albumin creatinine ratio (UACR) 178.12  vs 25.32 (0.65 – 123) mg/g and median calcium phosphate products 12.10 (4.85 – 74.39) vs 7.81 (4.10 – 50.01)mMol/L were higher among the cases compared to the controls, The frequency of Hypocalcemia , hyperphosphatemia , elevated FGF 23 , abnormal iPTH  were significantly higher among the cases compared to the controls, dialysis status Odd Ratio (OR), 2.94 95% Confidence Interval (CI) (1.2803 – 5.3645) and elevated FGF 23 OR 1.87, 95% CI (1.1782 – 5.4291) were independently associated with CKD-MBD, The symptoms of CKD-MBD were observed to be significantly higher among the cases than controls bone pain , pruritus , skin rash  and myalgia , Table 4CKD-MBD has been underdiagnosed among patients with CKD in sub-Saharan because the tests required for the diagnosis of CKD-MBD are not readily available and where available were not affordable by majority of the patients, who often pay out of pockets. And such, less attention is sometimes paid to the clinical features of CKD-MBD unlike that of the symptoms of uraemia and anaemia which are commonly looked for during the routine medical consultations for individuals with CKD. Majority of the participants with the non-diabetic CKD were caused by hypertension andCGN and more than 60% were pre-dialysis CKD.The average iPTH hormone was higher among patients with CKD compared to the healthy controls in addition to the high prevalence of elevated iPTH (59.0%) in the cohort with CKD. This finding is similar to the report by Abdu et al 29The prevalence of CKD-MBD varies with different markers of CKD-MBD, abnormal plasma iPTH (45.7%) and elevated plasma FGF-23 (53.3%). The abnormal iPTH represents elevated and low level of iPTH and are commonly seen among patients with CKD and has a direct correlation with severity of CKD. Suprisingly, a relatively high proportion (14.4%) of the controls had mineral bone disease (BMD) that were not related to CKD, the finding buttresses the fact that other causes of MBD may be prevalent among the controls. The secondary causes of MBD reported to be common in the population studied include osteoporosis, indiscriminate use of vitamin D analogues and calcium based medications.Plasma FGF 23 as a marker of CKD-MBD rises early in the disease compared to iPTH, and could be elevated as early as stage 2 CKD. FGF 23 is a phosphaturia hormone and are elevated in diseases associated with increased phosphate production or decrease phosphate excretion.33Although, FGF 23 has been reported to be homogenous in most population, its level is lower by 20 – 30% among the African Americans and Hispanics compared to the Caucasians.Hyperphosphatemia was observed in 48.6% of patients with CKD, this is similar to reports from Abdu et al The leading symptoms of CKD-MBD observed among patients with CKD were myalgia (27.6%), bone pain (26.7%), pruritus (23.8%) and skin rash (21.9%). These symptoms are non-specific and could be explained by other features of CKD that include uraemia and anaemia. These symptoms are similar in both high and low output CKD-MBD spectrums and it is pertinent to mention that the absence of symptoms as observed in about half of the patients with CKD-MBD does not exclude the disease.The study is not without its limitations, since patients with Diabetic kidney disease were excluded from the study, the findings of this study can be generalised to every individual with CKD. The relatively small sample size also makes it difficult to generalise the findings of this study. However, the study made use both plasma FGF 23 and iPTH in making diagnosis of CKD-MBD.The plasma FGF 23 and iPTH were useful assays in the diagnosis of CKD-MBD among Nigerians with CKD.


Introduction: Potential detrimental effects of hyperoxemia on outcomes have been reported in critically ill patients. Little evidence exists on the effects of hyperoxygenation and hyperoxemia on cerebral physiology. The primary aim of this study is to assess the effect of hyperoxygenation and hyperoxemia on cerebral autoregulation in acute brain injured patients. We further evaluated potential links between hyperoxemia, cerebral oxygenation and intracranial pressure (ICP).Methods: This is a single center, observational, prospective study. Acute brain injured patients  undergoing multimodal brain monitoring through a software platform (ICM+) were included. Multimodal monitoring consisted of invasive ICP, arterial blood pressure (ABP) and near infrared spectrometry (NIRS). Derived parameters of ICP and ABP monitoring included the pressure reactivity index (PRx) to assess cerebral autoregulation. ICP, PRx, and NIRS-derived parameters , were evaluated at baseline and after 10 min of hyperoxygenation with a fraction of inspired oxygen (FiO2) of 100% using repeated measures t-test or paired Wilcoxon signed-rank test. Continuous variables are reported as median (interquartile range).Results: Twenty-five patients were included. The median age was 64.7 years (45.9–73.2), and 60% were male. Thirteen patients (52%) were admitted for TBI, 7 (28%) for SAH, and 5 (20%) patients for ICH. The median value of systemic oxygenation  significantly increased after FiO2 test, from 97 (90–101) mm Hg to 197 (189–202) mm Hg, p < 0.0001. After FiO2 test, no changes were observed in PRx values (from 0.21 (0.10–0.43) to 0.22 (0.15–0.36), p = 0.68), nor in ICP values (from 13.42 (9.12–17.34) mm Hg to 13.34 (8.85–17.56) mm Hg, p = 0.90). All NIRS-derived parameters reacted positively to hyperoxygenation as expected. Changes in systemic oxygenation and the arterial component of cerebral oxygenation were significantly correlated .Conclusion: Short-term hyperoxygenation does not seem to critically affect cerebral autoregulation. Acute brain injury is a major cause of mortality and severe disability . The out2) target of 80–120 mm·Hg in the acute phase of acute brain injury. In patients with traumatic brain injury (TBI), PaO2 values of 150–200 mm·Hg seem to be associated with better functional and cognitive outcome at 6 months, while PaO2 >200 mm·Hg was found to be independently associated with 6-months mortality  the exposure to higher PaO2 and fraction of inspired oxygen (FiO2) in the first 7 days after ICU admission was independently associated with a higher 6-month mortality, independently of injury severity.Oxygen is essential for aerobic respiration within mitochondria, but mitochondrial respiration also produces reactive oxygen species (ROS). Excessive administration of oxygen can consequently increase ROS formation, and induce activation of the inflammatory responses, which may cause further cerebral damage . Acute hortality . Furtherortality  demonstrA specific threshold for oxygen neurotoxicity has not yet been identified, as well as the effect of hyperoxemia on cerebral autoregulation (CA) has never been evaluated thoroughly so far. In 2007, At present, the most established method to assess cerebral autoregulation in patients with ICP monitoring in real-time is through the pressure reactivity index (PRx), which is a moving Pearson correlation between slow waves in intracranial pressure (ICP) and arterial blood pressure (ABP). Numerous retrospective studies in different patient populations demonstrated strong correlations between averaged PRx and outcome .2 = 100%) on cerebral autoregulation assessed via PRx. Secondary outcomes include the assessment of the effect of hyperoxemia on cerebral oxygenation and ICP, and the correlation between changes in cerebral autoregulation and systemic as well as cerebral oxygenation parameters.The primary aim of this study is to evaluate the short-term effects of hyperoxemia . Approval for the study was obtained according to local regulations. This study was performed according to the “Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)” statement guidelines for observational cohort studies  Additio. InclusiDemographical , clinical data , reason for ICU admission , neurological status at admission as for Glasgow coma scale (GCS), pupils characteristics , type of ICP monitoring , ICU complications  and patients’ outcome, such as ICU length of stay, mortality and neurological status (Glasgow Outcome Score) at ICU discharge were collected from electronic medical