Objectives: To update the information about the prognosis of patients with primary membranous nephropathy (MN) and subnephrotic proteinuria and identify the relevant predictors.Methods: In total, 474 cases of biopsy-proven primary MN with at least 18 months of follow-up were reviewed to determine the outcomes of the subgroup of patients that presented with subnephrotic proteinuria. Clinical data included initial proteinuria and microhematuria, defined as the average proteinuria/microhematuria of the first 6 months during the course. Outcomes included partial remission (PR), complete remission (CR), nephrotic proteinuria progression, and kidney function progression, defined as ≥50% loss of kidney function or end-stage kidney disease.Results: In total, 205 patients with primary MN and subnephrotic proteinuria at biopsy were eligible. During a median follow-up of 43 months, 200 (97.56%), 167 (81.46%), and 53 (25.85%) patients attained PR, CR, and nephrotic proteinuria progression, respectively. Only one patient (0.49%) progressed to the kidney function progression. By multivariate Cox hazards regression analyses, the initial proteinuria was identified as the independent predictor for PR, CR, and nephrotic proteinuria progression with adjusted hazard ratios (aHRs) of 0.67 , 0.50 , and 2.97 , respectively. A higher level of initial microhematuria was also associated with an increased risk of nephrotic proteinuria progression. The corresponding aHR was 1.11 .Conclusion: Among patients with primary MN and subnephrotic proteinuria, although the overall prognosis is excellent, dynamic detection and effective management of proteinuria remain important. In addition, initial microhematuria may be another predictor of nephrotic proteinuria progression. Approximately 20% of patients with primary MN present with subnephrotic range proteinuria (24 h urinary protein excretion <3.5 g/d), however, 61% later develop nephrotic range proteinuria (24 h urinary protein excretion ≥3.5 g/d), usually within the first year . There ile, etc. . HoweverAlthough current studies suggest these patients overall do well, the prognostic assessment of this subset of patients is controversial to some extent due to the lack of sufficient attention and data support. In the clinical practice, by virtue of the initial benign presentation and absence of specific predictive markers, some of these patients were not properly monitored and treated, putting them at the risk of developing nephrotic range protenuria and kidney function loss. To our knowledge, the study with the most sufficient sample size and follow-up was the cohort of Hladunewich et al. which indicated that, compared with patients with primary MN and persistent subnephrotic range proteinuria, those who subsequently attained nephrotic proteinuria showed a rate of kidney disease progression ~4 times faster. However, the only baseline feature with statistical significance between the two groups was the level of proteinuria; besides, a few years have passed .Glomerular microhematuria is one of the most common symptoms of glomerulonephritis. Recently, it is considered as a biomarker of activity in IgAN, ANCA-associated vasculitis, or lupus nephritis, and some data indicated that persistent microhematuria in IgAN is related to a greater risk of kidney disease progression –17. In pIn this retrospective cohort, we investigated the clinical course and outcomes among patients with primary MN and subneprotic range proteinuria. Longitudinal analyses were done to determine the corresponding prognostic factors and to quantify the strength of relevance.2, calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation  between October 1, 2015, and June 30, 2019, with biopsy-proven primary MN and subnephrotic proteinuria (24 h urinary protein excretion <3.5 g/d) at baseline, established as the time of kidney biopsy. Additional inclusive criteria included: a baseline eGFR of >15 ml/min/1.73 mequation ; at leasPatients were collected retrospectively, and their medical history, clinical data, and standard laboratory parameters were documented. The follow-up data were last updated on 31 December 2020. Demographic characteristics included age, gender, body mass index (BMI), comorbidities, and smoking status at the time of kidney biopsy. Initial and follow-up variables involved the assessment of blood pressure (BP), serum creatinine, serum albumin, microscopic analysis of urinary sediment, as well as 24 h proteinuria excretion. As for the microhematuria, we only recorded the results of urine