The analyses will also be conducted with an intention-to-treat method and effect size. Dissemination: All results will be published in peer-reviewed journals as well as presented in conferences. Vascular endothelium insults caused by high serum glucose levels affect the oxygen supply to tissues, via the microvascular endothelium, resulting in an increased perfusion heterogeneity. These insults may lead to the underuse of blood capillaries, while other vessels are overused and effectively overload their oxygen supply capacity, which eventually causes damages to distal parts of the peripheral nervous system. Therefore, the proprioceptive and exteroceptive feedback information will be gradually lost and contribute to a mobility reduction. This study aims to assess the efficacy of whole-body vibration (WBV) associated with strength training (ST) on lower-limb blood flow and mobility in older adults with type 2 diabetes (DM2). Methods and analyses: This is a protocol (1st version) for Pa single-blind, randomized, controlled clinical trial guided by the SPIRIT guidelines. Our sample will consist of 51 older adults with DM2 randomly allocated to three groups: low frequency WBV (16–26 Hz) associated to ST (G1), WBV sham (G2) and nonintervention control (G3). The study protocol is set for a 12-week (three times per week) schedule. Primary outcomes: skin temperature using infrared thermographic imaging (ITI); mean peripheral arterial blood flow velocity (MBF) by a handheld Doppler ultrasound (DU), and functional mobility by Timed Up and Go (TUG) test. Secondary outcomes: quasi-static posture using the DX100 BTS Smart optoelectronic system, and plantar pressure and body balance using the MPS stabilometric platform. Data will be collected and analyzed at baseline and post-intervention, considering  The natural course of aging is characterized by a progressive decline in multi-organ function that entails metabolic changes and sarcopenia . HoweverDM is an emerging global public health issue of the 21st century . It is eDM involves a group of metabolic disorders marked by high blood glucose levels resulting from insufficient insulin production and/or action . Among tChronic hyperglycemia can result in damage, dysfunction, and multi-organ and system failures, mainly, related to microcirculation . FunctioAdditionally, sub-perfusion and tissue hypoxia generate progressive damage to somatic nerve fibers (sensitive and motor) and to autonomous nervous system , which mEvidence has shown that regular physical activity is an important ally for the endothelium function recovery . Among tThe whole-body vibration (WBV) training program is an alternative for a safe, effective, and low-cost exercise, which can present a satisfying compliance by previously sedentary patients ,21. It iOn the other hand, when WBV is associated with ST, a few studies reported substantial positive effect on musculoskeletal response in older women  and in uBased on the above considerations, this paper presents a detailed protocol for a single-blind, randomized, controlled clinical trial guided by the SPIRIT  guidelines , which aOur hypothesis is that the addition of WBV to ST enhances benefits in lower-limb blood flow and mobility of older adults with DM2.This randomized clinical trial was approved by ethics committee of the research institution, Universidade Federal de Pernambuco, under No. 2.449.800, and it complies with the ethical aspects based on Resolution 466/12 of the National Health Council and the Declaration of Helsinki. All volunteers will provide written consent after being informed of the study procedures, possible risks and their right to withdraw at any time, with no consequences for any further treatment. The confidentiality of volunteer data will be protected.According to the recommendations of the CONSORT extension, possible damages will be reported, resulting in the immediate interruption of treatment . The volThe dataset will be stored in a locked room in the LACIRTEM lab in password-protected computer files. These data will be disseminated after completion of the study in international peer-reviewed scientific journals and presented at conferences. Positive, negative and inconclusive results will be published in peer-reviewed journals and presented at national and international conferences. In addition, the data will be shared with the volunteers.This is a 12-week (3 times a week), single-blind, randomized, controlled clinical trial with three arms . The study will be developed in the Kinesiotherapy and Manual therapy Laboratory (LACIRTEM) of the Department of Physiotherapy in the Universidade Federal de Pernambuco (UFPE). Older adults with DM2 will be selected from a teaching clinic of physiotherapy waiting list, outpatients physical therapy department of a teaching hospital , Nucleo de Atenção ao Idoso (NAI) a healthcare center for old people, and Universidade Aberta à Terceira Idade (UNATI), an education service for old people. The sampling will be performed by convenience. Enrollment strategies will include social media advertisements and media relation communication service , as well as handouts distributions and lectures. In response to first contact, the volunteers will be invited for a full anamnesis and physical exam with an evaluator to assess their eligibility for the study.2) or with obesity class I (30.0–34.9 kg/m2) ..54].® software. From the anatomical points referenced, the following will be evaluated: pelvic obliquity (PO), pelvic tilt (PT), pelvic rotation (PR), hip ad/abduction (HA), hip flexion/extension (HF), hip rotation (HR), knee valgus–varus (KV), knee flexion/extension (KF), knee rotation (KR), ankle plantar/dorsiflexion (AP) and foot rotation (FR) [All volunteers will be invited to stand in a marked spot, keeping a rest position with arms extended by their side for a 10 s registration period. After capturing and reconstructing the 3D model, data will be imported and processed by SMART-Clinicion (FR) .Plantar pressure and body balance® Baropodometric Modular Platform  with 50–100 Hz acquisition and compatible with software Studio BIOMECH® (Letsense group) will be used to determine plantar pressure and body balance in open-eyed (OE) and close-eyed (CE) conditions.MPS BiomechThe barefoot volunteers will be instructed to stand in the middle of the platform, with a loose and habitual posture, bipodal stance and arms extended along their body. The volunteer will be asked to keep eyes directed to the fixed point in front of them in order to control possible changes in the visual field under OE condition . Before The evaluation of plantar pressure, bilaterally, will consider maximum and mean pressures, contact area and mean percentage of weight distribution. To measure the balance, the following variables will be analyzed: center of pressure displacement (COP), COP velocity, anteroposterior displacement (X axis) and mediolateral displacement (Y axis).Vital signs and capillary glycemiaBefore and right after each session, systolic (SBP) and diastolic (DBP) blood pressure will be measured by an aneroid sphygmomanometer and a stethoscope , and will be classified according to the recommendations from the Brazilian Society of Cardiology .The number of breaths per minute (RR) will be registered by the chest movement or abdominal compartment for a 60 s period, and the heart rate (FR) and peripheral oxygen saturation (SpO2) will be measured by a portable pulse oximeter  . ® Active, Roche Diabetes Care, model GU) in accordance with the parameters recommended by ISO 15197:2013 [Capillary glycemia will be monitored by a portable blood glucose meter  and lipid-related cardiovascular risk factors  will be analyzed .®, EUA), version 23.0, with 5% (p < 0.05) level of significance.All data records will be kept under custody of LACIRTEM lab and an allocation-blind statistician will conduct all analysis using Statistical Package for the Social Science . For nonnormal continuous variables, data will be expressed in median and interquartile intervals (Q25–Q75) and compared within the groups by Wilcoxon test and among the groups by Kruskal–Wallis H test. Size effect will be calculated to support the statistical significance. All analysis will be conducted in accordance with the intention-to-treat method (ITT) using the last observation carried forward (LOCF) method, which inputs baseline data at postintervention for the dropout cases . MissingWe will also investigate and register the possible adverse events during the treatment protocol. This study presents an overview of a training program and a detailed description of the assessment methods in an older population with DM2. A properly prescribed and regularly performed physical activity is considered an essential tool for the management of DM2 and its complications . HoweverThe assessment of vascular function is a primary outcome, aiming to reduce the risk of cardiovascular complications. The endothelium is essential to maintain vascular homeostasis; however, when dysfunctional, it loses its physiological properties and undergoes changes . Thus, tFunctional mobility is also a primary outcome of this study, considering that important loss occurs during the aging process of people with DM2. Therefore, TUG is a simple and effective assessment method, for which high scores are associated with impaired balance, reduced gait speed and difficulty in activities of daily living .Finally, if effective, this study will provide a nonpharmacological treatment option of innovative and scientific value.The development of a protocol study for a single-blind, randomized, controlled clinical trial that is able to identify whether whole-body vibration (WBV) provides additional benefits to strength training (ST) in lower-limb blood flow and mobility in older adults with type 2 diabetes mellitus (DM2). The vibrating platform is safe equipment, easy to handle and low-cost, which minimizes the need for conscious effort; therefore, it is most suitable for obese and sedentary patients. This new tool may be a strategy for lower-limb blood flow assessment associated with infrared thermographic imaging analysis and mean peripheral arterial blood flow velocity evaluated by a handheld Doppler ultrasound to identify physiological changes. The limitations are an absence of clinical outcomes such as quality of life, and that the vibration sham (a device emitting a similar noise to WBV) can produce physiological effects due to static squatting.


