Carotid artery stenosis is one of the most serious diseases that endanger human health in contemporary times. It is a frequently occurring and common disease of the middle-aged and elderly people. Its incidence is increasing year by year, bringing a heavy economic burden to society and families. Whether there is a relationship between the degree of carotid artery stenosis and blood pressure variability is less studied.  To investigate the correlation between the degree of carotid stenosis and blood pressure variability in patients with carotid stenosis.  A total of 200 patients with carotid artery stenosis who were treated in our hospital from January 2017 to January 2020 were selected as the subjects of prospective study and were divided into mild stenosis according to the degree of carotid stenosis (carotid artery stenosis rate was 0-50%), moderate stenosis (carotid artery stenosis rate was between 50% and 70%), severe stenosis (carotid artery stenosis rate≧70%), and the control group with 50 cases each. The correlations between the hemodynamics, the degree of carotid artery stenosis, and blood pressure variability in patients with carotid artery stenosis were analyzed. P < 0.05). The levels of PSV, EDV, and MV in the mild stenosis group and moderate stenosis group were lower than those in the control group, while the PI and RI indexes were higher than those in the control group. PI and RI levels were significantly higher than those in the mild stenosis group and moderate stenosis group (P < 0.05). Logistic analysis showed that EDV , SSD , and PSV  were closely related to the degree of carotid artery stenosis.  The levels of 24hSSD, 24hDSD, dSSD, dDSD, and nSSD in the mild stenosis group and moderate stenosis group were significantly higher than those in the control group. In the stenosis group, the levels of 24hSSD, 24hDSD, dSSD, dDSD, and nSSD in the severe stenosis group were significantly higher than those in the moderate stenosis group, with statistical significance ( Hemodynamics and blood pressure variability are related to the severity of carotid stenosis, which provides a reference and basis for clinical treatment of carotid stenosis. The causes of high blood pressure are not single, but mainly include related to tiny chemical assembly instructions inside of living thing factors, dietary nutrients, related to how people think and treat each other, stress, kidney-related factors, and neuroendocrine factors , 2. TherBefore enrollment, all patients in this study were given informed consent and signed the informed consent form. 200 patients with carotid artery stenosis who were treated in our hospital from January 2017 to January 2020 were selected as prospective study subjects. The degree of stenosis was divided into mild stenosis, moderate stenosis, and severe stenosis in 50 cases each. At the same time, 50 healthy subjects without carotid artery stenosis who were matched with baseline data such as age, gender, and occupation were selected as the control group.Inclusion criteria are as follows: (i) all patients with carotid artery stenosis in this study met the diagnostic criteria for carotid artery stenosis in the “Chinese Guidelines for the Prevention and Treatment of Hypertension (Revised 2018)” ; (ii) thAll patients underwent carotid ultrasonography with X300 color Doppler ultrasound diagnostic apparatus  within 7 days of hospitalization. Linear array probes with frequencies of 5 to 10 MHz were used. During the operation, the patient is in a supine position, and the head is tilted backward to fully expose the neck. The common carotid artery is detected in the order of the submandibular angle, the upper end of the clavicle, the posterior occipital angle, and the anterior border of the sternocleidomastoid muscle. Vessel diameter (D), peak systolic blood flow (PS), and peak diastolic blood flow (PD) were measured. Two-dimensional and color blood flow images (EDV), mean blood flow velocity (MV), resistance index (RI), pulsatility index (PI), etc. were used to determine the plaque situation. Blood flow status, carotid intima-media thickness (IMT), internal diameter of common carotid artery, presence or absence of plaque, plaque location, size, shape, echo, and spectral shape were observed.Within 3 days of admission, all patients were monitored with AB-PM6100 noninvasive portable ambulatory blood pressure monitor . During the day (6:00-2:00), monitoring was performed once for 30 minutes and at night (once at 22:00 at 6:00 a day) with an interval of 1 hour. The measured data were input into the computer for processing, and the monitoring indicators were 24 h systolic blood pressure (24hSSD), 24 h diastolic blood pressure (24hDSD), daytime systolic blood pressure (dSSD), daytime diastolic blood pressure (dDSD), nighttime diastolic blood pressure (nSSD), and nocturnal diastolic blood pressure (nSSD).Internal carotid artery stenosis rate = /the original inner diameter × 100%.Blood pressure rhythm changes are expressed by nighttime blood pressure drop rate: nocturnal blood pressure drop rate = [(daytime average blood pressure − nighttime average blood pressure)/daytime average blood pressure] × 100%. According to the different speeds of blood pressure drop at night, the change of blood pressure circadian rhythm is divided into 4 types, namely, dipper , nondipper , reverse-dipper type , and super-dipper type ; they are mainly systolic blood pressure. The carotid artery flow is the blood flow per unit area of the bilateral intracranial arteries. The sum of the flow: the cerebral artery flow is the sum of the blood flow of the bilateral intracranial arteries and the bilateral vertebral arteries.χ2. Univariate and logistic multivariate regression analysis was used to compare the influencing factors, and the risk factors with significant differences were screened. The statistical significance was P < 0.05.All statistical data in this study were entered into Excel software by the first author and the corresponding author, respectively, and the statistical processing software was SPSS25.0 for calculation. Count data expressed as a percentage (%) were tested by P > 0.05). See There were no a big change in numbers that means something important differences in the general data such as female status, average age, average course of disease, how fat or skinny you are based on height and weight, and case type between the two groups of patients (P < 0.05). See The levels of 24hSSD, 24hDSD, dSSD, dDSD, and nSSD in the mild stenosis group and moderate stenosis group were significantly higher than those in the control group. The detection index levels were significantly higher than those in the moderate stenosis group, with statistical significance (P < 0.05). See The levels of PSV, EDV, and MV in the mild stenosis group and moderate stenosis group were lower than those in the control group, while the PI and RI indexes were higher than those in the control group. PI and RI levels were significantly higher than those in the mild stenosis group and moderate stenosis group , SSD , PI , RI , and PSV . Logistic analysis showed that EDV , SSD , and PSV  were significantly different from each other. The degree of carotid stenosis is closely related. See P > 0.05). After nursing, the sleep quality scores, increased awakening scores, sleep instability scores, and night terrors scores of breast cancer patients with liver metastases in the two groups were significantly improved, and the sleep quality scores of the observation group were significantly lower than those of the comparison group. There was statistical significance (P < 0.05). See Before nursing, there was no significant difference in sleep quality scores between the two groups of breast cancer patients with liver metastases (P > 0.05). After nursing, the anxiety score, depression score, fatigue and distress score, and anger score of the two groups of breast cancer patients with liver metastases were significantly improved, and the psychological state score of the observation group was significantly lower than that of the comparison group, and statistics showed that the difference was statistically significant (P < 0.05). See Before nursing, there was no significant difference in the psychological state scores between the two groups of breast cancer patients with liver metastases (P > 0.05). After nursing, the scores of self-care skills, self-responsibility, health knowledge, and self-concept of the observation group were higher than those of the comparison group. The statistical difference was shown to be statistically significant (P < 0.05). See There was no significant difference in the scores of self-care ability of the two groups before nursing (P > 0.05). After nursing, the scores of mental vitality, social interaction, emotional limitation, and mental status of the observation group were significantly higher than those of the comparison group, and the difference was statistically significant (P < 0.05). See There was no significant difference in the quality of life scores between the two groups before nursing (Another important mechanism is autonomic regulation, which mainly affects long-term blood pressure variability . In addiThis study investigated the correlation between the degree of carotid stenosis and blood pressure variability in patients with carotid stenosis. The results showed that the levels of 24hSSD, 24hDSD, dSSD, dDSD, and nSSD in the mild stenosis group and moderate stenosis group were significantly higher than those in the control group. The 24hSSD, 24hDSD, dSSD, dDSD, and nSSD index levels in the stenosis group and severe stenosis group were significantly higher than those in the mild stenosis group. It can be seen that with the increase of the degree of carotid stenosis, the blood flow velocity gradually decreases, while the peripheral resistance increases significantly. The reason is that the wall thrombus and atherosclerotic plaques at the sclerotic stenosis of the arteries cause microthrombus embolism, which slows down the blood flow and increases the peripheral resistance .Logistic analysis showed that EDV, SSD, and PSV were closely related to the degree of carotid artery stenosis. The mechanism may be that the large fluctuation of blood pressure for a long time will increase the shear force on the inner wall of the blood vessel, thereby aggravating the damage to the vascular endothelium, resulting in an increase in blood flow resistance and a decrease in vascular compliance . It furtLike other body structure-related limits/guidelines of the body, blood pressure is not static. In common and regular people and most high blood pressure-related patients, blood pressure will go up and down with changes in sleep and wakefulness, day and night, rest and activity, and body position. This blood pressure quality of changing over time or at different places, which is the body's neuroendocrine energetic/changing regulation, results in a complete and thorough balance . Since bThere are still some limits in this study. The research objects are few, and the multi-deadliness of old patients leads to too many confusing factors in the study, which affects the experimental results. There was no association between hyperdipper patients and carotid intima injury, and no comparison was made with nondipper and reverse-dipper patients to understand the association of nondipper and reverse-dipper patients with carotid intima injury. At the same time, the study did not track the subjects and did not find out whether the daily rhythm of blood pressure before and after act of letting someone speaking the truth about something bad was agreeing matching up working regularly with that during time in a hospital, allowing for better supervising of blood pressure ups and downs and changes in daily rhythms. When looking at blood pressure quality of changing over time or at different places between people, changes were found to be strongly connected with later risk of related to the heart and blood vessels events, with some studies suggesting that in patients with blood vessel-related disease, higher blood pressure quality of changing over time or at different places is related to a higher risk of related to the heart and blood vessels events higher.In the end, hemodynamics and blood pressure quality of changing over time or at different places are related to the extreme harshness of carotid narrowing of a passageway, which provides a reference and basis for medicine-based treatment of carotid narrowing of a passageway.


