The implementation of individual clinical practice guidelines in patients with multimorbidity often results in polypharmacy. Our aim was to analyse medication use according to longitudinal multimorbidity patterns (MP) and determine during a 5-year period (2012–16) which MP are associated with abnormal liver and kidney function in primary care patients over 65 years of age living in Catalonia.Design: Longitudinal study (years 2012 to 2016) based on the electronic health records contained in Information System for Research in Primary Care database of the Catalan Institute of Health (SIDIAP). Variables: age, sex, MP, medication and polypharmacy (drug exposure obtained from the Pharmacy Invoice Registry). Medicines were classified in accordance with the Anatomical Therapeutic Chemical Classification System (ATC). Glomerular filtration rate was used to determine abnormal kidney function, and serum levels of alkaline phosphatase, alanine transaminase and gamma-glutamyl transpeptidase were used to diagnose abnormal liver function. Statistics: For medication use in MP, we calculated annual mean packages of each drug in each MP, and observed/expected ratios were obtained by dividing mean packages in the cluster by mean packages of the same drug in the overall population. Logistic regression models were fitted to estimate the association between MP at baseline and abnormal kidney and liver function tests during follow up.Nine hundred sixteen thousand six hundred nineteen patients were included, and 743,827 completed the follow up. We identified one polypharmacy profile per MP, and concluded that the most prescribed drugs in each pattern corresponded to the diseases overrepresented in that specific MP. The median of drugs ranged from 3 (Cluster 1 - Non-Specific) to 8 (Cluster 10 - Multisystem Pattern). Abnormal kidney function was most commonly observed in the Cluster 4 - Cardio-Circulatory and Renal  and Cluster 3 - Minority Metabolic Autoimmune-Inflammatory  MP. A higher risk of abnormal liver function was observed in the Cluster 8 - Digestive , and Cluster 4 - Cardio-Circulatory and Renal  MP.A higher risk of abnormal kidney and liver function was observed in specific MP. The long-term characterisation of MP and polypharmacy illustrates the burden of chronic multimorbidity and polypharmacy in the elderly population. Multimorbidity generally refers to the co-occurrence of multiple chronic medical conditions in a single individual . GloballGenerally, prescription in patients with multimorbidity is based on the recommendations of individual disease-specific clinical practice guidelines. This frequently results in polypharmacy , commonlThe dynamic changes in cellular biological processes associated with aging  influencThe pharmacological management of multimorbidity represents a challenge for health professionals, especially in elderly or frail patients, since it requires a person-centred approach as opposed to treating multiple diseases as independent entities . Few pubIn another article, we described MP in people over 65 years of age and followed their trajectories during 5 years. We used soft clustering techniques, which enabled us to study MP considering as the unit of analysis the patient plus all their diagnosed chronic diseases. We identified multimorbidity trajectories which were mostly stable . In addiThe main aim of this study was to analyse medication use according to longitudinal MP and characterize them annually in primary care patients over 65 years of age during the 2012–16 period in Catalonia. The secondary aim was to determine which patterns are more likely to present an abnormal liver and kidney function during follow-up.A longitudinal study was carried out in Catalonia (Spain), a Mediterranean region of 7,515,398 inhabitants (2012) . The SpaInclusion criteria were individuals aged 65–99 years on 31 December 2011 that survived until 31st of December 2012 (index date), with at least one PHCC visit during the 5-year study period (2012–2016). No new entries were allowed in the cohort. Attrition was caused by mortality or transfer to another healthcare provider. We included 916,619 people at baseline and 743,827 completed all follow-up  contains the clinical information from the electronic health records (EHR) of the CHI PHCCs since 2006 . The SIDAll variables were obtained directly from the SIDIAP database .In the SIDIAP, diseases are coded in accordance with the International Classification of Diseases, version 10 (ICD-10). An operational definition of multimorbidity was used, i.e., the presence of two or more chronic diseases, based on the selected 60 groups of chronic diseases determined by the Swedish National study of Aging and Care in Kungsholmen , with adDeath was measured as the occurrence of this event, regardless of cause. If a person transferred out of the CHI healthcare provider during the study period, they were considered lost to follow-up (drop-outs).Information on drug exposure was obtained from the Pharmacy Invoice Registry, which includes drugs prescribed by primary care and hospital physicians and subsidized by the national health system. The study included only systemic drugs, and excluded hospital medication, drugs dispensed by hospital pharmacies, drugs not subsidized by public health services and topical medication (e.g. ointments and lotions). Drugs were classified according to the Anatomical Therapeutic Chemical Classification System (ATC) . We used2 after the baseline year, we classified it as abnormal kidney function.Kidney function was calculated each follow up year using the four-variable Modification of Diet in Renal Disease (MDRD-4) creatinine calibrated to isotope dilution mass spectrometry (IDMS10) equation to estimate glomerular filtration rate (eGFR) . When onLiver function was determined each follow up year by analysing serum levels of alkaline phosphatase (ALP), alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT). Liver function was considered abnormal when after baseline, at least one of the values was as follows: ALP > 2 × 129 IU/L; ALT> 5 × 41 IU/L (men) or ALT> 5 × 33 IU/L (women); GGT > 61 IU/L .Demographic variables analysed at baseline and at the end of study were: age at baseline (years), sex , socio-economic status ; quintiles from least to most deprived)  and numbDescriptive statistics were used to summarize overall information. Participants’ characteristics and prevalence of chronic diseases and medication use were measured at baseline and final year, and during the follow-up period.MP were identified using two steps: 1) the dataset was pre-processed by applying a mixture of Principal Component Analysis and Multiple Correspondence Analysis (PCAmix). For the grouping of participants, it was assumed that the patient population was initially distributed into a fuzzy set of clusters, corresponding to the different MP ; 2) In oThe final clusters were defined as MP by the research team based on the clinical significance. We eventually obtained ten MP, and also drop out and mortality clusters. To describe the MP, prevalences of diseases in each cluster were calculated. Observed/expected ratios (O/E-ratios) were obtained by dividing disease prevalence in the cluster by disease prevalence in the overall population. Exclusivity, defined as the proportion of patients with the disease included in the cluster over the total number of patients with the disease, was also calculated. A disease was considered to be part of a MP when the O/E-ratio was ≥2. A more detailed description of the applied machine learning technique can be found elsewhere .To describe chronic medication use in each multimorbidity pattern (MP), we calculated annual mean packages for each drug in each cluster. Next, we defined O/E-ratios, obtained by dividing mean packages in the cluster by mean packages in the overall population. We also defined exclusivity as the number of medication packages included in the cluster over the total number of medication packages. A medication was considered part of a MP when the O/E-ratio was ≥2. As a complementary approach, we also investigated medicines that presented an exclusivity value higher than the percentage frequency of each cluster.Logistic regression models were fitted to estimate the association between MP at baseline and abnormal kidney and liver function values during follow up. Odds ratio (OR) and 95% confidence interval (CI) were adjusted for age, sex, socioeconomic status (MEDEA variable) and total number of packages in 2012. We used multiple imputation to minimize the selection bias resulting from the presence of missing values for MEDEA (7%). We used multiple imputation by chained equations to obtain seven imputed datasets . The finThe analyses were carried out using R version 3.6.1 . The significance level was set at α = 0.05.A total of 916,619 people over 65 years of age living in Catalonia were included at baseline , 853,085 (93.1%) met multimorbidity criteria, and 487,502 (53.2%) criteria for polypharmacy. At the end of the study period, 743,827 participants had completed follow-up , 3-hidroxi-3-metil-glutaril-CoA reductase (HMGCoA-reductase) inhibitors and anilides. During follow-up, the most common drugs remained unchanged, but the prescription had expanded to include more patients (Supplementary File Ten MP were identified at baseline (see characteristics of each MP in Table Cluster2 (C2)-Eye Impairment and Mental: The most used drugs at baseline were ophthalmologic beta blockers. It should be noted that more than half of the general population with glaucoma and under treatment with ophthalmic beta blockers are included in this cluster .Cluster3 (C3)-Minority Metabolic Autoimmune-Inflammatory: At baseline, the most overrepresented drugs were glucocorticoids, uric acid lowering agents, and Vitamin D and analogues.Cluster4 (C4)-Cardio-Circulatory and Renal: At baseline, people included in this pattern had 17 different drug groups overrepresented, mainly to treat ischemic cardiovascular disease, heart failure, valvular heart disease, cardiac arrhythmias, diabetes, kidney failure and anaemia -Cardio-Circulatory, Mental, Respiratory and Genitourinary: At baseline, people included in this pattern had 20 different drug groups overrepresented: peripheral vasodilators, bronchodilators, drugs for ischemic cardiomyopathy, heart failure, prostate diseases and diabetes.Cluster6 (C6)-Neurological, Digestive and Circulatory: Overrepresentation in this cluster is mostly constituted by patients with Parkinson’s disease and corresponding treatment, mainly dopamine, dopamine derivatives and other medicines used in neurological disorders. These diseases and related medications are practically exclusive to this cluster (more than 90.0% at the beginning of the study).Cluster7 (C7)-Respiratory and Ear: Drugs included in this cluster were glucocorticoids, adrenergics in combination with corticosteroids or other drugs excluding anticholinergics, selective beta-2-adrenoreceptor agonists, anticholinergics, corticosteroids, and antihistamines for systemic use.Cluster8 (C8)-Digestive: The most prescribed medication corresponds to drugs used for the treatment of chronic liver diseases.Cluster9 (C9)-Neurological, Musculoskeletal and Minor: In this group the most overrepresented drugs are anti-inflammatory and analgesics, in agreement with the MP.Cluster10 (C10)-Multisystem: The least common pattern, it has multiple overrepresented disorders from different systems, and the corresponding medications used to treat these disorders.Overall, we observed that overrepresented (O/E-ratio > 2) drugs (measured as mean packages) in each MP were associated with the overrepresented diseases in that same MP. Naturally, these drugs are intended to treat specific chronic diseases overrepresented in their corresponding MP  and C3-Minority Metabolic Autoimmune-Inflammatory MP  , probably due to emerging safety concerns of NSAIDs regarding the kidney [In e kidney , cardiove kidney , 40, ande kidney .This study shows that most patients with multimorbidity receiving polypharmacy present abnormal kidney and liver function. While the design of this study cannot explain the causes of the abnormal kidney and liver function observed, we hypothesise that they probably originate from the baseline disorders of the patients, adverse effects from the medication, inappropriate prescribing and lack of adjustment to the kidney and liver function of each patient, which are usually affected by old age , 41–43. C4 -Cardio-Circulatory and Renal, in addition to the baseline kidney and cardiovascular disorders of these patients, abnormal kidney function has been attributed to the hemodynamic effects of diuretics causing nephrotoxicity [C3-Minority Metabolic Autoimmune-Inflammatory includes patients with hypothyroidism [Abnormal kidney function is highest in patients from MP C4 and C3. In MP toxicity . The MP yroidism  and overC8 - Digestive, since this pattern represents patients with liver disease. C4- Cardio-Circulatory and Renal has the oldest patients and the highest prescription of vitamin K antagonists, which can cause cholestasis [Abnormal liver function is highest in patients from clusters C8 and C4. The risk is highest in patients in lestasis .Most studies on MP use a cross-sectional design. Some publications include longitudinal data, but to our knowledge no data on the association of MP and abnormal kidney and liver function have been published .. In theOne of the major strengths of this study is the use of a large, high-quality database that originates from the primary care EHR, which includes a large proportion of the population with multimorbidity and with polypharmacy . FurtherThis study also presents some limitations. Firstly, we only considered the medications for which at least three packages during each year of the study period had been dispensed. While this could underestimate some medicines, it is extremely unusual to dispense less than 3 packages per year of drugs treating chronic diseases. Similarly, we excluded the medication for acute conditions, some of which can cause temporary abnormalities in kidney and liver function. Secondly, the SIDIAP only collects information on drugs prescribed by primary care and hospital physicians which are dispensed by community pharmacies. Consequently, our analysis cannot rule out active ingredients included in hospital drug regimes, over-the-counter medicines and para-pharmacy products, which might also impair kidney and liver function. Thirdly and finally, censoring of people who died and people who transferred might have influenced estimations of risk associations in a competing-risk scenario, which was not an objective of this study.Our research shows that while prescription of polypharmacy might be justified with regard to clinical guidelines, it increases the risk of adverse drug reactions and might negatively affect kidney and liver function. Crucially, the risk of overtreatment, which occurs when the prescribed medications have no clinically significant benefit and when the risk of adverse effects associated with an additional medication outweighs the overall benefit of the treatment, is high in polypharmacy , 47.Polypharmacy is highly prevalent in older adults. The most frequently prescribed medicines were related to MP and their consumption was maintained throughout the follow-up period.Finally, this study provides real-world data on the evolution of polypharmacy and multimorbidity among older adults and describes the association between polypharmacy and abnormal liver and kidney function in this population.Additional file 1. Prevalence of Top 30 Drugs during the follow up period in people over 65 years in Catalonia.Additional file 2. Multimorbidity patterns with Hidden Markov models at baseline (year 2012) and final year (2016) of the study. Drug useAdditional file 3. Evolution of kidney function during follow up by clusters.Additional file 4. Evolution of liver function during follow up by clusters.