To explore whether long-term administration of valsartan or amlodipine can improve vascular endothelial function and reduce the production of reactive oxygen species in patients with H-type hypertension, so as to provide a reference for clinical treatment.  A total of 82 elderly patients with type H hypertension who were admitted to our hospital from March to August 2017 were selected as the research subjects. The study included a 4-week continuous irrigation period followed by a 24-week randomized treatment period. Forty patients in the valsartan group and 42 in the amlodipine group were treated with 5 mg amlodipine or 80 mg valsartan for 24 weeks. Clinical efficacy, 24 h mean DBP, SBP, and 24HSBP, DBP coefficient of variation, cardiac fatty acid-binding protein (H-FABP), vascular pseudohemophilia factor (VWF), nitric oxide (NO), endothelium-dependent vasodilation function (FMD), nonendothelium-dependent vasodilation function (NMD), malondialdehyde (MDA), GSH-Px, and SOD levels were observed. P > 0.05). After 24 weeks of treatment, the 24 h mean SBP, SDP, 24HSBP, and DBP variation coefficients of the two groups were significantly decreased, and there was no statistical significance between the two groups (P > 0.05). After treatment, the values of H-FABP, VWF, NO, and MDA in both groups decreased compared with before treatment, while the values of FMD%, NMD%, SOD, and GSH-Px increased compared with before treatment (P > 0.05), and the levels of H-FABP, VWF, and NO in the valsartan group were lower than those in the amlodipine group. Meanwhile, FMD%, NMD%, SOD, and GSH-Px levels were higher than those in the amlodipine group (P > 0.05).  The total effective rate was 80.0% (32/40) in the valsartan group and 85.71% (36/42) in the amlodipine group, and the difference was not statistically significant ( Valsartan and amlodipine reduce blood pressure, improve vascular endothelial function, and inhibit oxidative stress in elderly patients with H-type hypertension on average. However, valsartan has a better effect on vascular endothelial dysfunction and oxidative stress in elderly patients with H-type hypertension. Hypertension is one of the serious health problems in China. Endothelial dysfunction is a critical pathological basis for the early phase of hypertension, which leads to hypertensive vascular disease. The mechanism of endothelial dysfunction is complex and closely related to the massive generation of reactive oxygen species (ROS) in the vascular wall. Some in vivo studies have confirmed that antihypertensive drugs correct blood pressure by inhibiting vascular oxidative stress, thereby protecting vascular endothelial cells. Homocysteine (Hcy) is an important intermediate product of the methionine metabolism. Compared with isolated hypertension, hypertension with elevated plasma homocysteine, namely, H-type hypertension, will further aggravate vascular oxidative stress. Valsartan, an angiotensin II receptor blocker (ARB), and amlodipine, a long-acting dihydropyridine calcium channel blocker, are both widely used in the treatment of H-type hypertension. At present, the effect of antihypertensive drugs on vascular endothelial function has been clinically studied in a small population. However, few scholars have paid attention to the effects of valsartan and amlodipine on the function of vascular endothelial cells in patients with H-type hypertension and their antihypertensive effects. The purpose of this study was to investigate whether long-term administration of valsartan or amlodipine in H-type hypertension patients could improve vascular endothelial function and reduce the production of reactive oxygen species.µmol/L. Exclusion criteria were as follows: (1) refractory hypertension, symptomatic hypotension, hypertrophic, or restrictive cardiomyopathy, constrictive pericarditis, acute and chronic cerebrovascular disease, secondary hypertension, hypercalcemia, pregnancy, and chronic liver or renal insufficiency; (2) those with a history of ARB or amlodipine intolerance; (3) patients with cerebral infarction or coronary revascularization within 6 months; and (4) those who have been diagnosed with malignant tumor within 3 years and plan to undergo major surgery during the trial. The sample size was estimated according to the Kadam and Bhalerao method, and based on the above inclusion and exclusion criteria, we selected a total of 82 elderly H-type hypertension patients admitted to our hospital from March to August 2017 as the research subjects, aged ≥60 years. Among them, 50 were males and 32 were females, aged 60–89 years. The mean age was 70.32 ± 6.96 years, and the mean plasma Hcy level was 18.64 ± 6.39 μmol/L. The study consisted of a continuous washout period of 4 weeks followed by a randomized treatment period of 24 weeks. Based on an average of 6 consecutive blood pressure readings at both visits and 24-hour ambulatory blood pressure values at the end of the flushing period, they were randomly assigned to receive 5 mg of amlodipine or 80 mg of valsartan for 24 weeks if they met the inclusion criteria. Finally, 40 patients were included in the valsartan group, and 42 patients were included in the amlodipine group. The age, gender, average course of the disease, plasma Hcy level, and other data of the two groups of patients were basically the same, and there was no statistical difference (P > 0.05), which was comparable, as given in This study is a prospective randomized controlled trial, and the study protocol was approved by the institutional review board of our hospital. All patients provided written consent. Inclusion criteria were as follows: aged over 60 years old, diastolic blood pressure (DBP) ≥90 mmg or systolic blood pressure (SBP) ≥140 mmg, and plasma Hcy level ≥10 The patients in both groups were given conventional antihypertensive therapy, and the patients in the valsartan group were given valsartan tablets , with an initial dose of 80 mg/time, once a day. The patients in the amlodipine group were given amlodipine besylate tablets , 5 mg/time, 1 time/d. Both groups were treated continuously for six months. Study medication was provided free of charge throughout the study period. Patients take the study medication between 6 : 00 a.m. and 08 : 00 a.m. every morning before breakfast, except after blood pressure was measured on the day of the clinic and ambulatory blood pressure monitoring was started. Blood pressure was measured at baseline, 8 weeks, 16 weeks, and 24 weeks of treatment. DBP and SBP were measured after sitting for 10 min, and the average value was recorded. If blood pressure did not reach SBP <130 mmHg or DBP <80 mmHg at 8 weeks of treatment, the dose of each drug was doubled. If the blood pressure of both groups did not reach the target blood pressure (SBP <130 mmHg or DBP <80 mmHg) at 16 weeks, an additional 12.5 mg of hydrochlorothiazide was administered, as it has previously been shown to have no effect on oxidative stress. After 24 weeks of treatment with each drug, blood and urine samples were taken in the morning following an overnight fast.Blood pressure was measured using a noninvasive ambulatory blood pressure monitor (Model 6100). The 24 h mean systolic and diastolic blood pressure were calculated by computer. Before treatment and after 24 weeks of treatment, 3 mL and 4 mL of fasting peripheral venous blood were collected, placed in a heparin anticoagulant tube and a blood collection tube without anticoagulant, respectively, and centrifuged at 4000 r/min for 5 min to separate plasma; serum was separated by centrifugation at 3000 r/min for 15 min. The plasma Hcy concentration was determined by the Siemens Advia2400 automatic biochemical analyzer and the circulating enzyme method. Other relevant demographic, clinical, and laboratory data were collected.Serum heart type fatty acid-binding protein (H-FABP) and von Willebrand factor (vWF) were determined by enzyme-linked immunosorbent assay (ELISA). The serum NO level was detected by the nitrate reductase method, and the kit was purchased from Shanghai Enzyme Link Biotechnology Co., Ltd. Strictly follow the kit instructions.µg) was administered, and the inner diameter of the right brachial artery (D2) was recorded again. FMD%=(D1−D0)/D0×100%. Nitroglycerin-mediated nonendothelial relaxation function % = (D2−D0)/D0 × 100%. All ultrasound examinations were performed by an experienced sonographer operator with a coefficient of variation of 0.79 ± 0.23%.Using the Toshiba Power Vision 8000 high-frequency ultrasound instrument (11 MHz linear array transducer), the right brachial artery FMD was measured. An inflatable tourniquet was placed on the forearm to make the surrounding pressure exceed the systolic blood pressure by more than 50 mmHg for 5 minutes, and then, the cuff was quickly relaxed, and the blood flow velocity was measured by the Doppler echo method. After a 15 min rest, nitroglycerin , and the thiobarbituric acid method was used to determine glutathione peroxidase (GSH-Px), using the pyrogallol auto-oxidation method to determine plasma superoxide dismutase .The clinical efficacy of the two groups was compared, and the clinical efficacy of the two groups was evaluated according to the relevant standards in the “Clinical Research Standards for New Drugs” and divided into markedly effective, effective, and ineffective. Markedly effective: blood pressure dropped to the normal range or DBP decreased by ≥ 10 mmHg or SBP decreased by ≥ 20 mmHg; effective: DBP decreased by < 10 mmHg or SBP decreased by 10–20 mmHg, but blood pressure did not decrease to the normal range; invalid: after treatment, blood pressure did not drop significantly and did not reach the standard of markedly effective and effective. Total effective rate (%) = apparent rate (%) + effective rate (%).t-test, and the comparison before and after treatment in the same group was by the paired t-test; count data were compared using the chi-square test. All calculated P values are two-tailed and P > 0.05 was considered significant.The SPSS 26.0 software was used to process the obtained data, and the measurement data were expressed in the form of (mean ± variance). The data comparison was performed by the independent sample P > 0.05)  and 85.71% (36/42), respectively, and there was no statistical significance in the chi-square test ( > 0.05) .P > 0.05). The coefficients of variation were significantly decreased, but there was no significant difference between the two groups (P > 0.05)  .P > 0.05). FMD and NMD were higher than those before treatment (P > 0.05), and the values of H-FABP, vWF, and NO in the valsartan group were lower than those in the amlodipine group, while the values of FMD and NMD were higher than those in the amlodipine group (P > 0.05)  .P > 0.05). The SOD and GSH-Px values in the valsartan group were higher than those in the amlodipine group, and the difference between the two groups was statistically significant (P > 0.05)  .Hypertension is on the rise globally and is a major risk factor for cardiovascular mortality worldwide. Hypertension is present in 60–70% of people over the age of 60 and can lead to cardiovascular complications such as stroke, coronary heart disease, and heart failure . The WorAt present, drug treatment strategies are often adopted for elderly patients with H-type hypertension, and valsartan and amlodipine are usually designated as first-line antihypertensive drugs. Valsartan is an oral nonpeptide ARB for the treatment of hypertension that inhibits the type II angiotensin receptor associated with reduced aldosterone secretion. It regulates the renin-angiotensin-aldosterone system by blocking the activation of the angiotensin II AT type 1 receptor, resulting in vasodilation, decreased vasopressin secretion, and decreased aldosterone production and secretion. This causes the arterioles and veins to dilate, resulting in a drop in blood pressure (BP) . AmlodipP > 0.05). The results indicated that the improvement degree of each index of vascular endothelial function in the valsartan group was better than that in the amlodipine group, suggesting that the effect of valsartan in improving the vascular endothelial dysfunction in patients was more significant, and the ideal therapeutic effect could be achieved.Studies have shown that the vascular endothelium regulates vascular tone and structure, and endothelial dysfunction and structural changes may be responsible for the adverse effects of hypertension . Endothe2O2, which is a substrate for GSH-Px. When encountering and reacting with glutathione, GSH-Px reduces both H2O2 and organic hydroperoxides [Oxidative stress is defined as the excess production of reactive oxygen species (ROS) in the context of a decrease in antioxidant species, is characterized by an imbalance between ROS overproduction and antioxidant defenses, and is associated with the aging process . Sustaineroxides . Both caeroxides  showed tIn conclusion, valsartan and amlodipine can reduce blood pressure, improve vascular endothelial function, and inhibit oxidative stress in elderly H-type hypertension patients. Furthermore, valsartan has a more significant effect on improving vascular endothelial dysfunction and oxidative stress in elderly patients with H-type hypertension. However, this study has certain limitations, such as the small number of subjects included and the different clinical characteristics of the included patients. Therefore, more long-term follow-up and large multicenter clinical trials are still needed to confirm the improvement of endothelial dysfunction and the prevention of cardiovascular events.