Immune checkpoint inhibitors, medications that boost host immune response to tumor cells, are now at the forefront of anti-cancer therapy. While efficacious in the treatment of patients with advanced cancer, immune checkpoint inhibitors can lead to serious autoimmune side effects involving any organ in the body. Immune checkpoint inhibitor nephrotoxicity is an increasingly recognized cause of acute kidney injury in patients with cancer. This review discusses the clinical and histopathologic diagnosis of immune checkpoint inhibitor nephrotoxicity, highlighting the need for more reliable non-invasive diagnostic testing. We focus on the controversy surrounding the role of kidney biopsy in diagnosis and management of suspected immune checkpoint inhibitor toxicity with inclination toward pursuing kidney biopsy in certain outlined circumstances. Finally, we briefly discuss treatment of immune checkpoint inhibitor nephrotoxicity and the decision to re-challenge immunotherapy in patients who experience these adverse events. Immune checkpoint inhibitors (ICPIs) have revolutionized anti-cancer treatment since their introduction in 2011 –6. HumanBy releasing T-cells from signaled arrest, ICPIs allow for upregulation of immune surveillance and promotion of anti-tumor activity. Widespread disinhibition of T-cells also leads to a unique set of autoimmune side effects, termed immune-related adverse events (irAEs). Immune-related adverse events can affect any organ in the body, including most commonly the skin, gastrointestinal tract, pulmonary and endocrine systems , 13. RenThe overall incidence of AKI in patients receiving ICPIs is close to 17% (range 7 to 24%), although this estimate reflects both ICPI-related and non-ICPI-related etiologies –18. To dLack of a standardized definition has made it challenging to discern the true incidence of ICPI-AKI. However, one early study, which pooled data from phase II and III clinical trial data published between 2014 and 2015 that included at least 100 patients receiving ICPIs, estimated incidence of ICPI-AKI as approximately 2% . Severe The median time of onset to ICPI-AKI varies, ranging anywhere from 1 to 12 months depending on the specific ICPI prescribed. One review found that the average onset of AKI was shorter in patients treated with the anti-CTLA-4 agent ipilimumab (6 to 12 weeks), as compared to anti-PD-1 agents pembrolizumab (1 to 12 months) and nivolumab (6 to 12 months) . CortazaPatients with cancer are predisposed to AKI for a variety of reasons. Current expert opinion suggests evaluation for ICPI-AKI should begin once other more common causes of AKI have been ruled out. These include causes such as volume depletion, acute tubular injury secondary to hemodynamic fluctuations or sepsis, cancer-related urinary tract obstruction, exposure to other known nephrotoxins, or causes related to medical co-morbidities including cardiorenal and hepatorenal syndromes. In kidney biopsy proven cases of ICPI-AKI, acute tubulointerstitial nephritis (ATIN) was the most common manifestation of kidney injury followed by various glomerulopathies, and acute tubular injury (ATI) , 26–38.Potential mechanisms for development of ATIN following ICPI therapy have been described. One theory proposes that the widespread disinhibition of T-cells leads to loss of tolerance to potential haptens, low molecular weight drug compounds that bind to self-proteins, triggering an immune reaction . AnotherDue to this described loss of tolerance, concurrent use of medications that can trigger an immunoallergic response such as proton pump inhibitors (PPIs), non-steroidal anti-inflammatory medications (NSAIDs) and various antibiotics serve as important risk factors in the development of ICPI-AKI. For example, one multicenter study including 138 patients diagnosed with ICPI-AKI found that 54% of patients were also receiving a PPI. Furthermore, 22% of the study patients were taking NSAIDs and 9% were taking an antibiotic associated with ATIN . Nearly 2)  vs. zero patients treated with ipilimumab alone (n = 46) (n = 429) and without (n = 427) ICPI-AKI, older patients and patients with genitourinary cancers were also more likely to develop ICPI-AKI  , 24, 25.(n = 46) . One larWhile these kidney toxicities may be relatively uncommon, existence of other extrarenal irAEs may clue providers to the presence of an underlying ICPI-AKI. One study demonstrated concomitant extrarenal irAEs in 26 of 30 patients (87%), with thyroiditis and colitis being the most commonly associated immune adverse events . AnotherCertain laboratory findings may suggest ICPI-AKI, although no single feature or combination of features is specific enough to confirm a diagnosis. Studies featuring biopsy-proven ICPI-AKI highlighted the presence of sterile pyuria or white blood cell casts in 33 to 83% of cases –27, 41. n = 3/12) also demonstrated moderate to severe tubular atrophy and interstitial fibrosis   are not consistently present in many cases of biopsy proven ATIN including ICPI-AKI, as evidenced by the wide range of incidences reported in prior studies , 50, 51.= 0.037) . However= 0.037) , 56. Cas= 0.037) . In ligh= 0.037)  We agreeIn ICPI-AKI patients who require immunosuppressive therapy for extrarenal irAEs, it is reasonable to forego kidney biopsy and continue close monitoring of kidney function. Likewise, in the absence of another identifiable etiology of AKI after thorough evaluation, clinicians should consider proceeding with empiric corticosteroid therapy if there is a contraindication to kidney biopsy such as renal or perirenal infection, severe hypertension, or coagulopathy. Initiation of corticosteroids should not be delayed when there is a strong suspicion for ICPI-induced ATIN , as early initiation of corticosteroids (within 3 days of ICI-AKI occurrence) has been shown to enhance renal recovery . If empiCorticosteroids are the backbone of ICPI-AKI treatment. In one large multicenter study, 103 of 119 patients (87%) with ICPI-AKI who were treated with corticosteroids had partial or complete kidney recovery . ManagemPermanent discontinuation of ICPI therapy can have serious implications on patient outcomes, including progression free survival and/or overall survival. This is especially true in patients who have exhausted other non-ICPI treatments. As such, the decision to rechallenge patients with ICPIs should be explored with thorough review of the risks and benefits. Certain factors may influence the decision to re-challenge patients including clinical circumstances at the time of diagnosis . Current ASCO guidelines recommend the consideration of ICPI re-challenge in patients who have improvement in renal function after initial kidney injury . To support this recommendation, a large cohort study reported ICPI re-challenge in 121 patients with only 20 patients (16.5%) experiencing recurrent ICPI-AKI . Median ICPI-AKI is an increasingly recognized cause of kidney injury in patients with cancer. ATIN is the most common histopathologic finding on kidney biopsy although other kidney lesions may be seen. Medications known to cause ATIN such as PPIs, NSAIDs and certain antibiotics can increase the risk of ICPI-AKI, possibly through host immune system loss of tolerance to these potential haptens. Treatment with combination immunotherapy also carries greater risk for nephrotoxicity. Sterile pyuria, white blood cell casts, and eosinophilia have been reported in ICPI-AKI, although these clinical features are not reliable enough for diagnosis. While the role of kidney biopsy in diagnosis of ICPI-AKI is currently debated, a growing number of clinicians support the use of kidney biopsy to confirm cases of suspected ICPI-AKI and inform treatment choices. Timely pursuit of kidney biopsy may help clinicians avoid potentially harmful corticosteroids and allow continuation of immunotherapies in situations of non-ICPI-related AKI.As indications for ICPI use expand, future work should focus on identification of both sensitive and specific non-invasive diagnostic markers for early detection of ICPI-AKI (primarily ATIN). A recent externally validated diagnostic model for the prediction of ATIN using serum and urine markers shows modest area under the receiver operating characteristics curve . A model controlling for blood eosinophils and dipstick leukocytes and protein demonstrated an AUC of 0.84  for both biomarkers, suggesting potential utility for non-invasive diagnosis . FurtherEM made contributions to conception of the work and drafted the manuscript. MP made contributions to conception of the work and to the drafting and revision of the manuscript. Both 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.