sediment analyses, mainly of glomerular derived erythrocytes (dysmorphic erythrocytes >70%). The titers of serum anti-PLA2R antibody were tested using indirect immunofluorescence assays (IIFAs) and reported according to the fluorescence intensities and dilutions  of the serum samples. The intensities of PLA2R and C3 staining in pathological specimens (using the IIFAs) were standardly reported and recorded as -, +, ++, +++, or ++++. The exposure to immunosuppressive (IS) agents , statin class medications, and BP medications, including the angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), were reported as intent to treat regardless of the duration of exposure.2 or need of chronic dialysis. Hypertension was defined by systolic BP ≥ 140 mmHg, or diastolic BP ≥ 90 mmHg, or taking BP medications. Additionally, a high level of serum anti-PLA2R antibody was defined by a titer of ≥1:100, and high intensity of PLA2R or C3 staining was defined as an intensity of ≥ ++ in the IIFAs. Due to the high variability of proteinuria and microhematuria assessment at a single time, initial proteinuria  referred to the average proteinuria (microhematuria) of the first 6-month block during follow-up. Initial persistent microhematuria was defined by an initial microhematuria of >5 red blood cell counts (RBCs)/high-power field (HPF).The follow-up time referred to the interval between kidney biopsy and the last outpatient visit, death, or end-stage renal disease (ESRD), whichever occurred first. The ESRD was defined by an eGFR value of <15 ml/min/1.73 mAs for patients with primary MN and subnephrotic proteinuria, partial remission (PR) was defined by a proteinuria value of <3.5 g/d plus a ≥50% reduction from its peak value, with stable kidney function. Complete remission (CR) was a proteinuria value of ≤ 0.3 g/d, along with normal serum albumin (≥3.5 g/dl) and stable kidney function. Nephrotic proteinuria progression was defined by an appearance of proteinuria ≥3.5 g/d. The primary outcomes were the PR, CR, and nephrotic proteinuria progression. The secondary outcome was kidney function progression, defined by a ≥50% decline in the eGFR or ESRD.t-test for normally distributed variables, Wilcoxon-rank sum test for variables with skewed distributions, and the chi-squared test for categorical variables.Metric data were summarized as mean with standard deviation (SD) or median with interquartile range (IQR) according to its distribution. Categorical data were expressed as numbers with percentages. The included participants were classified into three groups  in reference to tertiles of initial proteinuria. The comparisons between groups were done using tests for trend, involving Cochran-Armitage trend test or Spearman's rank correlation test as appropriate. Clinical characteristics for never nephrotic and nephrotic proteinuria progression groups were compared using Student's P < 0.05 in univariate analyses were included in multivariate analyses. For all the analyses, complete case methods were adopted, for which each analysis was restricted to participants with complete data for all factors in models. A two-sided P < 0.05 was considered statistically significant. SPSS version 22.0  and Stata version 15.0  were used for statistical analyses.Cumulative incidence rates of PR, CR, and nephrotic proteinuria progression were plotted and compared using Kaplan-Meier analyses and Log-rank tests. Univariate and multivariate Cox hazards regression analyses were done to identify independent prognostic factors and yield hazard ratios (HRs) with 95% confidence intervals (CIs). The variables with 2 . In total, 64 (31.22%) patients were hypertensive, 15 (7.32%) patients had diabetes, and 38 (18.54%) were smokers. All patients had normal kidney function . The median proteinuria was 1.62 g/d , median microhematuria was 3 RBCs/HPF , and the mean serum albumin was 3.22 g/dl . Additionally, 73 (40.78%), 110 (65.87%), and 24 (13.79%) presented with a high level of serum anti-PLA2R antibody, high intensity of PLA2R staining, and high intensity of C3 staining, respectively. In the primary analysis, data were missing for 7.32, 12.68, 18.54, and 15.12% of patients for BMI, serum anti-PLA2R antibody, the intensity of PLA2R staining, and intensity of C3 staining, respectively.In the entire cohort, among participants with primary MN, 27.12% (205 of 756) presented with subnephrotic range proteinuria, and preserved kidney function were collected . Their bThe median follow-up time was 43 months . The medians of initial proteinuria and microhematuria