Hypertension (HTN) is a condition that affects nearly half of the adult population in the United States. HTN is the elevation of blood pressure (BP) 130/80 mm Hg or higher. Untreated high blood pressure may increase the risk of myocardial infarction, stroke, and other serious complications. BP over 180/120 mm Hg with end-organ damage is called a hypertensive emergency. Despite advancements in medicine and treatment options, the global burden of HTN has been increasing due to the advancing age of the population and an increasing prevalence of obesity. Non-pharmacological management of HTN has gained prominence worldwide due to its additional benefits and positive impact on the overall health of individuals, having almost no side effects and reducing the financial burden of medication expenses. This article has compiled studies like systematic reviews, meta-analyses, and randomized controlled trials and reviewed the role of non-pharmacological management of HTN, including lifestyle modifications like exercise, weight loss, dietary interventions like dietary approaches to stop hypertension (DASH) diet, low sodium diet, limiting alcohol consumption, smoking cessation and stress management to help control blood pressure. However, non-pharmacological interventions should be initiated in an early phase, and for proper management of HTN, we may need to include both pharmacological and non-pharmacological interventions. This article explored and integrated various studies to highlight the role of non-pharmacological interventions to manage HTN. We also examined the need for more research studies for strategies to alleviate morbidity and mortality associated with HTN. By 2025, hypertension (HTN) is estimated to affect one-third of the world's population . AccordiAccording to the American College of Cardiology and the American Heart Association, BP is divided into four general categories Table .HTN affects people with advancing age. It is more common in ethnically African and South Asian communities . Major rAccording to the American College of Cardiology, a BP higher than 180/120 mm Hg is considered a hypertensive emergency or crisis. Patients with these blood pressures need emergency medical help. Untreated high BP may increase the risk of myocardial infarction, stroke, and other serious complications. Monitoring BP every two years, starting at age 18, is important to diagnose and treat hypertension timely to prevent complications. HTN is diagnosed by performing repeated careful measurements of blood pressure. Blood pressure is categorized as follows: Normal blood pressure, defined as systolic blood pressure (SBP) less than 120, and diastolic blood pressure (DBP) less than 80. An elevated BP is an SBP of 120 to 129 and a DBP of less than 80. HTN is defined as a systolic pressure more than or equal to 130 or a diastolic pressure more than or equal to 80.One of the quintessential steps to manage HTN is lifestyle modifications like exercise, weight loss, dietary interventions, a low-sodium diet, limiting alcohol consumption, smoking cessation, and stress management to help control BP. The treatment of HTN is based on specific characteristics like stage of disease, compliance, and comorbid conditions. For proper management of HTN, we may need to include pharmacological and non-pharmacological interventions . DespiteThis article aims to emphasize the non-pharmacological management of HTN as it is an attractive approach to dealing with HTN in developed and developing countries due to the economic limitations and having additional benefits with few or almost no side effects . AnotherHigh BP can lead to complications like coronary artery disease, congestive heart failure, end-stage renal disease, and stroke . A studyConsidering aspects like cost, effectiveness, and the potential for side effects of antihypertensive medications, lifestyle interventions Table , includiWeight lossWeight loss is one of the most important non-pharmacological interventions to lower BP. Numerous interrelated pathophysiologic mechanisms stimulate higher BP in obesity . In overIntermittent fasting (IF) is an effective way to lose weight and thus helps lower blood pressure . The mec2 showed that IF helped lower BP with a p-value of 0.51 [2 revealed that 12 weeks of IF helped lower SBP (p = 0.254) and DBP (p = 0.570) [2 who followed IF for eight weeks showed a lowering of SBP (p<0.001) and DBP (p<0.05) [2, showed a lowering in SBP (p<0.05) and DBP (p<0.05) [Assorted studies have shown that IF lowers BP. Harvie et al., in their study involving 107 overweight or obese premenopausal women, showed that IF for six months helped lower SBP (p = 0.99) and DBP (p = 0.84) . Varady  of 0.51 . A study= 0.570) . In a stBP p = 0.4 and DBP(p<0.05) . Erdem e(p<0.05) . Practicality of ImplementationAlthough weight loss plays a significant role in lowering BP, it may be challenging to stay constantly motivated for long-term results . DevelopDietAfter originating in the 1990s, the dietary approaches to stop hypertension gained popularity in lowering blood pressure . The DASThe DASH diet has been funded by the National Institute of Health (NIH) in various research projects to know whether specific dietary interventions helped treat HTN . The subDASH recommends the consumption of: Healthy carbohydrates like green leafy vegetables , whole grains , low-glycemic-index fruits, legumes, and beans ; HealthyAccording to a study by Ozemek et al., healthy diets like DASH dietary patterns have been shown to decrease SBP by 11 mm Hg in hypertensive individuals and by 3 mm Hg in normotensive individuals. Ideally, the goal is to reduce sodium to <1500 mg/dl, but it is good to aim for at least a 1000 mg/day reduction, which has been shown to reduce SBP approximately by 5/6 mm Hg in hypertensive individuals and by 2/3 mm Hg in normotensive individuals [Hinderliter et al. performed the Exercise and Nutrition Interventions for Cardiovascular Health (ENCORE) study, a trial that involved observing the persistence of lifestyle modifications in 144 overweight participants with higher-than-normal BP for 16 weeks, randomly assigned to the DASH diet alone (DASH-A), DASH diet plus weight management (DASH-WM), or usual care . IndividThe Mediterranean diet (Med Diet) has also helped lower BP. As per the Maine-Syracuse Longitudinal Study conducted in the United States in 2020 by a group of researchers who followed 851 US older adults, for every one unit increase in the Med Diet score in participants, it was found that there was a corresponding reduction of 0.69 units in SBP, a reduction of 0.33 in DBP, and a reduction of 0.45 on mean arterial pressure (MAP) . AlthougPracticality of ImplementationPatients can find it increasingly difficult to maintain long-term dietary changes like low caloric intake, low salt intake, and limiting processed foods, which in turn may lead to a shift towards preintervention practices in some individuals, for example, increased calorie intake . This imExerciseIncreased physical activity has been advocated as the first-line intervention for preventing and treating patients with prehypertension and as a treatment strategy for patients with stage 1 or stage 2 HTN, according to the Duthe American College of Sports Medicine, the United States Joint Nations Committee on Prevention, Detection, Evaluation, and Treatment of High BP, the World Health Organization and International Society of Hypertension, and The National Heart Foundation . ExercisThe pathogenesis of HTN involves oxidative stress. Another mechanism involved is the decreased bioavailability of nitric oxide (NO) . PhysicaThe following four randomized controlled trials have been conducted to show that exercise helped lower both systolic and diastolic BP in participants: In the meta-analyses of randomized controlled trials conducted by Fagard et al., 72 trials have been conducted with an average of 40 participants per trial, which involved a 16-week study of 40 minutes of exercise sessions three times/week with an average intensity of 65% of heart rate . This stPracticality of Implementation Patients may be initially motivated to engage in exercise programs but can find it challenging in long-term maintenance, which may lead to weight regain . In ordeAlcoholThe health effects of alcohol intake are variable and are based on the amount of intake  and intake pattern  -47. In tAccording to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), low-risk drinking is considered four drinks per day or less than fourteen drinks per week for men and less than or equal to three drinks per day and less than seven drinks per day for women . Binge dAccording to a study performed by Fuchs et al. in 2021, it has been found that, especially in women, the risk has been found to start at moderate alcohol consumption, and alcohol withdrawal has been found to promote the reduction in BP in short-term trials . Suliga Briasoulis et al., in their meta-analysis of 16 prospective long-term studies, revealed that alcohol consumption of more than 20 g per day increases the risk of HTN significantly in women, whereas consumption of 31 to 40 g in men significantly increases the risk of HTN . NeverthIt should be taken into consideration that the effects of alcohol are not similar in all individuals . Also, iSmokingSmoking is an important risk factor for HTN. The following is the mechanism involved in the elevation of BP by smoking Figure .Physicians play a key role in encouraging and helping patients achieve smoking cessation . HTN hasPsychological stressPsychological stress is another contributor to HTN . Stress LimitationsIn this study, we focused on HTN as a single factor and outlined the management; however, we have not taken into consideration other comorbidities like diabetes and hyperlipidemia that may co-exist with HTN. Although various impactful studies were integrated, this study could not examine and evaluate all the available data. This study does not address the challenges with adherence to lifestyle modifications like exercise and dietary interventions, as well as the challenges with compliance with limiting alcohol and cessation of smoking. Although non-pharmacological management alone can be effective in patients with prehypertension or stage 1 HTN, however, for stage 2 HTN, pharmacological management is still considered the first line. Furthermore, this study did not outline the combined effects of medications and lifestyle modifications.It is evident that uncontrolled HTN can lead to serious complications like myocardial infarction, stroke, end-stage renal disease, and other manifestations of end-organ damage. In summary, the clinical implication of this review article is to establish a strong emphasis on the management of essential HTN with non-pharmacological interventions involving multiple elements of lifestyle modification, focusing on more permanent measures to help improve the overall quality of life and to decrease physician dependence and hospitalizations for serious complications. Weight loss is the most beneficial non-pharmacological intervention to manage HTN, followed by the DASH diet, exercise, alcohol, smoking, and management of stress. These should be initiated in the early phase and used along with pharmacological intervention only to be highly effective. Clinicians play a crucial role in explaining the risks of untreated HTN to patients and strongly encouraging them regarding long-term adherence to lifestyle interventions like weight loss, exercise, lowering alcohol consumption, and smoking cessation. The use of mobile technology and personal digital devices can be effective to help track and maintain healthy lifestyle changes like weight loss and exercise, especially when support and accountability through active intervention are not available. Even though various studies have been performed, more in-depth research studies need to be conducted to master the approach to minimize morbidity and mortality associated with HTN.