N = 511) displayed a significant increase in systolic blood pressure, hemoglobin A1c (HbA1c), diabetic medications, and dose of insulin (p < 0.05) as well as a decrease in low density lipoprotein (LDL) levels (p = 0.04). When patients were stratified by body mass index (BMI), those in higher BMI categories were more negatively impacted during the pandemic than those in lower categories. Results display the impact that COVID-19 had on the general well-being of diabetic patients, and should encourage providers to increase telehealth visits when in-person visits are not possible.Coronavirus disease 2019 (COVID-19) impacted those with chronic diseases worldwide, especially those with diabetes. Very few studies have explored the effect of COVID-19 on diabetic patients’ health markers. The present retrospective study compared various health markers of diabetic patients before and during the COVID-19 pandemic. Patients ( Early in the coronavirus disease 2019 (COVID-19) pandemic, it was determined that diabetic patients were at an increased risk of acquiring COVID-19 compared to the general population due to their compromised immune systems . Given tWhile the negative impact of COVID-19 on those with chronic disease was apparent in early reports, many physicians and outpatient offices were closed during the peak of the pandemic, leading to a lapse in follow-up visits for patients with diabetes -5. This Few studies have examined the impact that COVID-19 had on diabetic patients’ health and compared specific health markers to those prior to the start of the pandemic . This study was conducted to assess the impact of the COVID-19 pandemic on the overall health of patients with diabetes. Specifically, the current study explores several health markers across the span of the pandemic to determine whether or not patients were negatively impacted by the COVID-19 pandemic. We hypothesized that the COVID-19 pandemic introduced a detrimental negative effect on patients with diabetes, which can result in an increase in diabetic complications longitudinally.Data were collected using the electronic medical records of a large community outpatient internal medicine practice in the Northeast United States. Patients were gathered who matched the ICD codes for pre-diabetes and type 2 diabetes. The charts were reviewed to collect data. The data collected included age, sex, race, BMI, systolic blood pressure, diastolic blood pressure, HbA1c, urine microalbumin, LDL, number of diabetic medications, and dose of insulin. The sex was determined to be either male or female. The race category includes Caucasian/White, African-American/Black, Hispanic, American Indian/Alaska Native, Asian, and Unknown. The number of anti-diabetic medications included all oral and injectable antidiabetic agents. The dose of insulin included a total number of combined units for both long- and short-acting insulins. For each patient, data points from two different time periods were collected. Point A was prior to the start of the pandemic (January 2019-March 2020), and point B was a few months into the pandemic (June 2020-April 2021). If there were many data points for one variable during this time period, which was the case for patients who had more than one appointment during the selected time period, then an average was taken for the two most recent values in each time period. We excluded any patients with insufficient data for both time periods.To compare both of the groups, an average value for each variable was collected using data from all of the patients for both time periods. A paired t-test was simulated to produce the study results that are interpreted below.Data analysis Data were entered into Microsoft Excel . Patients who did not have sufficient data  were excluded. Data from the two time periods were compared using paired t-tests to display any significant differences, and the size effect was measured using Cohen’s d. Then, patients were broken into BMI groups and within group changes were measured using paired t-tests. Statistical analyses were performed using SPSS Statistics Version 25 .Descriptive statisticsThe current sample contained 511 patients, of which 45% (n = 230) were male and 55% (n = 281) were female. Patients on average were 58.31 years . Race was determined as follows: White (n = 178), Black (n = 230), Hispanic (n = 9), American Indian/Alaskan Native (n = 6), Asian (n = 12), and unknown/not reported (n = 54).Impact of COVID-19 on health markersPaired t-tests revealed that the change in BMI, diastolic blood pressure, and urine microalbumin were not significantly different from Point A to Point B. Systolic blood pressure was significantly higher at Point B M = 135.28) than Point A (M = 130.62): t(490) = -5.17, p < 0.001, d = 0.26. HbA1c levels also significantly increased from Point A to Point B: t(479) = -2.45, p = 0.015, d = 0.11. Impact on HbA1c was not calculated separately for patients with pre-diabetes versus patients with diabetes due to not having a significant amount of patients who fit into the pre-diabetic range. Additionally, LDL levels significantly decreased from Point A (95.99 mg/dL) to Point B (92.05 mg/dL): t(386) = 2.11, p = 0.036, d = 0.10. Lastly, levels of insulin and the number of diabetic medications both increased significantly (p < 0.05) from Point A to Point B. Table 35.28 thaFurther classification based on obesity class The patient sample was also separated into groups based on BMI. The underweight class included a BMI <18.5 (n = 0); normal weight BMI was 18.5-24.9 (n = 36), overweight BMI was 25.0-29.9 (n = 106), class I obesity BMI was 30.0-34.9 (n = 133), class II obesity BMI was 35.0-39.9 (n = 94), and obesity class III BMI was >40.0 (n = 123). The groups were then compared using a paired test to evaluate changes from Point A to Point B.Patients in the normal weight range (BMI = 18.5-24.9) reported no significant differences from the pre-post COVID pandemic. Patients in the overweight group (BMI = 25-29.9) reported minor, but statistically significant increase in diabetic medications used by 0.12 units: t(97) = -3.28, p < 0.001. In the obesity class I group (BMI = 30.0-34.9) there was a significant increase in systolic blood pressure by 5.58 mmHg (p = 0.001) and diabetic medications by 0.41 medications (p < 0.001). In the obesity class II group (BMI = 35.0-39.9) there was a significant increase in systolic blood pressure by 5.51 mmHg (p = 0.03) and diabetic medications by 0.35 medications (p < 0.001). Lastly, in the obesity class III group (BMI > 40.0) there was a significant increase in systolic blood pressure by 4.69 mmHg (p = 0.02), HbA1c by 0.5% (p = 0.01), and diabetic medications by 0.36 medications (p < 0.001). There was a significant decrease in BMI in this group by 0.89 points (p = 0.004).In this retrospective study, we analyzed the overall health of patients with diabetes before and during the COVID-19 pandemic. There were no significant changes in BMI, diastolic blood pressure, or urine microalbumin when comparing data as a whole for all participants. However, results displayed statistically significant increases in systolic blood pressure, the number of diabetic medications being used, and the dose of insulin. There was also a statistically significant decrease in LDL levels. As obesity is a known cause of increased mortality and morbidity in patients with diabetes, we further separated our patients based on BMI class. Our results indicated that the patients with a BMI of 40 or more (Class III) showed significant worsening of HbA1c, diabetic medications, and systolic blood pressure.According to the American Diabetes Association, the standard of care for diabetes should include a comprehensive assessment of complications, lifestyle management, glycemic control, medications, risk assessment, and prevention of diabetes-related complications . The panIt is also important to mention that although there were significant deteriorations in many of the studied variables, this change was not as drastic as we originally expected. The negative aspect of the pandemic mentioned above did impact our patients with diabetes, but there were also key positive outcomes of this pandemic that we observed. One possible explanation is the increased popularity of telehealth medicine during the pandemic. There was a reported 154% increase in telehealth visits during March of 2020 compared to the year before . As physWe hypothesize that another factor that led to better outcomes than predicted was that the COVID-19 pandemic inspired many to take better care of their health. We suspect that during a pandemic, many patients made more of an active effort to control their diabetes than perhaps they have done in the past due to fear of the consequences of being exposed to the COVID-19 virus as a patient with uncontrolled diabetes. This study carried many strengths, the most important being that it is one of the first studies to investigate the phenomenon of a pandemic affecting the health of patients with diabetes. The sample size used to collect data was satisfactory to observe the intended changes in our variables. We also had an even distribution in gender and obesity class which allowed our data to be evenly distributed. There are several ways this study could be improved further. Our study collected data from a single-center outpatient clinic. Collecting data from different centers with different locations and patient populations would provide a broadened view of the pandemic’s effect. In addition, when we collected data for the number of diabetic medications we did not differentiate between oral, injectable non-insulin, and insulin medications. A more detailed look into this could unveil further data points. Lastly, we did not have any group to serve as a control group. A possible improvement to this study could include comparing the group of patients with diabetes a year before the pandemic and seeing the change in their overall health even before the pandemic hit. This would allow us to isolate the effect of the pandemic even further.This study highlights the impact of a pandemic on the diabetic population, and the importance of close monitoring required in this population to avert morbidity and mortality. Diabetes has been a known risk factor for severe COVID-19 infection, but it was crucial to look at the effect of the pandemic itself on the overall health of these patients. Although initially, we thought that this project would only unveil negative outcomes of the pandemic on patients with diabetes, further investigations of the variables revealed that the COVID-19 pandemic instigated both positive and negative effects on their health. One thing is for certain, during periods of high stress, constant change, and poor conditions, it is imperative that patients with diabetes receive the same monitoring and access to treatment in order to avoid a decline in their health.


Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients. To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response. Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses. In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters. Unfortunately, large series of patients including kidney transplant recipients (KTR) who have already received two doses of mRNA vaccines showed poor seroconversion rates in comparison to the general population related to their immunosuppressive treatment. Different studies have shown the seroprotection rates are under 20% after the first dose, and less than 50% after the second one, while in the general population, these values are close to 100% . AlthougThe distribution of immune cell populations impacts the outcome of immune responses to different viral infections and vaccination settings such as the CD4/CD8 T-cell ratio in HIV-infected subjects , or the 22.1We designed a prospective monocentric longitudinal study of kidney transplant recipients (KTR) receiving three doses of mRNA-1273 COVID-19 vaccine (100 μg per dose) and healthy controls receiving two doses of BNT162b2 vaccine (30 μg per dose). KTR from the Virgen del Rocio University Hospital , were recruited if they received kidney transplant more than one month before the beginning of the study, and were older than 18 years old and signed informed consent to participate. In our region, KTR received the first dose of vaccine in April 2021. Blood samples were collected up to one month before the first dose (T0), 3-4 weeks after the first dose (T1) (i.e. just before the administration of the second dose), one month after the second dose (T2), four months after the second dose (T3) and one month after receiving the third dose (T4)  and run on a DiaSorin LIAISON XL platform . According to the manufacturer’s data, the sensitivity and specificity of this test were 98.7% and 99.5%, showing a good correlation with microneutralization test . Antibody concentration, expressed as BAU/mL, was automatically calculated by the analyzer from AU/mL by the following conversion formula: AU/mLx2.6=BAU/mL. A positive result was considered as ≥33.8 BAU/mL. The levels of IgG antibodies against the trimeric SARS-CoV-2 Spike protein were considered as a continuous variable, corresponding to the magnitude of the humoral response , but they were also transformed into a dichotomous variable, corresponding to the ability to response or seroconversion, defined as an antibody titter higher or equal to 33.8 BAU/mL (the established threshold for the used assay).IgG antibodies against the trimeric SARS-CoV-2 Spike protein were quantified in serum samples by chemiluminescence assay  by standard procedures at the Immunology Service of our Hospital.2.4®).Plasma and serum samples were collected and stored at -80°C until used. Biochemical and inflammation-related biomarkers were determined by standard procedures at Biochemistry Service of the Virgen del Rocío University Hospital, at T0, in serum or plasma samples when proceeded. Quantification of the homocysteine levels were determined by photometry, whereas high sensitivity C-reactive protein (hsCRP) and β2-microglobulin levels were determined by an immunoturbidimetric assay in Cobas 701 system . eGFR was calculated by CKD-EPI index. Tα1 was determined in baseline plasma samples using Human Thymosin Alpha 1 (Tα1) Elisa kit  were isolated from fresh blood using density gradient centrifugation. Then, PBMC were cryopreserved until DNA was extracted by using Omega BIO-TEK, E.Z.N.A blood DNA Mini Kit. The ratio between number of copies of the telomere sequence and the single copy gen Beta-globin was determined. Copy number quantifications were performed by qPCR following a standard protocol . For eac2.6Thymic output was calculated as the sj/β-TRECs ratio by Droplet digital PCR (ddPCR), in a single reaction, optimized from , and acc2.7Statistical comparisons between groups were performed using non-parametric Mann-Whitney U-test for continuous variables or the chi-squared test for the categorical variables. For multiple longitudinal comparisons, the Friedman test applied. Correlations were explored by the non-parametric Spearman´s ρ coefficient. A p-value <0.05 was considered statistically significant. Multivariable linear or logistic regression were performed to determine independent factors affecting to antibody titers or seroconversion rates after vaccination, respectively. Those variables statistically significant in the previous bivariate analysis and those clinically or biologically relevant were included. Statistical analysis were performed using IBM SPSS v21.0 and graphics were generated with GraphPad Prism 8.0 .33.1Eighty-seven kidney transplant recipients (KTR) were initially recruited before receiving the first dose of the COVID-19 vaccine, but only 74 KTR were included for analysis and 54 of them remained at the last time-point (see 3.2p<0.001) and T2   (Seroconversion rates (defined as ≥33.8 SARS-CoV-2 Trimeric-S IgG BAU/mL) were lower in KTR than HC group at T1  Table 1.vs. 44%, p=0.002) and higher antibody levels than before the booster dose . Fifty-four patients remained at the follow-up after the administration of the third dose of mRNA vaccine for the analysis of the humoral response to the booster dose in those patients (3.3p=0.04), as well as higher baseline thymic output, measured as the sj/β-TRECs ratio  (p=0.017). However, the baseline for the telomere relative length in circulating mononuclear cells did not associate with the seroconversion rate . We could measure the pre-vaccination mycophenolate blood level in 38 patients and we found that, non-responders presented higher baseline blood levels of this immunosuppressive drug (4.6 [3.1-6.3] vs. 2.6 [0.8-3.1] p<0.001), and such levels correlated to a lower antibody production   in patients who were treated with mTOR inhibitors in triple combined therapy instead of the mycophenolate-mofetil. No differences were found between these triple combinations and the dual therapy of corticosteroids plus tacrolimus (We observed that 19/19 (100%) of KTR non-responders to the third dose were under mycophenolate mofetil as immunosuppressive therapy compared to 25/35 (71%) among responders (3.5p=0.068) and presented higher baseline levels of β2-microglobulin (p<0.001) (p=0.026) and lower counts of several immune cell populations, such as lymphocytes (p=0.012), B-cells (p=0.010), T-CD3 cells (p=0.025) and T CD4-cells (p=0.010) but higher frequency of neutrophils (p=0.001)  (p=0.210). Regarding correlations, we found negative correlations between the specific antibody titer at T4 and age , proteinuria , ferritin , β2-microglobulin , neutrophils%  and mycophenolate-mofetil blood level , whereas positive correlations were observed between the specific antibody titers at T4 and T3 , baseline eGFR , B-cells/µL  and sj/β TRECs ratio .We obtained a data set comprised of the results from routine biochemical tests and hemograms which can provide insight into the immune response of patients to the vaccination. In addition to the demographical and immunosuppressive therapy related variables, we also analyzed inflammatory markers, kidney function markers and immune cell subsets. These variables are shown in 3.6p=0.011), β2-microglobulin  and T3 antibody titer  were independently associated with T4 antibody titers, whereas CD4 T-cells tended to  (p=0.037) whereas the blood concentration of mycophenolate-mofetil tended to .We performed a multivariable analysis including, besides sex and age, variables related to each of the following categories: demographical parameters, inflammatory-related markers, thymic function-related factors, immune cell subsets, kidney function parameters and immunosuppression therapy. Taking into account that, due to the sample size of our study, we were limited to include up to eight variables in a multivariable analysis, we selected at least one representative variable from each mentioned category, according also to its biological relevance in the vaccination response context. The best fitted model showed that baseline creatinine serum level  Table 3.4In our cohort of kidney transplant recipients (KTR), the humoral response against the COVID-19 vaccine was seriously impaired, even though a third dose/booster significantly improved the seroconversion rate and antibody titers. Not surprisingly, immunosuppressive therapy played a critical role in both, the capability of responding and the humoral magnitude achieved. Remarkably, the capability of responding was associated with baseline thymic-related factors, such as the concentration of thymosin-α1, while the magnitude of the response was associated with different factors, including age and baseline renal and inflammatory status.The KTR cohort showed an inferior response to the COVID-19 vaccine in comparison to the HC group, after two doses and even after an additional third dose, in the case of KTR. Although both groups were not age and sex matched, and were vaccinated with different vaccine mRNA platforms/doses, this result is consistent with previous data on similar cohorts , 19, 20.Due to the risk of developing severe disease in this population  and sincIn this study, we have analyzed immune-related factors potentially involved in the humoral response to vaccination. Interestingly, we found a strong positive correlation between the antibody titers after the two-doses schedule and the booster. Not surprisingly, we observed a poor response in those patients receiving mycophenolate-mofetil as immunosuppressive therapy. Moreover, age was related to lower antibody levels after three doses of vaccination. Both results are in accordance with those from a different KTR cohort receiving two doses of mRNA-1723 vaccine . RegardiA better renal function and lower plasma levels of inflammation-related markers, such as neutrophils and B2-microglobulin, were associated with a better response in our KTR patients. B2-microglobulin is commonly elevated in KTR due to the immunosuppressive status and deteriorated kidney function . FurtherIn this line, we also explored the thymic function, which plays a main role in the maturation and functionality of T-cells and has been outlined in several contexts of limited immune responses, such as HIV-infection, as well as in aging , 31. As We cannot conclude about the clinical protection achieved by the COVID-19 vaccine in our KTR cohort due to the low number of patients and the low rate of infection in our study period. However, from the five documented cases of SARS-CoV-2 infection after the administration of two doses of mRNA COVID-19 vaccine, three of them required hospital admission and one of those patients died due to a bilateral pneumonia. The other two patients presented mild symptoms. This is consistent with the rate of potentially seroprotected subjects in our cohort (50%), that is those patients reaching 260 BAU/mL, a threshold recently proposed for seroprotection , which iWe could not address the cellular response after vaccination in these patients, an important aspect to understand the full dynamics of the immune response after the immunization, and the role of thymic function in such response. Interestingly, an absence of correlation between SARS-COV-2 antibody titers and T cell response in kidney transplant recipients has been described .Our study has additional limitations, such as a low sample size and a large number of variables analyzed which limits the statistical power to conclude about the immune predictors as well as about the role of the combinations of immunosuppressive drugs in the humoral response to COVID-19 vaccine in kidney transplant recipients. In addition, the thymic output data were obtained from PBMCs samples, rather than the isolated T-cell compartment, comprising thymic emigrants, which would therefore have increased the sensitivity of quantification. However, our novel findings could help in the design of future immunization strategies aiming the improvement of the COVID-19 vaccine response in these immunosuppressed patients and suggest the possibility of the use of thymosin-α1 as a vaccination adjuvant to improve their response following the next boosters in this risk population.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comité de Ética de la Investigación de los Hospitales Vírgen Macarena y Vírgen del Rocío de Sevilla. The patients/participants provided their written informed consent to participate in this study.Patient recruitment and clinical data collection . Quantification of antibody titers (CL). Experiments of immune subsets . Experiments of biochemical and inflammatory markers (AA-R). Processing of samples and experiments of thymic function-related markers . Data base management and statistical analysis . Manuscript preparation . YP conceived the study, obtained funding and supervised the project. All authors contributed to the article and approved the submitted version.