were 1.26 g/d  and 3.00 RBCs/HPF , respectively. A total of 179 (87.32%) patients received treatment with either ACEIs or ARBs. In total, 125 (60.98%) patients received statin class medications. Additionally, 132 (64.39%) patients were treated with corticosteroids and/or other IS agents during follow-up.The numbers and sequences of the eligible patients that reached various outcomes are presented in P < 0.05).The eligible patients were classified according to the tertiles of initial proteinuria (0.96 and 1.53 g/d) . From T1P < 0.001). The results of Cox hazards regression analyses are summarized in P < 0.001).In our cohort, the 1-year and 3-year cumulative probabilities of PR were 92.68 and 98.54%, respectively. As shown in P < 0.001). The results of Cox hazards regression analyses are presented in P < 0.001) and 2.02 , respectively.During the follow-up, the 1-year and 3-year cumulative probabilities of CR were 53.17 and 82.41%, respectively. As shown in P < 0.001] and initial microhematuria , and a lower level of serum albumin .Clinical characteristics of patients in the never nephrotic and nephrotic proteinuria progression groups are summarized in P < 0.001). In P = 0.002).The cumulative probabilities of nephrotic proteinuria progression were 13.17, 22.96, and 33.15% after 1, 3, and 5 years, respectively. As shown in P = 0.016), 2.97 , and 1.11 .The results of Cox hazards regression analyses are summarized in During the course, 2.93% (six of 205) patients suffered a 40% loss of kidney function. Their main clinical characteristics are summarized in 2).Kidney function progression was observed in only one patient , 0.50 , and 2.97 , respectively. The result suggested that the dynamic detection and effective management of proteinuria contributed to improving the prognosis of this subset of patients. In the cohort of Hladunewich et al. the only distinguishing baseline feature between the never nephrotic group and the nephrotic post-presentation group was a higher level of proteinuria in the group that subsequently developed nephrotic syndrome [1.98  vs. 2.43  g/d]. Compared with the proteinuria at baseline, the advantage of initial proteinuria was that it not only avoided the bias and instability of single-point detection but also depicted the initial treatment response of proteinuria. It is reasonable to expect more large-scale and prospective studies to confirm the clinical implications of our findings.Microscopic hematuria has been previously considered as an indicator for a future flare in patients with systematic lupus erythematosus (SLE). Ding et al. suggested that changes in urinary sediments, either isolated microscopic hematuria or accompanied by sterile pyuria, were related to the disease activity among patients with SLE . Rhee etOur study also had several limitations. First, it was a single-center retrospective cohort accomplished with a review of medical records. The interpretation might be biased owing to selection error. Second, we did not make regression analyses because the number of patients who developed kidney function progression was relatively small. Even if we did, an excessively small number of outcome events could increase the risk of an unstable conclusion. So the influence of some confounding factors on the results could not be excluded. Furthermore, there was no standardized regimen for induction and maintenance therapy, and the treatment decisions were totally dependent on the preference of individual physicians. Therefore, these fundamental restrictions could not be avoided in the evaluation of the effect of each treatment. Additionally, the tests for serum anti-PLA2R antibody titers were conducted using the IIFAs, which enable only semi-quantitative measurement of the serum anti-PLA2R antibody. For follow-up research and monitoring, enzyme-linked immunosorbent assay (ELISA) is more suitable. However, before august 2017, the ELISA was not done in our nephrology laboratory.In summary, our data indicated that primary MN patients presenting with subnephrotic proteinuria overall had a benign prognosis. During our follow-up period, ~80% of patients achieved complete remission of proteinuria, and only ~20% of patients re-developed nephrotic range proteinuria. The initial proteinuria was an independent predictor of PR, CR, or nephrotic proteinuria progression. Besides, the initial microhematuria might be an additional indicator for the nephrotic proteinuria progression and provide reference indices for clinicians to monitor and manage this subset of primary MN patients.