Patients with sexually transmitted infections (STIs) experience difficulties with stability and trust in long-term relationships and have poor mental health, factors that may lead to suicidal ideation. We sought to verify whether psychosocial health problems among patients with STIs were associated with these patients’ suicidal ideation and to examine the syndemic effect of multiple psychosocial problems on suicidal ideation.This was a cross-sectional study of 519 STI patients at the Shanghai Skin Disease Hospital. Demographic, psychosocial, and suicidal ideation information about the participants was collected by questionnaire. Logistic regressions were performed to detect the association between demographic variables and suicidal ideation, as well as each individual psychosocial variable and suicidal ideation, and to verify the syndemic effect of psychosocial factors.Of the participants, 25.0% (130/519) reported having suicidal ideation. In univariable analysis, low self-esteem, loneliness, depression, entrapment, defeat, and unsatisfied interpersonal needs were associated with suicidal ideation. Multivariable analysis found depression  and entrapment  each had a more significant relation with suicidal ideation than the other psychosocial problems examined. STI patients who experienced two or more psychosocial health problems had approximately fourfold odds of suicide ideation  compared with those in the non-syndemic group, especially in the high-level  group .The study found the participants had a high rate of suicidal ideation and suffered from severe psychosocial problems. These results show a syndemic effect of psychosocial problems on increasing the odds of suicidal ideation. Our findings suggest an urgent need for efforts to prevent suicidal ideation among STI patients toward improving the social and health conditions of this population. According to the World Health Organization, one person in the world commits suicide every 40 s. However, suicide is preventable. Suicidal ideation, defined as thinking about, considering, or planning for suicide , may be One study in Canada found that 6.7% of STI patients had suicidal ideation and mental health needs over the previous 12 months . Other iIn one survey of STI patients in Jamaica, 65.5% of participants screened positive for at least one psychosocial problem, including depression and suicidal ideation . PreviouNotably, individuals with several psychosocial problems may have magnified suicidal ideation , 32, 33.In this study, we aimed to verify three hypotheses:  STI patiThis cross-sectional study, started in November 2017, was conducted for 6 months among STI clinic patients in two branch institutes of the Shanghai Skin Disease Hospital: Qiujiang Road and Baode Road. This hospital specializes in STIs and is one of the premier medical institutes in this field.In accordance with the Law of the People’s Republic of China on the Prevention and Treatment of Infectious Diseases, “STI patients” herein refers to those with any of five types of STIs that need preventive measures: syphilis, gonorrhea, genital warts, genital herpes, and HIV. All diagnoses  were conducted by sexually transmitted disease (STD) doctors at the hospital. Individuals who met the following criteria were invited to take part: ≥18 years old, clinically diagnosed with an STI disease, able to read the informed consent form, and no participation in a similar study in the previous 6 months.n = 88).Patients who had any of the following criteria, were excluded: severe mental or cognitive impairment , unconsciousness, or disinclination to participate . Background information on the survey was given orally to all participants, after which they were given written informed consent forms that set out the study’s goal, procedures, and potential risks. Participants signed informed consent forms before the study began. During the recruitment, participants were free to ask any questions and to withdraw.Our survey team signed cooperation agreements with the Shanghai Skin Disease Hospital before the investigation. All the doctors worked in the STD Department (inpatient or outpatient) were recruited and informed about the survey beforehand. All the investigators were students (seniors or postgraduates) from Shanghai Jiao Tong University School of Medicine. They received pre-survey training and several in-person reviews throughout the study. The training also incorporated quality-control strategies, such as reexamining and investigating the questionnaires and resolving issues that may arise during the fieldwork.The doctors informed each participant who met the inclusion criteria about the survey. After initial approval, participants were asked to enter a separate room to attend an interview conducted by our investigators. The interviews were divided into two parts:  Our inveOur investigators went to the two branch institutes of the Hospital every Wednesday and Saturday during the study period. Patients who visited one of the two branch institutes to see a doctor for STI treatment on a Wednesday and Saturday (when our investigators were present) were regarded as potential objects. Doctors at the institutes assessed whether patients met our eligibility criteria and inquired about participation. No appointment system was implemented at the two institutes, so our investigators meeting the patients was accidental. Thus, we employed accidental sampling.Demographic variables included age, sex, educational level, marital status, residency, income, insurance, sexual orientation, and HIV status.Suicidal ideation was measured via one question : “Have ySelf-esteem was assessed based on the 10-item Rosenberg Self-Esteem Scale (SES) . NegativThe initial version of the UCLA Loneliness Scale used 20 items  designed to estimate participants’ loneliness and related emotional states . Hays anDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Individuals were asked to recall how often they had experienced troubling problems  over the preceding 2 weeks, scoring from 1  to 4 (nearly every day) [Depression level was gauged using the Chinese version of Patient Health Questionnaire-9 (PHQ-9), a brief screening tool comprising nine items that match diagnosis criteria in the ery day) . A cutofery day)   , 45, whiFor the 16-item Chinese version of Defeat Scale (DS) , 46, parInterpersonal needs were measured using the 15-item Chinese version of the Interpersonal Needs Questionnaire (INQ-15), which measures perceived burdensomeness (items 1 to 6) and thwarted belongingness items 7 to 15) , 48. Res to 15 , The Chinese version of the Multidimensional Scale of Perceived Social Support (MSPSS) is a 12-item, seven-point Likert scale based on the self-reported measure of support received from family, friends, and/or other people of special significance  . ScoringPsychosocial problems included low self-esteem, high loneliness, high depression, high entrapment, high defeat, unsatisfied interpersonal needs, and low perceived social support. Low self-esteem was defined as individuals who scored ≤29 points on the SES. High loneliness was defined as those who scored > 18 on the ULS-8. High depression was defined as individuals who scored > 5 points on the PHQ-9. High entrapment was defined as those who scored > 21 points on the ES. High defeat was defined as individuals who scored > 23 points on the DS. Unsatisfied interpersonal need was defined any those who scored > 49 points on the INQ-15. Low perceived social support was defined as individuals who scored ≤59 points on the MSPSS.Two or more concurrent psychosocial problems in a participant indicated a syndemic phenomenon . The synStatistical analysis was performed using IBM SPSS Statistics for Windows, Version 22.0 . First, baseline descriptive statistics were calculated to summarize demographic characteristics, suicidal ideation, and psychosocial variables. Univariable analysis was then conducted via binary logistic regression to detect the association between demographic variables and suicidal ideation, and between univariable psychosocial variable and suicidal ideation. After adjusting for all significant demographic variables, univariate logistic regression analysis was performed to examine the psychosocial syndemic effect on suicidal ideation among these STI patients. Multivariable logistic regression was then used to evaluate all seven psychosocial problems associated with suicidal ideation, after adjusting for significant demographic variables. In the final stage, syndemic count variables were created by counting each individual’s number of psychosocial health problems, and different groups were established based on the number of variables.In all, 519 patients  were investigated: 25.0% (130/519) had experienced suicidal ideation; 9.6% (50/519) were HIV-positive; 47.6% (247/519) were diagnosed with genital warts; and 23.9% (124/519) were diagnosed with syphilis  were classified as lonely, 23.7% (123/519) at a high level of entrapment, 24.1% (125/519) with defeat, and 22.9% (119/519) as having unmet interpersonal needs. Of the participants, 25.8% (134/519) lacked social support. About half of the participants  showed depression via their PHQ-9 scores. A total of 38.9% (202/519) had a low level of self-esteem . Among people living with HIV/AIDS in the present study, 18 showed suicidal ideation . In this study, suicidal ideation was independently associated with six psychosocial problems, though not social support. Our most important finding is the syndemic effect of entrapment and defeat in addition to depression, self-esteem, interpersonal needs, loneliness, and social support in suicidal ideation among STI patients, especially in those who had five or more concurrent psychosocial problems.The difference in suicidal ideation prevalence between our sample (25.0%) and that of a Canadian sample (6.7%)  could beWhen we included all psychosocial variables in a single model, the association with suicidal ideation was removed for most variables, though it remained strongest for depression and entrapment. This should not be surprising, considering suicidal ideation and behavior are known outcomes of feeling trapped in a stressful situation, with no evident escape or rescue ; this reTo show that suicidal ideation also co-occurs among STI patients, we have extended previous research that confirmed there was a syndemic effect on suicidal ideation in MSM . We confPrevention and intervention efforts should be designed and implemented to reduce suicidal ideation in STI patients. Especially in hospitals, psychological counseling and interventions are needed to improve individuals’ mental well-being and reduce suicidal ideation –69. In CSeveral limitations should be considered in interpreting the present results. First, cross-sectional surveys have difficulty determining causality; therefore, a prospective study assessing recent STI diagnoses and suicidal ideation would be beneficial. Second, although the participants came from a representative hospital, the sample size was not especially large; multi-center research is needed. Third, although privacy was ensured, investigators were trained, and doctors’ cooperation ensured survey quality, self-reported and recall bias were unavoidable. Fourth, our findings do not indicate the incidence of suicidal ideation in newly diagnosed and revisited patients; future studies are needed to focus on and explore the differences between the two. Fifth, there was selection bias. For example, we excluded from this study neurosyphilis patients with severe mental or cognitive impairment; patients who had experienced associated stigma may also have been more reluctant to participate. And accidental sampling reduces the possibility of replicability and generalization. Sixth, we used a self-reported binary scale assess lifetime suicidal ideation, which potentially underestimated its prevalence. Finally, the syndemic effect examined classification variables using a cutoff point, which may not supply an adequate amount of information, although the results for continuous variables were similar.This study adds to the literature in several important ways. We demonstrated that not only PLWHA but also other STI patients have high rates of suicidal ideation, and this population suffers from severe psychosocial problems. This study identified a syndemic effect of psychosocial problems on increasing odds of suicidal ideation. The collective findings suggest that greater attention should be paid to STI patients’ psychosocial well-being; especially in hospitals. Efforts to prevent suicidal ideation, as well as other mental problems, among STI patients are therefore urgently needed to improve the social and health conditions for this population.