The current study employed a cohort of 294 patients from two hospitals in northern Italy initially assembled to highlight factors leading to one consequence of breast cancer (BC): upper limb unilateral lymphedema (BCRL). BCRL occurrence is a multi-factorial pathological condition that is not widespread, with a medium-long-term onset affecting not only physical function but also the quality of life of BC survivors. In the current study, we employed the data to stratify the risk of BCRL using unsupervised low-dimensional data embeddings and clustering. In the proposed approach, the ordinal and the binary patients’ clinical variables were modeled separately in two distinct embeddings. Afterward, they were merged; thus, the final representation was a single prognostic map displaying three clusters of patients with peculiar features. The characteristics of each group were extracted and evaluated, identifying the factors associated with the high-risk cluster. Our findings might provide future insight into a precise risk stratification to target high-risk patients with tailored therapeutic intervention and focus resources on patients who deserve more attention.Background: Breast cancer-related lymphedema (BCRL) could be one consequence of breast cancer (BC). Although several risk factors have been identified, a predictive algorithm still needs to be made available to determine the patient’s risk from an ensemble of clinical variables. Therefore, this study aimed to characterize the risk of BCRL by investigating the characteristics of autogenerated clusters of patients. Methods: The dataset under analysis was a multi-centric data collection of twenty-three clinical features from patients undergoing axillary dissection for BC and presenting BCRL or not. The patients’ variables were initially analyzed separately in two low-dimensional embeddings. Afterward, the two models were merged in a bi-dimensional prognostic map, with patients categorized into three clusters using a Gaussian mixture model. Results: The prognostic map represented the medical records of 294 women (mean age: Conclusions: The results of this study provide potential insight for precise risk assessment of patients affected by BCRL, with implications in prevention strategies, for instance, focusing the resources on identifying patients at higher risk. Similarly, the systematic review by Hayes et al. [Due to the increasing overall survival of breast cancer patients and the consequent increase in BC survivors, a growing interest has been raised in disabling the consequences of cancer and its treatment ,7,8,9,10urvivors ,12,13. Iurvivors . BCRL miurvivors ,16,17,18urvivors ,20,21,22urvivors ,24. On turvivors . In moreurvivors  underlins et al.  highlighurvivors . In this95% CI 0., 0.85). urvivors  realizedurvivors  developeurvivors ,32. Moreurvivors ,33, theiurvivors ,35. In turvivors ) is a di95% CI 0., 0.93, purvivors ,39, ableurvivors , a topolThe present study analyzed a multi-centric dataset from two northern Italy hospitals containing clinical information about BC female patients. The set of data comprised clinical factors from women who had undergone axillary dissection for BC, gathering twenty-three clinical variables and metadata from anonymized subjects. Patients’ clinical status was assembled over a period ranging from January 1998 to September 2018. The list of variables representing the clinical status of each patient included in the study was reported in The variables considered included patients characteristics , macroscopical cancer features , anatomopathological cancer attributes , surgical therapies (BREAST SURGERY and TOTAL NR DISSECTED LN), and medical therapies . Lymphedema-related measurements, for example, limb volume changes, were not considered.Among them, 9 were ordinal or categorical variables . At the same time, the remaining 12 were binary values . AGE and BMI were continuous data transformed into ordinal variables by binning the values into ten ordinal levels and renamed AGE GROUP and BMI GROUP. Categorical variables were converted into numerical values. Later on in the text, non-ordinal categorical, ordinal, and continuous converted to ordinal clinical variables will be called ordinal variables except where otherwise indicated. UMAP tries to preserve the local and global information contained in the input variables by capturing the latent structures of the initial high-dimensional dataset and representing them as a visualizable graph. This feature is one fundamental difference between UMAP and another well-known dimensionality reduction technique, Barnes-Hut-SNE, that preserves only the local data structure, as previously investigated by the same authors . PreservThe final bi-dimensional graph represented a low-dimensionality embedding of the original dataset over a unitless Cartesian plane. A Gaussian mixture model  determiThe next section of the study investigated the characteristics of the final map after clustering the patients to extract relevant patterns or factors present in the groups created by the unsupervised visualization. The UMAP bi-dimensional points representing patient data were labeled as belonging to A, B, or C clusters . Indeed,The clustering procedure found that each label  is associated with a different risk profile of BCRL occurrence. In particular, clusters A and C have lower percentages of BCRL patients than cluster B . Table 3The value counts in The new distribution of patients among clusters B and O are shown in Table 5In om 16.6%  to 20% [om 16.6% . ClusterThe dataset comprised clinical information on 294 women, 70 affected by BCRL and 224 without BCRL  and cluster O (lower risk) were found in the variables reported in The categorical  variables were compared in terms of modal value; it is the most common value encountered in the distributions and described in p-values at the statistical test or the most considerable difference between modes. Other relevant elements were G, N, and BMI GROUP.The clinical factors prominent in categorizing a patient in cluster B or O and identifying BCRL occurrence are NR METASTATIC LN, HR DRUG, and AGE GROUP. These three components show the highest Binary variables are those that assume precisely two values. During this analysis, two Binary variable values could be interpreted as whether a patient is exposed to a treatment or not; this holds except for SIDE, which means the body part affected by breast cancer. For the SIDE variable, the absolute risk difference calculation was less meaningful and resulted in balanced “risks” between clusters. Concerning the other variables, the top three differences between the risks associated with clusters were in TTZ, HER2, and TAXANE BASED CT variables . FurtherThe association between BCRL occurrence and the outcomes of the binary variables was tested statistically for each cluster: Five machine learning models have been trained to demonstrate the possibility of employing cluster labels to categorize patients. This numerical experiment tested whether models can accurately label patients or not using the whole set of ordinal and binary variables. In previous sections, it has been shown how each label represented a different risk profile of being affected by BCRL. Suppose the 23 variables can be automatically related to the risk profiles generated by the procedure employing UMAP. In that case, in the future, it could be possible to categorize new patients automatically through a trained machine-learning model. The classifiers evaluated during this numerical experiment were Logistic Regression (LR), Random Forest (RF), Linear Discriminant Analysis (LDA), Naive Bayes classifier, Adaptive Boosting Classifier (ABC), and Randomized decision trees (ET). The six classifiers were selected due to their different ability to handle heterogeneous input variables. LR is a statistical machine learning classifier that handles natively binary and categorical qualitative data, performing well on binary outcomes . LDA finds a linear combination in the input features through a discriminant function: it is more suited than LR to classify multiclass outputs . RF, ETThe best model has been selected by repeated stratified cross-validation (5-folds CV with ten repetitions) and used to evaluate the classifiers’ performance on the current dataset. It should be underlined that classifiers were not optimized and were left with their default hyperparameters as implemented in . SkippinThe results of this section were quite promising in establishing a model able to connect the 23 patient variables with the labels obtained by clustering the UMAP-derived low-dimensional map. With three labels , the peak performance is achieved by an RF classifier  to classify patients retrospectively. Two UMAP models were merged together, and this approach is uncommon in the previous literature, where UMAP was employed to model the data directly . The cluncidence . These oThe labels derived from clustering  employing the novel methodology of merging two UMAP low-dimensional representations have been adopted to classify patients from the initial set of 23 clinical variables . Five maTo the best of our knowledge, this is the first study integrating a machine learning technology in precisely assessing BCRL patients. The results of the present study might guide clinicians in the tailored management of BC patients based on objective data; in particular, a precise clusterization might identify patients at high risk, guiding the prescription of preventive strategies to reduce lymphedema onset and optimizing resources ,65. On tAnother advantage of the proposed procedure is the possibility of creating bi- dimensional maps showing patient positioning in the embedded space . Within Interestingly, the biomarker distribution using the unsupervised learning approach and two cluster mapping presented significant intra-cluster differences. In more detail, patients without BCRL and patients with BCRL in the two clusters were characterized by significant differences in age, grading, tumor local extension, and molecular subtype. The results of this machine learning clustering align with previous studies, underlining that these factors significantly impact the risk of lymphedema development ,33,68,69In conclusion, this multi-centric cross-sectional study developed a novel methodology integrating several variables for BC patients’ risk stratification, providing different clusters addressing the multilevel interaction of the most common risk factors for BCRL. However, it should be noted that this cross-sectional study is not free from limitations. First, all the patients considered underwent axillary dissection. Indeed, most available studies considered axillary dissection the most important risk factor for BCRL ,72. LastTo date, effective predictive tools for BCRL are an urgent need in the current literature due to the growing prevalence of BC survivors. Our results provided evidence about a novel procedure addressing the multilevel interactions between 23 common risk factors involved in BCRL onset. The clusters developed by UMAP might guide clinicians in a precision medicine approach to tailor preventive strategies to individual risk. Future research might further improve our artificial intelligence model to better characterize the role of different variables in reducing BCRL onset and improving long-term management of BC survivors through clinical status prediction.