records.2O. Respiratory rate was adjusted to aim to normocapnia. The decision to perform an FiO2 trial was based on clinician’s evaluation when optimization of mechanical ventilation was required occurring within 24 h of hospital admission, in order to obtain an estimation of the presence of shunt or low ventilation/perfusion ratio and as part of the evaluation of the respiratory function performed in our ICU  which consisted of applying FiO2 set at 100% (during 10 min for stabilization), as previously described (2) and of carbon dioxide (PaCO2) before and after FiO2 test were also collected.In the ICU, patients were sedated with Propofol/Midazolam and Fentanest and were mechanically ventilated using an endotracheal tube. Tidal volume was targeted to 6–8 mL per kg of predicted body weight (PBW). Higher values of tidal volume were allowed only if the airway driving pressure was maintained below 15 cm H our ICU . Data onescribed . Arteria® with O3® regional oximetry device , with a bilateral sensor applied in the frontotemporal region. Final values of rSO2 and its components at T0 and T1 were calculated as the mean between single instant measurements obtained from the right and left frontotemporal sensors. Different parameters of cerebral oxygenation can be obtained from this monitor: a) rSO2, which represents the regional cerebral oxygen saturation, and is derived as the ratio of the concentration of oxyhemoglobin (O2Hb) and total hemoglobin ; b) ΔO2Hbi, which is an index associated with changes of concentration of oxyhemoglobin, thus representing predominantly changes in the arterial component of regional oxygen saturation; c) ΔHHbi, an index reflecting changes in concentration of deoxyhemoglobin, approximately representing changes in the venous component of the oxygen saturation; d) ΔcHbi, an index representing the sum of ΔO2Hbi and ΔHHbi components (https://icmplus.neurosurg.cam.ac.uk) (2 test) and T1  periods.Invasive ICP monitoring was inserted for clinical reasons according to our local policies following the latest Brain Trauma Foundation Guidelines . Patientmponents . All conm.ac.uk) , a clinim.ac.uk) . A presem.ac.uk) . PRx wast-test for normally distributed variables, while non-normally distributed variables were compared by paired Wilcoxon signed-rank test. Graphical representations of these comparisons are presented as boxplots. Dependent variables were expressed as a change from baseline (T0) in absolute terms (Δ change = T1-T0). The correlations coefficients ) between systemic and the different neuromonitoring variables were verified using Pearson’s or Spearman’s method, for parametric and non-parametric variables, respectively. All statistical analyses were performed using RStudio software (version 4.1.1). A p-value <0.05 was considered statistically significant.The Shapiro-Wilk test was used to test the normality of the distribution of the variables. Continuous variables are reported as median and interquartile range (IQR = 25th–75th percentiles). Comparisons between different variables at T0 and T1 were made by repeated measures (paired) During the study period, a total of 110 patients with ABI were admitted to our ICU and were considered for inclusion. Fifty-two patients were excluded as they did not undergo multimodal neuromonitoring while 33 patients were not allocated to beds equipped with multimodal monitoring capability where ICM+ software was installed. A final number of 25 patients were included in the analysis. The characteristics of the patients are presented in 2 significantly increased after FiO2 test, from 97 (90–101) mm·Hg to 197 (189–202) mm·Hg, p < 0.0001  % to 100 (100–100) %, p < 0.0001 (paired Wilcoxon test), but PaCO2 did not significantly change (42 (39–44) mm·Hg at T0 and 42 (38–45) mm·Hg at T1, p = 1)  to 0.22 (0.15–0.36), p = 0.68), as well as on ICP (from 13.42 (9.12–17.34) mm·Hg to 13.34 (8.85–17.56) mmHg, p = 0.99), and CPP values (from 69.20 (60.47–74.72) mm Hg to 71.08 (62.56–75.34) mm Hg, p = 0.76) (2 test (Δ absolute changes). rSO2 increased by 3.12 (2.18–4.00) %, p < 0.0001; ΔO2Hbi by 3.10 (1.60–5.16) μM.cm, p < 0.0001; and ΔHHbi by 1.11 (0.49–2.10) μM.cm, p < 0.0001 (paired Wilcoxon test), respectively  ESM, . After F = 0.76) . On an iectively .2 and Δ ΔO2Hbi, r = 0.49 (95% CI = 0.17–0.80), p = 0.01 (Spearman’s rank correlation coefficient)] (Absolute changes in systemic oxygenation and concentration of oxygenated hemoglobin were significantly correlated [ΔPaOicient)] . No otheicient)] .2 at FiO2 100% oxygen for 10 min does not affect cerebral autoregulation. The use of specific indices derived from NIRS allowed for hypothesizing on the arterial and venous components of cerebral oxygenation and thus the pathophysiological interplay between systemic and cerebral oxygenations and CA.In patients with ABI and mechanically ventilated, we found that the increase in systemic PaOTo our knowledge, this is the first physiological study assessing the effect of hyperoxemia on CA using continuous monitoring of cerebrovascular pressure reactivity. Previous studies have questioned the effect of hyperoxemia on cerebral dynamics, but without focusing on the importance of cerebral autoregulation. This is clinically relevant, as recent evidence suggests that hyperoxemia can be detrimental to ABI patients and has been associated with poor neurological outcome and independently associated with higher in-hospital fatality . CerebraPRx is an index of cerebrovascular reactivity which assesses the response of ICP to spontaneous vasogenic changes in ABP . A posit2 does not necessarily increase the delivery of oxygen in the injured brain parenchyma. This is related to the fact that oxygen flux is complexly governed by a combination of diffusion and consumption rather than simply tissue difusion  at both T0 and T1. Moreover, increased systemic PaO2 promoted significant changes in all NIRS parameters, ΔO2Hbi, ΔHHbi and rSO2, suggesting a probable increase in both hemoglobin O2 saturation and cerebral blood flow, thus decreasing O2 extraction fraction. On the other hand, the observed change in PaO2 in our cohort after hyperoxia (ΔPaO2) was only directly correlated with the absolute changes in the arterial component of cerebral oxygenation (as indicated by Δ ΔO2Hbi). This suggests a potential modulation of the arterial component of cerebral oxygenation by increased systemic oxygenation.We found no significant change in PRx values after the FiO2 from normal levels is observed after hyperoxemia only when CA is impaired  of cerebral blood flow regulation. Cerebrovascular reactivity to oxygen, for instance, is hampered when cerebral autoregulation is impaired, so that rSO2 increases passively with increasing PaO2. The physiological cerebrovascular response to significant hyperoxia is vasoconstriction , while when oxygen reactivity is impaired hyperoxia does not change the vascular resistance . Despite a major increase in PaO2 (from 97 to 197 mm·Hg) after FiO2 test, we did not observe a considerable change in rSO2, nor was this correlated to changes in PaO2. This likely suggests that in our patient cohort CA was at least partially impaired, especially the metabolic component of CA which cannot be fully explained by PRx. Another important remark to consider in the interpretation of our findings is that CA was measured in the non-injured brain tissue, and while total brain PaO2 may be elevated, this increase may not be present in the injured tissue , and to a lesser extent the metabolic component , the nature of HHb and HbO2 dependent on the unknown scattering coefficient likely differing on an individual basis, and the unknown contribution of venous and arterial components to the measured signals, particularly the O2Hb, are potential confounders in our study.Several limitations of the present study should be addressed. First, the single center design and the small sample cohort limit the generalization of our results. Secondly, due to the lack of a control group, the impact of hyperoxemia on mortality and neurological outcome was not assessed. Thirdly, the FiO outcome  and to pIn mechanically ventilated neurocritical care patients with ABI, short-term hyperoxemia does not seem to critically affect cerebral autoregulation.