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Xijing Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.LH, PH, and HW designed the study, analyzed the data, and drafted the manuscript. PH, JL, and YZ collected and entered data. LH and HW contributed to data acquisition and interpretation. All authors read and approved the final manuscript.The study was supported by grants from the National Natural Science Foundation of China .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cerebral autoregulation is a homeostatic feedback mechanism that maintains a relatively constant cerebral blood flow despite changes in blood pressure. Impaired cerebral autoregulation results in unstable cerebral blood flow and is detrimental to the outcome of neurological diseases. Therefore, metrics of cerebral autoregulation were increasingly used to assess cerebrovascular health or to guide hemodynamic management. Intermittent sequential pneumatic compression (ISPC) is an effective physiotherapy technique that could improve motor deficits in patients with acute cerebral infarction. The present study focuses on the coupling relationships between arterial blood pressure and changes in oxygenated hemoglobin in the cerebral cortex to investigate the effect of ISPC on cerebral autoregulation in patients with cerebral infarction, as compared with the healthy controls. This study may help to advance the understanding of the physiological mechanisms of ISPC intervention and can provide a basis for evaluating the efficacy of ISPC interventions in patients with cerebral infarction.2Hb]). The coupling strength between the two physiological systems was estimated using a coupling function based on dynamic Bayesian inference. The participants were 22 cerebral infarction patients and 20 age- and sex-matched healthy controls. Compared with resting state, the coupling strength from ABP to Δ [O2Hb] oscillations was significantly lower in the bilateral prefrontal cortex (PFC), sensorimotor cortex (SMC), and temporal lobe cortex (TLC) during the ISPC intervention in cerebral infarction patients in interval II. Additionally, the coupling strength was significantly lower in the bilateral SMC in both groups in interval III. These findings indicate that ISPC intervention may facilitate cerebral circulation in the bilateral PFC, SMC, and TLC in cerebral infarction patients. ISPC may promote motor function recovery through its positive influences on motor-related networks. Furthermore, the coupling between Δ [O2Hb] and ABP allows non-invasive assessments of autoregulatory function to quantitatively assess the effect of rehabilitation tasks and to guide therapy in clinical situations.This study aims to explore the effect of intermittent sequential pneumatic compression (ISPC) intervention on the coupling relationship between arterial blood pressure (ABP) and changes in oxyhaemoglobin (Δ [O Stroke is a leading cause of disability worldwide, resulting in a substantial burden on caregivers and society . SurvivoRecent evidence suggests that a further insight of the regulatory mechanism of the brain–cardiovascular system might be obtained through research on both cerebral hemodynamics and other cardiovascular parameters . Cerebra2Hb]) and deoxygenated haemoglobin (Δ [HHb]) concentrations  and ABP, respectively, at rest and undergoing ISPC intervention. The phase was extracted from the measured variables using the continuous wavelet transform. Then, the coupling between ABP and the fNIRS-measured quantities was calculated from the coupling function based on the dynamic Bayesian inference technique. These results may facilitate the advancement of the comprehension of the physiological mechanisms of ISPC intervention and can provide a basis for evaluating the efficacy of ISPC interventions in patients with cerebral infarction.It has previously been observed that the activation of the bilateral prefrontal and parietal cortex might be involved in the recovery process after stroke . AdditioA total of 22 cerebral infarction patients (Group Stroke) and 20 age- and sex-matched healthy participants (Group Control) were recruited in this study. The demographic characteristics of all participants are summarized in None of the healthy participants had a history of cardiovascular or peripheral vascular disease and were not taking any medication known to affect neurological function. Patients who had experienced cerebral infarction were recruited through the inpatient Department of Rehabilitation Hospital, National Research Center for