The correlation and agreement between PtcCO2 and PaCO2, PetCO2, and PaCO2 were evaluated.Children aged 2–8 years with American Society of Anesthesiologists (ASA) class I or II who underwent laparoscopic surgery under general anesthesia were selected. After anesthesia induction and tracheal intubation, PtcCO2 = 7.89 + 0.82 × PaCO2 ; PetCO2 = 9.87 + 0.64 × PaCO2 . The 95% limits of agreement (LOA) of PtcCO2 – PaCO2 average was 0.66 ± 4.92 mmHg, and the 95% LOA of PetCO2 – PaCO2 average was –4.4 ± 4.86 mmHg. A difference of ≤ 5 mmHg was noted between PtcCO2 and PaCO2 in 122/128 samples and between PetCO2 and PaCO2 in 81/128 samples (P < 0.01).A total of 32 patients were eventually enrolled in this study, resulting in 128 datasets. The linear regression equations were: PtcCO2 and PaCO2. Compared to PetCO2, PtcCO2 can estimate PaCO2 accurately and could be used as an auxiliary monitoring indicator to optimize anesthesia management for laparoscopic surgery in children; however, it is not a substitute for PetCO2.In pediatric laparoscopic surgery, a close correlation was established between PtcCOChiCTR2100043636.The online version contains supplementary material available at 10.1186/s12887-023-03836-2. The gold standard for measuring PaCO2 in clinical practice is arterial blood gas analysis (ABGA) [2 level continuously [Arterial carbon dioxide pressure (PaCOs (ABGA) . The pat2) has become a routine monitoring item for patients undergoing general anesthesia with tracheal intubation. Anesthesiologists can estimate PaCO2 based on PetCO2. However, several factors, including patient’s age, different types of surgery, combined cardiopulmonary diseases, and changes in pulmonary blood flow, can affect the accuracy of PetCO2 monitoring results, increasing the difference between PetCO2 and PaCO2 in practice [2 and PaCO2 shows a decrease with the delay of pneumoperitoneum during laparoscopic surgery; thus, PaCO2 values should be monitored intermittently by ABGA [2 is not a reliable predictor of PaCO2.End-tidal carbon dioxide partial pressure (PetCOpractice . The cor by ABGA . Therefo2) can be used to estimate PaCO2. PtcCO2 monitoring is based on an electrochemical principle. The probe’s internal heating electrode raises the local skin temperature. This results in the arterialization of dermal capillaries and improvement in their permeability, making it easier for CO2 to enter the tissue space and diffuse away from the skin surface. CO2 permeates the electrolyte layer via a high-permeability membrane on the sensor’s surface, altering the pH value of the electrolyte layer, which is related to the variation in the CO2 partial pressure [2 value is obtained by the monitor’s internal programming algorithm. PtcCO2 monitoring is a continuous and noninvasive method; however, due to advancements in monitoring technology and the miniaturization of the device, it is gaining increasingly popularity in clinical practice. Also, previous studies have shown that PtcCO2 monitoring is effective in perioperative settings [2, PtcCO2 has a better correlation and a smaller difference with PaCO2. Nevertheless, Bolliger et al. indicated that PtcCO2 monitoring does not accurately reflect PaCO2 and does not provide more useful monitoring data than PetCO2 [Transcutaneous carbon dioxide partial pressure .Currently, there are no clinical reports regarding PtcCOThe present study was approved by the Shenzhen Children’s Hospital Ethics Committee , and written informed consent was obtained from the parents. A total of 35 children who underwent laparoscopic surgery, aged 2–8 years, and ASA class Ι or II were recruited for this study. Patients who required a vasoconstrictor to maintain blood pressure during the procedure and those with insufficient pneumoperitoneum time (< 90 min) were excluded from this study.2), and blood pressure (BP)were monitored; the heart rate (HR) and BP were recorded as baseline values. Tracheal intubation was conducted following intravenous administration of benzenesulfonate cisatracurium 0.1 mg/kg and fentanyl 3 μg/kg. Breathing settings were established on the anesthesia machine: intermittent positive pressure ventilation, tidal volume 6–10 mL/kg, inspiration/expiration 1/2, inhalation oxygen concentration 50%, gas flow rate 2 L/min, and respiratory rate 15–25 times/min. PetCO2 level was continuously measured using the side-stream capnography . The respiratory rate and tidal volume were adjusted to maintain PetCO2 35–45 mmHg and airway pressure 10–25 cmH2O. Anesthesia was maintained with inhalation sevoflurane concentration at 2–3%, intravenous pumping of remifentanil 0.2 μg/kg/min, and benzenesulfonate cisatracurium 0.1 mg/kg/h. The dosage of benzenesulfonate cisatracurium was adjusted according to the results of muscle relaxation monitoring.Children were escorted to the anesthesia room by their parents, and 2.5 mg/kg propofol was administered to induce sleep. The child was then transported to the operating room under the close supervision of the anesthesiologist. Electrocardiogram, pulse oxygen saturation  was attached. The monitoring site was located on the forehead, and the electrode-heating temperature was adjusted to 42 °C. The monitor was calibrated, and the electrode membrane was changed before each use. Radial artery catheterization was performed to facilitate invasive arterial blood pressure monitoring and the acquisition of blood gas analysis samples. The laparoscopic pneumoperitoneum pressure was chosen based on the children's ages  and it was fine-tuned according to the surgical field's size when the pneumoperitoneum has just been established. Throughout the course of the procedure, there was no change in the pneumoperitoneum pressure. HR and BP were maintained within the range of ± 20% of the baseline value. The nasopharyngeal temperature of the child was maintained at 36–37 °C using an inflatable thermal blanket; the operating room temperature was set at 23–25 °C.After tracheal intubation, a PtcCO2 monitor sensor was removed during the postoperative recovery period of anesthesia; the local skin was cleaned and examined for signs of injury. After the removal of the arterial cannula, pressure dressings were applied. The tracheal tube was withdrawn when the child’s spontaneous breathing was recovered, with SpO2 maintained at 95% under inhaled air settings. Finally, the vital signs were observed carefully, and the child was transferred to the anesthesia recovery room for further monitoring after stabilization.PtcCO2, PetCO2, and PaCO2 values were recorded at each time point. A blood gas analyzer  was used to measure PaCO2. HR, BP, SpO2, tidal volume, respiratory rate, and body temperature at each time point. HR, BP, and the anesthesia machine’s respiratory parameters were stabilized for at least 5 min before recording the measured values.ABGA was conducted before (T0) and 30 min (T1), 60 min (T2), and 90 min (T3) after pneumoperitoneum. Also, PtcCO2 and PaCO2 or between PtcCO2 and PaCO2. A difference of ≤ 5 mmHg between PaCO2 and the other two noninvasive variables was clinically acceptable [2) test. P < 0.05 indicated a statistically significant difference.Data were analyzed using SPSS version 26.0. Measurement data were presented as mean ± standard deviation (SD). Pearson’s correlation coefficient and linear regression analysis were conducted to establish the correlation, and the Bland–Altman method was utilized to assess the agreement between PetCOceptable , 9 and c2, PetCO2, and PaCO2 at four time points (Table Three children were excluded from the research due to the pneumoperitoneum’s short duration (< 90 min), and 32 children  were eventually recruited. The average height and weight were 103.63 ± 11.98 cm and 17.45 ± 3.75 kg. Among them, 26 patients underwent laparoscopic pyeloplasty, and 6 patients underwent laparoscopic choledochal cyst excision. A total of 128 datasets were collected, consisting of simultaneous measurements of PtcCO2 and PaCO2 was 0.84 , and the linear regression equation was PtcCO2 = 7.89 + 0.82 × PaCO2  , and the linear regression equation was PetCO2 = 9.87 + 0.64 × PaCO2  . The 95% limits of agreement (LOA) of PtcCO2 – PaCO2 average was 0.66 ± 4.92 mmHg (mean ± 1.96 SD) . The 95% LOA of PetCO2 – PaCO2 average was –4.4 ± 4.86 mmHg (mean ± 1.96 SD) .Difference between PtcCOSD) Fig. . Differe2 is the most common gas utilized to create a pneumoperitoneum and provide a good operating view for the surgeon. However, the diffusion capacity of CO2 is strong, and the absorption of CO2 is sufficient in children due to factors such as the small volume of the abdominal cavity, the proximity of the capillaries to the peritoneum, and the larger abdominal surface area related to weight compared to adults [2 alters the body’s acid–base balance and stimulates sympathetic nerves, thus increasing catecholamine and cortisol release and leading to hemodynamic fluctuations [2 level during laparoscopic surgery and timely adjustment of the ventilator parameters is essential to avoid the disruption of physiological functions. PaCO2 levels are stabilized after 60 min of pneumoperitoneum [Since the development of minimally invasive surgery, the laparoscopic operation has gained increasingly popular in pediatric surgeries due to its advantages of less trauma, a short hospital stay, less postoperative wound pain, and fewer complications. COo adults . A risk tuations , 11. Cloritoneum ; hence, 2 is a routine measurement during the perioperative period and one of the primary indicators used to adjust ventilator parameters. However, factors that affect lung ventilation/perfusion may interfere with the accuracy of PetCO2 measurements, and thus, the use of PetCO2 in non-tracheal intubated patients is restricted. The increased abdominal pressure during laparoscopic surgery results in a diaphragmatic rise and an increase in thoracic pressure; subsequently, airway resistance and airway pressure also rise, with pulmonary vasoconstriction and reduced pulmonary blood flow. Pediatric patients are vulnerable to pneumoperitoneal pressure effects. This study revealed that during the entire monitoring process, a good correlation was established between PetCO2 and PaCO2, r = 0.83 (P < 0.01). Nevertheless, as the pneumoperitoneum time was prolonged, the correlation between PetCO2 and PaCO2 decreased gradually, which was consistent with previous findings [PetCOfindings , 9.2 monitoring in different types of surgery and patients [2 monitoring. The current results showed a close correlation between PtcCO2 and PaCO2, r = 0.84 (P < 0.01), and although the correlation was decreased with prolonged pneumoperitoneum time, it was not very significant compared to PetCO2. According to Bland–Altman analysis, a lesser mean difference was detected between PetCO2 and PaCO2 than between PetCO2 and PaCO2. Therefore, PtcCO2 performed better than PetCO2 in estimating PaCO2, which is in agreement with the previous results [2, PaCO2, and PtcCO2 to regulate the patient's acid–base, so there is no accumulation of CO2 during the whole operation. However, due to the limitations of PetCO2 monitoring, especially in the case of prolonged pneumoperitoneum, relying solely on PetCO2 to regulate the patient's respiratory parameters cannot guarantee that the patient is in acid–base balance, particularly for young children. And PtcCO2 can more accurately estimate PaCO2, so its application can reduce the risk of CO2 accumulation. Conway et al. conducted a meta-analysis on the effectiveness of PtcCO2 monitoring [2 trend throughout the monitoring process.Several clinical studies have focused on the application of PtcCOpatients –17 underpatients , 19. The results , 7, 9. Initoring  and demo2 level measured by PtcCO2 monitoring consists of two parts: one derived from the blood , and the other from the metabolism of the tissue cells [2 by opening the precapillary sphincter [2. Therefore, the PtcCO2 monitoring value is theoretically higher than that of PaCO2. PtcCO2 monitors used in clinical practice correct the initial measured value based on the selected heating temperature to reduce the deviation from PaCO2 [2 monitoring values were less than PaCO2 in 