In type 2 diabetes mellitus (T2DM), the antidiuretic system participates in the adaptation to osmotic diuresis further increasing urinary osmolality by reducing the electrolyte-free water clearance. Sodium glucose co-transporter type 2 inhibitors (SGLT2i) emphasize this mechanism, promoting persistent glycosuria and natriuresis, but also induce a greater reduction of interstitial fluids than traditional diuretics. The preservation of osmotic homeostasis is the main task of the antidiuretic system and, in turn, intracellular dehydration the main drive to vasopressin (AVP) secretion. Copeptin is a stable fragment of the AVP precursor co-secreted with AVP in an equimolar amount.To investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients.The GliRACo study was a prospective, multicenter, observational research. Twenty-six consecutive adult patients with T2DM were recruited and randomly assigned to empagliflozin or dapagliflozin treatment. Copeptin, plasma renin activity, aldosterone and natriuretic peptides were evaluated at baseline (T0) and then 30 (T30) and 90 days (T90) after SGLT2i starting. Bioelectrical impedance vector analysis (BIVA) and ambulatory blood pressure monitoring were performed at T0 and T90.p = 0.001). BIVA recorded an overall tendency to dehydration at T90 with a stable proportion between extra- and intracellular fluid volumes. Twelve patients (46.1%) had a BIVA overhydration pattern at baseline and 7 of them (58.3%) resolved this condition at T90. Total body water content, extra and intracellular fluid changes were significantly affected by the underlying overhydration condition (p < 0.001), while copeptin did not.Among endocrine biomarkers, only copeptin increased at T30, showing subsequent stability . The extent of fluid reduction, but not the copeptin response, is affected by the patient’s baseline volume conditions.Clinicaltrials.gov, identifier NCT03917758. Copeptin, the C-terminal fragment of pre-provasopressin (CT-proAVP), represents a reliable biomarker of the activity of the antidiuretic system, being secreted by magnocellular hypothalamic neurons in equimolar amount with arginine-vasopressin (AVP) in response to osmotic, hemodynamic and stressful stimuli . The maiIt was shown that even in type 2 diabetes mellitus (T2DM) the antidiuretic system participates in the adaptation to osmotic diuresis, further increasing urinary osmolality by reducing the electrolyte-free water (EFW) clearance ; in thisIn recent years, both empagliflozin (EMPA) and dapagliflozin (DAPA) have gained indication in the treatment not only of T2DM, but also of chronic heart failure (HF) with reduced ejection fraction and chronic kidney disease (CKD), thanks to their ability to reduce disease progression and exacerbations, together with overall cardiovascular mortality .The pathophysiological basis of these favorable effects is not yet fully understood, but one of the hypotheses is that SGLT2i could induce a greater reduction of interstitial fluids (ISF) than traditional diuretics, thus avoiding hypovolemia and acute kidney injury due to intravascular volume depletion .Indeed, significant losses of isotonic fluid able to reduce the effective circulating volume (ECV) cannot be immediately replaced by the water present in the interstitial space, since these two compartments share the same osmotic pressure. This process, called extracellular dehydration, leads to extensive neurohormonal activation, in turn associated with known harmful effects on the cardiovascular system when persisting for a long time .Conversely, hypotonic or electrolyte-free water losses are responsible for a mainly intracellular dehydration process, associated with a lower activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, in favor of an isolated osmotic response of the antidiuretic system .The aim of this proof-of-concept study was to investigate the copeptin adaptive response to persistent osmotic diuresis due to SGLT2i administration, as well as the induced changes in body fluid distribution, in T2DM.The GliRACo study was a prospective, multicenter research involving the Division of Endocrinology, Diabetes and Metabolism of the University Hospital “Città della Salute e della Scienza di Torino” in Turin, and the Division of Endocrinology of the University Hospital “Maggiore della Carità” in Novara. Both Local Ethics Committees of the two University Hospitals approved the study protocol  and the clinical research was conducted in accordance with the principles of Declaration of Helsinki.2; (4) HbA1c ≥ 86 mmol/mol or clinical signs suspected of poor glycaemic control ; (5) any other ongoing antihyperglycemic treatment except for metformin.Sixty-eight consecutive patients with T2DM  were evaSince recruitment, any antihypertensive treatment potentially interfering with RAAS or antidiuretic system was discontinued  and substituted with alfa-blockers and/or calcium channel blockers. At the same time, all patients were instructed to follow controlled diet with 3–5 g of salt and up to 2 L of water per day.Twenty days later, patients were randomly assigned to EMPA  or DAPA (10 mg/die) alone or in addition to an ongoing metformin treatment. The day before SGLT2i starting (T0) and then at 30 (T30) and 90 days (T90) of treatment, a comprehensive fasting physical and biochemical evaluation  was performed; moreover, patients were instructed to avoid caffeine or nicotine on the day of study visit. In addition, at T0 and T90, all patients underwent to bioelectrical impedance vector analysis (BIVA) and 24-h ambulatory blood-pressure monitoring (ABPM).All the biochemical analysis were performed with automated assays in the same laboratory .As previously reported , copeptiPlasma samples for NT-proBNP determination were processed on Cobas e602 automated platform (Roche Diagnostics) by sandwich immunoassay with two monoclonal antibodies directed against N-terminal portion (1–76) of proBNP molecule (Elecsys proBNP II), using electrochemiluminescence analysis. The limit of detection was 5 pg/mL (0.6 pmol/L), with a 5–35,000 pg/ml  dynamic range, as well as intra and interassay coefficients of variation < 5% at three different concentrations .Serum aldosterone levels were measured by liquid chromatography coupled to mass spectrometry (LC-MS) assays. LC-MS analyses were conducted employing the MassChrom Steroids in serum/plasma kit  on a Nexera X2 LC system  coupled to a Triple Quad 4500MD MS . The lower limit of quantification of the method was 14 pg/ml; the intra and interassay coefficient of variation ranges from 0.9 to 1.9% and from 3.9 to 5.9%, respectively. As previously described , PRA , solute-free water (SFW) and EFW clearance have been calculated according to the following formulas: FENa = s-creatinine × u-Na/s-Na × u-creatinine × 100; SFW clearance = 24 h urine volume × [1–(u-Osm/p-Osm)]; EFW clearance = 24 h urine volume × [1–(u-Na + u-K/s-Na)].®, Akern, Loc. Montacchiello, Pisa, Italy). Both bioimpedance parameters  were normalized according to the patients’ height (H) and plotted on a Rz/H and Xc/H graph . This technique allows a reliable and reproducible assessment of the distribution of body fluids in several clinical settings . Recordings were made every 15′ for the daytime and every 20′ for the night-time. Valid 24-h ABPM had to have recorded >80% of successful measurements. Controlled ambulatory BP was defined according to current guidelines . Heart rt-test or the Mann–Whitney U-test; repeated measures ANOVA or the Friedman test were used to identify longitudinal differences over time. Correlation between categorical variables were identified by the Chi-square test or Fisher’s exact test, as appropriate. Multivariable linear regression models with stepwise backward variable selection were adopted to assess the relationship between continuous variables during treatment with SGLT2i. With respect to BIVA, mean vectors from independent groups were compared with the two-sample Hotelling’s T2 test, while mean Biavectors’ displacement between T0 and T90 was evaluated with the paired one-sample Hotelling’s T2 test (Continuous variables were expressed as mean and SD or median and interquartile range (IQR) depending on their distribution; categorical variables were expressed as number and percentage. Normality was assessed using the Shapiro–Wilk test. Between-group comparisons for continuous variables were performed with the Student  T2 test .The calculation of the sample size was based on the results reported in a recent study by ® version 20 .Statistical analysis was performed using MedCalcAmong the 68 patients with T2DM evaluated to enter the study, 32 did not meet the inclusion criteria, while 36 were finally enrolled  and randConsidering only patients who completed the study protocol, 20 were already assuming metformin [median duration of disease 6.5 (IQR 1.7–11) years]; at T0, HbA1c was ≥75 mmol/mol in three patients and fasting glucose levels were >180 mg/dl in five. Fourteen patients were already on antihypertensive treatment (mean duration of disease 9.0 ± 4.5 years), while in seven others a first diagnosis of arterial hypertension was made at T0. Among hypertensive patients, all drugs potentially interfering with the RAAS or the antidiuretic system were stopped at least 20 days before T0  and an acceptable control of blood pressure levels was achieved using alpha-blockers and/or calcium channel blockers .p = 0.004) with subsequent stability. Fasting glucose, but not HbA1c, resulted significantly lower at T90 . Both absolute urinary albumin  and urine albumin to creatinine ratio (ACR) on spot urine collection  increased at T90 , while SFW clearance further decreased , with subsequent stability of both. Just transient increases in daily diuresis  as well as in FENa were observed at T30 , not associated to significant modification in absolute u-Na values. EFW clearance showed a slight upward trend at T30  and serum electrolytes remained stable. Of note, a significant increase in hematocrit (HCT) was recorded at T90 , without any significant change in p-Osm . At all observation times p-Osm resulted a significant predictor of copeptin values  0.03; p = 0.022), particularly at T30  (p = 0.009). All other endocrine biomarkers remained essentially stable, in the absence of relevant clinical or biochemical signs of hypovolemia  . Finallyovolemia .p = 0.006) together with a slight decrease in mean night HR . Conversely, BP did not change significantly, as reported in At T90, ABPM revealed an increase in daytime HRV , although in the presence of normal and stable PhA , while ECF and total body water (TBW) decreased (p < 0.02). Conversely, in normohydrated diabetic patients, none of these variables changed remarkably. Finally, a significant displacement of the Biavector was confirmed at T90 only in subjects overhydrated at T0 (p < 0.001) (p < 0.001), while copeptin levels and daytime HRV did not.Bioelectrical impedance vector analysis recorded a tendency to dehydration at T90, estimating a prevailing reduction of the ECF  . RepeateAs attended, no significant differences in endocrine and hydro-electrolyte balance variables were detected between the three different arms of treatment. No treatment was significantly associated to over-hydration resolution at T90.Our results confirm an isolated response of the antidiuretic system to the administration of SGLT2i in patients with T2DM. In particular, the increase in copeptin levels seems attributable to a prevalent intracellular dehydration phenomenon, in the absence of evident signs of hypovolemia or a wide neurohormonal activation. Moreover, the dehydration process due to SGLT2i treatment led to remarkable changes in body fluid distribution only in basally overhydrated patients.SGLT2i represent new euglycemic drugs able to induce sustained glycosuria by the inhibition of glucose reabsorption in the renal proximal tubule. SGLT2i proved to be effective in reducing cardiovascular risk in patients with T2DM beyond glycemic control, even preventing HF exacerbation and CKD progression . Moreove+) and water from the kidney. Unfortunately, a similar persistent neurohormonal activation also leads to harmful cardiovascular effects and cardiac remodeling, at least in part attributable to chronic water retention and the combined profibrotic action exerted by AVP, angiotensin II and aldosterone , thereby reducing effective Na+ losses , serum glucose substantially represents an ineffective osmole, due to its presence both in the extracellular and intracellular compartment ; conversThe result of the sum of these combined effects is that, in a population of diabetic subjects not severely hyperglycemic, but affected by ECF overload, SGLT2i would favor a progressive loss of substantially hypotonic fluids compared to plasma; thus, determining a prevalent phenomenon of intracellular dehydration .Noteworthy, our results also confirm an evident increase in HCT a few months after treatment with SGLT2i. Although HTC levels are reliable indicators of a prevalent extracellular dehydration phenomenon, several evidence gathered in recent years supports the hypothesis that this new class of drugs directly and indirectly improves erythropoietin production .We also found a significant increase in HRV in our population, accompanied by a reduction in mean nocturnal HR , apparenConsistently, a recent Japanese study identified during SGLT2i administration a significant reduction in HR at rest, another well-known indicator of the autonomic nervous system activity . Taken tFinally, recent evidence, collected from large observational studies conducted on diabetic patients, has shown a clear association between the values of copeptin and albuminuria . In our No variables among copeptin, HVR, TBW, ECF, and ICF were significantly associated with the arms of treatment in our population. Although the number of subjects required for our study was calculated to find a significant difference in copeptin levels before and after SGLT2i treatment, these data support the hypothesis of a class effect; furthermore, a low dose of EMPA may be sufficient to achieve the same beneficial draining effect of ECF, as hypothesized based on other previous studies .+ excretion, due to its ability to promote the adenylate cyclase system in the thick ascending limb of the nephron . The extent of fluid reduction, but not the copeptin response, is affected by the patient’s baseline volume conditions. In view of the known association between T2DM, essential arterial hypertension and volume overload, even in the absence of HF, our results offer some new insight into the pleiotropic benefits derived from SGLT2i treatment in patients with T2DM.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.n. D026280; Novara: protocol n. CE76/19). The patients/participants provided their written informed consent to participate in this study.The studies involving human participants were reviewed and approved by the Local Ethics Committees of the Turin and Novara University Hospitals (Turin: protocol AMB and MP-C conceived and designed the study. FR, FP, and FS performed the biochemical analysis and collected the results. CL and CB performed the instrumental evaluation and edit the cases report form. AMB, MP-C, NP, MC, and FB performed the data analysis, the figures designing, and the manuscript writing. VG, GM were in charge for overall direction and planning. SG, MM, and ASB gave the needed encouragement and support to investigate and supervised the findings of this work. All authors revised the manuscript for important intellectual content and approved the definitive version.