These suggest that BMI directly affects BP, kidney injury markers, and the activation of the intra-tubular RAS even in normotensive young adults. Given that BMI measurements and urine analyses are non-invasive, our findings may pave the way to developing a new and simple method of screening for the risk of chronic kidney disease in adults.Obesity has been firmly established as a major risk factor for common disease states including hypertension, type 2 diabetes mellitus, and chronic kidney disease. Increased body mass index (BMI) contributes to the activation of both the systemic and intra-tubular renin angiotensin systems (RAS), which are in turn associated with increased blood pressure (BP) and kidney damage. In this cross-sectional study, 43 subjects of normal or increased body weight were examined in order to determine the correlation of BMI or body fat mass (BFM) with blood pressure, fasting blood glucose (FBG), and urinary kidney injury markers such as interleukin-18 (IL-18), connective tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Our results showed that: (1) subjects with increased body weight showed significantly higher BP, BFM, total body water and metabolic age; (2) BMI was positively correlated to both systolic (R In individuals classified as overweight (BMI = 25–29.9 kg/m2), there is a higher probability of acquiring metabolic syndrome, which contributes to the development of Type 2 diabetes, hypertension and cardiovascular disease3. Type 2 diabetes and hypertension are the main risk factors for CKD5. Obesity is characterized by activation of the systemic renin angiotensin system (RAS), a key regulator of blood pressure, fluid and electrolyte balance7. Under pathological conditions, RAS activation plays an important role in the progression of hypertension. The systemic RAS is controlled by renin production in the juxtaglomerular (JG) cells of the kidney, which release renin into the circulation. Once in the systemic circulation, renin acts on angiotensinogen (AGT) produced by the liver to form angiotensin (Ang) I. Ang I is cleaved and converted to Ang II by angiotensin converting enzyme (ACE) in the lungs. Finally, Ang II promotes vasoconstriction and aldosterone release by the adrenals, thus promoting sodium reabsorption8.Obesity is an epidemic affecting more than 1.4 billion adults worldwide10. Adipocytes have been suggested to possess an additional RAS and to generate angiotensin peptides which serve as a source for systemic RAS components11. Because of this, increases in adipose tissue, as seen in overweight and obese individuals, may lead to an increase in blood pressure.It has been reported that systemic RAS activity correlates positively with body weight and body fat13. Renin and ACE are expressed in collecting ducts15 while AGT is expressed in proximal tubules16. The local availability of AGT allows renin to form Ang I, which is converted to Ang II by ACE. In contrast to the inhibitory effect that Ang II exerts on JG renin, Ang II stimulates the expression of renin in the collecting duct and of AGT in proximal tubules, leading to further intratubular Ang II formation20. Substantial evidence supports the critical role that activation of this intra-tubular RAS has in the development and maintenance of hypertension23 and CKD24. Urinary renin and AGT have been proposed as biomarkers for intra-renal status of RAS activation26. Furthermore, the presence of urinary AGT precedes the development of Stage 3 CKD in patients with type 1 diabetes27.The RAS components are also expressed in the kidneys and are able to form Ang II31. Candidate biomarkers of early kidney injury have been proposed to be segment-specific in the nephron32. Among them, neutrophil gelatinase-associated lipocalcin (NGAL) and kidney injury molecule-1 (KIM-1) have emerged as promising biomarkers for early renal injury of the proximal and distal tubules. Interleukin 18 (IL-18) has been shown to be an early biomarker of tubular injury32. Connecting tissue growth factor (CTGF) is also associated with early profibrotic signals that will eventually lead to tubule-interstitial fibrosis33.Tubular damage markers have been used to assess several forms of kidney diseasesIn this study we measured the urinary mRNA levels of renin, AGT and kidney injury markers in young adults who are overweight or of normal weight, to determine if these measurements accurately reflect intra-tubular RAS status. Our non-invasive approach included anthropometry, urine collection, bioelectrical impedance analysis, blood pressure, fasting blood glucose levels (FBG), and additional biometric parameters. We found not only that urinary mRNA for renin and AGT were higher in subjects within the overweight range or above (BMI ≥ 25), but IL-18 and CTGF mRNA levels were augmented as well. Interestingly, systolic and diastolic blood pressure (BP) correlated positively with BMI, although none of the individuals were diagnosed with clinical hypertension.Initially, 50 students aged 19–22 years old were recruited, and their written informed consent was obtained. Eight patients were subsequently excluded due to associated diseases  ≥ 25 or waist ≥ 85 cm (women) or ≥ 90 cm (men).The ethics committee which approved the study was the Measurements of body weight, BMI, and height were performed on the day of biochemical analysis. Body composition was assessed by bio-impedance analysis (Tanita BC 420 S MA Class III), which calculated percentage of fat and index of fat mass and water content among other parameters Table .34.Measurements were performed by the auscultatory method using a certified mercury sphygmomanometer in a quiet room with comfortable temperature. The subject was asked not to talk during measurements. The arm was bare and placed at heart level. A standard cuff (12.5 cm bladder) was used and fitted appropriately to the subject’s arm size. Systolic and diastolic blood pressure was recorded as the mean value of 3 measurements. Because obese individuals may be wrongly identified as hypertensive due to ill-fitting blood pressure cuffs that are too small, we verified that all six of the obese subjects had arm circumferences of less than 33 cm (28.7 ± 3 cm), which is compatible with the standard cuffUrine samples (20–30 mL) were collected in the morning. The urine was deposited in a sterile container which was kept at 4 °C in the laboratory for subsequent RNA extraction the same day. An aliquot of the sample (1 mL) was observed microscopically to evaluate for the presence of bacteria. Samples were discarded if they contained bacteria. Chemical parameters were measured in each sample using test strips , and included glucose, ketones, pH, proteins, nitrites, leukocytes, relative density, urobilinogen, bilirubin, and the presence of blood (i.e. hemoglobin or erythrocytes). Urinary protein concentration was measured after a 10 min sample centrifugation.Urine samples (20–50 mL) were centrifuged at 3000 g for 10 min at 4 °C. Samples were maintained on ice (4 °C) at all times to avoid RNA degradation. The supernatant was removed, and the pellet was re-suspended in 750 µL of Trizol solution  to obtain a pink cloudy solution. Total RNA extraction was performed using the Trizol-chloroform method according to the manufacturer's instructions. RNA quantification was performed by absorption spectrophotometry using the Epoch Spectrophotometer System  measuring at 260 and 280 nm.The 28S/18S ribosomal RNA (rRNA) ratio (> 2) was used to assess the quality of total RNA purified from each sample. Total RNA integrity was also evaluated in a 0.8% agarose gel prepared in 1X TAE buffer with nuclease free and deionized water. RNA (500 ng per well) was loaded at a final volume of 10 µL. Ladder 1 kb  plus (3 µL) was loaded and the samples were run at 80 V for 45 min. The criteria used to establish RNA integrity was the presence of 28S (~ 5070 kb) and 18S (1869 kb) rRNA bands at an 28S/18S ratio of ~ 2.7. The intensity of each band was analyzed using Image J. In addition, we determine 18S rRNA levels to ensure polymerase chain reaction (PCR) quality and reproducibility considering the effect of total RNA degradation.−ΔΔCT and the ratio of the gene of interest versus 18S rRNA abundance.RNA sequences for human renin, AGT, IL-18, CTGF, NGAL and KIM-1 were BLASTed using NCBI software. After the analysis of sequence complementarity using Primer-BLAST software, we proceeded to design the specific primers in the Primer3 website. Primers are shown in Table P value < 0.05 was considered statistically significant.Statistical analyses were performed using GraphPad Prism Software Version 6 . Clinical characteristics and laboratory data of all patients at baseline are reported as the mean ± S.E.M. Comparisons between normal weight (n = 25) and overweight (n = 17) groups were performed using non-paired (one-tailed) t-test. Normal distribution of each parameter analyzed was tested by using Shapiro–Wilk. The correlation coefficient was used to verify the relationship between systolic or diastolic blood pressure and BMI, or fasting blood glucose and proteinuria in the population analyzed. A 2 = 0.1384, P = 0.014) and diastolic BP versus BMI . The association of BMI and SBP is shown in Fig. 2 = 0.0499, P = 0.1602); however, diastolic blood pressure showed a significant correlation , see Fig. Linear regression of BP and BMI in the overall sample showed significant deviation from zero when analyzing systolic BP versus BMI . We examined whether there was an association between BFM% and fasting blood glucose in the study population. Although linear regression of BFM% and fasting blood glucose correlations in the overall sample showed no significant deviation from zero , it did show a positive slope Fig. 2 = 0.07 (P = 0.06). Similarly, there was a weak but positive correlation between fasting blood glucose and proteinuria . Renin mRNA levels were also greater in this group .To determine the status of the intra-tubular RAS, we evaluated the mRNA levels of renin and AGT in the study groups. As previously described, the criteria used to establish RNA integrity was the presence of the 28S and 18S rRNA bands with a ratio ~ 2.0. Expression levels are presented as biomarker versus 18S mRNA. Therefore, the mRNA of interest is normalized with a housekeeping gene (18S RNA) independently of the number of desquamated cells obtained. After two urinary sample