51/128 data sets; hence, the correction method for PtcCO2 monitors needs to be investigated further.The COue cells , 22. Thephincter . A rise om PaCO2 . In the 2 monitoring, including the temperature of the electrodes, the monitoring location of the sensor, and the patient’s clinical state. Nishiyama et al. demonstrated that when the anterior chest (between the clavicle and nipple) was chosen as the monitoring site, PtcCO2 correlated best with PaCO2 at 43 °C (R2 = 0.7568) among the different electrode-heating temperatures  in its setting, and the monitoring required less time to stabilize at higher temperatures as blood CO2 levels change, but required > 150 s [2 in preterm infants, the mean difference between PtcCO2 and PaCO2 was the smallest at 42 °C [2 monitoring; no adverse events were observed.Several factors affect PtcCO > 150 s . Accordiat 42 °C . A highe2 was correlated with PaCO2 when the monitoring sensor was located on the chest (R2 = 0.76) but not when it was located on the upper arm and forearm (R2 < 0.5) [2 showed a close correlation with PaCO2 than PtcCO2 before pneumoperitoneum; however, the mean difference between PtcCO2 and PaCO2 was smaller than the mean difference between PetCO2 and PaCO2. However, whether PetCO2 correlates better with PaCO2 than PtcCO2 in pediatric patients under non-pneumoperitoneal conditions with the forehead as the monitoring site needs to be studied further with a large sample size.Nishiyama et al. reported that PtcCO2 < 0.5) . When th2 produced by tissue metabolism cannot be carried away quickly, and PtcCO2 monitoring values increase gradually [2 can be utilized as one of the indicators for assessing a patient’s microcirculatory status, which is useful in guiding the treatment [2 monitoring in surgical patients with circulatory failure has been rarely reported, and the correlation between the PtcCO2 gradient changes and skin tissue perfusion status requires further clinical investigation. Other factors, such as poor skin contact with the fixed connection loop and insufficient gel, may allow contact between the probe and air, thus interfering with the monitoring results. CO2 permeability films that have not been replaced for a long time or are damaged or air bubbles under the film can also affect the accuracy of PtcCO2 monitoring.In the event that patients’ peripheral tissues and organs are not supplied adequately with blood, such as in shock, the COradually . Thus, Preatment . However2 monitoring is a continuous and noninvasive method that can be used to assess PaCO2 to some extent, its perioperative application is promoted in the different types of surgery and populations. Endotracheal intubation is not required for gastrointestinal endoscopy or other operations that can be performed using nerve blocks. The use of intravenous anesthetic medications intraoperatively can improve operating conditions and increase patient comfort during these procedures. When the nerve block is unsatisfactory, or when specific operations call for an enhanced level of sedation, supplemental narcotic medicines are required. Understanding the CO2 level of patients allows us to more precisely regulate the intravenous anesthetic medicine dosage. However, it is often difficult to accurately monitor the CO2 levels of patients during these operations. In this situation, PtcCO2 monitoring is a good choice. It has been shown [2 monitoring is an effective way to detect hypoventilation in patients, which reduces the incidence, extent, and duration of hypercapnia, improving the safety of patients under sedation. High-frequency ventilation is often used to maintain oxygenation in some airway procedures performed with a rigid bronchoscope. However, evaluating the ventilatory status of patients with PetCO2 in the open ventilation mode of high-frequency ventilation is challenging. As a result, we can adjust the parameters of high-frequency ventilation to avoid the accumulation of CO2 according to PtcCO2 [Since PtcCOen shown , 19, 28 o PtcCO2 .2 and PaCO2, and patients are more likely to develop respiratory acidosis. Oshibuchi M's study [2 can more accurately predict PaCO2 compared with PetCO2 in both two-lung ventilation and one-lung ventilation. It has been shown [2 monitoring remains highly accurate even when one-lung ventilation is prolonged (more than 2 h) and permissive hypercapnia is present.Usually, patients undergoing thoracic surgery have chronic lung diseases and require one-lung breathing in the lateral decubitus position during operation. These factors can affect lung ventilation/perfusion, leading to the increase of the difference between PetCO's study  showed ten shown  that Ptc2 monitoring effectively reflects PaCO2 levels and is more suitable for observing changes in CO2 fluctuations over time so that we can take appropriate treatment measures [2 monitoring, anesthesiologists are able to determine in time whether CO2 accumulation in patients is occurring so that the appropriate treatment can be administered.Most patients need to recover in anesthesia recovery room after surgery. Due to the presence of residual opioids and muscle relaxants, patients are at potential risk of developing respiratory depression, especially in elderly and obese patients. PtcCOmeasures . For ped2 monitoring also has some limitations. The monitoring site should be cleaned in advance to remove the hair and grease; also, the PtcCO2 monitor requires a calibration time of approximately 15 min before use and needs to be recalibrated either after the patient is removed from the monitoring site or after prolonged monitoring. When CO2 in the blood changes, PtcCO2 monitoring takes about 2 min to reflect PaCO2 with a degree of delay [2 monitor needs further improvement to facilitate its use during the perioperative period. Some studies have reported that PtcCO2 monitoring techniques are not based on electrochemical principles [2 is susceptible to various factors, it plays an essential role in determining the position of the tracheal tube, tube folding, and accidental decannulation [2 provides information about the patient’s pulmonary blood flow status and circulatory function [2 waveform, thereby deeming that PtcCO2 is not a substitute for PetCO2.PtcCOof delay . These finciples –36. Becanulation . Additiofunction , and the2 shows a close correlation with PaCO2 when the forehead is chosen as a monitoring site in children undergoing laparoscopic surgery. Compared to PetCO2, PtcCO2 can accurately estimate PaCO2 and could be used as an auxiliary monitoring indicator to optimize anesthesia management for laparoscopic surgery in children; however, it is not a substitute for PetCO2.In conclusion, PtcCOAdditional file 1.


Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease, which is usually type 2-mediated in the western hemisphere, associated with severe therapeutic and socioeconomic challenges. The first targeted systemic treatment option for severe uncontrolled CRSwNP is a human monoclonal antibody against the interleukin-4 receptor α (IL-4Rα) subunit called dupilumab, which was approved for subcutaneous administration in Germany in October 2019. The purpose of this study is to investigate the efficacy of dupilumab in real life in patients treated with dupilumab in label according to license in our department in 2019–2021.Since October 2019, we have investigated 40 patients  treated with dupilumab in a single-center, retrospective single-arm longitudinal study. The following parameters were collected before treatment (baseline), at 1 month, 4 months, 7 months, 10 months, and 13 months: the Sino-Nasal Outcome Test-22 (SNOT-22), the forced expiratory pressure in 1 s (FEV-1), the olfactometry using Sniffin' Sticks-12 identification test (SSIT), a visual analog scale of the total complaints, the Nasal Polyp Score (NPS), histologic findings as well as total serum IgE, eosinophilic cationic protein in serum and blood eosinophils.p < 0.001). Adverse side effects were mostly only mild, and no rescue therapy was needed.The average age was 52.7 years (± 15.3). The follow-up period was 13 months. The SNOT-22 average was 60 points (± 22.2) at the first visit, 28.2 points (± 17.1) after 4 months and 20.8 points (± 17.7) after 13 months. The NPS was 4.3 points (± 1.5), after 4 months 2.1 points (± 1.3) and after 13 months 1.4 points (± 1.1). Olfactometry showed 3.2 points (± 3.7) at the baseline, 7.0 points (± 4.0) after 4 months and 7.8 points (± 3.5) after 13 months. The other parameters also improved. Most parameters showed linear dependence in the slopes under therapy (There is a clear improvement in the medical condition and symptoms in all categories mentioned under therapy with dupilumab, as well as a reduction in the need for systemic glucocorticoids and revision surgery as rescue treatment. Our results show that dupilumab tends to be an effective therapy alternative for severe CRSwNP. Chronic rhinosinusitis (CRS) is a collective term for inflammation of the nasal cavities and paranasal sinuses that is associated with severe clinical, therapeutic and socioeconomic challenges . CRS is Furthermore, CRS can be divided into CRS with (CRSwNP) or without nasal polyps (CRSsNP) depending on phenotype, which is crucial for possible treatment options and prognosis of the disease course , 5. An e®, Sanofi, Paris, France and Regeneron, NY, USA), that is approved for the treatment as subcutaneous administration of CRSwNP through the pivotal studies LIBERTY NP SINUS (LNPS)-24 and LNPS-52, which has been shown to potently suppress key inflammatory pathways in CRSwNP by inhibiting interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling [Initial target strategies include the monoclonal antibody dupilumab  synthesis and should adjust the inflammation progress . After sThere are various explanations that could explain the better disease control by dupilumab and its effect on the pathomechanism leading to CRSwNP. One possible explanation is that dupilumab, when it binds primarily to IL-4Rα, inhibits IL-4 signaling and subsequent inflammation-promoting responses in this pathway. Consequently, by suppressing Th2 differentiation, it would downregulate essential onward steps to T2 inflammation, such as mast cell activity and IgE synthesis. In addition, auto-inflammatory cascades leading to eosinophilia are inhibited. However, if dupilumab is more likely to prevent IL-4Rα from associating with the IL-13Rα1 subunit, consequently, inhibition of IL-13-driven disease will predominate. Moreover, dupilumab may thus block both signaling pathways, IL-4 and IL-13, and thus modulate the inflammatory response and eosinophilia via both signaling pathways . MoreoveThe present study is a mono-center, retrospective single-arm longitudinal study. The primary aim of this study is to investigate the influence of dupilumab in real life on the long-term course on nasal symptoms , olfactory function, nasal polyps, pulmonary function, and blood counts , absolute eosinophil count) in patients with CRSwNP.40 adult patients (> 18 years) were included in this study at the outpatient center of the University Hospital Hamburg–Eppendorf from November 2019 until April 2021. The study was approved by the ethics committee of Hamburg, Germany (2020-10264-BO-ff).Patients with severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP). This defines patients that got at least one nasal sinus surgery without a long-term benefit of their symptoms in their medical history, the continuous usage of topic corticosteroids in the maximum dosage and nasal rinses with saline, the therapy with systemic corticosteroids once a year or contraindications thereto. In addition, there should be evidence of a Th2-Inflammatory reaction in histopathological findings in nasal mucosal tissue of previous operations (more than 10 eosinophils per High-Power-Field), more than 100 kU/L of total serum IgE or more than 250 eosinophils per µl in blood samples. Moreover, these patients must suffer from anosmia and have a high symptom burden of an SNOT-22-Score over 40 Points. When patients met three or more criteria as described above, referring to the EPOS2020 criteria, the indication of