Rehabilitation Technical Aids, China. The inclusion criteria were: (1) right-handed; (2) within 6 months after the onset of stroke; (3) unilateral hemiplegia and moderate to severe motor deficits of the upper and lower extremities on the hemiplegic side; and (4) stable condition after stroke without neurofunctional disabilities. The exclusion criteria were: (1) patients with varicose veins; (2) patients with local leg problems in the area where the ISPC sleeves would be applied, such as dermatitis or open wounds on the legs; (3) patients with severe atherosclerosis as indicated by an absence of pedal pulses or a history of definite intermittent claudication; and (4) patients with severe leg edema or pulmonary edema from congestive heart failure. 2Hb] and Δ [HHb]) were monitored with a multichannel fNIRS system  at two wavelengths (760 and 850 nm). The raw sampling frequency was set to 10 Hz. Eighteen light sources and eight detectors interlacing at a spatial distance of 3.0 cm were plugged into a soft but inelastic plastic probe holder and placed on the head of the participants. These source-detector pairs constituted 24 measurement channels that were symmetrically distributed on the bilateral hemispheres and covered cerebral regions of the PFC, SMC, and TLC. The probes were positioned according to the international 10/10 system. The channel configuration of the probes is shown in The hemodynamic data  at a sampling frequency of 2000 Hz. The ABP signal was acquired by the software AcqKnowledge .Simultaneous with the fNIRS signals, continuous ABP signals were measured by a noninvasive blood pressure device  consisted of a pneumatic pump, inflatable auxiliary sleeves, and pressure lines. The inflatable auxiliary sleeves were wrapped around the upper and lower extremities on the hemiparetic side and secured by Velcro. The sleeves were connected to the air pump via pressure lines. The inflation pressure range of the ISPC device was 10–200 mmHg.All measurements were performed with the participants resting in the supine position. Prior to the experiment, each participant was required to rest in a quiet environment for 5 min to eliminate the existing hemodynamic reactions induced by previous activity. Each participant then underwent a 10-minute resting-state session. During this stage, participants were instructed to close their eyes and relax, while remaining awake and as still as possible. Subsequently, ISPC intervention (20 min) was performed on the hemiplegic limb for Group Stroke and on the left limb for the Group Control. The 10-minute resting-state session was defined as State_R, and the data from 3 min to 18 min in the ISPC rehabilitation training state were defined as State_ISPC. One full compression from distal to proximal is called a cycle. The compression rate of the ISPC device was 2 cycles/min (15 s inflation/15 s deflation). The clinical pressure range used was 100–150 mmHg. To ensure patient safety, the inflation pressure was adjusted mainly according to the patient’s comfort and tolerance. All operations were performed by a professional therapist.2Hb] [2] signal was analyzed in the following study. To measure the coupling between the Δ [O2Hb] and ABP signals, it is necessary to extract the information characteristics representing the measured data.The Δ [HHb] signal may be less contaminated by global processes compared with the Δ [O2Hb] . Therefo2Hb] [2Hb] signals to reduce the dimensionality of the hemoglobin data. Subsequently, independent component analysis was used on the reduced dimensional data to identify typical noise components, removing the technical and physiological artifacts, including nonspecific activity of the superficial layers  . Then, fl layers . The prol layers , and indl layers . Finallyl layers . The win2Hb] [Continuous wavelet transforms were employed to extract the frequency range into three physiological bands of interest as previously defined from Δ [O2Hb] ,25: inte2Hb] . The spo2Hb] . The spo2Hb] .2Hb] signal can be used to reflect the intensity of activity in cerebral regions [2Hb] during ISPC is shown in The oscillatory component in a signal can be characterized by its instantaneous frequency and corresponding amplitude . The wav regions . A repre2Hb] signals is established based on dynamic Bayesian inference, which has previously been explained in detail  in different cerebral cortex regions. It allows one to obtain the posterior density Then, dynamic Bayesian inference is used to establish the coupling function between ABP and Δ  signals increased following