IBP, DBPIBP, and MAPIBP, respectively) and to detect SBPIBP fluctuations. Methods: PES/PCS and IBP measurements were performed in 20 patients undergoing abdominal, urological, and cardiac surgery. A Pearson’s correlation analysis (r) between 1/PTT and IBP was performed. The predictive ability of 1/PTT with changes in SBPIBP was determined by area under the curve . Results: Significant correlations between 1/PTT and SBPIBP were found for PES (r = 0.64) and PCS (r = 0.55) (p < 0.01), as well as MAPIBP/DBPIBP for PES (r = 0.6/0.55) and PCS (r = 0.5/0.45) (p < 0.05). A 7% decrease in 1/PTTPES predicted a 30% SBPIBP decrease , while a 5.6% increase predicted a 30% SBPIBP increase . A 6.6% decrease in 1/PTTPCS detected a 30% SBPIBP decrease , while a 4.8% 1/PTTPCS increase detected a 30% SBPIBP increase . Conclusions: Non-invasive beat-to-beat PTT via PES/PCS demonstrated significant correlations with IBP and detected significant changes in SBPIBP. Thus, PES/PCS as a novel sensor technology may augment intraoperative hemodynamic monitoring during major surgery.Background: Non-invasive tracking of beat-to-beat pulse transit time (PTT) via piezoelectric/piezocapacitive sensors (PES/PCS) may expand perioperative hemodynamic monitoring. This study evaluated the ability for PTT via PES/PCS to correlate with systolic, diastolic, and mean invasive blood pressure (SBP Perioperative hemodynamic optimization, particularly optimal blood pressure (BP) management and early detection of BP fluctuations are critical for perioperative outcomes ,2,3,4. BTracking PTT through PW analysis can be accomplished by vascular unloading techniques using optical or ultrasound-based sensors via pulse plethysmography (PPG). While these techniques have their respective advantages, they can be associated with patient discomfort, high cost, and potential problems with optical sensors such as light interference, as well as accuracy issues ,7. OtherAn emerging sensor technology that can non-invasively track peripheral PWs is dual piezoelectric (PES)/piezocapacity (PCS) film sensors. PES/PCS sensors have been a mainstay in the industrial sector and are now being used as biomedical sensors . These nPES/PWPCS) and compare it with PWIBP. In addition, PTT via PES/PCS was evaluated to determine correlations with invasively acquired systolic, diastolic, and mean BP , as well as their potential to predict intraoperative SBPIBP fluctuations.However, there is a lack of data regarding the applicability of these novel PES/PCS to reliably track PTT in the perioperative period in high-risk surgical patients. It also remains unclear whether PTT obtained from these types of sensors could correlate with invasively acquired blood pressure (IBP) better than or equal to studies using other sensor technology. Another critical point of investigation is to determine if beat-to-beat PTT via PES/PCS could detect early-onset BP fluctuations. Therefore, this study aimed to deploy non-invasive PES/PCS to determine valid PW morphology  and registered at ClinicalTrials.gov (NCT 03263988). Informed written consent was obtained from all patients enrolled in the study.2, inability to place the PES/PEC around the index finger, a difference in blood pressure measured between the two arms >12 mmHg, severe valvular disease, left ventricular ejection fraction (LVEF) < 35%, tricuspid annular plane systolic excursion (TAPSE) < 16 mm or the need for any type of left ventricular assist device or the inability to give informed consent.All adult patients admitted for elective major abdominal, urological, and cardiac (including cardiopulmonary bypass [CPB]) surgery under general anesthesia were screened for study inclusion. Exclusion criteria were defined as follows: American Society of Anesthesiologist (ASA) classification ≥ 4, pregnancy, atrial fibrillation or other serious cardiac arrythmias, presence of cardiac pacemakers, arteriovenous fistulas in the upper extremities, body mass index (BMI) > 35 kg/m2 (etC02) between 35 and 40 mmHg.Upon arrival in the anesthesia induction area, standard monitoring was initiated, including a 3-lead electrocardiogram (ECG), pulse oximetry monitoring, and initial non-invasive oscillometric blood pressure monitoring. All patients underwent general anesthesia according to the local standard operating procedure (SOP). For patients undergoing major abdominal or urological surgery, anesthesia was induced with fentanyl (1–2 µg/kg), propofol (1–2 mg/kg) and cisatracurium (0.15 mg/kg). Anesthesia was maintained with sevoflurane or propofol with intermittent boluses of fentanyl and cisatracurium as needed at the discretion of the anesthesiologist. If clinically indicated, a peridural catheter was placed (TH 8–12), infusing a solution of 0.2% ropivacaine (6–8 mL/h). For patients undergoing cardiac surgery, induction was performed with propofol (1–2 mg/kg), sufentanil (0.1–0.5 µcg/kg) and cisatracurium (0.1 mg/kg). Prior to CPB, anesthesia was maintained with sevoflurane (approximately 1.0 MAC) and a continuous infusion of sufentanil (0.2–0.5 µg/kg/h) and on-CPB pump with propofol (6 mg/kg/h) for regulatory reasons. Ventilation was performed by pressure-controlled ventilation (PCV) with the goal of maintaining an end-tidal C0For IBP monitoring, an arterial catheter was placed in the left radial artery using the Seldinger technique and values were recorded on a beat-to-beat basis. General intraoperative hemodynamic management in all patients was aimed at maintaining mean arterial pressure (MAP) ≥ 65 mmHg via judicious administration of vasoactive medications or balanced intravenous crystalloid fluids.PES/PEC sensors were attached to the patient’s right index finger after induction to reduce artifacts, and measurements began after signal quality was checked. Data from these sensors were collected from this point until the end of surgery.The PES/PEC sensor system used was developed and manufactured by SectorCon . The dual sensors were composed of a piezoelectric and a piezocapacitive section, both relaying 2 unique PWs with distinct characteristics . They could measure a pressure range between −5 and 50 kPa at a sampling rate of 250 Hz. PWs and PTT were recorded and captured using a handheld device developed by the same company, including a separate 3-lead ECG cable as reference. PW amplitude was reported in arbitrary units (a.u.) and PTT (measured from the beginning of the R-peak of the ECG) was defined as milliseconds. A total of 2 unique PWs and 2 PTTs were recorded and analyzed on a beat-to-beat basis. The data were converted to an ASCII file for offline analysis. An example of a PES/PEC sensor is shown in PES/PWPCS were analyzed in the following steps to determine the frequency of reliable PW morphology:PW(1) Detection of R-peaks in the ECG using a Hilbert transformation-based algorithm  which weρ > 0.85;The absolute relative difference in magnitude from the mean PW (Δmag) was less than 0.5;(2) Calculation of the mean PW from the non-invasive sensors and the correlation p of each beat-to-beat PW to the mean PW. The area under the PW was defined as its magnitude (mag). A PW was marked as an outlier if one of the following two conditions was not met:(3) PTT was defined as the time interval from the R-peak to the steepest rise in PW;(4) This procedure resulted in a PTT time series with missing values that were interpolated using the 4th order weighted essentially non-oscillatory (WENO4) technique .This was performed for each patient and for all non-invasive and invasive PWs . Two patIBP either increasing or decreasing by more than 30% compared with the mean BP of each patient. Because absolute PTT is specific to each individual, 1/PTT was converted to relative changes from baseline. The performance of the 1/PTT predictor was adjusted by AUROC analysis to determine the optimal cutoff based on maximizing sensitivity and specificity. PW reliability and correlation data were reported as median and interquartile range (IQR). Patient data were reported as mean with ± standard deviation (SD). Statistical analysis was performed using the Julia programming language version 1.6.3 with the StatsBase library ) required for a PW to travel from the left ventricle to any  anatomical location is defined as the PTT, which includes the pre-ejection period (PEP) and pulse arrival time (PAT) ,19. PTT PES/PWPCS rate in our study but was able to do so in a rigorous perioperative environment from high-risk surgical patients, where rapid changes in BP are common.Previous studies using piezo-based sensors have been able to reliably detect PWs in healthy volunteers ,26, voluPW/PCSPW validity was found to be >90%, compared with a 97% validity for PWIBP. Despite these confounding factors, PES/PSC were able to decipher a high rate of beat-to-beat PTT for all valid PWs, which has also been demonstrated in ambulatory hypertensive patients [Disruptive perioperative factors such as electrocauterization, extreme BP fluctuations, positional changes, intra-abdominal pressure, and changes in vascular tone due to bleeding, pain and vasoactive medications contribute to a challenging environment for testing novel non-invasive sensors. However, PESpatients . Anotherpatients . The advIBP was found in healthy volunteers undergoing dobutamine infusion, while a lower yet significant correlation between PTT and DBPIBP was also determined [While no study has investigated the correlations between piezosensor-based PTT and IBP, as well as the ability of piezosensor-derived PTT to predict IBP fluctuations in the perioperative environment, there are a handful of comparable PPG studies of this nature. The correlation between non-invasively acquired PTT measured from the delay between the R-peak of the ECG and the peak of a PPG signal with BP has been well established in theoretical models . Non-invtermined . In a retermined . Finallytermined . Similartermined . The resIBP, while moderate correlations were found with MAPIBP and DBPIBP [The only directly comparable study examining non-invasively acquired PTT in hypertensive renal transplant patients in the perioperative setting, found a good correlation between PTT and SBPd DBPIBP . Its maiIBP and DBPIBP, which supported the findings of Kim et al., and refuted the findings of Payne et al. These significant correlations may be due to the residual effects of