Asthma is a heterogeneous disease with variable symptoms, which presents with cough either as the sole or predominant symptom with or without wheezing. We compared the clinical and pathophysiological characteristics of cough predominant asthma (CPA), cough variant asthma (CVA) and classic asthma (CA) in order to determine any differential phenotypic traits.In 20 clinics across China, a total of 2088 patients were finally recruited, including 327 CVA, 1041 CPA and 720 CA patients. We recorded cough and wheezing visual analogue scale, Leicester cough questionnaire (LCQ) and asthma control test scores. Fractional exhaled nitric oxide (FeNO), induced sputum cell counts, and capsaicin cough challenge were also measured and compared.CPA patients more frequently presented with cough as the initial symptom, and laryngeal symptoms (p < 0.001), had less symptoms related with rhinitis/sinusitis and gastroesophageal reflux (p < 0.05) than CA patients. Comorbidities including rhinitis and gastroesophageal reflux were similar, while the proportion of COPD and bronchiectasis was higher in CA patients. There were no differences in FeNO levels, sputum eosinophil and neutrophil counts, FEV1 (%pred) decreased from CVA to CPA to CA patients (p < 0.001). Cough sensitivity was higher in CVA and CPA compared to CA (p < 0.001), and was positively correlated with LCQ scores.CVA, CPA and CA can be distinguished by the presence of laryngeal symptoms, cough sensitivity and airflow obstruction. Asthma-associated chronic cough was not associated with airway inflammation or comorbidities in our cohort.Trial registration The Chinese Clinical Trial Registration Center, ChiCTR-POC-17011646, 13 June 2017The online version contains supplementary material available at 10.1186/s12931-022-02104-8. Asthma is a chronic inflammatory disease of the airways. According to onset, triggers, clinical features, airway inflammation, response to treatment, and prognosis, asthma can be divided into different phenotypes, such as early onset asthma, severe asthma, classic asthma or atypical asthma , 2. AsthAsthma is often accompanied by comorbidities such as allergic rhinitis (AR), chronic rhinosinusitis, and gastroesophageal reflux, which are also common causes of chronic cough , 17–20. In order to fill this knowledge gap, we conducted a prospective, multicenter, CPA Cohort (CPAC) study in 2016 in China in order to elucidate the characteristics of these 3 phenotypes of asthma defined by the presence or absence of cough as a symptom. Within this framework, our objectives were to describe the baseline profiles of CPA versus CVA and CA patients in terms of demographics, symptoms (respiratory and other), co-morbidities, airway inflammation, cough sensitivity and lung function.This was a prospective, multicenter, observational study that was conducted between February 2016 and March 2019, in 20 hospital centers from 11 provinces and municipalities across China . It has also been registered in the Chinese Clinical Trial Registration Center (ChiCTR-POC-17011646). All participating patients provided written informed consent.Patients aged 14 years old or older were recruited amongst those attending the recruiting centres with a history of wheeze or dyspnea and/or cough and those with a history of chronic cough alone. All patients were diagnosed as asthma by physicians according to the Global Strategy for Asthma Management and Prevention Guidelines , and the Chinese Guidelines of Diagnosis and Management of Chronic Cough , 25. On The details of cough and wheezing VAS scores, cough symptom score (CSS) and Leicester Cough Questionnaire (LCQ) are provided in Additional file Spirometry and bronchial challenge were performed according to the current ATS/ERS guidelines , 30. The2 test or Fisher’s exact probability method. We used the Bonferroni correction method for the comparisons in two-group analyses. Two-sided p < 0.05 indicated statistical significance.SPSS 23.0 software was used for analysis. Age, FEV1% pred, body mass index (BMI), cough day and night integral values were expressed as means ± standard deviation. Due to non-normal distributions, the duration of disease, blood eosinophil counts, FeNO values, induced sputum cytology, logC5, cough VAS score, LCQ scores and ACT scores were presented as medians (interquartile range). When the measurement data for two or more groups presented with normal distributions, two independent sample t-tests or one-way analysis of variance (ANOVA) was used. Otherwise, Mann–Whitney U tests or multi-sample Kruskal–Wallis H test for independent samples were performed. The comparison of categorical variables was performed by the χA total of 2088 patients with a mean age of 45.4 ± 14.5 years, were enrolled in the study, and were divided into 1041 patients with CPA, 720 with CA and 327 with CVA . A lower proportion of patients with nasal symptoms and reflux symptoms was observed in the CVA patients as compared with that in CPA and CA patients  Table . CA patiFEV1, FEV1/FVC (%) and the maximum mid-expiratory flow in % predicted (MMEF% pred) were lowest in CA group, followed by CPA and CVA . Forced vital capacity in % predicted (FVC % pred) of CVA patients was significantly higher than that of CPA and CA patients  Table . No signA total of 264 patients completed the capsaicin cough challenge test, including 84 CVA, 120 CPA and 60 CA patients. CVA and CPA patients showed similar values of logC5, but lower values than that of the CA patients  Fig. . For allOur study, for the first time, divided asthma into the three phenotypes of CVA, CPA and CA based on the presence and severity of cough in relationship to the presence of other asthmatic symptoms of wheeze and chest tightness and compared the clinical and pathophysiological characteristics. We found that CPA patients had a higher proportion of females, usually presenting initially with cough predominantly. There were no significant differences with regard to comorbidities related with cough, reflux-related symptoms, rhinitis/sinusitis-related symptoms, and sputum eosinophil and neutrophil counts and FeNO levels between CPA and CA. However, the proportion of those with laryngeal symptoms was higher in CPA compared to CA. Cough sensitivity in CPA patients was similar to that in CVA patients, but significantly higher than that in CA patients. In addition, from the asthma severity point of view, both CPA and CA were less well-controlled and had evidence of airflow obstruction compared to CVA. Thus, our study confirms that CVA, CPA and CA phenotypes are distinct in terms of the features of asthma, airflow obstruction and cough severity as well as cough sensitivity.CPA had a similar female predominance as CVA, as we previously reported . In a woCough is one of the most common symptoms reported by asthmatic patients. Although CPA patients showed lower wheezing scores and better lung function, they had higher cough scores and lower LCQ scores than CA, indicating worse quality of life due to cough. Furthermore, there was no