collections and implementation of the inclusion/exclusion criteria for RNA integrity, 17 individuals with normal weight and 11 of the overweight group were selected. As shown in Fig. P < 0.05 and 2.0 ± 0.9 vs. 1.0 ± 0.4, P < 0.05, respectively) , promoting proliferation, fibrosis, and renal injury40.Obesity is linked to hypertension and Type 2 diabetes, the most important causes of CKD40, it is possible that higher urinary IL-18 mRNA levels reflect filtered mRNA from a systemic inflammatory response in obesity. Although the same can be expected of CTGF, most of the evidence suggests that elevated urinary CTGF is more likely to be caused by local production and tubular dysfunction in kidney disease42. We further investigate the expression levels of more specific kidney injury markers, KIM-1 and NGAL. KIM-1 is a transmembrane glycoprotein. Protein expression is not detectable in the normal kidney; however, it can be detected in the urine samples of patients with acute kidney injury (AKI) and has been proposed to be a biomarker for tubular injury43. As shown in Fig. 45. The expression of NGAL was low in healthy subjects with normal weight, which is evident as judged by a representative image in Fig. In this study, we demonstrate that overweight subjects had higher levels of transcripts of urinary RAS components, renin and AGT Fig. A,B, in aThe population analyzed showed positive correlations between BMI versus SBP and BMI versus DBP Fig. A,B. We a−ΔΔCт method. Although some reports suggest that GAPDH are preferable to 18S rRNA for urine analysis46, quantification and amplification of 18S rRNA ensure PCR quality and reproducibility (see “Method” section). The 18S rRNA has been used for normalization of the expression of a specific gene in urinary cell mRNA profiles for the prediction of human kidney allograft status47 and in inflammatory cells for the detection of variations in cytokine and inflammatory expression48. In our study, the 18S rRNA transcript levels were not significantly different between the patient groups and showed low variability among samples examined by melting curves in different urine samples (data not shown). Urine samples from healthy subjects were additionally used to perform non-quantitative PCR using the qPCR primer sets. Figure Urine samples from healthy and injured kidneys contain tubular-derived cells expressing a variety of molecules that reflect the ongoing intra-renal and intra-tubular status. Urine samples represent a useful tool to detect biomarkers for kidney disease. In this study we have successfully used RNA detection in non-invasively collected urine samples to perform quantitation of mRNA transcripts for AGT, renin, IL-18, CTGF, KIM-1 and NGAL by qPCR. The qPCR technique has been widely used and validated in absolute and relative quantification of mRNA from tissues and body fluids. Transcript mRNAs levels were normalized in relation to 18S RNA using the 249. Singh et al. showed that urinary TNF-alpha is significantly elevated in obese adolescents and correlates with urinary endothelin-1, a biomarker for endothelial dysfunction. The authors also propose that TNF-alpha may be used as a non-invasive tool to monitor the level of inflammation in obesity, which is a chronic inflammatory state50.Our findings are supported by previous studies demonstrating that injury and inflammatory markers are augmented in obesity and associated with increased oxidative stress51. Tang et al.52 demonstrated that renin levels are greater in the urine of both patients with diabetes and mice with induced diabetes type I. To examine the role of filtration and tubular reabsorption on urinary renin, the authors used mice infused with recombinant renin and lysine, which is an inhibitor of proximal tubular protein reabsorption. Lysine infusion markedly increased urinary renin levels between both nondiabetic and diabetic mice, such that there was little difference between the two groups. The authors also showed no differences between the levels of renin transcripts in micro-dissected collecting ducts of diabetic mice and that of wild-type mice, suggesting that most of the renin detected in the urine under diabetic conditions is a result of altered renin filtration and impaired reabsorption at the proximal tubules52.It has been suggested that changes in urinary renin levels in patients with diabetes occur independently of changes in plasma renin, indicating involvement of the activated renal RAS. Therefore, urinary renin may be a better indicator of renal RAS activity than urinary angiotensinogen or aldosterone54. Then, early detection of kidney injury markers and other RAS components in intra-tubular epithelial cells along the nephron may help to establish an imminent risk of renal disease in overweight young adults. Moreover, BMI is easy to measure in pediatric and young populations, and the non-invasive collection of urine can provide information on renal status using qPCR. This may represent a new strategy for CKD risk screening in the adult. As suggested by other studies, the use of BMI is also recommended to predict and screen hypertension55.Despite this evidence other studies have suggested that renin transcript is augmented in CD in diabetic miceDespite the limitation of small sample size in our study, we observed a clear phenomenon that has been described in several recent clinical studies that employed large numbers of patients and in which the same association between BMI and BP was observed. Our study adds further molecular information to explore the intra-renal status of the RAS and tissue injury. This additional analysis might be adopted as a complementary approach in future studies using large sample numbers.In conclusion, we have demonstrated that SBP and DBP augmented significantly and linearly across BMI levels in a normotensive population of young adults. Using a non-invasive methodology, we found that overweight individuals have higher mRNA levels of urinary renin and AGT, a reflection of intra-tubular RAS activation. This group also showed high expression of IL-18 and CTGF. This suggests that BMI may have direct effects on blood pressure and the activation of intra-tubular RAS, which can lead to kidney injury. Therefore, BMI likely poses a risk factor for incipient kidney disease even in normotensive young adults.Supplementary Information.


Hypertension is a common health problem, and one of the most important risk factors for cardiovascular disease. Hypertension treatment is usually based on drug administration, yet lifestyle changes and especially diet have also been proven to be almost as effective in hypertension therapy. Dietary components may act favourably in many pathophysiological mechanisms responsible for blood pressure elevation, both acutely and after long-term use. The Special Issue “Nutritional Therapy for High Blood Pressure” aimed at offering a valuable insight into how diet as a whole or via individual components can serve as valuable means for blood pressure control in patients or apparently healthy populations, thus bringing together some of the latest relevant scientific evidence.The association of diet with blood pressure has been thoroughly investigated both holistically, through the examination of the whole diet and dietary patterns, but also at a single food item or nutrient level, via the examination of specific foods, nutrients and certain bioactive compounds. There is also variability with regards to the design of the studies that have provided evidence related to the association or the effects of nutrition on high blood pressure, considering that the Special Issue combines data from reviews, observational studies and clinical trials.According to evidence coming from observational studies that examine the associations between the whole diet and blood pressure, the cross-sectional study by Valle et al. used data from the ESTEBAN survey that was conducted with a representative sample of French adults and reported that adhesion to the DASH (Dietary Approach to Stop Hypertension) diet was associated with lower systolic and/or diastolic blood pressure levels . The DASOther observational studies have reported associations between the dietary intake of specific nutrients and vascular outcomes related to high blood pressure. In this regard, the review by Tsirimiagkou et al. investigated the association between dietary sodium intake and major vascular damages, which include atheromatosis, arteriosclerosis and arterial remodeling, and lead among others also to hypertension . ArterioConsidering the inappropriateness of observational studies to provide a causal pathway in the associations observed between the whole diet or its individual components and high blood pressure, clinical trials can more accurately address the therapeutic effect of diet, foods or single nutrients on hypertension. In terms of the blood pressure-lowering properties of certain food items, Cashman et al. conducted a randomized crossover pragmatic intervention trial on 97 apparently healthy adults in Ireland, with slightly to moderately elevated blood pressure . These aThe clinical trials published in this Special Issue, provide strong evidence that support the therapeutic potential of reduced salt (or sodium) intake through staple foods, as well as of bioactive nutrients, such as polyphenols in olive oil and nitrate in beetroot juice, in the management of hypertension. Nevertheless, the blood-pressure properties of diet are not limited to these specific foods and/or nutrients. In this regard, the systematic literature review and meta-analysis by Aboud investigated whether vitamin D supplementation reduces BP in children and adolescents . AlthougIn conclusion, despite the wide range of pharmacological treatments for high blood pressure control, hypertension remains one of the leading health problems, highlighting the need for additional, non-pharmacological solutions. Diet therapy has been repeatedly proven to be effective in blood pressure control, either as a whole through healthy dietary patterns, such as DASH or the Mediterranean diet, or through bioactive nutrients that include vasoactive compounds. Future experimental studies should aim to assess the long-term compliance to these healthy dietary patterns, as well as the effective and safe dose of individual dietary compounds and their combination in the control of high blood pressure.