the pulse reflection wave during DBP, thereby influencing MAP [Another clinical study tracking PTT during spinal anesthesia showed a good correlation between PTT and non-invasively measured MAP, while no information was given on correlations between SBP and DBP . A retrocing MAP .Our patient cohort consisted of high-risk patients with comorbidities that may have affected PTT measurements. The presence of cardiovascular comorbidities may impact the relationship between PTT and systemic BP, as the structural changes in the myocardium and vascular architecture may alter PW propagation . Other cThe ability of PTT to predict significant intraoperative BP fluctuations is a major advantage of this particular biosignal. There are a handful of clinical studies that highlight the potential of PTT to detect significant BP fluctuations. The most relevant study by Kim et al. found that a 15% change in 1/PTT could predict a 30% change in systolic blood pressure during induction of anesthesia . During IBP, DBPIBP, and MAPIBP correlations, as well as the ability of these sensors to track intraoperative BP fluctuations. Detecting early onset BP fluctuations is a valuable tool for the anesthesiologist, however the ability to determine if an intervention is successful in correcting these fluctuations with PPG or PES/PCS warrants further investigation A recent report examining PTT via PPG found that PTT has a poor ability to determine fluid responsiveness in patients undergoing major abdominal surgery [The ability of PTT to serve as an early indicator of systemic BP fluctuations has shown promise in theoretical models , however surgery . Thus, PA limitation of the study was studying a small heterogeneous group of surgical patients receiving either inhalation (sevoflurane) or intravenous (propofol) anesthesia. While it is theorized that propofol may lead to greater peripheral arterial distension, no significant differences between propofol and sevoflurane-based anesthesia on PTT have been found . The majIBP on a beat-to-beat basis than DBPIBP and MAPIBP. Finally, PTT from PES/PCS demonstrated the ability to detect early onset SBPIBP fluctuations with a high degree of sensitivity and specificity, providing critically important hemodynamic information. The major advantage of PES/PCS sensors, over PPG technology, is the ability to use these sensors at sites other than the finger, as a PW can be detected with the appropriate applied pressure. Recent research has demonstrated the feasibility of using PES/PCS sensors to record continuous heart tones [This study used novel PES/PCS to track intraoperative beat-to-beat PWs and PTT in a heterogeneous cohort of patients undergoing major surgery. The results demonstrated a > 90% beat-to-beat PW reliability detection rate. PTT from these sensors showed a higher significant correlation with SBPrt tones , and to rt tones . In addi


Efficacy of systemic corticosteroid therapy (CS) for long-term kidney survival in patients with IgA nephropathy (IgAN) is controversial. Therefore, prospective studies evaluating targeted therapies to lymphatic tissues in mucosal immune system responsible for production of nephritogenic IgA have been desired worldwide. Here, we aimed to evaluate the associations of CS and combination therapy of CS and tonsillectomy (CS + Tx) with kidney survival, using database from a nationwide multicenter prospective cohort study on IgAN. Primary outcome was a 50% increase in serum creatinine from baseline or dialysis induction. The analysis included 941 patients (CS/CS + Tx/non-CS 239/364/338), 85 (9.0%) of whom reached outcomes during median follow-up of 5.5 (interquartile range 2.0–8.0) years. On overlap weighting analysis with balanced baseline characteristics, CS and CS + Tx were associated with lower risk of kidney events when compared with non-CS . Notably, when compared with the CS, CS + Tx was associated with a lower risk of kidney events . Present study demonstrated, keeping with favorable association of systemic CS with kidney survival, concurrent tonsillectomy as one of targeted interventions to lymphatic tissues may provide additional improvement to kidney survival in patients with IgAN. The KDIGO international clinical practice guideline recommends the systemic administration of corticosteroids (CS) in patients with IgAN who remain at high risk of ESKD despite maximal supportive care7. Nevertheless, the effect of CS on kidney events among patients with IgAN has been controversial11. Lv et al. demonstrated the efficacy of CS on kidney survival by the largest randomized controlled study (RCT) for IgAN5. On the contrary, Rauen et al. found no differences in kidney survival in IgAN patients randomized to receive added CS on top of supportive care compared to supportive care alone12. In addition, adverse effects of CS which cannot be overlooked were observed in some studies5. Therefore, new strategies improving the efficacy and safety of CS have been desired worldwide13.Immunoglobulin A nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, and 30–40% of affected patients develop end-stage kidney disease (ESKD) within 20 years from its onset20. Mucosa-associated lymphoid tissue includes gut-associated lymphoid tissue (GALT) and nasal/upper respiratory mucosa-associated one (NALT). Regarding GALT, an enteric targeted-release formulation of budesonide excellently reduced proteinuria in patients with IgAN in the recent NEFIGAN trial14. The long-term kidney survival on budesonide treatment may be clarified elsewhere. Gross hematuria following acute upper respiratory infections and COVID-19 may indicate the apparent association between NALT and IgAN22. Compared to CS alone, reduction in proteinuria by tonsillectomy combined with CS (CS + Tx) has been demonstrated in two RCTs from East Asia16. A meta-analysis in 2017, our recent matched study in 2019 and other retrospective studies after 2020 reported an association between tonsillectomy and kidney survival24. However, these two studies were retrospective in nature and did not include an assessment of wide spectrum baseline clinicopathological characteristics. Therefore, further clinical implications of CS + Tx should be clarified by long-term prospective observational studies.Targeted therapies to lymphatic tissues in mucosal immune system responsible for production of nephritogenic IgA may improve kidney survival in patients with IgAN25, the current study assessed associations of CS and CS + Tx with kidney survival compared to non-corticosteroid use (non-CS) and further compared CS + Tx with CS on kidney survival.Using data from the nationwide prospective cohort study (Japan IgA Nephropathy Prospective Cohort Study [J-IGACS])In total, 1130 participants were registered in J-IGACS spanning 33 university hospitals and 11 local leading hospitals in Japan Fig. . After eAfter performing an overlap weighting analysis Fig. , the disThe associations between initial treatments and kidney outcomes described above were not affected by almost any baseline characteristic stratifications with explored overlap weighting analyses and multivariate adjusted analyses Fig. . In thes2) was seen in the IPW-ATU cohort, followed by the overlap-weighting and IPW-ATT cohorts.The inverse probability treatment weighting on the average treatment effect in the population that received CS + Tx (IPW-ATT) cohort had the highest frequency of patients with greater hematuria, E1 and C1 + 2, followed by the overlap-weighting and inverse probability treatment weighting on the average treatment effect in the non-CS group (IPW-ATU) cohorts  and IgAN susceptibility30. The same variant was also associated with IgAN progression in other studies32. Similar to the recent NEFIGAN trial, which was designed to deliver an enteric targeted-release formulation of budesonide to the distal ileum in patients with IgAN and demonstrated a significant antiproteinuric effect of the drug, tonsillectomy may be associated with better kidney outcome as one of the targeted therapies to lymphatic tissues responsible for production of nephritogenic IgA14. Recent findings from basic research indicate that tonsillar B lymphocytes or nasal-associated lymphoid tissue play a pivotal role in the production of nephritogenic IgA1, providing substantial support for this hypothesis34. In a similar vein, Kawabe et al. reported that conducting a tonsillectomy one year after kidney transplantation was correlated with a reduced incidence of histological recurrence of IgAN35. Further studies are needed to clarify how overtreatment with CS + Tx can be reduced, as the present study demonstrates that CS alone is associated with lower adverse kidney outcomes compared with non-CS treatment.The favorable association between corticosteroid use and kidney outcomes was greater in patients in the CS + Tx group than in the CS group Fig. . Two RCT37. It is worth emphasizing that physicians should not hesitate unduly to administer corticosteroid treatment (+/− tonsillectomy) to patients with lower proteinuria than 1.0 g/day, in addition to providing supportive care. This perspective is substantiated by a study from China, which reported that patients with time-averaged proteinuria levels ranging from 0.5 to 1.0 g/day exhibited worse kidney outcomes38. However, it is crucial to highlight that our findings should be validated through further extensive observational studies and RCTs to establish their reliability.As indicated in KDIGO Guideline 2021, the present study found a significant association between initial treatment and kidney outcome among individuals with severe proteinuria (≥ 1.0 g/day). Meanwhile, there was no significant interaction observed between the proteinuria level (≥ 1.0 g/day and < 1.0 g/day) and the type of initial treatment (non-CS/CS/CS + Tx), as depicted in Fig. 41. Nagai et al. reported higher 2-year eGFR slope and improved eGFR trajectory after methylprednisolone pulse therapy in patients with greater baseline hematuria whereas eGFR was stable in those with relatively mild hematuria42. A recent meta-analysis reported that baseline macroscopic hematuria was associated with a decreased risk of ESKD whereas baseline microscopic hematuria was associated with an increased risk for ESKD43. Overall, isolated hematuria at the time of biopsy might have increased the sensitivity for early