Ambulatory blood pressure monitoring (ABPM) in patients with diabetes mellitus (DM) and hypertension (HTN) show the dipping patterns, identify masked uncontrolled hypertension (MUCH), and demonstrate the effectiveness of the blood pressure (BP) treatment. MUCH is associated with a two-fold higher risk of adverse events. Prevalence in patients with DM is between 13.3 and 66.4%. Our study aims to investigate the prevalence of MUCH and the BP patterns in a population of apparently well-controlled hypertensive patients with type 2 DM (T2DM). A second aspect was the assessment of the effectiveness of antihypertensive treatment.One hundred and sixty-three consecutively treated hypertensive patients with T2DM and an office BP between 130–139 and 80–89 mmHg performed a 24 h ABPM. The circadian BP variation, the presence of MUCH, and the correlations with the treatment were assessed..There were 75 dippers (46.02%), 77 non-dippers (47.23%), 4 reverse dippers (2.45%), and 7 extreme dippers (4.30%). Eighty-one patients  had isolated nocturnal MUCH according to the mean night ABPM criteria. Dippers and extreme dippers  did not have any MUCH criteria. The patients took, on an average, 3 antihypertensive drugs with no difference between those with controlled HTN and the isolated nocturnal MUCH group. Significant factors associated with isolated nocturnal MUCH and a non-dipping BP pattern included age > 65 years (OR = 1.9), DM duration > 10 years (OR = 1.4), HTN duration > 6.5 years (OR = 1.2), obesity (OR = 1.6), and cardiovascular comorbidities (OR = 1.4)The current study shows that half of the treated hypertensive patients with T2DM and office clinical normotension are non-dippers or reverse dippers. They experience isolated nocturnal MUCH due to their elevated nocturnal BP values, which comply with the actual definition of masked nocturnal hypertension. Bedtime chronotherapy in those patients could be linked to better effectiveness of antihypertensive treatment during the night with the important goal of reducing cardiovascular and cerebrovascular adverse events. ABPM should be performed in hypertensive patients with DM for better risk stratification and more effective control of HTN.The online version contains supplementary material available at 10.1186/s13098-022-00899-6. Ambulatory blood pressure monitoring (ABPM) seems to be a stronger prognostic tool than clinic measurement and predicts mortality better than clinic measurement . ABPM caUncontrolled treated hypertension (UHTN) was defined as a systolic blood pressure (SBP) ≥ 140 mmHg and diastolic blood pressure (DBP) ≥ 90 mmHg, which is equivalent to a 24 h ABPM average of SBP ≥ 130 mmHg and/or DBP ≥ 80 mmHg, in accordance with the 2018 ESC/ESH guidelines (2). UHTN raise the risk of both cardiovascular and cerebrovascular complications and increase mortality . DiverseThe ideal treatment target for office SBP in patients with DM is under 130 mmHg, but not less than 120 mmHg. The SBP target range is 130–140 mmHg in patients aged ≥ 65 years, if tolerated. The target for DBP should be < 80 mmHg . DM and Our study aims to investigate the prevalence of MUCH and the BP patterns in a population of apparently well-controlled hypertensive patients with type 2 DM and office BP between 130–139 and 80–89 mmHg. A second aspect was the assessment of the effectiveness of antihypertensive treatment  approved this study (Decision Nr 3034/ 21.11.2019). A written informed consent to participate and publish the data was signed by all the enrolled patients. Patients’ records/information were anonymized and de-identified before the analysis.2 calculated using chronic kidney disease/Epi Info formula (eGFR CKD- EPI). Stroke was assessed by self-reported diagnosis. Measured height and weight were used to calculate body mass index (BMI).Our research is an observational, nonrandomized, prospective study that enrolled between 2020 and February 2021 two hundred and five consecutive hypertensive patients with T2DM and ambulatory followed up at the Diabetes, Metabolic and Nutrition and Cardiology Wards of Emergency County Hospital Baia Mare, Romania. Those patients were under antihypertensive treatment and must have had office BP readings between 130–139 and 85–89 mmHg for at least two visits, 1 month apart. The values of BP were standard measured, as recommended by the 2018 ESC Hypertension guidelines  to achieve a good clinical BP control of 130–139/85–89 mmHg. However, the ideal target is under 130/80 mmHg. The mean number of drugs was 2.1 ± 0.4 with no difference between the controlled HTN group and the isolated nocturnal MUCH group (refer Table To our knowledge, this is the first study to report the prevalence of MUCH among treated hypertensive patients with T2DM and office BP between 130–139 and 80–89 mmHg. These patients represent a population less or not specially investigated in trials. Some data showed that they are prone to an increasing rate of MUCH and a more frequent presence of HMOD correlated with a poorer prognosis , 19, 20.The current study demonstrated that non-dipping or reverse dipping phenomenon in apparently well treated hypertensive patients with T2DM are frequently encountered in about half of them. Those patients have isolated nocturnal MUCH due to their elevated nocturnal BP values, which comply with the actual definition of masked nocturnal hypertension. ABPM should be performed in every hypertensive patient with DM to identify the dipper or no-dipper status and the presence of MUCH. The non-dippers and reverse dippers could have a personalized treatment approach for normalizing nocturnal hypertension or restoring abnormal BP dipping. Further research should clarify the importance of these therapeutic steps for the best management of HTN in patients with DM.Additional file1. STROBE Statement—Checklist of items that should be included in reports observational studies.


Background: Both high and low percentages of carbohydrate diets were associated with increased mortality and new-onset hypertension. However, few studies have aggregated to explore the association between carbohydrate intake and blood pressure (BP) control in patients with hypertension. This study aimed to explore the association between carbohydrate-to-energy proportion (CEP) and the rate of poorly controlled BP in patients with hypertension. Methods: A cross-sectional survey was conducted in one comprehensive hospital and one community clinic in China. Dietary CEP was obtained through two-24 h dietary recalls. According to the quintiles of CEP, the participants were divided into Q1–Q5 groups. The average of two BP values was adopted as the final BP value, and poorly controlled BP was defined as systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg. Results: A total of 459 hypertensive patients were recruited. In univariate analyses, CEP was associated with the control of SBP and DBP. After the covariates were adjusted for, fewer CEPs in Q1  and Q2  were significantly associated with higher rates of poor SBP control. Conclusions: A lower dietary CEP is a risk factor for SBP control, whereas an appropriate CEP of 56% to 66% is beneficial for BP control in patients with essential hypertension. By 2019, the worldwide prevalence of hypertension was estimated at 34.0%. Among this population, blood pressure (BP) of only 31.7% was controlled to <140/90 mmHg . EffectiA healthy diet plays an important role in the prevention and management of hypertension ,7,8. CarThis study was a cross-sectional survey. Convenience sampling was used to enroll hypertensive participants who met the inclusive and exclusive criteria from Jul. 2019 to Oct. 2020 in the Jin-chang community and the first affiliated hospital of Soochow University in China. Based on the rate of poorly controlled BP of 46.7% in Suzhou in Qi et al.’s study . The incAfter finishing the survey of demographic and clinical data, the patient rested for at least five minutes. Using the corrected OMRON sphygmomanometer (HEM-8102), the office BP (oBP) was evaluated in the patient’s upper arm at a sitting position in a community service room or a teaching room of the hospital. A repeated oBP measurement was performed after a five-minute interval. The average of two oBP values was adopted as the final BP value. Poorly controlled BP was defined as an average SBP ≥ 140 and/or DBP ≥ 90 mmHg .The data on carbohydrate and other nutrient intake were assessed using two 24 h diet records (a weekend and a day on a weekday) . Six traA general information questionnaire covering demographic and clinical data was developed by the team. The demographic data included age, gender, educational degree (below high school/high school or above), medical insurance (yes/no), regular exercise (yes/no), duration of sleep (h/d), quality of sleep (fair/poor), smoking and alcohol (yes/no), body mass index (BMI), duration of hypertension (y), taking antihypertensive drugs (yes/no), complication (yes/no), comorbidity (yes/no), and family history of hypertension (yes/no). Regular exercise was defined as exercising ≥ 3 times a week, ≥ 20 min each time, and continuous time ≥ 3 months . The evaThe data collection process was as follows. (1) The researcher informed participants of the purpose of the study, and participants who met the inclusion criteria signed an informed consent form. (2) The participant filled in the general questionnaire, which contained demographic and clinical data and took about ten minutes. (3) Then, the participant’s parameters were measured, including oBP. (4) The participant’s detailed diet data one day before the survey were recalled and recorded. (5) The researcher obtained the participant’s contact method (WeChat or cellphone numbers). (6) On the second or third day after the survey, the researchers obtained the second 24 h dietary data through WeChat or telephone.