a therapy with 300 mg of dupilumab, administered subcutaneously, every 2 weeks, was given, and were included in the retrospective analysis [Patients with immunosuppressive diseases, cystic fibrosis, pregnancy or breastfeeding and patients under therapy with other biologics.Age, gender, clinical history, the number of nasal sinus surgeries, the FEV-1 and the olfactometry were evaluated. Sniffin' Sticks-12 identification test was used in olfactometry . In eachThe coprimary endpoints were the NPS and VAS . FEV-1, olfactometry, SNOT-22 questionnaire and blood results  were set as secondary endpoints. All these primary and secondary endpoints were examined at baseline as well as in follow-up visits with respect to a linear trend of outcomes over time.Baseline characteristics were collected before therapy and subsequent examinations were performed at 1 month, 4, 7, 10, and 13 months in therapy. At every visit the primary and secondary endpoints were noted as described above.We assume that the mentioned parameters will improve in favor of sinusitic complaints in the sense of a reduction of the points in the questionnaires and visual analog scales, a reduction of the points in NPS, as well as an improvement of the points of olfactometry and FEV-1. Furthermore, we think that only a transient increase in the absolute eosinophil count in whole blood, the total serum IgE as well as the ECP in serum will be seen.Categorical data are summarized by absolute and relative frequencies. Continuous data are summarized by mean, standard deviation, median, interquartile range, minimum, and maximum. These measures are presented for the total sample.To model the linear trend of outcomes over time, mixed linear models were calculated with time as the fixed effect and patientID as the random intercept. The target variable is the respective outcome under consideration. The baseline variable was included in the model as a covariate. If a linear trend is assumed over time and across all patients, then the slope (+ 95% CI) indicates how the respective target variable changed on average every 3 months.40 patients  were included in our study. The average age was 52.7 years (SD ± 15.3) with a minimum age of 20 and maximum age of 84 years. The follow-up period was 13 months. 57% of the patients had a history with confirmed allergies , allergic conjunctivitis, allergic contact dermatitis, food or drug allergy in the patient's history or other allergic reactions documented by a treating physician) and 88% of the patients had a history of bronchial asthma. 21 patients had known N-ERD . The average number of FESS before biological treatment was 3.7 (± 1.9). Out of 22 available histopathological reports all showed more than 10 eosinophils per high power field (see Table p < 0.001)  after 1 month and improved after 4 months to 2.1 points (± 1.3), to 1.9 points (± 1.4) after 7 months, 1.5 points (± 1.1) after 10 months and up to 1.4 (± 1.1) at the end of this study, respectively , too .The average SNOT-22 questionnaire score before treatment was 60 points (± 22.2). The average score improved after 1 month to 37.3 points (± 22.9), after 4 months up to 28.2 (± 17.1), to 25.6 points (± 18.2) after 7 months, to 21.8 points (± 16.7) after 10 months and at the end of the study to 20.8 points (± 17.7)) ).The scores of the VAS on the baseline visits were ± 6.0 points (± 3.0) regarding nasal airway obstruction, 7.2 points (± 2.0)-related sinusitic complaints, 6.7 points (± 2.9) based on rhinorrhea, 4.4 points (± 3.6) regarding facial pain and 5.4 points (± 3.5) on sleep disorder. All VAS-scores improved markedly under therapy .The olfactometry results were 3.2 points (± 3.7) at the baseline, 5.6 points (± 4.2) after 1 month, 7.0 points (± 4.0) after 4 months, 7.6 points (± 3.7) after 7 months, 7.8 points (± 3.6) after 10 months and 7.8 points (± 3.5) after 13 months. Furthermore, it improved clearly after 10 and 13 months .The average FEV-1 was 73.9% (± 15.4) before treatment and slightly improved to 77.0% (± 12.9) after 1 month. From then, it was 80.4% (± 11.4) after 4 months, 77.9% (± 12.7) 7 months, 78.2% (± 11.1) after 10 months and 78.4 (± 9.8) after 13 months  in serum, the total serum IgE 308.4 kU/l (± 554.9) and the absolute eosinophils 0.5 billion/l (± 0.3) in whole blood at the baseline visit. There were not any substantial changes at the ECP throughout the study period. The average absolute eosinophils changed to 0.3 billion/l (± 0.2) after 1 month and increased markedly to 0.7 billion/l (± 1.0) after 4 months, to 0.5 billion/l (± 0.5) after 7 months and to 0.7 (± 2.0) after 10 months and to 0.4 billion/l after 13 months (± 0.3) see Fig. . HoweverThe dupilumab therapy was well-tolerated. Two patients had mild joint pain and one had an obstipation tendency under therapy, three patients suffered from mild xerophthalmia and in one case a keratoconjunctivitis. Another three patients suffered from mild herpes labialis, which, however, was well-controlled with topical therapy. We documented a case of genital herpes, which spontaneously regressed. One patient had mild xeroderma in the midface, but this also recovered after a few weeks with local therapy.In one patient we diagnosed moderate myalgias and cephalgias that caused the discontinuation of the therapy. In addition, we documented another patient who independently discontinued the medication for 8 weeks due to a vacation trip without consultation, but continued to show good disease control after continuation of treatment. After admission, the patient showed a blood eosinophilia of 1.89 billion per liter, so that a pulmonologist and a rheumatologist also evaluated the patient and decided to continue the therapy.Last but not least, we have documented a case of severe angioedema of the right upper and lower eyelid after 4 months of therapy, but a direct link to therapy was unclear. Thus, we continued the therapy after allergological co-evaluation, and the angioedema did not reoccur.We documented no non-responders under therapy. No rescue therapies in the form of systemic corticosteroids or revision surgery were necessary during the study. Furthermore, there were no infections in the sense of a possible immunosuppression.For the first time, there is now the possibility to use an antibody for targeted therapy in a disease that is often difficult to treat specifically, away from systematic corticosteroids and recurrent paranasal sinus surgery. Now, a lot of data from clinical practice is needed to see if this treatment model can be implemented in clinical practice and if the double signal blockade of IL-4 and IL-13 can provide the desired success and disease control. In this study, we strictly adhered to the EPOS2020 criteria to see if we could see a regular benefit for our patients with uncontrolled CRSwNP in a clinical setting, reduce the need for surgery and cortisone therapy, and still provide a safe form of therapy. In this study on a limited number of patients and under the parameters above, we saw a clear improvement in the symptoms of CRSwNP and an improved lung function with only rare complications and no need for rescue therapy. On one hand, the coprimary endpoints in the form of the VAS and the NPS improved markedly, so that objective, as well as subjective improvement was shown. On the other hand, the SNOT-22 questionnaire and olfactory ability improved substantially as secondary endpoints, resulting in a better quality of life for the patients. A linear trend can be seen here over time and across all patients. This improvement of the objectively reduced nasal polyps and the subjective improvement of sinusitic complaints and nasal blockage caused by the steady reduction of nasal polyps fits the known registration studies . The staThe strength of this study lies in its real context from a diverse cohort of patients from Hamburg, the second biggest city in Germany. It reports a cohort with standardized indication criteria, treatment regimen and follow-up schedule for 13 months. The therapeutic success as well as adverse events were monitored for 13 months, providing a benchmark for decisions in the therapy of CRSwNP for otolaryngologists.The results of our study are consistent with the results of other studies . HoweverFurthermore, we saw a remarkable increase in absolute eosinophils in whole blood as a secondary endpoint under therapy with dupilumab, even though no linear trend could be seen here. Changes in blood eosinophils on dupilumab therapy varied by disease type, with minimal changes in atopic dermatitis, transient increases readily followed by decreases in asthma and CRSwNP, and significant decreases in eosinophilic esophagitis. The authors of the LIBERTY NP SINUS (LNPS)-24 and the LNPS-52-Trial postulate that the transient blood eosinophilia can be due to a decrease in eotaxin-3, which prevents eosinophils from migrating from the serum to the tissues. The reduction of total serum IgE has already been seen in other studies as well, since IL-4 is also required for immunoglobulin isotype switching to IgE, an important downstream mediator in the type 2 adaptive immune response, and dupilumab interferes in this cascade , 34–36. Limitations also apply to this study. Since only purely descriptive values of a real world cohort are presented here, we decided to present the trend of improvement in terms of the slope factor of the change in the parameters of the patients under dupilumab. A dedicated statement about the effectiveness of the drug can, therefore, only be made in terms of tendencies. Selection bias may also have occurred, due to the fact that the recruiting hospital was the university medical center, so that perhaps patients with more severe symptoms were referred. Thus, a transfer of our results to the clinical routine of colleagues practicing purely in private practice may be difficult. As with any new medication, hypervigilance and monitoring of patients will be needed until further safety data are available. It is essential that the right agent is given to the right patient, and as more biologics that target key points of the T2 inflammatory cascade appear on the horizon, identification of disease traits and associated biomarkers that predict treatment response with a particular biologic will become even more important. This underscores the importance of regularly updated clinical guidelines (such as EPOS) which help—in addition to a detailed history and clinical examination, as well as histopathologic and blood testing when appropriate—to identify patients with a Th2 inflammatory response.To treat these patients adequately, a multidisciplinary approach with ear, nose and throat surgeons working alongside with pulmonologists, dermatologists and rheumatologists must become the norm and not the exception. In particular, the joint work with pulmonary specialists is essential, since a change in lung function under therapy with dupilumab and a high comorbidity with type 2 asthma.Regarding the safety of therapy, only minor adverse events were observed for the most part, and only in one case therapy was discontinued due to complaints that may have been associated with the therapy. In the pivotal studies LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52, as well as other studies, mostly mild adverse events  were found, similar to our cohort. In the pivotal trials, however, these adverse events were found more frequently in the placebo group. In comparison, more adverse events were found in our cohort (in 14 of 40 patients), but in the absence of a control group, it is questionable whether there is always a direct relationship to drug administration. In general, a safe adverse event profile was shown , 49, 50.Our study with real life data from a university medical center confirms the statement that dupilumab tends to be an effective therapy alternative for severe, uncontrolled CRSwNP. Under dupilumab therapy, there was a remarkable improvement in the medical condition and symptoms in all categories investigated, as well as the absence of a need for systemic glucocorticoids or rescue revision surgery was necessary with mostly only mild adverse side effects.