detection of IgAN. The non-significant association between corticosteroid use and kidney outcomes in patients with lesser hematuria noted in this study may provide a clue to avoiding overtreatment with CS in the clinical management of IgAN3. However, this issue should be examined in future studies.The association of corticosteroid monotherapy with better kidney outcomes was not observed in patients with lesser baseline hematuria but in those with greater baseline hematuria in a subgroup analysis Fig. a. To the7. Implications of those two acute glomerular lesions may be limited by that of microscopic hematuria as some previous studies have reported an association between baseline microscopic hematuria and those pathological glomerular acute lesions44. Future studies with pathological data from repeated kidney biopsy after corticosteroid therapy may help identify the effects of corticosteroid therapy on pathological changes in patients with IgAN.Two glomerular acute lesions including endocapillary hypercellularity and crescent formation statistically influenced the response to CS and CS + Tx. Similar results were observed in a VALIGA sub-study and a Tokyo cohort sub-study45. East Asia is known as a region with patients with the highest susceptibility to IgAN. Therefore, the applicability of these findings to other populations is unknown.This study has several limitations. Despite robust statistical techniques due to the nature of the observational study, possibility of residual and unmeasured confounding remains. Regimens for corticosteroid therapy and tonsillectomy, adverse events after initial treatment and relapse/recurrence during follow-up might affect kidney prognosis. Subsequent studies to investigate those issues are planned. Longer follow-up data from observational studies are required to assess whether the effects of initial corticosteroid therapy are sustained over time. The present cohort included only Japanese patients and data from Japanese clinical practices. Racial differences in the susceptibility genes for IgAN have been suggested in genome-wide association studiesIn conclusion, a favorable kidney survival response to corticosteroid monotherapy and an even more favorable response with combined corticosteroid therapy and tonsillectomy was demonstrated in a nationwide prospective observational overlap-weighted cohort. More attention to baseline microscopic hematuria and glomerular acute lesions including endocapillary hypercellularity and crescent may improve the clinical practice of IgAN and may avoid overtreatment in corticosteroid-treated patients with IgAN.25. Briefly, the registration period in J-IGACS was from April 1, 2005, to August 31, 2015. The database contains information on all inpatient and outpatient encounters, prescriptions, diagnostic codes, laboratory measurements, and pathologic data collected between April 1, 2005, and May 31, 2021. Clinical datasets were uploaded every 6 months to the J-IGACS website by each investigator. Patients were followed up from the date when kidney biopsy was performed until migration or departure from the practice or database, death, or the last date of data collection.J-IGACS is a nationwide, multicenter, electronic health record-based registry of patients with biopsy-proven primary IgAN described elsewhereFor the current analyses, we selected records of patients from J-IGACS database who had kidney pathological data and measurements of arterial BP, eGFR, proteinuria, and uRBC when kidney biopsy was performed and at least one follow-up measure of kidney outcomes.The study was approved by the Ethical Committee of the Jikei University School of Medicine (16–174 [4402]) and each local ethics committee where participants were enrolled. The current study was performed according to the Declaration of Helsinki and adhered to STROBE reporting guidelines. All patients and/or parents/guardians provided written informed consent before enrollment in J-IGACS.46. Both regimens involved corticosteroid pulse therapy, although the treatment duration varied between them (six versus twelve months).The exposure of interest was corticosteroid treatments comprising two types: CS and CS + Tx. Both were defined by initiation within 1 year after kidney biopsy. Each of the two exposure groups was compared to a group of patients who did not receive corticosteroid treatment within 1 year after kidney biopsy (non-CS). In further analyses, the CS + Tx group was compared with the CS group. Thus, the initial treatment categories included CS, CS + Tx, and non-CS, following intention-to-treat approach. Although the regimen of corticosteroid administration depended on each institute, principle one was one of two regimens: the Italian method and the Sendai method47. For patients < 20 years of age when kidney biopsy was performed, the primary outcome was a composite endpoint of dialysis induction or a reduction in eGFR of ≥ 25% (confirmed by subsequent measurement). Patients were followed up from the date when kidney biopsy was performed until the occurrence of the outcome of interest or the last examination date.For patients aged ≥ 20 years when kidney biopsy was performed, the primary outcome was a composite endpoint of dialysis induction or a ≥ 50% increase in serum creatinine from baseline (confirmed by subsequent measurements)48. In patients aged < 20 years at the time of kidney biopsy, eGFR was calculated using Uemura’s equation, and their follow-up eGFR measurements, collected at age > 20 years, were calculated using the revised CKD-EPI equation for Japanese adults49. The following equation was used to estimate mean arterial BP (MAP): MAP (mmHg) = 1/3 × pulse pressure + diastolic BP. The magnitude of microscopic hematuria was classified into two groups by its median value in the overall population. Regarding histological variables, we used the Oxford classification method (MEST-C score)51. The MEST-C score includes mesangial hypercellularity , endocapillary hypercellularity , segmental sclerosis , tubular atrophy/interstitial fibrosis , and crescents . The collected virtual slides were analyzed by five pathologists who were blinded to the clinical data. Final determinations of MEST-C scores were based on the agreement of three or more pathologists. Regarding renin–angiotensin–aldosterone system inhibitors (RAASi) use, if patients had already received RAASi at the time of kidney biopsy, such therapies with RAASi were also recorded as an initial prescription.Serum creatinine and spot urine specimens were collected for each participant. Serum creatinine was assayed using an enzymatic method. In patients aged ≥ 20 years, eGFR was derived using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation modified by a Japanese coefficientDescriptive statistics are presented as means and standard deviations (SDs), median and interquartile range (IQR), and numbers and proportions as appropriate. Incidence rates for the primary outcome were calculated as the frequency of the outcome per 1,000 person-years of follow-up.52. In total, 25 baseline covariates, which were grouped into covariate set 1 and covariate set 2, were chosen a priori as potential confounders and included in the propensity score models. There were 13 variables in covariate set 1: age, gender, diabetes mellitus, MAP, eGFR, proteinuria, uRBC, five types of MEST-C scores, and RAASi use. Covariate set 2 included 12 variables: hypertension, past history of macrohematuria, body mass index, serum uric acid, serum IgA, serum complement 3, Japanese clinical grading score53, Japanese histological grading score54, antiplatelet use, registered year, registered hospital area, and category of registered hospital . Covariate set 1 had no missing data. A multivariate singular value decomposition imputation method was used for selected variables in covariate set 2 if data were missing.A multinomial logistic regression model was used to estimate the generalized propensity score of treatment with CS or CS + Tx compared with non-CS, conditional on patient covariates measured at baseline55. Balance in baseline covariates among CS, CS + Tx, and non-CS groups before and after overlap weighting was assessed using a measure of absolute standardized difference (ASD), where a standardized difference of ≤ 0.1 was considered to ensure balance between groups56. Two types of ASD were measured: max of the pairwise ASDs (MASD) and all of the pairwise ASDs (PASD).An overlap-weighting approach was then used to construct a weighted cohort of patients receiving CS, CS + Tx, and non-CSp values within each stratum of baseline characteristics57. Multivariate Cox proportional hazard modeling adjusted with all variables in covariate set 1, except for stratifying factor, was performed in this subgroup analysis; however, overlap weighting was used to estimate survival curves according to initial treatment and incidence rate of kidney outcomes in each stratum per 1000 patient-years. A statistically significant interaction was defined as p value for interaction < 0.1. All statistical analyses were performed using R 4.2.1 with package PSweight, JMP13.2.0 , and STATA MP16.1 (STATA Corp.). Statistical significance was defined as a two-sided p < 0.05.The weighted cumulative incidence rate of the primary kidney outcome according to the initial treatment categories was evaluated using Kaplan–Meier analysis. The weighted incidence rate in each group was calculated as the weighted number of incident events divided by the weighted overall number of 1000 person-years at risk. For the main analysis, weighted Cox proportional hazards models were used to estimate the weighted hazard ratios (HRs) for the study outcome in comparisons of CS with non-CS, CS + Tx with non-CS, and CS + Tx with CS. The consistency of findings observed in the main analysis was assessed by the test to determine the interaction 52. To assess the potential effects of unmeasured confounders on the identified associations between the exposures and the primary outcome, E-values were calculated58.Different inverse probability treatment weighting (IPW) analyses were employed in sensitivity analysis. Patients were weighted to derive the average treatment effect in the population that received CS + Tx (IPW-ATT) and the average treatment effect in the non-CS group (IPW-ATU)Supplementary Information.