(1)25, P75). Comparisons of demographic, clinical, and nutritional data between the two groups: for categorical variables, Pearson’s Chi-square test or Fisher’s exact test was used; for continuous variables, if they were normally distributed, the comparison between groups was made using the independent samples t test; otherwise, the Manne–Whitney U test was used.Description of demographic, clinical, and nutritional data: for categorical variables, the results were described as the frequency (percentages); for continuous variables, we determined if data were normally distributed using the Kolmogorove–Smirnov test before analysis. If normal, they were expressed as mean ± SD; otherwise, data were expressed as median (P(2)Pearson’s Chi-square test was used to initially analyze the relationship between the CEP and the rates of poorly controlled BP.(3)p < 0.10 in the demographic, clinical, and nutritional data.In order to adjust for the impact of covariates on BP, multivariate binary logistic regression was used to analyze the associations between the CEPs and the rates of poorly controlled BP. The covariates were those indicators with (4)p value of <0.05 was considered statistically significant.A Statistical analyses were performed using SPSS 25.0 software . The analysis mainly included the following aspects:Initial questionnaires were collected from a total of 471 participants. Among those collected, the 459 were considered valid, and the effective recovery rate was 97.5%. The mean age of participants was (51.31 ± 12.62) years, and 288 (62.75%) were men. The mean duration of hypertension was four  years. Participants’ socio-demographic and clinical characteristics are presented in Among all participants, the mean dietary carbohydrate intake was (286.12 ± 79.22) g/day, and the median dietary CEP was 58.53%. The subjects were divided into five groups by the quintiles of CEP. The median percentages of CEP in Q1, Q2, Q3, Q4, and Q5 were 40.99%, 53.14%, 58.53%, 62.99%, and 69.48%, respectively; the fat-to-energy proportions were 43.1%, 32.0%, 27.9%, 24.6%, and 26.6%, respectively; and the protein-to-energy proportions were 16.2%, 16.2%, 13.3%, 13.3%, and 14.3%, respectively.Among the patients with hypertension in our study, the mean of SBP and DBP were (136.37 ± 13.49) mmHg and (86.28 ± 11.21) mmHg, respectively. The number (rate) of patients with poor BP control was 237 (51.63%). There were 171 (37.25%) poorly controlled SBP cases, with a median BP of 146.00 mmHg, and 179 (39.00%) poorly controlled controlled cases, with a median BP of 96.00 mmHg.2 = 20.767, p < 0.001; DBP: χ2 = 10.441, p = 0.034). Q4 had the lowest poorly controlled rates of SBP and DBP . See The rates of the poorly controlled SBP and DBP in each group with different CEPs are presented in p < 0.10) as covariates, the controlled rates of SBP and DBP as the dependent variables, respectively; taking Q4 (the lowest rates of poor controlled BP) as a reference group, the results showed that the fewer dietary CEPs in Q1  and Q2  were significantly associated with the higher poorly controlled rates of SBP, whereas there were no statistically significant associations with those in other CEPs groups; and there were no statistically significant associations between dietary CEPs and the poorly controlled rates of DBP. See In order to explore the associations between CEP and BP, a binary logistic regression was performed, with the CEP as an independent variable, the demographics, clinical indicators, and nutrient intake  in the group with <49% of CEP, whereas the lowest risk of poorly controlled SBP (25.81%) was in the group with 61% to 66% of CEP. In addition, those with poor BP control in this study were younger, had a shorter duration of hypertension and higher BMI level, consumed more cholesterol, and did take antihypertensive medications, which is consistent with several previous studies ,28.In the traditional Chinese diet, staple foods are mainly coarse grains; therefore, carbohydrate intake accounts for a high proportion of energy  ,30. In tUnhealthy dietary habits contributed to poorly controlled BP ,34. The Elevated SBP, as a significant predictor of cardiovascular events after age 50 ,38, accoA prospective study of 1.3 million people showed that diastolic hypertension is also an independent predictor of adverse cardiovascular outcomes, although it is often overlooked . Less caCurrently, it is well-known the Mediterranean and Dietary Approach to Stop Hypertension (DASH) diets are commonly recommended for patients with hypertension. These dietary regimens are not overly restrictive on carbohydrates, but rather make recommendations for healthier, more carbohydrate-rich foods ,56. CombThere are some limitations to this study. First, we did not investigate the source and quality of carbohydrates, since dietary carbohydrates consist of sugars, starches, and fiber, which can affect health outcomes in different ways. Savoia et al.  also higA lower dietary CEP is a risk factor for SBP control, whereas an appropriate CEP of 56% to 66% is beneficial for BP control in patients with essential hypertension. In this study, approximately 40% of patients with essential hypertension had a dietary CEP of less than 56%. Considering that carbohydrates are an important part of the diet of Chinese residents, these insights should be taken into account when formulating rational dietary programs for hypertensive patients.


However, two important limitations have been raised, the use of high ventilation pressures and a regression slope calculation that is difficult to apply at bedside. This ancillary study aimed to reanalyse absolute variations of CVP (ΔCVP) and PP (ΔPP) values at lower stages of the LRM,  for their ability to predict fluid responsiveness.Maintaining a constant driving pressure during a prolonged sigh breath lung recruitment manoeuvre (LRM) from 20 to 45 cmHRetrospective analysis of a prospective study data set in 18 mechanically ventilated patients, in an intensive care unit. CVP, systemic arterial pressure parameters and stroke volume (SV) were recorded during prolonged LRM followed by a 500 mL crystalloid volume expansion. Patients were considered as fluid responders if SV increased more than 10%. Receiver-operating curves (ROC) analysis with the corresponding grey zone approach were performed.20 (P = 0.89), respectively, and 0.92 and 0.95 for ΔPP at 45 and 30 cm H20, respectively (P = 0.51)]. Using a maximum of 30 cmH2O inspiratory pressure during the LRM, ΔCVP and ΔPP had a threshold value to predict fluid responsiveness of 2 mmHg and 4 mmHg, with sensitivities of 89% and 89% and specificities of 67% and 89%, respectively. Combining ΔPP and ΔCVP decreased the proportion of the patients in the grey zone from 28 to 11% and showed a sensitivity of 88% and a specificity of 83%.Areas under the ROC to predict fluid responsiveness for ΔCVP and ΔPP were not different between the successive stepwise increase of inspiratory pressures [0.88 and 0.89 for ΔCVP at 45 and 30 cm H20 may predict fluid responsiveness as well as 45 cm H20. The combination of ΔPP and ΔCVP optimizes the categorization of responder and non-responder patients.A stepwise PEEP elevation recruitment manoeuvre of up to 30 cm HThe online version contains supplementary material available at 10.1186/s12871-022-01815-1. Fluid therapy is a key component of cardiac output optimization . However20) during the LRM which may have deleterious physiological impacts [Lung recruitment maneuvers (LRM) have been proposed in mechanically ventilated patients to optimize oxygen delivery by increasing gas exchange and to decrease pulmonary complications in both the perioperative setting and in acute respiratory distress syndrome patients , 6. LRM  impacts .20 of peak inspiratory pressure) for their ability to predict fluid responsiveness solely and by combining both parameters.This ancillary study aimed to analyse absolute variations of CVP (ΔCVP) and PP (ΔPP) values at lower stages of the step PEEP LRM  and the baseline . Next, a volume expansion (VE) of crystalloid  500 mL over 10 min was performed, as prescribed by the current standard care protocol in our department.The LRM consisted of a 30 s stepwise increase in PEEP from 5 to 30 cm H2O, 5 cmH2O PEEP) and at four steps of the LRM: 30, 35, 40, and 45 cm H20 of peak inspiratory pressure  and the highest LRM stage (45 cm H2O). We defined the grey zone to be when the combination of ΔPP and ΔCVP had opposite value. A p-value < 0.05 was considered statistically significant. Statistical analyses were performed with XLSTAT software (version 2019.3.2) and Medcalc version 19.6.4.Subjects were grouped according to the percentage change in CI induced by VE after the LRM. Fluid responder patients (FR) were defined by an increase in CI ≥ 15% . Four va20 of peak inspiratory pressure) are summarized in Table Demographic characteristics and reasons for ICU hospitalization have been previously