Several studies have emphasized the heterogeneity of fibromyalgia patients. Furthermore, fibromyalgia patients are considered a high-risk suicide group. The ideation-to-action framework proposes a set of transdiagnostic psychological factors involved in the development of suicidal ideation. The present study aims to explore the existence of different subgroups according to their vulnerability to suicidal ideation through these transdiagnostic psychological variables and a set of variables typically associated with fibromyalgia. In this cross-sectional study, 151 fibromyalgia patients were assessed through the Revised Fibromyalgia Impact Questionnaire, Beck Depression Inventory-II, Plutchik Suicide Risk Scale, Interpersonal Needs Questionnaire, Defeat Scale, Entrapment Scale, Psychache Scale, and Beck Hopelessness Scale. A K-means cluster analysis identified two clusters, one (45.70%) according to a low vulnerability, and a second (54.30%) with a high vulnerability to suicidal ideation. These clusters showed statistically significant differences in suicidal ideation and suicide risk. However, no differences were observed in most socio-demographic variables. In conclusion, fibromyalgia patients who present a clinical condition characterized by a moderate-high degree of physical dysfunction, overall disease impact and intensity of fibromyalgia-associated symptoms, along with a high degree of perceived burdensomeness, thwarted belongingness, defeat, entrapment, psychological pain and hopelessness, form a homogeneous group at high risk for suicidal ideation. Fibromyalgia (FM) is a multisystemic syndrome characterized by the presence of generalized pain, tenderness, stiffness, and other associated symptoms such as fatigue, insomnia, anxiety, depression, and somatic complaints of various kinds ,2. The aIn general, the treatment of FM is symptomatic and requires a multidisciplinary approach combining non-pharmacological  and pharmacological treatment ,9. PharmThere is evidence in the literature that groups with chronic pain, such as people with FM, are at high risk for suicide ,18. AddiIn a systematic review of studies conducted primarily in the U.S. population, Tang and Crane  found thSuicidal ideation is defined as the state characterized by thoughts or desires of being dead or ending one’s life . SuicidaPrevious studies ,26 have The first model that was developed within this theoretical perspective was the IPTS . This moAccording to IMV , the keyFinally, the most recent ideation-to-action theory is 3ST . AccordiThe multifaceted expression of FM, with marked variability in presentation and severity of symptoms, suggests that FM patients are a heterogeneous group ,45. ConsThe present study aims to explore the existence of different subgroups of FM patients according to their vulnerability to suicidal ideation. To this end, key variables included in the ideation-to-action theories and that are essentially involved in the development of suicidal ideation  will be taken into account, as well as variables essentially related to the fibromyalgia syndrome, such as physical function, overall impact of FM, intensity of physical pain and symptoms associated with FM and severity of depressive symptoms. This will allow us to establish profiles that cover the wide spectrum of physical and psychological symptoms of these patients, as well as to evaluate whether the degree of physical dysfunction or severity is consistent with the presence of high values in the variables involved in suicidal ideation and, therefore, could be part of a potential profile of patients vulnerable to suffering from it. The results of this work could orient psychological therapy towards new therapeutic targets that have not been explored among FM patients , as well as emphasize the relevance of a holistic approach  of FM patients in the screening and treatment of suicidal ideation. According to the ideation-to-action framework, preventing suicidal ideation is reducing distress and preventing suicidal behavior, since the development of suicidal ideation is the first and most common step on the pathway to more serious suicidal behavior.The selection of participants was carried out by incidental sampling. The sample consisted of a total of 151 FM patients residing in Spain  who completed an online questionnaire. The inclusion criteria were: (1) to be older than 18 years old, and (2) self-report being diagnosed with FM according to the criteria of the American College of Rheumatology 1990 [Fibromyalgia Impact Questionnaire Revised  was adaBeck Depression Inventory, version II  adaptedPlutchik Suicide Risk Scale  adaptedInterpersonal Needs Questionnaire  adaptedDefeat Scale  adaptedEntrapment scale  adaptedPsychache Scale  adaptedBeck Hopelessness Scale  adaptedhttp://encuestas.ual.es/limesurvey/index.php/539641?lang=es). Participation was anonymous and voluntary. All the participants gave their informed consent. They were provided with a contact address to answer any questions about their participation in the study. This study was approved by the Bioethics Committee on Human Research at University of Almería, Spain (Ref: UALBIO2018/018).The present study has a cross-sectional design. The managers of a group of FM patient associations located in different parts of Spain were contacted and they promoted and distributed among their members a questionnaire in line with the scales and socio-demographic questions of the study , overall impact of FM , intensity of FM associated symptoms , intensity of physical pain  and severity of depressive symptomatology . And, on the other hand, the variables involved essentially in the development of suicidal ideation of the IPTS , of the IMV  and of the 3ST . Prior to the cluster analysis, the scores of all variables were standardized.Due to the exploratory nature of the study, a hierarchical cluster analysis was first performed in which a dendrogram was obtained . This det-test . Finally, the independence of the sociodemographic characteristics of the participants was analyzed according to their belonging to each cluster through the Chi-squared test. All analyses were performed with IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY, USA: IBM Corp.Also, as a cross validity procedure, three additional K-means cluster analyses were performed with a random case selection of 25%, 50%, and 75% of the total sample to compare the degree of stability between the different solutions. Likewise, to obtain validity evidence on the meaning of the profiles, we compared the suicidal ideation (item 9 of the BDI-II) and the suicidal risk  of both clusters through the U-Mann–Whitney test  and the Student Since the dendrogram showed a clear solution of two clusters, a K-mean cluster analysis was executed requesting two clusters. The ANOVA  shows thCluster 1  is characterized by moderate values in the dimensions of FIQ-R  and in the item of physical pain intensity, mild-moderate values in the severity of depressive symptomatology, low values of perceived burdensomeness and thwarted belongingness, low values of perception of defeat and entrapment, moderate values of psychological pain and low hopelessness . This fip < 0.001) in suicidal ideation between low profile (average range = 54.93) and high profile (average range = 93.73), with participants from the latter being the most vulnerable to suicidal ideation and therefore having higher values of suicidal ideation. In addition, using item 15 of Plutchik Suicide Risk Scale “Have you ever tried to take your own life?” in the low profile, 13% had tried to end their own life compared to 34.1% in the high profile who had done so . Similarly, when comparing suicide risk, statistically significant differences are observed  between low profile  and high profile . Therefore, as with suicidal ideation, participants in high profile  obtain higher values in suicidal risk.In order to obtain validity evidence on the meaning of the profiles, scores for suicidal ideation and risk were compared between both profiles. There are statistically significant differences , educational level completed , marital status  and religion . However, work activity does show statistically significant dependence between both subgroups , with a higher proportion of employees in low profile (43.5%) compared to high profile (32.1%), as well as a higher proportion of retirees/pensioners/rentiers in low profile than in high profile (26.1% vs. 9.0%). In contrast, high profile has higher frequencies of unemployed (25.6% vs. 13.0%) and permanent disability pensioners (15.4% vs. 2.9%) than low profile.Regarding the differences between profiles in the sociodemographic variables , no statThe heterogeneous presence and severity of symptoms among FM patients limits understanding of fibromyalgia and makes it difficult to choose appropriate treatment . DespiteThe present study aimed to explore the existence of homogeneous subgroups of FM patients according to their vulnerability to suicidal ideation. The main novelty is the use of psychological variables of transdiagnostic relevance  and considered as key elements in the development of suicidal ideation of the three predominant theories  of the ideation-to action-framework. A cluster analysis was carried out, consisting of these psychological variables  together with other variables associated with fibromyalgia syndrome . Our findings show that, as expected, these variables adequately identify and discriminate fibromyalgia patients who may be at risk of suffering from suicidal ideation, reducing the variability to two groups (high risk/low risk), despite the heterogeneity of these patients. Additionally, the variables of the theories behave in a similar and concomitant way, showing a high relationship among them and their association with the intensity of the typical symptoms of fibromyalgia , physical functioning, and impact. In short, this is an exploratory study that positions a set of variables to be examined among fibromyalgia patients and a claim for exploring the theoretical assumptions of these theories to clarify the high prevalence of suicidal ideation in fibromyalgia and to optimize screening and psychological management.The result showed a solution of two clusters (or profiles) of FM patients. A first profile characterized by patients with low-moderate values in all the variables implemented in the analysis, affected to a lesser extent by the fibromyalgia syndrome, physically and psychologically, and with low values in the psychological variables involved in suicidal ideation. Therefore, this is a group of participants that is predictably less vulnerable to suffering suicidal ideation. It should be noted that this subgroup represented 45% of the sample, so that more than half of the FM patients (cluster 2) obtained scores reflecting more severe physical and psychological symptoms and scores on the variables related to suicidal ideation comparable to a high risk of suffering from suicidal ideation. Although this proportion does not show the specific prevalence of suicidal ideation in these patients . However, despite the limitations related to the capability of a single item to capture the complexity of the construct, this item has been used frequently in the literature and it has an outstanding reputation based on the concurrent validity with the Beck Scale for Suicidal Ideation . AnotherIn conclusion, FM patients who present a clinical condition characterized by a moderate to high degree of physical dysfunction, overall disease impact and intensity of FM-associated symptoms (including high severity of depressive symptoms), along with a high degree of perceived burdensomeness, thwarted belongingness, defeat, entrapment, psychological pain, and hopelessness, form a homogeneous group at high risk for suicidal ideation. According to the ideation-to-action framework, preventing suicidal ideation is not only about preventing the suffering and distress that it causes, but also limiting the transition to suicidal action ,84. Ther