Prolonged length of stay in post-anesthesia care unit (PLOS in PACU) is a combination of risk factors and complications that can compromise quality of care and operating room efficiency. Our study aimed to develop a nomogram to predict PLOS in PACU of patients undergoing elective surgery.Data from 24017 patients were collected. Least absolute shrinkage and selection operator (LASSO) was used to screen variables. A logistic regression model was built on variables determined by a combined method of forward selection and backward elimination. Nomogram was designed with the model. The nomogram performance was evaluated with the area under the receiver operating characteristic curve (AUC) for discrimination, calibration plot for consistency between predictions and actuality, and decision curve analysis (DCA) for clinical application value.2, American society of Anesthesiologists Physical Status (ASA), surgery type, chill, delirium, pain, naloxone, operation duration and blood transfusion. The C-index value was 0.773 [95% confidence interval (CI) = 0.765 - 0.781] in the development set and 0.757 (95% CI = 0.744-0.770) in the validation set. The AUC was > 0.75 for the prediction of PLOS in PACU. The calibration curves revealed high consistencies between the predicted and actual probability. The DCA showed that if the threshold probability is over 10% , using the models to predict PLOS in PACU and implement intervention adds more benefit.A nomogram was established based on the selected ten variables, including age, BMI < 21 kg/mThis study presented a nomogram to facilitate individualized prediction of PLOS in PACU for patients undergoing elective surgery. A post-anesthesia care unit (PACU) is a vital part of hospital surgical suites and ambulatory care centers. The responsibility of medical staff in PACU is to transfer patients who have undergone anesthesia to the ward after satisfactory recovery , 2. ProlSeveral clinical predictive models for different populations have been reported. Rodney A Gabriel et al. analyzed data from 4151 outpatients and identified risk factors for PLOS in PACU, including morbid obesity, hypertension, surgical specialty, primary anesthesia type, and scheduled case duration . In addiIn the current study, a nomogram was constructed to predict the PLOS in PACU by collecting clinical data on general characteristics, perioperative complications, surgery, and anesthesia from 24017 patients covering various types of surgery. We aim to provide anesthesiologists and nurses in PACU with a convenient predictive tool for the individualized prevention and intervention of associated risk factors.https://www.chictr.org.cn/showproj.html?proj=192900, Date: 29/03/2023). This manuscript adheres to the applicable STROBE guidelines.The research was in accordance with the Ethical Principles for Medical Research Involving Human Subjects, outlined in the Helsinki Declaration of 1975 (revised 2013). This study was conducted at The First Affiliated Hospital, Zhejiang University School of Medicine, a tertiary hospital. The protocol was approved by the clinical research ethic committee of the hospital(IIT20230068A). Informed consent was waived by the institutional review board due to the retrospective nature of this study. The trial was registered prior to patient enrollment in the Chinese Clinical Trial Registry .Data were collected from 24017 patients undergoing elective surgery between June 2019 and February 2021. The data set only included patients over 18 years of age who were admitted to PACU for resuscitation after elective surgery with tracheal intubation anesthesia. Patients were randomly divided (7: 3) into development (16753) and validation (7264) sets. Exclusion criteria were patients with emergency surgery, brain surgery, heart surgery, mental disease, missing data. Demographic data and clinical characteristics including sex, age, Body Mass Index (BMI), hypertension, diabetes, American Society of Anesthesiologists physical status classification (ASA), type of surgery, operation duration, temperature at admission to PACU, chill, delirium, pain, naloxone, neostigmine, transfusions of red blood cells, plasma, platelets, whole blood, and autologous blood were collected through the electronic medical record system. Continuous variables were converted into categorical variables such as age, BMI, temperature, and operation duration. To determine the diagnostic reliability of age and operation duration, summary statistics were calculated including sensitivity, specificity, positive predictive value, negative predictive value, Cohen’s Kappa coefficient and the area under the receiver operating characteristic (ROC) curve. On this basis, the cut-off values of age and operative duration were calculated to be 55 and 110, respectively. BMI and temperature were transformed into multinomial variables. Therefore, the first and third quartiles were chosen as the classification basis, which were 21 kg/mP < 0.05 were used to build predictive model. Student's t test was used to compare the area under the receiver operating characteristic curve (AUC) of model 10 and model 11.All statistical analyses were performed using R software (version 4.2.0). Categorical variables were described as percentages (%). whereas continuous variables were reported as medians and interquartile ranges (IQRs). The least absolute shrinkage and selection operator (LASSO) regression model was used to screen for statistically significant variables with the R package “glmnet”. These variables were then put into multivariate regression analysis with a combination method of forward selection and backward elimination based on the Akaike Information Criterion. Variables, satisfying a significance level of p < 0.05.The performance of the nomogram was evaluated for both the development and validation sets using calibration and discrimination . CalibraThe data collection process was illustrated in Fig. 2, ASA, surgery type, chill, delirium, pain, naloxone, PLOD, blood transfusion and temperature < 36.2℃. After multiple logistic regression analysis, the above factors were still statistically significant (Table p = 0.12). In addition, chills are defined: during recovery from anesthesia, the brain's central response to cold is reduced, and the spinal cord's central response is restored to normal, resulting in rigidity or parochial muscle tremors as a result of an involuntary nervous reflex. In this study, when chills were recorded by nurse in PACU, patients were required to present rigidity or parochial muscle tremors. The record of chills was relatively objective.A total of 19 variables were entered into LASSO regression analysis after setting dummy variables for unordered categorical variables such as BMI and temperature. The LASSO result was determined with development set. The lambda. min was 0.0003744695 and 17 variables are selected, while lambda. 1se = 0.01409854, and 11 variables were selected Fig. . In the https://ffq11051.shinyapps.io/DynNomapp/). The regression equations constructed on Model 10 can be seen in the summary model panel of the dynamic nomogram. The C-index value of the development set was 0.773 (95% CI = 0.765-0.781), and the verification set was 0.757 (95% CI = 0.744-0.770). In both sets, the AUC was > 0.75  was a statistically significant risk factor. Some studies had reported that BMI ≥ 40 kg/m2 was a risk factor for delayed postoperative recovery, mainly because morbid obesity increase the risk of sleep apnea especially in the setting of opioid utilization [2 was 13, accounting for 0.05%, which may be caused by regional dietary and living habits. One of the five diagnostic criteria for frailty syndrome is weight loss. These patients have a poor tolerance to anesthesia and surgery, therefore requiring longer recovery time after surgery [Age and BMI were analyzed as risk factors. Rodney A et al. found that age ≥ 65 was not a risk factor for PLOS in PACU . Howeverlization . The rea surgery . In addiIt is not surprising that ASA, major surgeries, and operation duration are risk factors for PLOS in PACU. Major surgeries have been thought to cause inflammatory induced postoperative cognitive decline , which iThis study showed that pain and naloxone use were risk factors of PLOS in PACU. Anesthesiologists use different opioids depending on surgery and individual patient. By converting different opioids into morphine and then standardizing them according to the patient's weight and length of operation, this would make nomogram complicated and impractical. So, this study collected data on the use of naloxone, indirectly reflecting opioid overdose. Since both insufficient analgesia and opioid overdoses can lead to PLOS in PACU, it is necessary to explore better methods of monitoring analgesia. In recent years, various monitors have been invented for quantifying pain, such as analgesia nociception index, skin conductance, pupillometry, nociceptive flexion reflex threshold, surgical pleth index and qNOX . The nocThis study found that intraoperative transfusion of blood products prolonged postoperative recovery. Disruption of physiological homeostasis is the main reason. In addition, transfusion of blood products had been reported to cause postoperative residual neuromuscular blockade and affect neuromuscular functional recovery in the PACU . It remaThe study has several limitations. First, some variables that may contribute to improving the predictive ability of the model were not included, such as cerebral apoplexy etc. Second, we did not collect detailed usage and types of opioids and neuromuscular blockers. Third, the nomogram was not verified externally. In future clinical work, we will further verify the feasibility of the model.In summary, we have developed a predictive model with excellent differentiation and clinical utility that can help identify patients with a higher probability of PLOS in PACU. The screening of high risk factors and the establishment of nomogram are helpful to improve the quality of ERAS and the efficiency of the operating room.