published . BrieflyROC Curves comparing the ability of ΔPP and ΔCVP at each step of the LRM to discriminate FR from NFR are presented in Fig. 2O) showed no significant difference for ΔPP (p = 0.51), and for ΔCVP (p = 0.89), respectively. At the lowest step pressure, combining both parameters left 11% of patients (2 out of 18) in the grey zone, versus 28% for ΔPP alone and 50% for ΔCVP alone. Negative and positive predictive values were 88% and 80% respectively, sensitivity and specificity were 89 and 78%, respectively , the combination of ΔPP and ΔCVP left 17% of patients (3 out of 18) in the grey zone  and 0.88 (95% CI 0.64 to 0.98), respectively. Comparison of ROC curves between the extreme steps of the LRM (peak airway pressure 30 versus 45 cmH2O versus 45 cm H20). The absolute cut-off value during the lower step pressure was 4 mmHg for ΔPP with a sensitivity of 89% and a specificity of 89% and an AUC of 0.95 (95% CI 0.74 to 1.0). The cut-off value was 2 mmHg for ΔCVP with a sensitivity of 90% and a specificity of 67% and an AUC of 0.89 (95% CI 0.64 to 0.98). Comparison of areas under the ROC curves between the extreme LRM step pressures showed no significant difference for ΔPP, and for ΔCVP, respectively. Finally, by combining ΔPP and ΔCVP, we observed a decrease in the percentage of patients in the grey zone from 17 to 11%. By comparison this percentage is lower than other methods used to predict fluid responsiveness, such as stroke volume variation induced by LRM [This retrospective analysis of the original STEP-PEEP study  showed td by LRM  or pulsed by LRM , both of20 peak pressure used in the OR [20 of the LRM allows precise discrimination of FR from NFR patients with only 11% of patients in the grey zone when combining ΔPP and ΔCVP, we now propose a less aggressive LRM in the ICU setting to optimize fluid status. The second objection was the use of an indirect parameter to predict fluid responsiveness, i.e. the calculated angle between the correlation line  and the horizontal line. We confess that the bedside applicability of this angle calculation is poor. Conversely, measuring the absolute value of a parameter before and after a dynamic test is routine, for example when calculating a significant variation of cardiac output when testing fluid responsiveness. We therefore reanalysed absolute variations of CVP and PP between the baseline and each pressure step of the LRM, from 30 to 45 cm H20. By showing that analysis of absolute variations at the lowest step is as effective as at the highest step, we can recommend the use of absolute variations of PP and CVP as an easy method to determine fluid responsiveness using a lower peak pressure and a more straightforward calculation. The good sensitivity and specificity of ΔCVP allows the use of this index when PP is not accurate, such as atrial fibrillation for which the rate in ICU ranges from 10 to 60% [This ancillary analysis was conceived after reviewers of the initial study raised several limitations. The first objection was the use of high peak pressure during the LRM, when compared with the usual 30 cm Hn the OR . Indeed,0 to 60% , 15.Combining a right cardiac preload variable (CVP) and a left cardiac function parameter (PP) is advantageous in potentially limiting the impact of confounding factors such as diastolic and systolic right and left cardiac function as well as arterial compliance when analysing the preload dependency state. Combining two parameters such as CVP and the shock index (HR/SAP) has been used to improve the positive or negative predictive value to better discriminate non FR patients . InteresIn 2008, Marik included 24 studies in a meta-analysis to test the ability of baseline CVP before VE or the variation of CVP before and after VE to predict fluid responsiveness. The pooled area under the ROC curve was only 0.56 . CVP has therefore been abandoned as a marker of fluid responsiveness, but its absolute value is still proposed as a marker of fluid overload . Indeed,2O to 20 cm H2O during an end-expiratory pause can predict FR with a moderate AUC of 0.72 (95% CI 0.50–0.94) [Systemic arterial pulse pressure (PP) depends on the stroke volume (SV) and on the arterial compliance. The SV component can also be stressed by a variation of the ITP. The increase in ITP decreases the venous return and increases the right afterload, ultimately decreasing the SV. The inverse is observed when ITP decreases. If the hemodynamic status of the patient is on the steep part of the Frank Starling curve (low preload zone) then there may be a significant variation of SV when ITP changes. In the ICU setting, the pulse pressure variation (PPV) concept is based on the comparison between a zero-end-expiratory pressure (ZEEP) and the application of a PEEP during the mechanical respiratory cycle . This ap50–0.94) . In the 50–0.94) .20, we did not find a better specificity for ΔCVP or a better sensitivity for ΔPP at a peak inspiratory pressure of 30cmH20. Calculation of sensitivity and specificity depends on the chosen cut off value, and bedside application should depend on the clinical scenario. If the clinician feels that the potential risk associated with VE is low, a lower range of the grey zone should be chosen favoring high sensitivity. However if the clinician feels that the risk associated with VE is high (i.e. may lead to volume overload), then the upper range of the grey zone should be chosen, favoring high specificity.Compared to a peak pressure of 45 cm HA major strength of this study is the mode of data recording, wherein a video of the entire hemodynamic monitoring was recorded during the LRM, with the clinician announcing the time and pressure level for each step; thus, allowing for objective data collection and limiting bias introduced by the scope data filtration process, which is unique to each brand. Our data were later collected by pausing the video during the two last seconds of each LRM step, therefore ensuring no data loss.2O. The STEP-DOWN phase, by prolonging the delay between the STEP-UP phase and the VE may have biased the result of the fluid responsiveness [2O versus a LRM up to 45 cmH2O without the STEP-DOWN phase to verify our results. Moreover, our data comes from a small sample of patients. Extrapolation is therefore limited, and we emphasize that this is a pilot study. Finally, only data for pulse pressure and central venous pressure were tested in our study as they proved to be the two best parameters in the previous study.This study has several limitations. As mentioned in the original study, norepinephrine infusion during this observational study may have impacted cardiac preload and reduced preload dependency . Howeversiveness . Future 20 seems to give similar results for fluid responsiveness prediction as the previous linear interpolation model proposed in the STEP-PEEP study. Variations of central venous pressure and pulse pressure provide respectively good specificity and sensitivity for fluid responsiveness prediction and could be easily applicable at the bedside after validation by a larger prospective cohort study.A step-up lung recruitment maneuver with a peak inspiratory pressure of 30 cm HAdditional file 1.


We would like to thank Drs. Hungerford and Bart for their kind comment  on our rWe absolutely agree with Drs. Hungerford and Bart on the growing challenge caused by the increasing prevalence of arterial hypertension worldwide . This neThe unrestricted availability of blood pressure measurement devices comes with a certain risk. If the number, i.e., the blood pressure reading produced by the device, is perceived by the patient and the health care worker as a correct value, but is in fact incorrect, there is a risk of both under- and over-treatment. The patient  may believe no further action is needed when values are in the normal range and thus could refrain from further measurements for up to five years, according to the European Guidelines for the management of arterial hypertension . On the Keeping this in mind, we should always use devices that have been validated according to an international standard, for example, the “Universal Standard for the Validation of Blood Pressure Measuring Devices” (AAMI/ESH/ISO) ,11. The Accordingly, we have to stress that while the results of this smartphone application examined in our pilot study are very promising, we are far from a clinical utility . First, The developers of the RIVA Digital application should be applauded for their decision to submit their application at an early stage to test for comparability with conventional blood pressure measurements. Such actions are crucial to prevent the flooding of the market with unvalidated blood pressure measurement devices, and should be facilitated in any future validation protocols, particularly for cuffless devices. An attempt to approach this for the AAMI/ESH/ISO-protocol has been undertaken by our group .In conclusion, while we are very satisfied about the promising results revealed in our pilot study regarding this smartphone application, we first need an internationally accepted validation protocol for cuffless blood pressure measurement devices. Furthermore, we encourage further improvement of the data assessment and refinement of the data interpretation of such a smartphone application, followed by proper validation, before such an application can be used in clinical practice.