Wearable sensors to continuously measure blood pressure and derived cardiovascular variables have the potential to revolutionize patient monitoring. Current wearable methods analyzing time components  still lack clinical accuracy, whereas existing technologies for direct blood pressure measurement are too bulky. Here we present an innovative art of continuous noninvasive hemodynamic monitoring (CNAP2GO). It directly measures blood pressure by using a volume control technique and could be used for small wearable sensors integrated in a finger-ring. As a software prototype, CNAP2GO showed excellent blood pressure measurement performance in comparison with invasive reference measurements in 46 patients having surgery. The resulting pulsatile blood pressure signal carries information to derive cardiac output and other hemodynamic variables. We show that CNAP2GO can self-calibrate and be miniaturized for wearable approaches. CNAP2GO potentially constitutes the breakthrough for wearable sensors for blood pressure and flow monitoring in both ambulatory and in-hospital clinical settings. Realizing wearable sensors for blood pressure (BP) monitoring with clinically-acceptable performance remains a significant challenge. Here, the authors report a continuous noninvasive blood pressure measurement system featuring a volume control technique for small wearable sensors. Innovative wearable sensors for monitoring of cardiovascular dynamics have the potential to revolutionize the monitoring of vital signs and their response to therapy in both ambulatory and in-hospital clinical settings. Continuous real-time monitoring of cardiovascular dynamics—including arterial blood pressure (BP) and advanced hemodynamic variables that are derived from its waveform , and dynamic cardiac preload variables)—is a mainstay of patient care in perioperative and intensive care medicine but, for the most part, still requires invasive or stationary noninvasive sensors3. With the availability of noninvasive and wearable sensors, advanced cardiovascular monitoring may become part of patient surveillance on normal wards4 and even outside the hospital5. Upgrading patient monitoring capabilities with wearable solutions designed for normal wards may help avoid intensive care unit overload (as seen during the COVID-19 crisis)6.The digital revolution is about to bring innovations to physiologic monitoring7 and have, therefore, not been adopted into clinical practice.For these clinical applications, wearable sensors have to fulfill all regulatory and clinical demands of medical-grade devices—just as their stationary counterparts. Challenges for future developments in the field of wearable miniaturized monitoring sensors will be to provide measurements with clinically acceptable accuracy, precision, and reliability and to ensure clinical usability and patient safety. Ideally, miniaturized monitoring sensors measure in the background without user interaction. At the moment, wearable sensors for continuous BP monitoring still show poor measurement performance8. Other time-based methods for BP estimation use sensors that decompose the pulse into a forward and a backward wave to analyze their time differences10. There are also attempts to use photo-plethysmographic (PPG)11 or piezoelectric12 pulse detection for the estimation of BP based on amplitude and time information. However, a direct translation of the pulse signal—which is a surrogate for volume changes—into continuous BP is challenging because of confounding effects of the cardiovascular, respiratory, and autonomic nervous systems. By enhancing model complexity , the measurement performance of these approaches may be improved14. Although their sensor hardware is very simple, significant work is still needed to achieve clinically acceptable performance16. The difficulty with time-based approaches for wearable BP measurement devices seems to be that the variables of the mathematical models need to change along with changes in vasomotor activity of the vascular smooth muscles which are determined by the autonomic nervous system. All of these cuff-less attempts of continuous BP monitoring require frequent re-calibration, for example using cuff-based sphygmomanometers, rendering them unfeasible for wearable wireless monitoring18.Most current wearable BP monitoring systems estimate BP based on time information. Pulse time interval or pulse velocity methods use a proximal and a distal sensor for the measurement of the pulse transit time or pulse arrival time19. Another innovative approach measures oscillometric curves by pressing a finger on a cell phone screen21. While this research shows that oscillometric BP measurement at the finger is feasible, these methods need user interaction (keeping the sensor at heart level or pressing a finger on the screen) and automated continuous BP monitoring (including monitoring during night sleep) is not possible.Other wearable approaches based on the oscillometric principle provide BP values intermittently. For example, the HeartGuide  is a wrist-worn watch-type oscillometric BP monitoring device22. These devices are based on the vascular unloading technique (VUT), also referred to as volume clamp or Peňáz method25. The VUT measures BP and derives the complete pulsatile BP waveform by controlling fast inflation and deflation of a finger cuff in combination with PPG. As with time-based technologies, the VUT is influenced by changes in vasomotor activity; different devices have found differing methods to detect and compensate for changes in vasomotor tone28. VUT devices do not necessarily need calibration for proper functioning. Instead, the Finapres  and successor devices use a heart level sensor and/or a transfer function to provide estimates of brachial BP values30. CNAP devices  have a different approach: they routinely use an upper arm cuff for orthostatic/heart level correction and for calibration to brachial BP level31. A transfer function approach is also used as a temporary correction until the calibration is performed or if the user does not want to use the upper arm cuff.Stationary finger cuff devices have been successfully introduced for direct continuous noninvasive BP monitoring in various medical fields, especially in critical care and anesthesiologyExisting VUT systems are, however, too bulky to be used for wearable monitoring devices because the systems consist of mechanical elements like pumps, valves, and air hoses to follow the pulsatile nature of BP with high fidelity.It was generally believed that, for correct BP measurement based on VUT, a constant (or clamped) blood volume in the finger over the complete period of pulsation and therefore full vascular unloading of the blood vessels is essential. Whether this is indeed physiologically or metrologically necessary was never examined.The basic idea behind our novel art of continuous noninvasive BP measurement, CNAP2GO, is to perform the blood volume control substantially more slowly to be able to use slow-moving and, therefore, small-scaled hardware. Most importantly, such hardware requires neither a pump nor a valve. The basic principle of the CNAP2GO method is the volume control technique (VCT). In contrast to the VUT, which keeps the blood volume in the finger artery constant on a millisecond basis to accurately follow the full cardiac cycle, the VCT keeps the volume constant on a time scale of heartbeats. Blood volume is allowed to oscillate over heartbeats, balancing inflow and outflow of blood in the finger artery over each heart cycle. Controlling blood volume by VCT without fast oscillations poses a non-trivial control engineering problem, which is solved using a set of signal processing algorithms. Most importantly, as we will demonstrate, this method is resistant to changes in vasomotor tone.In this paper, we first describe the elements of CNAP2GO and how they interact to derive a continuous BP waveform from the directly measured mean BP (mBP) and the PPG signal. We show that the BP waveform can be used to estimate advanced hemodynamic variables. The VCT was implemented in software and placed on the hardware of an existing VUT-device that emulates slow VCT. The accuracy of the CNAP2GO software prototype was clinically validated in comparison with invasive BP measurements obtained using a radial arterial catheter in patients having surgery with general anesthesia. The CNAP2GO method can, in the future, be used for small wearable sensors integrated in a finger-ring utilizing a light transmitter (LED) and a receiver (photodiode). The contact pressure of LED and photodiode can be modified by an actuator changing the ring diameter with a rate-of-change as fast (or rather: as slow) as mBP.v(t), which is the basis for VCT. Using this envelope, the method can automatically self-calibrate to oscillometric systolic BP (sBP) and diastolic BP (dBP). For a clinically meaningful continuous BP signal, an integrated heart level sensor utilizing an electronic XYZ-axis accelerometer and gyroscope in addition to a suitable transfer function will be applied. As user interaction is not required, CNAP2GO may be used in a broad range of medical applications.A wearable approach of an actuator is demonstrated and its feasibility is shown. This actuator is able to produce a typical oscillometric curve measurement including its envelope derived from the PPG signal The CNAP2GO sensor is a PPG probe which comprises an LED and a photodiode. The contact pressure of these light elements to the skin can be modified. Even simple PPG probes  have elements that couple the light components to the body with pressure: this is usually a spring, Velcro, or another simple clamp mechanism. A constant pressure (around 20–30 mmHg) ensures good light coupling. Within CNAP2GO, a simple actuator can vary the contact pressure of the light elements as fast as mBP may change Fig. . As a coThe basic idea of varying contact pressure is also implemented in all existing devices based on the VUT. When using the VUT, the speed and amplitude of the changes in contact pressure must match pulsatile arterial BP, requiring pressure changes of 30–100 mmHg per systolic upstroke of the beat to ensure high-fidelity pressure waveforms. For example, the pressure system of the CNAP devices can apply pressure changes with more than 1500 mmHg/s.v(t) is an inverse surrogate for blood volume changes inside the finger artery: Rising blood volume increases absorption and therefore decreases the amount of light transmitted through the finger.The CNAP2GO contact pressure is determined by a closed-loop control system using the PPG signal and its components as input signals. Figure pc(t) of the light elements can be altered by the actuator and is measured by a pressure gauge. v(t) is led into digital filters producing vPulse(t), vRhythm(t), and vVCT(t). The signal components vRhythm(t) and vVCT(t) are used to control pc(t), whereas vPulse(t) together with pc(t) are needed for the calculation of the pulsatile BP signal pC2G(t). The control loop between the controller and the pressure is closed using antiresonance elements. Note that v(t) and its components are dimensionless digital signals representing a surrogate of blood volume in the finger.The contact pressure vPulse(t). Figure v(t) when a pressure ramp pc(t) is applied. The p-v transfer function corresponds to an S-shaped arcus tangent with superimposed pulses32. The upper asymptote of v(t), where pc(t) is far above sBP, corresponds to the maximum light that can be detected from the finger when all blood is squeezed out and no pulses can be detected. The lower asymptote is at pc(t) = 0 where no deformation of the finger and its artery occurs . The amplitudes of the v(t)-pulses are derived from the high-pass filtered vPulse(t). The amplitudes of vPulse(t) are fitted using a Gaussian-style envelope curve, as can be seen in Fig. 33, a principle which also holds true when using PPG signals36. After oscillometric envelope determination, the system applies mBP as initial contact pressure pc(t) and stores this value as the starting setpoint P0 and its PPG companion v0. For calibration purposes, sBP and dBP can be determined.Closing the CNAP2GO control loop requires an initial open-loop phase to determine the initial value of mBP by altering the contact pressure and detecting the corresponding PPG pulse-amplitudes from the signal While this open-loop phase is very similar to the basic oscillometric principle, as well as to standard VUT, the closed-loop