significant difference in ACT scores between CPA and CA, indicating that chronic cough caused an impairment of quality of life while ACT scores were not different. This may not be surprising because the ACT does not specifically request information on cough as a symptom of asthma, despite the recognition that cough can be a troublesome as is breathlessness in asthmatic patients . Cough cThe proportion of current smokers, COPD and bronchiectasis in CPA was significantly lower than that in CA patients, indicating that smoking, COPD and bronchiectasis could not fully explain the chronic cough of CPA. Rhinitis/sinusitis and gastroesophageal reflux are common causes of chronic cough , 34. OurChronic cough associated with asthma and non-asthmatic eosinophilic bronchitis typically respond well to therapy with corticosteroids, thus leading to the general assumption that the suppression of eosinophilic airway inflammation is the cause of basis for the improvement in cough , 39. HowWe found that the cough sensitivity of CPA and CVA was significantly higher than that of CA, supporting a role for the increased cough sensitivity in the pathogenesis of cough in asthma. The mechanism of increased cough sensitivity in asthmatic patients is currently unclear. Cough sensitivity in patients with asthma and COPD has been related to the severity of cough, but not to the degree of airflow obstruction . Cough sThe current questionnaires used to assess asthma control pay little attention to cough symptoms and their impact on quality of life. ACT and asthma control questionnaire (ACQ) scores are important indicators used to evaluate asthma control levels in the GINA guidelines , but theOur study has some limitations. First, medical history and symptom assessment were assessed by questionnaires, which may lead to recall bias. Second, induced sputum tests, FeNO measurements and cough challenges were not conducted in all enrolled patients, this cohort nevertheless represents the largest sample of CVA and CPA patients studied. Third, a small number of patients were found to have concomitant COPD or bronchiectasis, that could have contributed to chronic cough symptoms. Finally, the details of drug name and dose of regular anti-asthma treatment were not collected in the questionnaires. However, we took the effect of treatment into consideration, which was important because inhaled corticosteroids could be effective in controlling asthma symptoms including cough. We divided the patients into groups according to whether they received regular treatment or not in the past 3 months, and found that though there was lower VAS scores in CPA patients with regular treatment, cough still was a prominent symptom, and there was no significant difference in cough VAS scores between those who received regular treatment and those who did not receive regular treatment in CVA, CA patients, indicating that the difference of the proportion of patients who received anti-asthma treatments between CA, CPA/CVA could not explain the presence of cough.Our analysis supports the concept that CVA, CPA and CA represent distinct phenotypes of asthma when defined according to the presence of cough as a predominant symptom in association with wheeze and/or dyspnea. Asthmatic cough is more likely to be related to cough hypersensitivity rather than to comorbidities and airway inflammation. Our study also highlights the need to include an assessment of the severity of cough which could also be a marker of the severity of asthma independent of eosinophilic inflammation.Additional file 1. List of all clinical centers participating in the study.Additional file 2. Case Report Form of the study.Additional file 3. Questions for indicating diagnosis of CVA, CPA and CA from questionnaire.Additional file 4. Comparison of clinical characteristics among CVA, CPA and CA patients with regular and without regular treatment.


PA correlated positively with BCM% , MM% , and inversely with s-CRP . By univariate and multivariate conditional regression analysis, total body water (OR: 1.186), extracellular mass (OR: 1.346), s-CRP (OR: 2.050), MM% (OR: 0.847), PA (OR: 0.058), and s-albumin (OR: 0.475) were significantly associated among cases to controls. Nutritional parameters and BIA-derived measures appear as prognostic entities in patients with stage 4–5 ACKD compared to matched controls in this Mediterranean cohort.Nutritional status is a predictor of adverse outcomes and mortality in patients with advanced chronic kidney disease (ACKD). This study aimed to explore and evaluate risk factors related to nutritional status, body composition, and inflammatory profile in patients with ACKD compared with age- and sex-matched controls in a Mediterranean cohort of the Spanish population. Out of 200 volunteers recruited, 150 participants (64%) were included, and a case-control study was conducted on 75 ACKD patients (stages 4–5), matched individually with controls at a ratio of 1:1 for both age and sex. At enrolment, demographic, clinical, anthropometric, and laboratory parameters were measured. Bioimpedance analysis (BIA) was used to assess both body composition and hydration status. ACKD patients had lower body cell mass (BCM%), muscle mass (MM%) phase angle (PA), s-albumin, and higher C-reactive protein (s-CRP) than controls (at least,  The world’s population is aging, with those over 65 years of age being the largest and fastest-growing age group. One out of four people could be over the age of 65 in the forthcoming decades, and those over 80 years of age are also expected to triple, from 143 million in 2019 to 426 million in 2050 , where Scr is standardized serum creatinine expressed in mg/dL; κ is a constant 0.7  or 0.9 ; α = −0.241  or −0.302  and min-max  is indicating the minimum or maximum of Scr/κ or 1.0 and, age is expressed in years.Sociodemographic and clinical data were examined from the medical records of all participants. The etiology of CKD, and nutritional and laboratory parameters of each participant were collected. The estimated glomerular filtration rate (eGFR) was measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) using 2021-CKD-EPI Creatinine equation  as folloThe eGFR was classified according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines  in ACKD 2). A BMI of 25–29.9 kg/m2 was set for overweight and BMI ≥ 30 kg/m2 for obesity  and controls  was DM. p < 0.001).This case-control study included 150 older adults (75 ACKD patients and 75 controls) matched by age and sex. The main etiology leading to CKD among cases [n = 57; 76%) that ACKD patients  (p = 0.005). Analyzing WC by sex as a CV risk factor, 61 females presented a high frequency of WC ≥ 88 cm  while high frequencies were also found with the cut-off point of WC ≥ 102 cm proposed in 31 males  (data not showed). High mean conicity index values were obtained with WC ≥ 88 cm in either control females (1.41 ± 0.12) or females with ACKD (1.38 ± 0.05) (p = 0.146). Relatedly, in 31 men with WC ≥ 102 cm, mean conicity index values