Self-monitoring of blood pressure is a key strategy in managing hypertension but may be challenging and burdensome for patients. The aim of the study was to describe the perspectives and experiences of self-monitoring of blood pressure in patients with hypertension.MEDLINE, Embase, PsycINFO, and CINAHL were searched from database inception to March 2022. We used thematic synthesis to analyze the data.Thirty-five studies involving 872 patients aged 18–95 years were included. Four themes were identified: enabling autonomy and empowerment of own health ; providing reassurance and convenience ; triggering confusion and stress ; financial and operational burden of device .Inadequate knowledge about the benefits of lowering blood pressure, home blood pressure monitoring, blood pressure goals, and interpretation of blood pressure values, limited access to home blood pressure monitoring devices, and psychological burden with home blood pressure monitoring limit home blood pressure monitoring.  The synthesis of multiple qualitative studies can generate comprehensive insights on patient perspectives regarding self-monitoring of blood pressure in people with hypertension. We aimed to describe patient perspectives and experiences in self-monitoring of blood pressure, to inform strategies for optimizing the acceptability of self-monitoring of blood pressure.8We followed the Enhancing Transparency of Reporting the Synthesis of Qualitative Research framework to report our study.9) on self-monitoring of blood pressure or home blood pressure monitoring were eligible. Studies that reported epidemiologic or nonprimary studies, quantitative surveys, or reported perspective from health professionals, caregivers, or people without hypertension were excluded. Studies that addressed only ambulatory blood pressure or pulmonary artery pressure measurements were also excluded. Non-English articles were excluded.Qualitative studies that reported the perspectives and experiences of adults aged 18 years and over with hypertension as defined by the authors of the included studies 11 All participant quotations and text of each study were extracted. Two reviewers coded the data line by line by using HyperRESEARCH (version 4.5.1) and inductively identified preliminary themes and subthemes that captured patient perspectives on self-monitoring of blood pressure. We coded the text from each study into these concepts, creating new concepts, and then categorized similar concepts into broader themes. Investigator triangulation was achieved by discussing the preliminary themes with a third reviewer to ensure the findings captured the full range and depth of the data. We developed an analytical thematic schema to identify conceptual patterns and links among the themes.Thematic synthesis was used to inductively identify concepts.We included 35 studies involving 872 patients aged from 18 to 95 years (2 studies did not specify the number of patients) . The stuThe comprehensiveness of reporting among the included studies is shown in We identified 4 themes: enabling autonomy and empowerment of own health, providing reassurance and convenience, triggering confusion and stress, and financial and operational burden of device. Selected participant quotations to support each theme are provided in Allowing access to comprehensive and accurate data. Patients found that regular monitoring of blood pressure provided objective data about trends in their blood pressure readings. Self-monitoring of blood pressure allowed them to be “able to interpret (results) correctly.”31 They believed this information supported better communication with their clinicians about their blood pressure. Patients believed that self-monitoring of blood pressure “confirmed blood pressure readings which were measured at the clinic”15 and helped them receive “quick responses” regarding their blood pressure.19 Some mentioned that the readings taken by their clinicians could be inaccurate due to anxiety and discomfort leading to higher blood pressure readings—“I get a more accurate reading when I’m not stressed when I’m at home.”19Bolstering motivation for lifestyle changes. Patients felt a stronger sense of responsibility while monitoring their blood pressure, and were motivated to improve their blood pressure levels through lifestyle changes and setting targets for blood pressure. They felt more proud, excited, and satisfied in having the autonomy to manage their condition and “more confident where (they) have had to speak to (doctors) about (blood pressure).”19Encouraging diligence in medication taking. Patients were motivated to take antihypertensive medications diligently upon seeing lower blood pressure readings after taking medications—“You can see whether the medicine is effective.”12 Patients voiced that “seeing those high numbers”14 on home blood pressure monitoring devices prompted them to take medications to avoid serious consequences.Gaining interest in self-management. Monitoring blood pressure at home allowed patients to take responsibility in managing their health—“It’s important for me to be more intentional and more in with my healthcare.”32 Patients also used their blood pressure readings to negotiate the management of hypertension with their general practitioners (GPs) and “take me off (medications).”43Increasing awareness of health status. With home blood pressure monitoring, participants felt they gained awareness about their blood pressure and what numbers meant. Patients reported that checking their blood pressure frequently made them “aware of the high readings and encourage them to seek medical help.”36 Patients gave more attention to blood pressure and were prompted to think about their disease more regularly.Instilling a sense of security. Patients felt reassured in being able to monitor blood pressure at home and in knowing their blood pressure readings were stable—“I get peace of mind to know that my blood pressure is more or less (doctors) say on a level.”25 This was particularly relevant for those who waited long periods of time between clinical appointments—“Because of this device, I feel at ease.”34Readiness for troubleshooting. Patients expressed relief in being able to check their blood pressure when they were feeling unwell or had symptoms. This allowed them to self-assess and take action to manage their blood pressure. They also thought that early flagging of symptoms related to hypertension was possible with blood pressure monitoring, and as such helped to get “psychological relaxation.”12Reducing the frequency of clinical appointments. Patients reported a reduction in the frequency of routine follow-up or urgent visits. This was particularly relevant for those who lived in remote areas, had mobility issues, or lacked resources and time—“Having (blood pressure device) at home would be a lot less stressful than having to go out and have it monitored.”39 Others reported discomfort in sitting in the waiting room—“It was really uncomfortable to sit for half an hour, so by the time I got upstairs, my blood pressure was high.”19Anxiety and panic over “bad” numbers. Some patients felt that home blood pressure monitoring was intrusive, triggering feelings of anxiety when numbers were high or there were fluctuations in readings—“If you get a bit of a neurotic person you could end up with (taking readings) up every 5 minutes.”40Constant reminder of illness identity. Some did not want to measure blood pressure to avoid being constantly reminded of their condition—“I don’t want to be too aware of doing it.”43 They avoid any negative associations with the readings, and “they do not want to be confronted with (hypertension) too much.”22Disregarded by clinicians. Some patients reported that GPs had not offered them the option to monitor blood pressure at home.15 People felt ignored when clinicians did not pay attention to their home blood pressure readings or did not trust them to self-monitor blood pressure—“Intrinsically (doctors) were a bit sort of dubious about whether I could do it myself accurately.”19 Some lost motivation to persist with self-monitoring and felt disempowered because they perceived self-monitoring as a “waste of time,”25 if their clinicians did not give “feedback”25 on their readings.Lack of confidence in interpreting and responding to results. Some were uncertain about the target ranges and frequency of monitoring. Patients were hesitant about taking responsibility for interpreting and responding to blood pressure measurements because “they are unfamiliar with the machine.”36 Some chose not to take their medications when they saw fluctuations in their blood pressure readings because they felt uncertain about their benefits—“I have to take the same (medication). I checked my reading: not different from what it was. Then should I stop?.”12Redundancy of continuous monitoring. Some believed that daily monitoring of blood pressure was redundant because blood pressure was already being managed by their GPs. Patients felt that continuous monitoring could make people “hypochondriac.”19 Some thought that self-monitoring of blood pressure added more responsibilities in their daily lives and “it would be overwhelming.”39 Some felt “bored”25 with continuous monitoring. Some remarked that if patients “are adherent to medications, there was no need to check blood pressure.”15Uncertainties around targets and frequency of measures. Some patients did not know the recommended target blood pressure. Others believed that the target blood pressure was individualized, and the goal was to achieve lower blood pressure compared to the previous readings—“Because my previous readings are 180 (mm Hg), when I get reading of 159 (mm Hg), I felt happy.”12 Patients were uncertain about the frequency of measuring their blood pressure—“Some measured their blood pressure daily without fail, others did it only when they had symptoms.”12Concerns of unreliability. Some were concerned about the reliability of their home blood pressure monitoring readings—“I worried about making mistakes and to have inaccurate readings.”36 This was particularly the case when their home blood pressure measurements varied substantially from clinic measurements, or when there was considerable variability between readings. Some were concerned about mechanical problems and had difficulties in trusting a machine.Vulnerability preventing use. For some patients, particularly those with advanced disease, physical limitations, impaired eyesight, or the elderly, the use of home blood pressure monitoring devices was too challenging and burdensome because they felt too weak to use the device, or were highly dependent on others for self-management tasks. Also, those with limited technology and health literacy found it difficult to use—“I don’t understand what this number means.”34Unsustainable cost. Patients in low resources settings were not able to afford blood pressure monitoring devices, and including those who installed home telemonitoring systems where there would be ongoing costs involved for software—“Patients with this disease usually have already purchased their own sphygmomanometer, and this device probably is not cheap either!.”34 However, patients also voiced that a shift to self-monitoring of blood pressure could reduce burden and cost on the healthcare system.For patients with hypertension, self-monitoring of blood pressure encouraged autonomy and empowerment of their own health. Self-monitoring of blood pressure provided patients with a sense of safety and helped them to be prepared for managing their symptoms. On the other hand, some patients reported that self-monitoring of blood pressure triggered stress and confusion due to uncertainty in interpreting results. They were also concerned that the blood pressure monitoring device was unaffordable or too complex.While many of the themes were similar across the studies conducted in different populations and settings, there were apparent differences in perspectives based on age and resource settings. Older patients raised concerns around operating the device and were unfamiliar with and reluctant to engage with technological devices. Some participants in low-resource settings noted that they could not afford the devices due to the financial burden or purchasing the equipment.47 People with hypertension who self-monitor blood pressure felt more inclined to adopt lifestyle changes48 and were confident in communicating their readings to clinicians.49 However, other patients with hypertension felt confused about the utility of home blood pressure monitoring, particularly if they were not aware of how to interpret the results.47 Previous work has also highlighted challenges including inaccuracy in self-monitoring blood pressure,50 patients being unaware about targets,49 or lack of training from clinicians.51 Our synthesis suggests that patients were more engaged and had a sense of achievement in taking control of their care, and felt reassured in being able to monitor blood pressure at home between clinical appointments. On the other hand, some patients felt that continuous monitoring of blood pressure was a constant reminder their condition, and could potentially lose motivation if they felt that clinicians did not provide feedback or expressed doubt about the patients’ ability to self-monitor blood pressure.Previous studies have found that patients with hypertension have expressed that self-monitoring of blood pressure provided more accurate readings compared with the clinical assessment of blood pressure, and was easy to use.In our systematic review, we conducted a comprehensive search, assessed the transparency of study reporting, and used an explicit framework to assess and synthesize the findings. We used investigator triangulation to ensure that we captured the breadth and depth data across the included studies. However, our study has some potential limitations. We only included studies published in English, and most studies were conducted in high-income countries, which may limit the generalizability of our findings We have also included people with either gestational hypertension/preeclampsia or on dialysis  and these populations may differ from other hypertensive patients, thus the transferability the findings from these studies may need to be considered in the context of the patient population. The home blood pressure monitoring was evaluated using different devices across the studies included, and this may prevent our capability to evaluate possible differences among patient experiences and expectation.52 There may also be a need to reassure the patients and manage the psychological impacts, including anxiety of receiving readings that are outside the recommended range, and discussing impacts on illness identity and depression.53 Addressing uncertainties about correct procedures, inaccuracy of the readings, and technical issues in operating home blood pressure monitoring may also reduce patient concerns.54This study identified potential areas of relevance to clinical practice. Patients identified that home-based self-monitoring of blood pressure was valuable in identifying white coat or masked hypertension, and helped them in adopting protective behaviors such as higher adherence to drugs, lifestyle changes, and early warning to inform clinicians regarding fluctuations in readings to prevent complications. However, patients identified limitations in their understanding, training, and a need for technical support. We suggest that clinicians provide education about blood pressure targets, frequency, how to read and interpret the results.55 There is also potential for e-health tools  to promote behavioral change.57 However, as technology advances, it is important to also ensure that devices are optimized so vulnerable populations are not excluded from their use. For dependent patients, or those with visual impairment, our findings highlighted the need to improve the display of the results.58 We also advocate for financial assistance for patients in low-resource settings to access blood pressure devices.Incorporating self-monitoring of blood pressure into digital health technologies has the potential to enhance the delivery of health care for the individual. Since the COVID-19 pandemic, there has been a surge in the use of telemedicine, where the results may be automatically sent to clinicians for review and inform treatment strategies for managing hypertension.59 Further research on interventions to improve self-monitoring of blood pressure should integrate patient perspectives and include outcomes of importance to patients. Based on the INVOLVE60 and Patient-Centered Outcomes Research Institute (PCORI)61 initiatives, which provide frameworks and recommendations for involving patients across all stages of research, we recommend that patients should be involved both in developing and evaluating interventions to strengthen uptake. Trials of blood pressure monitoring often assess surrogate outcomes, whilst mortality, cardiovascular events, and patient-reported outcomes 62 have been inconsistently reported. This limits the ability to evaluate the impact of self-monitoring of blood pressure on longer-term outcomes.56 Economic modeling studies have shown that home blood pressure monitoring is cost-effective for diagnosing and treating hypertension.63Home blood pressure monitoring for hypertension management has been identified as a high-priority research question by patients and health professionals.Home blood pressure monitoring can increase patient motivation, empowerment, autonomy, and provide reassurance in managing hypertension. However, the challenges of uncertainty in readings, technical complexities, and cost remain. Education and support for patients may help to reduce the practical and psychological burden of blood pressure monitoring and may thereby improve patient outcomes.American Journal of Hypertension .Supplementary materials are available at hpad021_suppl_Supplemental_MaterialClick here for additional data file.