Seven trials were included that assessed the effect of adding RDN to pulmonary vein isolation (PVI) in patients with hypertension and AF. A total of 711 patients , with an age range of 56 ± 6 to 68 ± 9 years, were included. Pooled analysis showed a significant lowering of AF recurrence in the PVI + RDN (31.3%) group compared to the PVI-only (52.9%) group (p < 0.00001). Pooled analysis of patients with resistant hypertension showed a significant mean reduction of systolic blood pressure (SBP) , but not diastolic blood pressure (DBP)  in favor of PVI + RDN. Additionally, the pooled analysis showed that PVI + RDN significantly improved estimated glomerular filtration rate (eGFR)  compared to PVI alone. RDN procedures in these trials have proven to be both safe and efficacious with an overall complication rate of 6.32%. Combined PVI and RDN is beneficial for patients with hypertension and AF. Combined therapy showed improvement in SBP and eGFR, reducing the risk of AF recurrence. RDN may serve as an innovative intervention in the treatment of AF.The study aims to compare clinical outcomes following renal denervation (RDN) in hypertensive patients with atrial fibrillation (AF). Three online databases were searched  for literature related to outcomes of RDN on hypertension and AF, between January 1, 2010, and June 1, 2021. Where possible, risk ratios (RR) and mean differences (MD) were combined using a random effects model. Significance was set at  Atrial fibrillation (AF) is the most common type of heart arrhythmia currently affecting 0.51% of the population globally . In addin = 2152) showed that RDN of main renal artery branches in addition to antihypertensive therapy is most effective in reducing office blood pressure and that RDN using this approach was superior in reducing ambulatory blood pressure compared to sham or antihypertensive therapy alone [Despite the availability of a variety of pharmacological and lifestyle interventions, around 50% of patient with HTN remain resistant to such strategies . This hipy alone .Catheter ablation through pulmonary vein isolation (PVI) in patients who fail to demonstrate a reduction in AF recurrence following pharmacological agents is currently a highly effective intervention . DespiteThis study utilised the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Revised Assessment of Multiple Systematic Reviews guidelines to perform and design the review , 12. Thi2), (4) congestive heart failure, (5) left-ventricular ejection fraction (LVEF) < 35% (6) studies published in non-English language.Two authors searched three online databases  for papers published from January 1, 2009, to June 1, 2021, using the following combination of keywords: RDN, renal sympathetic denervation, catheter-based RDN, kidney denervation, renal artery denervation. Studies that were retrieved from the initial database search were published in English and from human trials. Additionally, any missed studies were included into screening following a full reference screen of relevant studies. The inclusion criteria were as follows: (1) Original research articles, (2) published after January 1, 2009, in English language, (3) Level I or Level II prospective comparative studies that (4) assessed the effect of RDN on AF in patients with essential HTN that are undergoing PVI. The exclusion criteria were as follows: (1) Studies that assessed patients with secondary HTN, (2) type I diabetes mellitus, (3) late-stage kidney disease/failure  independently and in duplicates by two authors (KN and AM). Disagreements were internally discussed before moving to the subsequent stage of screening. A PRISMA flow chart of the literature screening is shown in Fig. The Cochrane risk of bias (ROB) tool was used to assess quality and publication bias of the individual studies that were randomized   scores were used at each stage of the screening process in order to determine inter-rater reliability as well as agreement . The k sTwo authors (KN and AM) independently collected and extracted data into a standardized form, in Excel 2019 . The following information, if available, was extracted from the studies: primary author and year, study design and purpose, sample size, age and gender information, country of study, follow-up time frame, baseline study sample characteristics , LVEF, and left-atrial diameter (LAD), AF type, and systolic and diastolic blood pressure), follow-up data on AF recurrence and blood pressure, and safety complications.This analysis primarily aimed to compare the effects of RDN on AF recurrence in hypertensive patients that were undergoing PVI for treatment of AF. The main outcomes were AF recurrence, the blood pressure lowering effect of RDN as well as the effect of RDN of eGFR. AF recurrence was defined as episodes of atrial tachyarrhythmias lasting >30 s during the follow-up period. Secondarily, the analysis aimed to assess the safety, efficacy, and sustainability of RDN.I2 values were used [I2 > 65% by removing each study separately and examining the effect on the I2 value [The pooled analysis of quantitative results was synthesized using RevMan 5.3 . Pooling of data was conducted using a random effects model and study weighing was based on inverse variance. A minimum of three studies was required for outcome pooling. To assess for heterogeneity due to differences in study methods and populations, the ere used . MoreoveI2 value .Cochrane Handbook for Systematic Reviews [Treatment effects for dichotomous variables were compared using risk ratios (RR) and 95% confidence intervals (CI), and those for continuous variables were compared using mean difference (MD) and 95% CI. For studies that did not report standard deviations (SD), the values were estimated according to the guidelines outlined in the  Reviews .Figure The seven trials included a total of 711 patients, with 329 patients in the PVI + RDN group and 382 patients in the PVI-only group (Table p < 0.00001)  Fig. .Table 3Ap = 0.05)   Fig. . The poo16) Fig. . The poop < 0.00001 for SBP and a significant difference of p = 0.006 for DBP demonstrating the superiority of the blood pressure lowering effect of the PVI + RDN group and the heterogeneity for both SBP and DBP decreased to I2 to 0% and 63% respectively    Fig. . Sensiti01) Fig. .Table 4en = 316) and 11.8% (n = 245) respectively.Five trials reported data on complications following the procedure and during the follow-up period in both the PVI + RDN group and the PVI alone groups , 20–22, We examined the findings from six studies investigating the use of RDN in addition to PVI in the treatment of paroxysmal and/or persistent AF in 711 patients with HTN and AF. The pooled results from these studies showed the following in favor of the RDN and PVI treated group in comparison to PVI alone: (1) A significant reduction in the risk of AF recurrence at follow-up; (2) a significant reduction in SBP at 12-month follow-up; (3) a significant increase in eGFR at 6-month follow-up; (4) a low overall rate of complications in both groups both during the procedures and during the follow-up period.Currently, the main treatment for HTN is often a combination of lifestyle and drug therapy. First-line agents according to the latest American College of Cardiology and American Heart Association guidelines include angiotensin-converting enzyme inhibitors (ACE-I), thiazide diuretics, and calcium channel blockers . While vStudies suggest that HTN can also have neurogenic roots as sympathetic nervous system (SNS) tone is higher in hypertensive patients as opposed to non-hypertensive patients . Increasn = 1539) and showed that catheter-based RDN is not only effective in the reduction of office blood pressure compared to sham or antihypertensive therapy alone but is also safe for patients [RDN proposes ablation of the renal efferent and afferent nerves to interrupt the communication between the kidney and the autonomic nervous system and thus reduce blood pressure. SYMPLICITY HTN-3, the first of its kind, was a prospective, blinded, sham-controlled trial that included 367 patients and aimed to investigate the effect of RDN on HTN . The tripatients . Initialn = 1332) significantly showed that a reduction in SBP into lower hypertensive categories reduced the odds of AF recurrence [p = 0.05) and a reduction of DBP by 4.11 mm Hg (p = 0.16) at follow-up.With recent trials supporting the revival of RDN, further findings have also emphasised the potential of its therapeutic uses beyond blood pressure lowering in HTN into AF treatment where HTN is an established risk factor. One of which is seen in a recent post-hoc study of 226 patients from SPYRAL HTN-OFF MED where RDN lowered renin and aldosterone during the follow-up period . For thecurrence . The preThe pathophysiological link between HTN and AF is unclear. However, a review proposed that the link mainly stems from the structural changes associated with HTN, such as LV hypertrophy and LV systolic/diastolic dysfunction which subsequently lead to an increase in left-atrial pressure and fibrosis . Simulta2 [Uncontrolled HTN has been implicated in the development of kidney disease with an average yearly decrease in eGFR of 0.5–2.7 mL/min/1.73 m2 –40. The 2 . Therefo2 . Owing t2 .p < 0.001). This may be explained in part by the reduction in sympathetic overdrive following RDN. Kiuchi et al. further noted that more rigorous methods of assessment of renal function should be used in future studies to clearly elucidate the effect of RDN on renal function and CKD [The treatment efforts to dampen RAAS clinically, such as with pharmacological therapy, have failed to yield significant improvements in eGFR and CKD . The pro and CKD .Regarding the safety of RDN, a recent meta-analysis assessing renal function as a safety parameter included 52 quantitative and 14 qualitative studies and concluded that no adverse effects were present following treatment with RDN deeming it as a safe method for use in treatment of HTN .The present study, in addition to the aforementioned evidence outlines the critical interplay between HTN, AF and kidney disease, and given the high rate of AF recurrence following PVI alone, the development and consideration of incorporating RDN in addition to current therapeutic strategies to treat both HTN and AF is clinically justified. The pooled analysis further revealed that the use of RDN led to a significant increase in eGFR and hence supported the clinical application of this technology in the context of kidney disease.Our study supplemented the extensive body of literature on the topic that proved that both procedural and follow-up complications of RDN are low and that the technology has proven to be safe and efficacious with an overall complication rate of 6.32%.Although multiple reviews have been published on the topic, they failed to account for patients that were concurrently included in multiple studies within the analysis, and have therefore duplicated patients , 44–47. This review has common limitations to all reviews/analyses as well as specific limitations pertaining to the included studies. Hence, the findings presented are based on the quality of the included studies. Although all studies were prospective, two of those were non-randomized , 19. FurThis review demonstrated that the introduction of RDN to PVI in hypertensive patients with AF is more efficacious and superior to using PVI alone in treating AF. RDN + PVI was also shown to reduce SBP more significantly in patients with resistant HTN as well improve eGFR outcomes. Moreover, analysis of the safety of the technique proved it to be safe and hence the introduction of RDN to PVI should be considered clinically in patients with AF. Larger and longer-term trials are required to substantiate these findings including those that utilise sham-controls to improve robustness of the assessed outcomes. Future trials should also assess the effect of the autonomic reduction of blood pressure on AF and hence examine whether the effect of RDN on AF is dependent solely on autonomic reduction or if there is a mechanism independent of blood pressure that contributes to the improvement in AF.There is an established interaction between renal denervation, renal sympathetic tone, and hypertension. The recent introduction of endovascular catchers to lower moderate/resistant hypertension has yielded promising results due to its ability to dampen the renin-angiotensin-aldosterone axis.The success rate of pulmonary vein isolation in reducing atrial fibrillation is limited (20–50%). The significant morbidity associated with atrial fibrillation and the complex interaction of atrial fibrillation and hypertension has prompted the investigation of the additive benefit of renal denervation, with preliminary results of multiple trials demonstrating the superiority of such method in improving outcomes compared to conventional therapy.The pooled analysis demonstrates that combined renal denervation and pulmonary vein isolation reduces atrial fibrillation recurrence compared to pulmonary vein isolation alone. This supports the inclusion of renal denervation in the management of atrial fibrillation. The overall safety of the technique has proven it to be safe and efficacious.The analysis outlines the critical interplay between atrial fibrillation, hypertension, and kidney function, and demonstrates the significant blood pressure lowering effect of renal denervation.Renal denervation was also shown to have a significant effect on kidney function via an improvement in estimated glomerular filtration rate, which is hypothesized to be due to the dampening effects on the renin-angiotensin-aldosterone axis.Supplementary Table S1 and Figure S1