of CNAP2GO differs in almost all fundamental aspects.pC(t) is located on the inflection point of the S-shaped p-v transfer function. As shown in Fig. vPulse(t) (light blue trace) has maximum amplitude and the integral of vPulse(t) over a full beat is zero. Thus, the main condition of the VCT, which keeps blood volume in the finger artery balanced over a heart cycle, is fulfilled.After the closed-loop phase, the mean cuff pressure pC(t) is lower than mBP (p<), vPulse(t) has a lower amplitude (purple trace) and differs in pulse shape: the pulses are fat. In contrast, if pC(t) is higher than mBP (p>), vPulse(t) has also a lower amplitude, but the pulses are spiky (dark blue trace).As soon as BP or vasomotor changes occur, the situation becomes different. If p-v transfer function: while the upper asymptote for pC(t) >> sBP remains unchanged, the lower asymptote for pC(t) << dBP shows a higher v(t) because finger blood volume decreases during vasoconstriction. This results in a setpoint lower than the inflection point and a change from v0(t) to a smaller but fat v1(t) with the negative half-wave of the fat pulse being greater than the positive half-wave. On the other hand, vasodilation increases the setpoint over the inflection point, thus producing a spiky signal.Figure 0 and resulting pC(t) need to be altered after each heartbeat until balance is achieved .For both fat and spiky pulses, the integral of the pulsatile volume signal over a beat is no longer equal to zero. The CNAP2GO controller is responsible for restoring this condition of balanced volume control: in particular, the setpoint pved Fig. . A propop-v transfer function to the right—tends to move the setpoint towards the lower asymptote of the p-v transfer function. The integral over the beat will be negative resulting in an increase of the setpoint pn. Vasodilation shifts the S-curve in the opposite way and VCT decreases pn.This mechanism not only works for vasomotor changes but also for pure mBP changes. An increase in mBP—which is a shift of the pC(t) tracks mBP and, with a simple calculation, the pulsatile nature of BP can be superimposed using vPulse(t):CNAP2GO’s init and dBPinit are calibration values and vsys and vdia are maxima and minima of vPulse(t) during the initial phase.where sBPinit and dBPinit can be obtained as external  values or from the initial phase  to turn its VUT into VCT (CNAP2GO). Although the CNAP hardware in principle allows for the fast pulsatile BP changes as necessary for VUT, the speed of pressure changes was inherently limited by the software design of CNAP2GO as described in this article.There were three reasons for this approach: First, the hardware of the CNAP Monitor HD has international regulatory approval for use in patients. Second, the experiments could be performed prior to expensive investments into miniaturization. And finally, the CNAP HD technology allows the calculation of hemodynamic variables derived from the BP waveform.CNAP2GO was implemented as software code (C++) and loaded as firmware on the CNAP Monitor HD. The final device was CE-marked as a class 2b device for clinical use in patients in the operating room. The sphygmomanometer of the CNAP Monitor HD was used for calibration.Lab tests were performed in 20 healthy subjects Table . In Fig.The mean of the differences and its standard deviation between mBP measured with CNAP2GO and with CNAP Monitor HD were 0.3 ± 4.4 mmHg.Occasionally, unexpected motion artifacts appeared synchronously in BP signal streams of both the CNAP2GO and the CNAP Monitor HD. Movement only very briefly disturbed BP signal quality for both the CNAP2GO and the CNAP Monitor HD and the BP signal quality recovered immediately. Rapid signal recovery after signal alterations by finger movement is a characteristic feature of the existing CNAP method that we also implemented in the CNAP2GO method.39. The bias between CNAP2GO CO and CNAP Monitor HD CO was 1.4 ± 0.6 L/min with a percentage error (PE) of 22%. As shown in Fig. 40. The PE of 22% indicates that the CO trending information in the CNAP2GO BP signal is very similar to standard CNAP. This means that despite the nonlinearity of the vascular wall, the information in the PPG and BP waveform shapes are about the same, when contact pressure is at mBP and thus the artery is unloaded.CO was calculated using the proprietary CNAP HD pulse wave analysisWe included 46 patients having neurosurgery with general anesthesia in a clinical study. Invasive blood pressure (IBP) was recorded during routine care. We compared mBP measured using CNAP2GO and mBP measured using a radial arterial catheter  during a period of about 45 min Table , we usedWhen individually analyzing the data of each measurement, the mean of the differences for mBP ranged from −14.6 to 11.4 mmHg (interquartile range from −4.0 to 2.9 mmHg) with standard deviations ranging from 1.1 to 6.3 mmHg (interquartile range from 2.0 to 3.4 mmHg), indicating that the intra-subject difference to invasive reference was both stable as well as small for mBP values.n = 97,432) were inspected together with the corresponding pulse intervals and the resulting need for actuator speed. The contact pressure of CNAP2GO required a median changing speed of about 1.4 mmHg per beat or 1.3 mmHg/s, the maximum values were 24.4 mmHg per beat or 25 mmHg/s.The rate of actuator pressure change, which according to VCT follows mBP, was analyzed in detail. The absolute changes in mBP of consecutive heartbeats (pc(t) in comparison with the frequency content of the whole pulsatile BP signal, demonstrating how much the control was slowed down for CNAP2GO.Figure The results of the clinical study reveal important findings for miniaturization of CNAP2GO. Miniaturized CNAP2GO requires a small, low power actuator with a maximum speed of at most 25–30 mmHg/s, with an average speed of about 1.4 mmHg per beat. The actuator in interaction with the PPG system has to provide a correct oscillometric signal, needed for both the initial calibration and VCT principle. Here, correct means that the PPG signal has its origin only in the body segment and is not influenced by the mechanics of the sensor, e.g., a better signal coupling of the PPG elements due to higher actuator pressure. A constant signal-coupling over the complete pressure range can be achieved only with a homogenous pressure at the finger which underlines the essential role of sensor geometry.Different prototypes were tested, the most promising system being a fluid-filled bladder containing the PPG elements in combination with a small motor compressing the fluid. Fluids can be incompressible gels or oils, for our experiment we used distilled water. Figure pC(t) higher than a minimum contact pressure of about 20–40 mmHg. The fluid-filled bladder was located in a finger-ring. While we were focusing in this present prototype on the wearable sensor geometry, we used a small commercially available infusion pump as a fluid compressing driver.Signal coupling of the PPG elements stayed constant with a We were able to demonstrate that this wearable fluid-filled bladder concept is able to produce correct oscillometric signals by testing the system within 7 subjects in comparison to the existing CNAP sensor. Results in comparison to a standard CNAP device are shown in Fig. Drivers for actuators such as small printable piezoelectric motors are available with two important features: Low power consumption, but high enough stall torque to keep the actuator in its current position when no movement is needed. This has the effect that no energy is needed if mBP does not change.We made basic calculations for a wearable CNAP2GO sensor using the data from a commercially available step motor  to prove that the required pressure changes are feasible. We chose a printable motor with an outer diameter of 30 mm that can be integrated in the plate of a CNAP2GO finger-ring. This motor can change the volume in the fluid-filled bladder and thus contact pressure of the PPG elements via a gear from the motor. With a transmission ratio of the gear element higher than 20.27, this component has a high enough stall torque so that no energy is consumed as long as mBP is stable. With such a fluid-filled transmission system, the motor should theoretically change contact pressure for 1 mmHg within 10 ms. Assuming additional time due to control loops and further tolerances, we assume that a rate of pressure changes of up to 30 mmHg/s could be achieved with this particular piezo motor.pc(t) to follow mBP will be done as soon as the beat detector of the system has detected a heartbeat . Then the VCT criteria are used to derive the resulting new pc(t). In the validation experiments, pc(t) was adjusted using the CNAP pressure system and the finger cuff. In miniaturized CNAP2GO, the fluid-filled actuator will be activated until the new pc(t) is applied to the finger. Then the actuator will stop and keep pc(t) constant, at best, without power until the next heartbeat is detected.In miniaturized CNAP2GO, readjustments of Very significant BP changes of 2 mmHg per beat and a heart rate of 120 bpmMeasurement phase including 45 s initial phase followed by 2 min of VCT-phase13 min of low power interpolation mode (explanation next chapter)An essential requirement for practical use and user acceptance is at least a 24 h use without battery reloading. We have performed estimations on the power consumption of CNAP2GO, with the following assumptions:The power needed to run the actuator will be 45.19 mW according to our calculation. Together with the PPG system (5.64 mW), a low-power bluetooth microcontroller (1.66 mW) and a motion sensor (6.21 mW), the power requirement of the CNAP2GO system is 58.7 mW or 1409 mWh during 24 h. For comparison, a single AAA-battery has 1500 mWh; when using two batteries or a rechargeable accumulator with more than 2000 mWh, a 24 h operation should be easily possible. As another example, the CNAP module, which is the core measurement unit without a user interface, has an average power consumption of 2.5 W with peaks up to 5 W.There are still some challenges regarding the implementation of this method in a wearable solution.First, we did not perform our validation experiments using the final wearable hardware. Miniaturization will be a key task with this sensor. Based on the present data set, all steps of miniaturization and technological refinement can be assessed and monitored in lab tests. Based on our tests, there is a well-founded assumption that the final CNAP2GO wearable can be located in a finger-ring as shown in Fig. dv) between the heart and the finger can be measured41. As the density of blood is known, hydrostatic pressure can be calculated from dv and simply subtracted from pC(t). Although the measurement of dv during motion needs further research and validation, this form of heart level correction is implementable as opposed to analog corrections for time-based wearable approaches, where the influence of posture and arm movement on, e.g., pulse transition is evident but solutions are unclear42.Second, for the wearable solution of CNAP2GO, the measured mBP needs a correcting element for orthostatic pressure whenever the finger level differs from the heart level. Heart level correction can be achieved using low-power motion sensors. Using small XYZ-axis accelerometers and gyroscopes, the orientation of human body segments and movements can be reconstructed and thus vertical difference (v(t) or vPulse(t) during this low pressure and low power consumption mode. The system will restart “measurement mode”, either periodically or triggered by physiological changes . Figure Third, the described CNAP2GO method still needs a continuous external pressure for correct measurements, but a 24 h continuous VCT measurement is clinically not necessary. Thus for better patient compliance, CNAP2GO will switch between a measurement mode and an interpolation mode. The measurement mode starts with the initial phase followed by the VCT-phase, where hemodynamic values are measured. These values will be fed into a mathematical model, which can be sufficiently trained after a short period of measurement (approximately 2 min). Afterward the external pressure can be reduced to a minimum, just