People with mild cognitive impairment (MCI) may be at higher risk of death than normal aging ones. On the other hand, patients with cardiovascular risk factors are also with higher risk of death. It may be logical to question then if the combination of MCI and cardio-vascular risk factors  can lead to higher mortality rate than expected both for high cardio-vascular risk patients and for the general population. This hypothesis is important in the light of effective early screening and prophylaxis. The general death rate of patients with very high-cardio-vascular-risk was compared in the subgroups of normal cognition and MCI. We used MMSE and MoCA (reassessment 6 months apart), Geriatric Depression scale and 4-point version of the scale for evaluating the performance in instrumental activities of daily living (4-IADL) in 249 patients. The patients also had laboratory testing, ambulatory blood pressure monitoring, ECG and echocardiography. The general mortality rate of this very high cardio-vascular risk group was assessed 8–10 years afterwards and also compared to the general national death rate published for the corresponding period from the National Social Security Institute of Bulgaria. We registered significantly higher general death rate in patients with MCI and very high cardio-vascular risk as compared to the group without MCI. The logistic regression analysis attributed approximately 14.6% of the mortality rate in this high-risk group to MCI. The major cardio-vascular risk factor was arterial hypertension—with 63.85% of the patients with home blood pressure values not in the target range at the initial cognitive screening. During the neuropsychological reevaluation 56.43% were with poor control despite the multidrug antihypertensive regimen. It is known that MCI is correlated with cardiovascular risk factors with the leading role of arterial hypertension. We found that the combination of MCI and arterial hypertension can lead to higher mortality rate than in the general aging population. This has important clinical implications for the everyday practice. That makes dementia the seventh cause of death, with very high and ever rising rate of years of life lost, lost to disability and disability-adjusted life years2. For Bulgaria—around 100,000 people (out of 5 millions) are currently diagnosed with dementia, with possibly very high covered morbidity3. Dementia is correlated with elevated risk of death4. Mild cognitive impairment is a bridging state between normal aging and dementia, and is characterised with cognitive impairment with minimal impairment of instrumental activities of daily living as a main difference from dementia, and very high age adjusted prevalence rate , cumulative dementia incidence 14.9% and no proven pharmacological treatment5. There are some studies in the general population of aging adults, that show higher mortality in people with cognitive impairment without manifest dementia6. Population-based studies suggest high impact of education, exercise and heart disease on death rate in advance-aged people (70–89) with mild cognitive impairment (MCI)7. A Norwegian register showed a significant loss in life expectancy for patients with MCI and all dementia subtypes 8. Patients with cardiovascular risk factors  are also with elevated risk of death9. This high cardio-vascular risk group is also at an elevated risk for transition from MCI to dementia10. The leading risk factor is arterial hypertension. According to NCD Risk Factor Collaboration (NCD-RisC)11 hypertension morbidity doubled in the last 20 years and despite the universal measures control rates remained insufficient in the developed countries (around 50%) and poor in the developing countries (around 25%). Hypertension is the leading cause of more than 8.5 million deaths from stroke, ischemic coronary artery disease, renal disease12. Hypertension is associated with higher risk of dementia and MCI in young adults13 and optimal blood pressure control before age of 70 was important for the reduction of cognitive impairment morbidity14, but not in the very elderly group16. Cardio-vascular risk factors, with the leading significance of arterial hypertension, modify the risk of death from dementia or MCI17. Daen et al.18 found an U-shaped age-dependent association between mortality rate form dementia and systolic blood pressure. The conclusion for the diastolic blood pressure was the same, but less distinct. Based on the current knowledge, cardio-vascular risk factors, and especially arterial hypertension, in midlife lead to morphological and functional changes in the brain associated with cognitive decline later in life. The major mechanisms involved may be: lacunar infarcts, strategic strokes, small vessel disease, impaired blood–brain barrier and neuro-vascular unit functioning, reduced beta- amyloid clearance19. A study form Mayo Clinic20 found that mortality in MCI patients varied with sex, education, history of heart disease, and physical activity. However, studies which make triple correlation between MCI, cardio-vascular risk factors and death rate are scarce.More than 55 million people worldwide are diagnosed currently with dementia, with annual diagnosis rate of 10 millionThe combination of MCI and hypertension (and other cardio-vascular risk factors as well) may lead to even higher mortality rate than the current baseline.21. This cardio-vascular death rate is between 1.6  and 1.8  times higher than the average rate in the Eastern European Region.This finding would be important in the light of effective early screening and prophylaxis, for real patients in the every day practice, who are not with a single isolated disease or risk factor. Crude death rate of Bulgaria for 2013 year for example was 14.4 per 1000 and it was much higher than the specific for EU 13 and WHO European region. Similarly, the mortality profile for Bulgaria is with very high percent for leading major cause of death per 100,000 population for diseases of the circulatory system We aimed at analyzing if there was any difference in the mortality rate between the groups of high-cardio-vascular risk patients with and without MCI.For the given period from 2009 to 2012 year 269 patients with arterial hypertension underwent screening for MCI and reevaluated minimum 6 months after the initial evaluation. For 249 of them we found mortality data from the national registries and only these were included in the current analysis after 8–10 years of follow-up. All of them were with arterial hypertension and the majority of them—with additional cardiovascular risk factors . The group was studied twice during the initial screening period. The second evaluation was at least 6 months after the inclusion  assessment. That was the first phase of the study. During that phase we studied the cognitive performance of patients with arterial hypertension and various other cardio-vascular risk factors by performing a clinical screening with neuropsychological tests. After the second reevaluation the mortality rate of the patients was followed for 8–10 years. The first and the second evaluation included full medical history, physical examination, laboratory testing, ECG, echocardiography, ambulatory blood pressure monitoring, neuropsychological testing. The survey was conducted by two professionals: a cardiologist and a neurologist–neuropsychologist. The mortality rate was assessed via the national data base and was done in mid 2019 year, before the beginning of the SARS Cov19 pandemic.All the patients signed a written informed consent for participation in a scientific study mentored by Medical University Sofia, Bulgaria . The follow-up and mortality check were conducted in accordance with the Helsinki declaration for human research, GDPR recommendations and the local Ethical committee of Medical University Sofia, Bulgaria.Arterial hypertension with history of at least 1 year; left ventricular ejection fraction above 35%; antihypertensive treatment; regular self-measurement of brachial blood pressure.Acute coronary syndrome with or without ST elevation and indications for urgent coronary intervention; acute stroke; acute or chronic heart failure with ejection fraction less than 35%; acute kidney dysfunction or end stage chronic kidney disease and chronic dialysis; coma, sopor or somnolence; taking antidepressants during the last 2 weeks; with impaired speech, vision, hearing; heavy head trauma; epilepsy; anemic syndrome; atrial fibrillation with suboptimal anticoagulation, verified with INR testing on enrollment; poorly controlled diabetes mellitus; hypo- or hyperglycemic coma; astenoadynamic syndrome; alcoholism; diagnosed psychiatric disease, diagnosed Alzheimer or other type of dementia.Anamnesis and a comprehensive hypertensive history were gathered for every patient from the doctor in charge of the study. The responsible cardiologist took the physical examination. Basic laboratory testing was done as per protocol at hospitalization and included biochemistry, full blood count, liver enzymes, cardiac enzymes, lipid profile, TSH. Neuropsychological tests were conducted in private, by the certified doctor in charge of the study.22. The target values were in compliance with current scientific recommendations23.We taught the patients how to properly measure their blood pressure and to keep a diary for 3–7 daysConducted with oscillometric sphygmomanometer TM2430 (Boso), validated to the requirements of the European Society of Hypertension and the British Hypertension Society. The protocol was accepted as suitable for interpretation and diagnosis if it consisted of at least 70% valid measurements, distributed proportionally during the day and night. The patients were encouraged to behave without limitation in their daily activities and to keep the regular medication regimen. Mean test duration of the recording—24 h. The cuff was put on the non-dominant hand, with measurement intervals at 15 min during the day and at 30 min during the night, with passive day and night period registration (7.00 a.m.