were found high in both controls (1.44 ± 0.10) and patients with ACKD (1.46 ± 0.10) (p = 0.673). Similarly, elevated mean values of TST% and MAMC% were found, although the results remained non-significant when the case-control comparison was made .As shown in p < 0.01) (p < 0.001) (data not shown). The PA was correlated positively with BCM% , ICW% , MM%  and s-CRP  but negatively with exchangeable Na/K , ECW%  and ECM .Cases had significantly lower mean values of BCM, FM, MM, and PA than controls  . PA < 4°p < 0.05). Total cholesterol, lymphocyte count, hemoglobin, and PNI not differed in a significant manner between ACKD patients and controls. S-albumin was directly correlated with PNI , and inversely with s-CRP . The median of PNI was in ACKD patients of 48.37 vs. 49.35 points in controls (p = 0.828). Only 2 ACKD patients and 2 controls (2.67%) had a PNI < 39 points. Significant differences were found only with the cut-off point of the PNI (<39 and ≥39 points) and s-CRP in ACKD patients (PNI < 39 points: 4.25 ± 5.16 and PNI ≥ 39 points: 0.95 ± 1.05) and controls (PNI < 39 points: 3.95 ± 3.46 and PNI ≥ 39 points: 0.29 ± 0.55)  (data not shown).Univariate conditional regression analyses showed that BIA-derived measurements, as well as hydration indicators , body composition measures  and laboratory data  were individually and independently associated between patients with ACKD and controls (dependent variable) .p < 0.05) , ECM (OR: 1.346), MM% (OR: 0.847), PA (0.058) such as well-recognized predictor biomarkers as s-albumin (OR: 0.475) and s-CRP (OR: 2.050) were significantly associated in cases and control after controlling for potential confounders  .The study results suggest that a miscellaneous combination of nutritional indicators, body composition measurements, and inflammatory markers were significant risk predictors in patients with ACKD compared with age- and sex-matched controls. In this study, older age, DM, overweight and abdominal obesity were classic CV risk factors in a Mediterranean cohort population. Among the universally recognized and accepted causes in the Western world, hypertension and DM are the main traditional risk factors involved in CVD ,44, bein2) were associated with a lower risk of death in stages 3–5 CKD. In contrast, the usefulness of BMI as a single measure of body composition in CKD patients is limited, and hydration status and other measures of body composition must be taken into account. Conversely, the usefulness of BMI as a single measure of body composition in CKD patients is limited and should be considered in conjunction with hydration status and other measures of body composition. Overweight, obesity, and increased central fat distribution have been associated with microalbuminuria, reduced eGFR [BMI is one of the most widely used and simpler measures of body adiposity. Overweight and obesity accounted for 76.0% of controls and 60.0% of ACKD patients, it is noteworthy that BMI in the univariate analysis had a significant protective effect . In factced eGFR , and CVDced eGFR .n = 29; 39.1%), both had a WC above the threshold values, suggesting a high CV risk associated with central abdominal fat (p = 0.46). Likewise, in males, higher abdominal WC was non-significantly found in controls  compared to ACKD patients . Similarly, the conicity index as a surrogate measure of CV risk and death was also found to increase in females and males in age-sex matched groups in a non-significant manner (p = 0.13). A study conducted on 1740 patients with stage 3 CKD [Waist circumference (WC) and conicity index are clinically suggested to assess abdominal obesity and as a predictor of mortality in non-CKD subjects and CKD patients . Additioge 3 CKD  examinedge 3 CKD .The conicity index appears to be a good indicator of central fat distribution, both in patients with ACKD and in controls, as it identifies changes in body composition and thereby also allows comparisons to be made between individuals with different BW and height measurements . HoweverOverhydration, uremia-induced alterations in body composition, and inflammation are significant predictors of morbidity, poor prognosis, and mortality in patients with ACKD ,49,50. IMost notably, PA has been recognized as a reliable prognostic indicator of cellular integrity in elders, CKD patients, and other underlying diseases ,49,51. LIn CKD, specific markers such as serum concentrations of creatinine, uric acid, phosphorus, and potassium tend to be higher as kidney function declines, as observed in this study compared to controls. Higher mean serum uric acid levels, which were identified in previous studies as an independent CV risk marker in individuals with  and withS-albumin is one of the most studied markers related to nutritional status and mortality predictor in CKD patients ,56. In tThe PNI has emerged as an independent predictor risk factor in elderly people with certain disease states ,40,41,422 has been shown to reduce CV mortality in some meta-analyses [Some limitations and strengths should be taken into account in this study. Firstly, this is a single-center study conducted in an ACKD unit with small Mediterranean sample size. Diabetes mellitus was the main cause of CKD in cases while a lower proportion was found in controls. To date, there are a limited number of studies on elderly non-dialysis ACKD patients. However, to the best of our knowledge, this is the first case-control study in older adults with stages 4–5 ACKD, in which nutritional indicators, body composition measurements, and inflammation profile were jointly compared with age- and sex-matched controls. Nonetheless, the results obtained do not infer causality and may be biased by other biomarkers not analyzed in the present study. Secondly, BMI is a global indicator of adiposity that does not distinguish within adult age groups, body compartments , or central fat distribution. In particular, in older adults and elderly patients with ACKD, it should be noted that BMI between 25–35 kg/manalyses ,10. Addianalyses . Thirdlyanalyses ,39,42. LIn conclusion, this study highlights that the conjoint use of nutritional and inflammatory markers and BIA-derived measures appear as significant prognostic entities in patients with stage 4-5 older ACKD compared to matched controls. Overweight was the distinctive phenotype in both older adults and patients with ACKD, along with increased central abdominal fat, especially in women as a CV risk factor. Nutritional factors such as TBW, ECM, and s-CRP increased the likelihood of nutritional risk while independent predictors such as MM, PA, and s-albumin were shown to diminish the risk of nutritional disorders in ACKD. The results from the present study demonstrate the importance of regular nutritional care and monitoring as a preventive and/or therapeutic measure before starting dialysis. Further longitudinal studies in ACKD stages 4–5 are needed to assess the prognostic role of nutritional factors on both kidney disease progression and survival outcomes.