ISPC intervention in the LSMC and RSMC (p < 0.0083) in patients with cerebral infarction. The wavelet amplitude was significantly increased in the bilateral RFC, TLC, and SMC (p < 0.0083) in interval II in the cerebral infarction patients. Additionally, the wavelet amplitude was significantly increased in the bilateral TLC and SMC (p < 0.0083) in interval II in patients with cerebral infarction. For the healthy controls, the wavelet amplitude of Δ [O2Hb] was higher in State_ISPC than in State_R in each interval and significantly higher in RTLC (p = 0.0047) and RSMC (p = 0.0013) in interval III.A comparison of the group-averaged wavelet amplitudes for each state in the three frequency bands is shown in 2Hb] signals of all 24 channels in different states and frequency intervals were computed. To more clearly characterize the coupling between ABP and Δ [O2Hb], channel-wise coupling strength values were averaged in six regions of interest. The region-wise coupling strength mutually directed interactions between the ABP and Δ [O2Hb] of the six regions were as follows: ABP → LPFC, ABP → RPFC, ABP → LSMC, ABP → RSMC, ABP → LTLC, and ABP → RTLC (oscillation 1 → oscillation 2 indicates that oscillation 1 influenced on oscillation 2). The coupling strength quantifies how the amplitudes of the oscillations in ABP are transmitted to the oscillations of Δ [O2Hb].For each participant, coupling interactions between ABP and Δ  was significantly lower in both groups in interval III, which suggests that the physiological mechanism of ISPC for improving cerebral autoregulation function might be related to neurogenic regulation. The autonomous nervous system participates in vasoconstriction by regulating the release of substances that affect the activities of smooth muscles  oscillations was significantly lower in State_ISPC than in State_R in interval I, which indicates that the response of the respiratory activity to ABP fluctuations following ISPC intervention was weakened. This may be due to the less stable cardiorespiratory coupling in cerebral infarction patients  in the bilateral PFC, SMC, and TLC in interval II in State_ISPC indicated that ISPC intervention facilitates cerebral circulation in those cerebral regions in patients with cerebral infarction. The lower coupling strength in interval III in the SMC indicates that ISPC intervention may be promoted to motor function recovery through positive influences on motor-related networks. The obtained results on the coupling between Δ [O2Hb] and ABP offer new insights into the potential therapeutic effect of ISPC intervention on cerebral hemodynamic and guide therapy in clinical situations.In conclusion, the lower coupling strength from ABP to Δ [O


Spaceflight associated neuro-ocular syndrome (SANS) alters the vision of astronauts during long-duration spaceflights. There is controversy regarding SANS being similar to patients with idiopathic intracranial hypertension (IIH). IIH has been shown to be due to an elevation in venous sinus pressure. The literature suggests an increase in jugular vein pressure secondary to a headward shift of fluid occurs in SANS but this may not be enough to significantly alter the intracranial pressure (ICP). The literature regarding cardiac output and cerebral blood flow (CBF) in long-duration spaceflight is contradictory, however, more recent data suggests increased flow. Recent modelling has shown that an increase in CBF can significantly increase sinus pressure. The purpose of the present paper is to review the SANS vascular dynamics literature and through mathematical modelling suggest the possible underlying cause of SANS as an elevation in venous sinus pressure, secondary to the redistribution of fluids towards the head, together with a significant increase in pressure drop across the venous system related to the CBF. Although 15% of astronauts have clinically significant optic disc oedema, subclinical oedema has been detected in many astronauts returning from long-duration flights1.Spaceflight associated neuro-ocular syndrome (SANS) refers to the pathological effects of long-term microgravity on the eyes and orbital physiology of astronauts. The clinical manifestations of SANS include unilateral and bilateral optic disc oedema, globe flattening, choroidal and retinal folds, hyperopic refractive error shifts, and focal areas of ischaemic retina1, however, others disagree2. IIH is characterised by an increased intracranial pressure (ICP) in the absence of parenchymal brain lesions, vascular malformations, hydrocephalus