high enough to ensure good light coupling. The trained mathematical model can then be used in the interpolation mode to estimate hemodynamic values from p-v transfer function. In this unloading state, the p-v transfer function is most linear allowing for the highest signal quality needed to derive advanced hemodynamic variables such as CO. This will assure clinical accuracy of BP and CO for the entire measurement.The purpose of the regularly occurring “measurement mode” phases is to record BP signals on the inflection point of the The mechanism shown in Fig. During the measurement phase of Fig. In patients with anticipated acute hypertensive or hypotensive episodes, two-finger rings may be used to avoid continuous external pressure on one finger. Two-finger rings may be used on contralateral hands or a double finger sensor—as already available for the standard CNAP system—on the same hand.We have introduced the CNAP2GO method based on the art of VCT which requires only slowly changing actuators and is robust against vasomotor changes. We discovered that the pulsatile control in the standard VUT mainly avoids control system resonances. For CNAP2GO, we achieved the prevention of resonances by adaptive antiresonance filters.43.We were able to demonstrate validity of CNAP2GO. mBP differed by −1.0 ± 7.0 mmHg in comparison with the intra-arterial gold standard, which is well within the limits of 5±8 mmHg demanded in the ISO 81060-2 standard for intermittent noninvasive sphygmomanometersHydrostatic correction between finger and heart level may be achieved by using small XYZ-axis accelerometers and gyroscopes.The lab tests show that CNA2GO is already resistant to motion artifacts. Artifacts may happen, but after stopping the movement, the system finds back to its correct trace. However, the system has not been tested during sport activities and other heavy movements.Miniaturization of the hardware components can be realized using PPG sensors with an LED and a photodiode. The contact pressure of the light elements to the skin is modifiable by a slow and thus low-energy actuator using a fluid-filled bladder, all of which make wearable CNAP2GO sensors feasible.A continuous external pressure has to be applied on the finger during VCT measurement. Figure CNAP2GO can be self-calibrated by an oscillometric measurement at the beginning of the measurement phase. Further validation work with the self-calibrated system needs to be done to prove clinical accuracy.Challenges of CNAP2GO are addressed in the article and reveal where further development has to be done:In conclusion, we were able to demonstrate that the CNAP2GO method enables mBP to be measured with clinically acceptable accuracy and precision, also during hypo- and hypertensive phases, in patients having surgery and subjects performing physiological maneuvers with hemodynamic activation. According to our experiments, this technique seems to be very well suited for wearable sensors integrated in a finger-ring, as shown in Fig. λ = 890 nm) as well as a light-to-frequency converter  for light detection that produces a digital pulse-width modulation signal. This signal goes directly to a timer input of the DSP producing the digital PPG )44. The output of the DSP controls two valves . Both valves are arranged like transistors of a CMOS gate having one valve always closed. This allows for a high-fidelity contact pressure of the PPG elements in the finger sensor45.To obtain a CNAP2GO prototype, we modified a standard CNAP Monitor HD, especially its core unit (the CNAP module). The CNAP module is an electronic system where almost all components are implemented as software on a 32-bit digital signal processor . Attached to the CNAP module is a double finger sensor system for alternating use on the index and middle finger. Each CNAP sensor contains a PPG system utilizing an LED  remained the same as in the original CNAP Monitor HD software V5.2.14.vPulse(t) obtained at different contact pressures pc(t). The initial setpoint P0 and its PPG counterpart v0 are found according to the maximum amplitude rule. The filter variables of the cascades vFilt are then set to v0.In the open-loop phase, a Gaussian-style oscillometric envelope is calculated by using the amplitudes of v(t) has a sampling frequency (fs) of 250 Hz. A recursive digital IIR-filter was designed to obtain vPulse(t), vRhythm(t), vdRhythm(t), and vVCT(t). In Fig. After ambient light removal, yi = (1 − UC)*yi-1 + UC*xi). The recursive function provides down-sampling functionality to enable reasonable filter parameters for low cut-off frequencies.Each single filter stage contains a first-order IIR low-pass filter  is not only influenced by BP but also by vasomotor activity. In the case of vasoconstriction, smooth vascular muscles close the arteries and arterioles, and finger blood volume decreases  goes up), although BP typically rises during vasoconstriction  should go down). The opposite behavior occurs during vasodilation. This means that the information from the PPG signal v(t) below 10−2 Hz is not reliable. Therefore, this frequency range is removed from all further calculations by filtering and using vVCT(t).In very slowly changing frequency components, blood volume and thus vPulse(t), also the very-low-frequency components below 10−2 Hz of v(t) are removed from vVCT(t) and vRhythm(t) by the digital filter design.Figure vVCT(t) over the actual beat. If the area over the negative half-wave differs from that over the positive half-wave, the integral over the complete beat is different from zero  and beat-based proportional (BBP) control approach, respectively. The continuous summation starting with the first beat allows for the reconstruction of the long-term BP information that is filtered away from vVCT(t).Within the VCT algorithm, pulses are inspected whether they have become spiky or fat within the previous beat by calculating the integral of ero Fig. . Thus, t Pn Fig. :2\documetb is the time t at which beat b is detected and PI the pulse interval from tb.The integral function for the beat is:vRhythm(f), which covers physiological rhythms in BP that are related to breathing as well as to Traube–Hering–Mayer waves49. The signal vRhythm(t) is led into a kind of a proportional-integral-differential (PID) control mechanism in order to keep vRhythm(t) as small as possible by altering pc(t). Note that a rise in BP increases blood volume in the finger and thus decreases v(t), whereas a fall in BP increases v(t). The PID-control coefficients provoke negative feedback: if BP rises, pc(t) rises too while blood volume in the finger (indicated by vRhythm(t)) is kept constant.VCT ensures a stable long-term tracking of mBP, corrects for vasomotor activity, and reconstructs slow-changing BP information. Theoretically, this mechanism should be a sufficient control signal, but it turned out that CNAP2GO did not follow physiological BP changes correctly. The control deviation of the system was too high and thus an additional mechanism for tracking fast mBP changes and physiologic BP rhythms was needed. Figure vdRhythm(f), takes care of pronounced BP changes . In order to follow the overall CNAP2GO principle, where actuator changes shall be slow, pulsatile blood volume is not clamped. Rather, the pulsatile frequencies are cut off, and the differential controller part acts as a second band-pass filter producing nonpulsatile vdRhythm(f).The differential part of the controller, v(f) indicates the frequency domain of the signal v(t), as shown in Fig. Note: The CNAP2GO control system continuously keeps track of the required contact pressure with the following control structure:cP, cD, and cI are constants for the proportional, differential, and integral approach of the continuous control system, respectively, that keeps pc(t) at the inflection point of the S-curve and thus makes it equal to mBP.The final CNAP2GO contact pressure is:pC(t). As a result, the speed of tracking is limited to the cut-off frequency of vRhythm(f) and vdRhythm(f). This produces the control engineering problem that the stability of the system is reduced if the actuator is slow. Slow-reacting pC(t) creates a so-called pole in the z-plane indicating a tendency to oscillate. These oscillations especially occur when the patient calms down, parasympathetic tone increases, and the breathing frequency (about 0.2 Hz to 0.3 Hz) appears in the BP signal. A digital antiresonance system was developed that makes this pole ineffective. The basic considerations of this system were inspired by a method for suppressing mechanical resonance in high track density hard disk drives50.The complex control system outlined above follows the inflection point and thus mBP is tracked by From CNAP2GO’s need for antiresonance we see that a benefit of pulsatile VUT control systems is to inhibit this kind of resonance: Even in very fast pressure generators, pressure in the finger cuff will always lag behind true pulsatile BP. However, the resulting pole in a VUT control system is ineffective as long as the system can be faster than the BP signal.pc(t), which typically occurs between 0.1 Hz to 1 Hz. This information tunes a high-sensitive IIR notch filter which eliminates resonance phenomena. Pseudocode of the antiresonance system is shown in Supplementary Method Our antiresonance system inhibiting the resonances also for nonpulsatile control is thus a leap forward in the development of miniaturized BP measurement devices with acceptable clinical accuracy. It works as follows: The resonance detector indicates frequency and amplitude of a resonance oscillation in Written informed consent was obtained from all participants. We performed measurements with the participants lying in the supine position. The finger sensor of the CNAP2GO system was attached to the same hand as the CNAP Monitor HD sensor. As usual for CNAP, both sensors were placed on the proximal phalanx. Both devices were initially calibrated to the same sBP/dBP values using the sphygmomanometer of the CNAP Monitor HD. Study measurements were performed over 30 min and included 6 physiological maneuvers.51 and calculated the bias , the standard deviation of the differences, and the 95% limits of agreement  was performed in the Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf  after approval by the ethics committee . We obtained written informed consent from all patients. Adult patients scheduled for neurosurgical procedures in whom continuous BP monitoring with an invasive arterial catheter was planned, independently of the study, were eligible for study inclusion. Exclusion criteria were the presence of vascular abnormalities or anatomical deformities of the upper extremities or peripheral edema.The finger sensor of the CNAP2GO system was attached to the hand opposite to the arterial catheter. CNAP2GO continuous noninvasive BP measurements and invasive reference measurements using a radial arterial catheter were recorded simultaneously over a period of 45 min. According to clinical standards, general anesthesia was maintained with remifentanil and propofol. Norepinephrine was given whenever clinically indicated.51 and calculated the bias , the standard deviation of the differences, and the 95% limits of agreement  were placed on opposite hands. Measurements were performed simultaneously on index fingers, then simultaneously on middle fingers before switching the sensors between hands and repeating the procedure again on index and on middle fingers.In order to obtain a finger oscillometric curve, finger cuff pressure was stepwise increased from 0 to 200 mmHg with approx. 2 mmHg/s. Cuff pressure was then plotted versus maximum light amplitude to visually compare the results obtained with the fluid-filled bladder prototype with the standard CNAP Monitor HD. While it was not expected that the prototype CNAP2GO would result in identical curves as the reference CNAP Monitor HD, the quality of the relationship between cuff pressure and maximum light amplitude was investigated: visual assessment found that the fluid-filled bladder driven by the slow actuator (infusion pump) provided oscillometric envelopes with a quality comparable to those provided by the CNAP Monitor HD (see Figs. Supplementary InformationPeer Review File