Preoperative medical preparation with an alpha blockade has been implemented early 1960s to prevent intraoperative hemodynamic instability and consequently decrease morbi-mortality in patients at a high risk of complications. Indeed, surgery at that time consisted of open adrenalectomies with a high morbidity and mortality rate. Current clinical guidelines are based on these early experiences. However, emerging technologies have permitted a drastic reduction of the morbi-mortality rate in patients treated for pheochromocytoma. However, the clinical guidelines have not evolved at the same rate. The aim of this systematic review is to assess the evolution of the management of pheochromocytomas and to appraise the current clinical guidelines to the current clinical practices.The management of pheochromocytomas has significantly evolved these last 50 years, especially with the emergence of new technologies such as laparoscopic procedures in the 1990s. A preoperative blockade using antihypertensive medications to prevent intraoperative hemodynamic instability and cardiocirculatory events is recommended by current clinical guidelines. However, these guidelines are still based on former experiences and are subject to discussion in the scientific community. The aim of this systematic review was to assess the evolution of the management of pheochromocytomas. Laparoscopic procedure is established as the standard of care in current practices. Preoperative medical preparation should be questioned because it does not significantly improve intraoperative events or the risk of postoperative complications in current clinical practice. Current clinical recommendations should be revised and upgraded to current clinical practices. Pheochromocytomas and paragangliomas are rare tumors of chromaffin cells responsible for autonomous and unregulated secretion of catecholamines such as norepinephrine, epinephrine or even dopamine . PheochrThe PRISMA guidelines were followed for this systematic review . A searcRandomized controlled studies (RCT) and non-RCTs evaluating on the one hand surgical treatment of pheochromocytomas and one the other hand preoperative medical preparation (PMP) for patients with pheochromocytoma were eligible for inclusion . EligiblFrom each included study, the following criteria were extracted: title, author, year of publication, journal, language, trial design and trial period, number of patients included, treatment groups, loss of follow-up and withdrawals. Outcomes of interest were, on the one hand, operative time, maximum diameter of tumor, estimated blood loss, postoperative hospital stay, complications and conversions between laparoscopic and open procedures. On the other hand, intraoperative hemodynamic instability  mortality and morbidity in patients with and without PMP were collected. These outcomes were chosen because of their relevance regarding the aim of this study and their availability in the papers of interest.Adrenalectomy is the standard treatment for pheochromocytomas . Before The management of pheochromocytoma has significantly changed in current clinical practices. Since the first successful laparoscopic adrenalectomy was performed in 1992, laparoscopic adrenalectomies as a treatment for pheochromocytoma has widely expanded ,17,18 ThThere is no randomized controlled trial comparing the laparoscopic approach to the open approach. However, several studies have evaluated the laparoscopic approach as treatment for pheochromocytoma  Table 1Table 1. PMP using antihypertensive medications (blockade) was introduced in the fifties when it was shown that without adrenergic blocking agents, adrenalectomy for pheochromocytoma was a dangerous procedure causing a hypertensive crisis, arrythmias, severe fluctuations when manipulating the tumor or even cardiac arrest . From thThe rationale of the alpha blockade is to control blood pressure to avoid intraoperative hemodynamic instability and prevent complications due to a massive surge release of catecholamines ,5. PhenoThere is no consensus on which preoperative cardiac parameters should be obtained after preparation to improve intraoperative hemodynamic instability. In 1987, Roizen et al. established the criteria to reach before surgery to avoid intraoperative hemodynamic instability episodes: BP < 160/90 mmHg for 24 h prior to surgery, no postural hypotension <80/45 mmHg and no ST-T waves changes . BruynzeIn addition, another remaining problem is that the definition of an episode of intraoperative hemodynamic instability is not consensual in the available literature . In a reBeyond these definitional issues, the relationship between target blood pressure after preparation and the risk of occurrence of episodes of hemodynamic instability also remain controversial. Lentschener et al. were among the first teams to question the significant association between preinduction blood pressure and intraoperative hemodynamic fluctuations . A multiIn a systematic study, tumor size and levels of urinary norepinephrine were associated with perioperative hemodynamic instability . Howeverp = 0.02).In 2020, a meta-analysis showed that peak systolic and diastolic blood pressure and heart rate during an adrenalectomy for pheochromocytoma were not different in patients with and without alpha-blocker preparation . A recenIn conclusion, some risk factors associated with intraoperative hemodynamic instability are nonmodifiable, such as tumor size and catecholamine levels. No study has shown that the use of a specific type of hypertensive medication during preparation can prevent the occurrence of hypertensive and hypotensive episodes during surgery. Some studies have suggested that the more effective and nonselective the drug used to control blood pressure, the lower the observed intraoperative hypertensive peaks but the more important the hypotensive phases are likely to be.The link between intraoperative hemodynamic instability and complications during and after surgery is central to the principle of medical preparation before pheochromocytoma surgery. However, data showing a significant association between intraoperative blood pressure fluctuations and complications are almost nonexistent in the current clinical setting. A retrospective study including 225 patients and analyzing predictors of morbidity in five international medical centers showed that only two definitions of intraoperative hemodynamic instability correlated with the occurrence of postoperative complications: SBP >= 160 mmHg + MAP < 60 mmHg and SBP >= 200 mmHg + MAP < 60 mmHg . HoweverIn the end, most of the available studies against and also historical studies in favor of the preparation present similar methodological biases. All these studies are retrospective, without a control group and with a retrospective analysis of complications observed in operated patients (inducing a risk of under- or overestimation bias) . In one Intraoperative anesthetic management has become an important part of the care of patients with pheochromocytoma. This management requires a multidisciplinary team that has experience in adrenal cases. Communication between surgeons and anesthesiologists is crucial for good execution of surgeries. There are three critical intraoperative moments during an adrenalectomy for pheochromocytoma: orotracheal intubation, tumor dissection and phases after ligation of the main adrenal vein . HemodynFrom the point of view of the anesthesiologist, several different complications can occur during an adrenalectomy. Hypertension crises are usually related to manipulation of the tumor . SPB > 2The Clinical Endocrine Guidelines of 2014 recommend that patients with pheochromocytoma undergo a preoperative blockade to prevent perioperative cardiovascular complications . This reTo conclude, the management of pheochromocytoma has significantly changed over the last decades, leading to a drastic decrease in morbi-mortality. Consequently, the use of PMP to improve intraoperative hemodynamic instability should be put into question because preoperative blood pressure normalization does not improve postoperative outcomes in current clinical practice. The current recommendations should be upgraded, and the role of anesthesiologists during an adrenalectomy for pheochromocytoma should be defined better and evaluated.