or central nervous system infection3. To diagnose IIH, a cerebrospinal fluid (CSF) pressure above 25 cm H2O (18.4 mmHg) is required according to the published guidelines4. A patient is suggested of having IIH if they have 3 out of 4 additional imaging criteria i.e. compression of the pituitary, flattening of the posterior globe, distention of the optic nerve sheath diameter (ONSD) or transverse venous sinus stenosis4. In long flight astronauts, globe flattening was seen in 26%, optic nerve protrusion (optic disc oedema) in 15% and pituitary flattening in 11%5. Seven astronauts with globe flattening had a mean ONSD of 7.2 mm compared to 20 without globe flattening who had a mean ONSD of 5.8 mm (p = 0.01)5. Although it should be acknowledged there was no pre-flight control data, the ONSD findings in the seven with orbital flattening are above the level associated with IIH5. Thus, three of the imaging criteria for IIH are found in long flight veterans. Three of the astronauts underwent post-flight lumbar puncture showing pressures of 23, 28 and 29 cm H2O5 (inflight data is not available), with 2 of these pressures being in the diagnostic range for IIH4. A counterpoint paper suggests there is no evidence of ONSD enlargement secondary to spaceflight6 but the study was underpowered and had only one individual who developed SANS. This individual had an increase in ONSD in the range suggestive of IIH.It has been suggested the findings in SANS may be similar to terrestrial idiopathic intracranial hypertension (IIH)It can be seen that by utilising the revised IIH criteria, there are some astronauts who would fulfil the criteria for IIH. The purpose of this perspective is to review the literature in SANS with respect to the blood and CSF dynamics. Following this, computational fluid dynamics modelling will be utilised to suggest the possible causes of SANS in astronauts undergoing long-duration space flight and to suggest a vascular aetiology for SANS which is similar to IIH.7. IIH presents more often as bilateral eye changes, predominately in women, but SANS has a higher asymmetric or unilateral presentation and is more common in men1. Transient visual obscurations or diplopia secondary to a non-localising sixth nerve palsy have never been reported in astronauts with SANS, unlike IIH1. Despite these differences, there remain enough similarities to suggest some commonality may exist in the pathophysiology of both.There are similarities between SANS and IIH, however, there are also differences. Terrestrial symptoms of IIH include headache and pulsatile tinnitus, but astronauts with SANS do not complain of these symptomsCSF is the CSF formation rate, Rout is the CSF outflow resistance and SSSp is the superior sagittal sinus pressure. The sagittal sinus pressure is analogous to Ohm’s law, i.e. pressure is the product of the outflow resistance and blood flow through the outflow plus the jugular bulb pressure8. So Eq. 4. Thus a prolonged increase in venous sinus pressure of approximately 7 mmHg would be required if SANS were analogous to IIH. As previously described, the venous sinus pressure depends on the combination of the jugular bulb pressure, venous outflow resistance and the total blood flow passing through the venous system. In adults with IIH, 71% are obese14. Obesity raises the jugular bulb pressure by up to 20 mmHg15. Up to 90% of adults with IIH have been found to have outflow stenosis mostly sited at the middle of the transverse sinus, raising the venous resistance and therefore the venous pressure16. Sixty-six per cent of the increase in ICP in IIH is due to venous stenosis and 34% is due to obesity17. Astronauts are not obese1. A recent paper comparing the venous sinus volumes, both before and after spaceflight, showed a significant increase in the size of the superior sagittal, transverse and sigmoid sinuses (not stenosis) in those who developed SANS, compared to those who did not18. In another paper, in three long-duration astronauts with borderline or elevated CSF opening pressures, the MRV images were reported as normal with no evidence of stenosis or thrombosis19.The normal ICP is 15.6 cm HTherefore, if the physiology of SANS is similar to IIH, there must be other factors elevating the venous sinus pressure.1. Similar to obesity, this would have the effect of directly raising the venous sinus pressure. A second hypothesis suggests that CSF accumulates in the optic nerve sheath due to a one-way valve mechanism20. This hypothesis would explain the eye findings but not the elevated ICP