–10.00 p.m.). Dipping index and blood pressure variability were automatically acquired.They were conducted after full explanation of the purpose, in private, at least 1 h apart.The “Gold Standard” in dementia clinical screening, however, quite insensitive to the earliest phases. The cognitive domains, tested in MMSE are: orientation, registration, attention and calculation , recall, language and praxis . We used a threshold for cognitive impairment 24 points from total of 30. The time given for completion of the test was 5–10 min.More sensitive and specific for the clinical diagnosis of the earliest stages of cognitive impairment. It is a 10-min compilation of neuropsychological tests aimed at evaluating frontal executive functioning and attention. We used the generally accepted threshold of 26 . Cognitive domains tested via MoCA were: attention, concentration, executive functioning, language, memory, visual-constructional, abstraction, delayed recall, orientation.The coexistence of depression and dementia and the unclear association of depression with MCI led us to include this test in the initial evaluation. The test was used to study dementia patients and to explain whether it was correlated with earlier stages of cognitive impairment.Impaired daily functioning is art of dementia diagnosis. The test was used to better define patients with advanced cognitive impairment.t test, correlation analysis is used depending on the particular question. A possible association between neuropsychological tests’ results and mortality in high risk patients was assessed with logistic regression analysis. The statistic was done by a certified statistician from the National Statistical Institute of Bulgaria. The precise method, which was used depended on the means were compared, or we studied the correlation. The standard for the medical statistics 95% confidence interval was used.SPSS 19 was used for the statistical analysis. Descriptive analysis, Written informed consent was obtain from all participants in the study. The study was mentored by Medical University Sofia, Bulgaria—under Contract number 9D/26D/2011 from Medical University Sofia. The study and the follow-up were conducted in accordance with the Helsinki declaration for human research and with the local Ethical committee of Medical University Sofia, Bulgaria. For the mortality rate check—ethical approval was not required as the data were fully anonymised.Not applicable as this was a retrospective analysis—ethical approval was not required as the data were fully anonymized. The initial phase of neuropsychological testing and reevaluation of cardio-vascular patients was done under Contract number 9D/26D/2011 from Medical University Sofia. All initial physical examination and neuropsychological tests we done after signing informed consent.30.Here we describe the follow-up results for the difference of all-cause mortality of the initially studied population. Results from the first phase have already been published249 patients were included in this analysis of the mortality rate . During the follow-up 64 patients (25.7%) died, out of whom with MCI (MoCA < 26) were 53 (82.81%). The sex distribution was: 174 (69.9%) females and 75 (30.1%) males. The mean age was 67.83 ± 8.93 years.All the patients had arterial hypertension (100%). The majority had also a variety of other cardio-vascular risk factors. The valid percent for high and very high cardio-vascular risk as assessed with SCORE was 19.7% (49 patients) for the high-risk group and 48.2% (120 patients) for the very high-risk group. Twenty-four—24 (9.6%) had proven stroke; 23 (9.2%) had suffered myocardial infarction and 61 (24.5%) had proven coronary artery disease. Low or intermediate kidney disfunction had 26 (10.4%). The diabetic patients were 74 (29.7%).The comparison between dead and alive patients in terms of cognitive markers and cardio-vascular risk factors is given on Table The valid percent of the distribution in the various risk factor groups in shown on Fig. Twenty-three (23–9.2%) were with proven atrial fibrillation, all of whom were on anticoagulation therapy.The distribution in the various educational levels was: university education had 106 (42.6%); high school education had 111 (44.6%); primary −31 (12.4%).Depression had 25 (10%) of the patients. The majority 234 (94%) of the patients were autonomous. Only 10 (4%) were mildly limited in their daily activities and 2 (0.8%) were fully dependent.All the patients were on antihypertensive medications at the time of the neuropsychological assessment. ACE inhibitors took 152 (61%); ARB—61 (24.5%); beta-blockers 182 (73.1%): diuretics 186 (74.7%); centrally acting medications 66 (26.5%); calcium channel blockers 140 (56.2%). One hundred twenty one (48.6%) were also on a statin and 186 (74.7%) on antiaggregant. Despite medical treatment 159 (63.85%) at the initial neuropsychological testing were with home blood pressure values not in the target range and 114  during the reevaluation. All of the patients were on combination therapy, based on the recommended first line antihypertensive classes. As we had no fixed/recommended drug from a given class during the follow-up and all the patients were on combination therapy, it was not possible to compare death rates in patients taking certain drugs or antihypertensive classes because of overlap of effects and lack of groups on monotherapy. The study was also not designed as one for drug-related mortality reduction, we did not perform such an analysis.Every patient had 2 neuropsychological tests taken at least 6 months apart. They were designated as MMSE initial and reevaluation, respectively MoCA initial and reevaluation. We assessed mortality rate 8–10 years after the second test. Sixty-four (25.7%) of the patients died for this period.The yearly all-cause mortality rate for the last few years before the SARS Cov19 pandemic for Bulgaria was about 14.1–15.4/1000. The relative all-cause mortality rate of this studied population was about 25.7/1000 patient on yearly basis—1.67 times higher.The relative percent of dead patients with low MoCA results (≤ 25 points) was 21.28% in comparison with only 4.42% dead in those with MoCA > 25. The distribution of the percent of the dead for MMSE is 6.83% in the group of MMSE ≤ 24 and 18.87% in those with MMSE > 24.We used logistic regression model to analyze to what extend MMSE reevaluation and MoCA reevaluation influenced death rate in this group of patients with arteria hypertension and primarily high or very high cardio-vascular risk. The Omnibus Tests of model coefficients showed p < 0.0001, t.i. the model had some explanatory capacity. However, the Negelkerke R square was 0.146 and thus only 14.6% of the death rate could be explained by the values of the given neuropsychological test. The regression coefficient only for MoCA reevaluation was significant  0.864). Thus, for every point elevation of the MoCA reevaluation result, the odds that the patient was dead was elevated with 0.864, that means that it was actually lowered with 13.6%. For MMSE reevaluation the odds the patient was dead was lowered with 8.9% for every point elevation of the value of the test. We could not comment on the MMSE mortality rate as there was no significant difference if the P-value is 0.324 (Exp(B) 0.911). Much larger group should be analyzed to properly define if there was significance.R2). We used Forward LR binary logistic regression with dependent variable mortality for the selected time period. The CI for exp(B) was 95%, probability for stepwise entry was 0.05 and for removal—0.10. The percentage accuracy in classification was 79.7%. The variables, that remained in the equation at step 6 were MoCA reevaluation p = 0.002, B = − 0.184, Exp(B) 0.832, CI 0.741–0.934 (higher MoCA points had a protective effect); MMSE initial p = 0.049, B = − 0.201, Exp(B) 0.818, CI 0.670–0.999 (higher MMSE points had a protective effect); atrial fibrillation frequency p = 0.032, B = 1.123, Exp(B) 3.073, CI 1.104–8.553 (risk factor); diastolic blood pressure p = 0.048, B = − 0.032; Exp(B) 0.969, CI 0.939–1.000 .For further analysis we controlled for confounders such as: age, blood pressure variables, smoking, diabetes, peripheral artery disease, stroke, myocardial infarction, atrial fibrillation, chronic kidney disease, creatinine values, obesity, IADL, dyslipidemia, neuropsychological tests’ results. The explained variation in the dependent variable (death rate) based on our model was 35.5% —the Kangwha Cohort Study34 and Gerontological Regional Database cohort study35. The second one, also with the finding that low SBP in elderly above 85 years was associated with increased mortality risk, with the possible explanation – hypoperfusion.The results support the thesis, that lower results from neuropsychological tests (the more sensitive one—MoCA) and MCI in patients with arterial hypertension and high/very high cardiovascular risk lead to an elevated death rate. The mean all-cause mortality (25.7/1000) in the group as a whole is higher than the mean for Bulgaria (1.67 times higher), for the region and for Europe (10.8/1000). An important result is that 82% of the deceased in our studied group were with MCI. The regression analysis showed that 14.6% of the death rate can be explained by MCI (assessed with MoCA), that leads us to the conclusion that the cumulative negative effect of MCI and arterial hypertension may be very high with respect to mortality rate. A study of Contador et al.Several possible explanations can be given for the observed association between MCI and high cardio-vascular risk profile and hypertension. Reduced compliance to treatment, accelerated vascular impairment and impairment of the central autoregulatory mechanisms of cerebral perfusion, blood pressure, neurohormonal and vascular tone maintenance. All these mechanisms have been proven in models of hypertension and of dementia. However, their simultaneous action has been understudied in pathophysiological models. If they were proven both preclinically, clinically and on population level, that can lead to better surveillance of patients with MCI and hypertension—a screening for hypertension in MCI patients and vice-versa for timely prophylaxis.There was not any statistically significant difference between the mean blood pressure values, cardio-vascular risk factors and diseases between the deceased and the alive patients, except for hypertension history (higher in the dead), serum creatinine (higher for the dead), pulse pressure (higher in the dead), age and neuropsychological tests’ results. The results from MoCA and MMSE were lower in the patients who were registered dead in the following years. The logistic regression analysis showed that every single point elevation in MoCA leads to 13.6% lower death rate. Such results are being reported for the first time for an Eastern European population with high cardio-vascular risk.36. There was not any significant difference between the two sexes in terms of cardio-vascular disease or MCI.It should be noted that women were more than men in the group. There were several reasons for this. Women were relatively more willing to participate in such studies. Also, the relative percent females above age 65 years was relatively higher than males37 found that in patients with stable coronary heart disease, cognitive performance was associated with modifiable risk factors, educational status and ethnical region.These results show that 14.6% of the death rate can be explained by the results from the neuropsychological test (MoCA). This percent, however low in general, is relatively high if we consider that the group consists of patients with primarily high and very high cardio-vascular risk. In a study of Stewart et al.38. With lower threshold of MMSE, the death rate distribution is in accord with the general tendency, registered with MoCA. However, our aim was to show the real-world results, strengths and disadvantages of the neuropsychological tests in high-risk cardio-vascular patients, the way we see them in the everyday practice. Recently there have been papers, that review the diagnostic thresholds of MMSE and MoCA. This can lead to significant change and clarification of the general mortality rate39. However, we stuck to the initial official recommendations40, as these new and different thresholds are only in isolated studies.Discussing the relative percent dead in those with MCI we should bear in mind the following commentaries: The correlation between MMSE and MoCA is very high positive . Thus this discrepancy can be attributed to the very high MMSE threshold used (24), and to the low sensitivity of the testIt is known that MCI is correlated with cardiovascular risk factors and primarily arterial hypertension. We found that the combination of MCI and AH can lead to higher mortality rate. This has important clinical implications for primary prophylaxis of cognitive decline and primary secondary prophylaxis in high risk patients. We will study further this issue to define in detail the factors responsible for the higher death rate in this group.It could have been interesting to find the rate of progression for the given time of 8–10 years of patients with MCI at the first two neuropsychological assessment events. We plan to conduct a second reevaluation with neuropsychological testing and ambulatory blood pressure monitoring in the upcoming months.