P < 0.05. Fasting reduced ambulatory mean arterial pressure (81 ± 1 vs. 78 ± 1 mmHg) and heart rate (69 ± 2 vs. 65 ± 2 beats/min). CB revealed enhanced HRV through increased R-R intervals  and normalized high frequency (HFnu) R-R interval spectral power (55 ± 3 vs. 62 ± 3%). Estimated stroke volume was higher after fasting (by 13%) as was cvBRS (20 ± 2 vs. 26 ± 5 ms/mmHg) and cvBRS during phase IV of the VM (9 ± 1 vs. 12 ± 1 ms/mmHg). MSNA (n = 12) did not change . Our results show that acute fasting is consistent with improved cardiovascular health: such improvements are driven by reduced ambulatory arterial pressure and enhanced vagal-cardiac modulation.Evidence suggests that intermittent fasting improves cardiovascular health by reducing arterial blood pressure, but contributing mechanisms are unclear. The purpose of this study was to determine the influence of an acute fast on hemodynamics, muscle sympathetic nerve activity (MSNA), and autonomic control at rest and during an arterial pressure challenge. Twenty-five young normotensive volunteers were tested twice, in the fed and fasted (24 h) states (randomized). Twenty-four hour ambulatory blood pressure was measured before an autonomic function test, which consisted of a 10-min period of controlled breathing (CB) at 0.25 Hz followed by 3, 15-s Valsalva maneuvers (VMs). We recorded the ECG, beat-to-beat arterial pressure, and MSNA throughout the autonomic test. Vagal-cardiac modulation via heart rate variability (HRV) was assessed in both time and frequency domains, cardiovagal baroreflex sensitivity (cvBRS) was assessed with linear regression, and stroke volume was estimated from pulse contour. All fed versus fasted comparisons presented are different at  Obesity is a multifaceted disorder that is a risk factor for the development of cardiovascular disease and is characterized by sympathetic overactivity , 2. ReceIn humans, the influence of fasting on autonomic balance has not been fully elucidated. When compared with food consumption, an overnight fast (∼12 h) enhances parasympathetic modulation of the heart as suggested by spectral analysis of heart rate variability HRV; , 15. OnlAccordingly, the primary aim of this study was to determine the influence of an acute 24-h fast on ambulatory blood pressure and autonomic cardiovascular and neurovascular control. We assessed HRV, cardiovagal baroreflex sensitivity (cvBRS), and MSNA to test the hypothesis that ambulatory blood pressure reductions after an acute 24-h fast are associated with increased cvBRS and HRV, and reduced MSNA.2, and body surface area (BSA) of 1.9 ± 0.2 m2) participated. All participants had no history of autonomic dysfunction, hypertension, respiratory disease, diabetes, tobacco, or vaporized nicotine usage and were not taking any prescription medications. Participants were screened for hypertension (systolic <130 and/or diastolic < 80) via three seated blood pressures taken with an automated sphygmomanometer . All female participants were tested during the early follicular phase of their menstrual cycle. Participants were instructed to abstain from exercise and caffeine for 24 h before laboratory testing. All participants signed a consent form that had been approved by the Institutional Review Board for human subject research at Michigan Technological University.Twenty-five healthy young adults  of 24 ± 4 kg/mTwenty-four-hour ambulatory blood pressure monitoring  and actigraphy data  were collected twice leading up to the autonomic test. ABPM and actigraphy data were collected when the participant ate their normal diet for 24 h (ABPM-fed), and then again when the participant was fasting for 24 h (ABPM-fasted): data collection periods were separated by 4 wk. Sampling frequency was set to collect brachial blood pressures every 20 min between 0700 and 2200 h and every 30 min from 2200 to 0700 h. Participants were instructed to immobilize their arm upon cuff inflation and to only remove the cuff and the actiwatch during showering. Wake and sleep blood pressure values were defined and adjusted to the sleep and wake times recorded by the actiwatch. A minimum of 20 valid wake recordings and seven valid night recordings during both conditions was required for a satisfactory ABPM recording . Whole blood was also utilized to measure blood ketones (β-OHB) using a Precision Xtra  ketone monitor. Urine was also collected to assess hydration status via urine specific gravity, using a PALS-10S urine refractometer .Beat-to-beat arterial blood pressure was recorded continuously throughout all time points of the autonomic function test using a NOVA Finometer . Heart rate was recorded via a three-lead electrocardiogram, and respiratory rate was continuously measured using a pneumobelt. Three brachial blood pressures  were used to calibrate finger plethysmography. Data were sampled at 500 Hz  and analyzed with specialized software . R waves generated from the ECG signal were automatically detected and marked. Heart rate variability was assessed in the frequency domain using a Fourier transform with a Hann window. Heart rate variability was quantified by calculating the total integrated area under the R-R interval power spectrum from 0.04 to 0.4 Hz. Integrated areas were separated into high-frequency  and low-frequency  bands. Systolic arterial pressure at the low frequency  was calculated as an additional estimate of peripheral sympathetic activity . To compMultifiber efferent sympathetic nerve traffic was recorded from the peroneal nerve muscle fascicles at the popliteal fossa by inserting a tungsten microelectrode . A reference electrode was inserted subcutaneously 2–3 cm from the recording electrode. Both electrodes were connected to a differential preamplifier and then to an amplifier  where the nerve signal was band-pass filtered  and integrated  to obtain a mean voltage display of nerve activity. Satisfactory recordings of MSNA were defined by spontaneous pulse-synchronous bursts that did not change during tactile or auditory stimulation and increased during end-expiratory apnea. Muscle sympathetic nerve bursts were automatically detected based on their amplitude, and a 1.3 s expected burst peak latency from the previous R wave. All automated detection results were checked manually. Sympathetic bursts of activity were expressed as burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats).This study was a randomized controlled crossover design with repeated measures. Each participant was tested twice, once in the fed condition  and once in the fasted condition . Trial order (fed vs. fasted) was randomized, and participants were informed 3 days before scheduled autonomic testing to which condition they would be assigned. Tests were performed ∼4 wk apart. Participants reported to the laboratory 24 h before their scheduled autonomic test to be fitted with an actigraphy watch and ambulatory blood pressure cuff that they wore for 24 h leading up to the autonomic test. A standardized caloric-controlled meal was provided for each condition. The caloric intake of the standardized meal was estimated to be one-third of the total caloric intake needed to maintain the individual participants’ weight. Macronutrient composition of the meal was estimated to be ∼55% carbohydrate, ∼20% fats, and ∼25% protein. To estimate total daily energy needs, resting metabolic rate was estimated using the Mifflin-St. Jeor equation and multiplied by a physical activity factor . ParticiUpon arrival at the laboratory, participants turned in 24-h measurement