We, therefore, tested whether low-dose daily UVA phototherapy might be an effective treatment for mild hypertension. 13 patients with untreated high-normal or stage 1 hypertension (BP 130-159/85-99 mm Hg), confirmed by 24-h ambulatory blood pressure (ABP), were recruited. Using home phototherapy lamps they were either exposed to 5 J/cm2 full body UVA (320–410 nm) radiation each day for 14 days, or sham-irradiated with lamps filtered to exclude wavelengths <500 nm. After a washout period of 3 ± 1 week, the alternate irradiation was delivered. 24-h ABP was measured on day 0 before either irradiation sequence and on day 14. Clinic BP was recorded on day 0, and within 90 min of irradiation on day 14. There was no effect on 24-h ABP following UVA irradiation. Clinic BP shortly after irradiation fell with UVA (−8.0 ± 2.9/−3.8 ± 1.1 mm Hg p = 0.034/0.029) but not sham irradiation (1.1 ± 3.0/0.9 ± 1.5 mm Hg). Once daily low-dose UVA does not control mildly elevated BP although it produces a transient fall shortly after irradiation. More frequent exposure to UVA might be effective. Alternatively, UVB, which photo-releases more NO from skin, could be tried.Latitude and season determine exposure to ultraviolet radiation and correlate with population blood pressure. Evidence for Vitamin D causing this relationship is inconsistent, and temperature changes are only partly responsible for BP variation. In healthy individuals, a single irradiation with 20 J/cm Hypertension is a major risk factor for myocardial infarction, stroke, cardiac failure and peripheral vascular disease and is now the leading cause of Disability Adjusted Life Years (DALYs) globally . Robust Both latitude and season correlate strongly with blood pressure (BP). Incident ultraviolet (UV) radiation from the sun rises in intensity during summer and is inversely associated with latitude. Systolic and diastolic BP are higher in winter than summer in higher latitude countries , and thiUV irradiation alters expression of some BP regulatory genes , and we We hypothesised that UVA radiation itself may lower BP and conducted a trial with UVA phototherapy lamps used once daily as a potential treatment for mild hypertension.Our study was approved by the South East Scotland Research Ethics Committee (16/SS/0120) and registered with ClinicalTrials.gov NCT02621866). We recruited patients diagnosed by their primary care doctor with ESC/ESH defined high-normal or stage 1 hypertension [66. We re2 of UVA delivered from Waldmann UV100 home phototherapy lamps fitted with 8 of the same Waldmann F85/100 W UVA (320–410 nm) bulbs used in our previous study [The study used a randomised sham-controlled crossover design. Active treatment was 5 J/cmus study . For theBaseline characteristics including Fitzpatrick skin type, constitutive skin colour and full physical examination were performed at the screening clinic visit and instruction given on use of the home phototherapy lamps. Informed consent was taken. On day 1 and day 15 of the irradiation sequences, clinic BP and skin colour were recorded, and blood drawn for serum vitamin D (both 25(OH)D2 and 25(OH)D3), nitrite and nitrate levels. The day 1 measurements were taken before any irradiation. Day 15 measurements were taken after the final irradiation, when participants were advised to have their home UV treatment immediately before travelling to the University of Edinburgh’s Clinical Research Centre, where measurements were taken within 90 min of irradiation.http://members.eunet.at/cie/) was recorded. Pigmentation was scored using the L* measure which represents lightness on a scale of 0 to 100 where 0 is black and 100 is pure white [Skin colour was recorded on the volar forearm with a Minolta chromameter CM2500d . The mean of triplicate measurements using the L.a.b system . After sitting at rest for 10 min, three serial BP measurements were taken with a 1-min pause between measurements. The mean of the second and third reading was recorded. 24-h ABP was measured from day 0–1 (before any irradiation) and day 14–15.t-tests with Minitab Statistical software (version 20.4). Change in L* score, vitamin D and nitrogen oxide levels were similarly handled.The change in 24-h ABP between day 0–1 and day 14–15 was calculated together with the change between days 1 and 15 clinic BP readings. Change in BP in the sham-irradiated treatment period was compared to change in BP in the active irradiated treatment period using paired p = 0.034) and diastolic BP (p = 0.029). Following active irradiation subjects developed subtle, but significant adaptive pigmentation represented by a fall in the L* score of −1.62 ± 0.64 (p = 0.023), while there was no significant change with sham irradiation . NO could not be measured directly, but plasma concentrations of the more stable oxidation products, nitrite and nitrate, showed no significant changes. The serum nitrite concentration change over sham and active irradiation periods was −0.01 ± 0.10 μM and 0.02 ± 0.08 μM. Serum nitrate concentration change over sham and active irradiation periods was 6.6 ± 14.8 μM and 0.7 ± 18.8 μM. However, patients were not on controlled diets, and dietary nitrate intake is the major determinant of circulating nitrogen oxide levels.We had significant problems recruiting patients. 800 patients registered as having mild hypertension were invited from eight general practices. Most of our local population in Edinburgh live in tenement flats, with no lift access and limited space to house a lamp. This limited the number of households to which heavy (40 kg) phototherapy lamps could be delivered, which severely hampered recruitment. Of those invited, 27 attended for screening, but 14 patients failed to meet the entry criteria. Three patients withdrew after the screening visit, one because they could not tolerate the 24-h ABP measurements and two for lack of time. Eight patients were found to be normotensive on clinic or 24-h ABP measurement, and three patients had BP higher than the inclusion criteria and were referred on for pharmacological BP management. Thirteen patients were enrolled, all of whom completed the study Fig. . The difion Fig. . Those sion Fig.  than thoion Fig. . Serum 2This is the first clinical trial to assess the possibility of using daily phototherapy to treat mild hypertension. We had unanticipated difficulty recruiting subjects, largely because of the problems of delivering lamps to subjects’ homes. Dermatology patients with an unsightly and highly symptomatic condition may be more accepting of the drawbacks of bulky phototherapy lamps than patients with asymptomatic and invisible hypertension. In any case, the practical challenges of home phototherapy mean that its use is largely restricted to geographically remote areas where access to hospital phototherapy units is difficult. Limited recruitment meant that the study was underpowered to detect our primary endpoint of reduced 24-h ambulatory BP. Nonetheless, we show a significant fall in clinic BP, our secondary endpoint. Clinic BP was recorded within 90 min of patients receiving their final UV irradiation at home and thus probably represents the acute fall in BP following a single UVA irradiation  rather t2 UVA with which we irradiated subjects is equivalent to the amount in midday sunshine in December of 124 min in Edinburgh, or 79 min in London. The midday June equivalent would be 17 min and 16 min, although in summer there is also a UVB component to sunlight which was not emitted by our lamps.Sustained reduction in BP is needed to reduce incident cardiovascular disease making it unlikely that UVA phototherapy as we have delivered it will reduce cardiovascular disease. The 5 J/cm−3), nitrite (NO−2) and nitrosothiols (-SNO) in human skin at levels around ten times as high as those in the circulation [2 UVA leads to direct arterial vasodilatation, a fall in BP, and rise in heart rate and NO (indicated by measurement of its more stable oxidation product nitrite) [NO is not stored biologically and has a half-life of seconds , but we culation . Nitrateculation , such thculation . Nitrosoculation . Arteriaculation , and theculation . More reculation . Irradianitrite) . The falnitrite) . UVA wasnitrite) , and in nitrite) . Vitaminnitrite) .Interactions between dietary nitrate and environmental UV should be considered. Oral nitrate derived NO can reduce oxygen demand by enhancing mitochondrial efficiency  which isSubjects were given daily phototherapy for 2 weeks, followed by a washout period and then 2 weeks of the alternative intervention. This short intervention period was to reduce confounding by changes in background environmental UV during each treatment period of the study. Total daylight length varies by 3 h 47 min between the start and end of the 7-week period around the equinoxes in Edinburgh, reducing to no change in the 7-week period around the solstices. To minimise confounding by environmental UV changes over the course of the study we thus limited the overall study period to the shortest time in which we anticipated identifying an effect.no benefit from oral vitamin D supplements on these conditions [Significant seasonal variation in BP, myocardial infarction, stroke, and cardiovascular and all-cause mortality have been appreciated for the last 50 years with the effect size being similar to that produced by pharmacological agents . UVB wavnditions , 27–29. nditions , 31 but nditions . This isnditions . Thus, wSun exposure is associated with a reduction in all-cause mortality . BP reduOur study failed to show a sustained hypotensive effect of a single moderate daily irradiation of UVA, although it confirmed that a transient fall in BP is produced. Summer reductions in blood pressure with the associated falls in cardiovascular deaths occur in the context of continuous exposure to full spectrum (UVA and UVB) sunlight. For those in high latitude countries, environmental UV is inadequate to produce a significant fall in BP in winter, and clothing worn to protect against the cold limits skin exposure to what UV there is. As our study has demonstrated, conventional fluorescent bulb technology is unlikely to be practicable as a source of artificial UV. Rapid advances in LED technology may produce a range of alternative more convenient and safer phototherapy sources. Further research on the action spectrum and pharmacokinetics of UV-related BP regulation may offer new therapeutic options for the treatment of high BP as we define more accurately the wavelength, dose, and length of exposure necessary to reproduce environmentally driven seasonal falls in BP.Blood pressure and cardiovascular mortality are lower in summer than winter, independently of vitamin D and only partly due to temperature change.UVA irradiation releases the vasodilator NO from stores in the skin to the systemic circulation.A low dose of daily whole body UVA for 2 weeks does not reduce 24 h ambulatory BP, but does reduce clinic BP measured within 90 min of irradiation.Higher fluences of UVA, or exposure to UVB wavelengths, may account for summertime fall in BP.