equipment, and blood and urine samples were collected and analyzed. Participants were then situated in a supine position on a cushioned laboratory table for hemodynamic and microneurographic instrumentation. After instrumentation, participants were provided a minimum of 5-min unrecorded rest to confirm hemodynamic and neural stability. Three supine brachial blood pressures  were used to calibrate finger plethysmography. During the controlled breathing (CB) portion of the experiment, participants breathed in time to a computer display showing a waveform set at 0.25 Hz (15 breaths/min). Controlled breathing was followed by three Valsalva maneuvers (VMs) each separated by 1 min of rest. The experimental protocol is summarized in During each VM, participants were asked to forcefully exhale to 40 mmHg for 15 s into a mouthpiece attached to an analog manometer. A nose clip was used to seal the nose, and a small leak was allowed in the manometer to keep the glottis open during each strain. Each of the three Valsalva maneuvers was separated by a 1-min recovery of spontaneous breathing. For each participant, we identified the four Valsalva phases as outlined by Smith et al. . Phase Ir value of >0.7 was used as criteria for accepting a sequence.Spontaneous cardiovagal BRS was assessed via the sequence method  during tt test to calculate power based on published literature . To assure fasting compliance, glucose, blood ketones, and lipids were measured. Blood triglycerides and glucose were significantly decreased, and ketones were increased in the fasted condition compared with the fed condition. Participants’ characteristics and blood biomarkers from the fed and fasted conditions are displayed in P = 0.02), diastolic  and mean arterial pressure  compared with the ABPM-fed condition. Heart rate, measured from the ambulatory cuff, was also decreased in the fasted condition. These reductions in overall blood pressure were primarily driven by reductions in wake SAP  were similar during controlled breathing between conditions, but SAPLF power decreased in the fasted condition. Stroke volume estimated from the pulse contour method was increased in the fasted condition. The increase in stroke volume did not significantly alter estimated cardiac output or total peripheral resistance between conditions (seen in P = 0.07).During controlled breathing in the fasted condition, R-R interval and normalized HF R-R interval spectral power measured via frequency domain analysis were increased. Absolute HF power was not different. Absolute HF and normalized HF power are shown for comparison in  seen in . In addi seen in . cvBRS dTwenty-two participants were included in the Valsalva analysis. Three participants were excluded because they did not have SAP-RRI correlations above 0.70. Average SAP-RRI correlation coefficients for included participants were 0.88 for phase II and 0.81 for phase IV. Phase II MSNA burst frequency, ΔSAP, ΔRRI, and cardiovagal baroreflex sensitivity were similar between conditions. Phase IV ΔSAP was similar between conditions, however, ΔRRI was increased in the fasted state. In addition, enhanced cardiovagal baroreflex sensitivity was observed during phase IV of the Valsalva maneuver Seen in , or the We tested young, healthy, normotensive individuals twice, once in a fasted condition  and once in a fed condition . Our purpose was to determine how acute fasting influences ambulatory blood pressure and autonomic cardiovascular and neurovascular control. We report four novel findings: First, fasting reduces overall ambulatory SAP, DAP, MAP, and HR. The measured reductions in overall 24-h blood pressure are driven primarily by reductions in wake SAP and HR. Second, acute fasting increases vagal modulation at the heart without altering directly measured peripheral sympathetic nerve activity, although estimates derived from SAPLF provide indirect evidence of peripheral sympathetic reductions. Specifically, fasting is associated with increased RRI and HFnu with no change in MSNA. Third, fasting enhances cvBRS measured both spontaneously during controlled breathing (cvBRS-up) and when baroreceptors are challenged with a naturally induced hypertensive stimulus (VM phase IV and cvBRS). Fourth, estimated stroke volume is increased in the fasted condition with no changes in blood pressure, cardiac output, or peripheral resistance during controlled breathing.Chronic intermittent fasting regimens of 8–12 wk have been reported to reduce blood pressure . IndividIn normotensive rats, the hypotensive effect of fasting is primarily driven by suppression of cardiac sympathetic activity . The supThe Valsalva maneuver is an easily administered and reliable hemodynamic stressor that provokes both hypotensive (phase II) and hypertensive (phase IV) stimuli . The ValContrary to our hypothesis, we did not observe a change in directly measured peripheral sympathetic outflow at rest between the fed and fasted conditions. We did, however, find that SAPLF is reduced with fasting. Low-frequency systolic pressure oscillations are linked directly to peripheral sympathetic activity in dogs  and withIn the fasted state, ketone bodies are utilized as the main energy source once glycogen stores are depleted. Recent evidence suggests that ketone bodies may act as endogenous signaling molecules capable of influencing sympathetic activity by acting as meditators of cardiovascular function. In mice, ketones have been reported to suppress sympathetic activity and reduce heart rate . In humaIntermittent fasting is currently the most popular dieting strategy in the United States. Our current findings provide new mechanistic and potentially prepotent insight into how acute, short-term fasting reduces arterial pressure. An acute 24-h fast decreases overall 24-h blood pressure and heart rate, increases vagal modulation of the heart, and enhances cardiovagal baroreflex sensitivity without altering directly measured peripheral sympathetic nerve activity compared with a period of normal eating. Potential cardiovascular health benefits of fasting are underscored by increased heart rate variability and cardiovagal baroreflex sensitivity both at rest and during the hypertensive phase IV of the Valsalva maneuver.This study is not presented without limitations. Although we included a population of 25 participants, we report MSNA data from only 12 participants. The microneurography procedure is delicate, and it is sometimes difficult to obtain adequate nerve recordings from some participants. This problem is made worse by the requirement of obtaining adequate nerve recordings from the same person twice. We cannot speculate how inclusion of MSNA for all 25 participants might have impacted our results and interpretation. Initial ABPM fitting and initiation were performed by experimenters, and participants were informed about the specific monitoring process. However, participants were given the opportunity to remove the ABPM for showering, potentially introducing an error upon cuff replacement.This work was supported by a grant from the Michigan Space Grant Consortium , an endowment from the Portage Health Foundation , and by an Oregon Health and Science University Fellowship for Diversity in Research .No conflicts of interest, financial or otherwise, are declared by the authors.J.E.G. and W.H.C. conceived and designed research; performed experiments; analyzed data; interpreted results of experiments; prepared figures; drafted manuscript; edited and revised manuscript; approved final version of manuscript.