or pituitary compression found in some astronauts. A third hypothesis suggests that SANS is due to upward shift of the brain putting tension on the optic nerve sheath21. This hypothesis is not necessarily mutually exclusive of hypothesis 1 but of itself does not explain the elevation in ICP.The main hypothesis regarding the cause of SANS centres on a rise in ICP due to the cephalad fluid shifts occurring during long-duration spaceflight22.Ideally, all hypotheses would be tested on astronauts whilst in space, during a long-duration flight. However, the numbers of subjects available are limited, an astronaut’s time in space is precious and the technique used must be achievable in space and must match the expertise of the subjects. For example, performing magnetic resonance imaging (MRI) or lumbar punctures on board the International Space Station is not feasible. Thus, ground-based space analogues are utilised. Analogues such as supine bed rest, head-down tilt bed rest (HDTBR), wet and dry immersion, lower-extremity limb suspension and parabolic flight have been tried23. Note that this is very close to the 7 mmHg increase in pressure required to trigger terrestrial IIH. Head-down tilt experiments, similar to the jugular vein compression study, indicate that a headward redistribution of fluid brings about a dilatation of the jugular veins with some evidence of increased ICP24. Strict head-down tilt experiments can cause retinal thickening and chorioretinal folds but no changes in refractive error or perimetry developed25. This suggests the headward shift is able to produce a syndrome similar to mild SANS.One space-based study used ultrasound-guided jugular vein compression. The terrestrial jugular venous pressure varies between the two-thirds of the day one spends upright and the one-third supine. If one weighted the pressures found (66% of the upright figure plus 33% of the supine) then the 24-h weighted average jugular venous pressure was found to be 9.2 mmHg when on the ground and increased by 6.6 mmHg at day 150 during long term weightlessness27. Hughson et al. used the continuous finger blood pressure contour technique and found no changes in stroke volume28. However, Norsk et al. found significant increases in stroke volume and CO of as much as 35 and 41%, respectively, between 3 and 6 months of flight on the ISS29. A foreign gas rebreathing technique was used29. Hughson et al. later measured CO and stroke volume by the same method as Norsk et al. and found similar increases30. They concluded that their previously unchanged stroke volume and CO estimations had been incorrect30. The increase in CO of 41–56% after months30 is higher than the increase measured by the same technique i.e.18–26% reported from shorter week long-Space Shuttle missions33. Thus, long durations in space produce higher stroke volumes and COs than a short duration. Norsk comments, both foreign gas rebreathing and ultrasound techniques have been validated thoroughly and multiple times against invasive more direct, gold standard techniques. The foreign gas rebreathing method is observer-independent and obtains data over a longer time period (20 s) than the ultrasound Doppler (three cardiac cycles) and that the breathing frequency and depth are controlled and kept constant during the measurements. Thus, he suggests the gas technique is probably correct34. The cerebral blood flow (CBF) at rest is 15–20% of the total CO35 and the renal blood flow is 20% of CO36, In a low powered study of only 5 individuals, the renal plasma flows increased by 17% at 1 week in orbit but this was not significantly different to preflight values37. If a larger cohort had found this difference to be significant then this would be similar to the 18–26% increase in CO found by Norsk33. The CO must all pass through a capillary bed to return to the heart. If the CO is increased by 41% then the renal and CBFs cannot be normal.During spaceflight, the cardiac output (CO) appears to depend on which technique is used. Two studies using ultrasound echocardiography observed a decrease in stroke volume and CO during flight38. Impedance rheoencephalography has shown increased CBF both during and immediately after flight43. Transcranial Doppler (TCD) showed an increase in straight sinus velocity in 9/13 astronauts, with flow velocities ranging from 30–47 cm/sec and the normal range being 14–28 cm/sec44.Similar to the findings in CO, the CBF findings seem to depend on the technique being used. A 5-day flight of a Rhesus monkey on the Cosmos 1514 biosatellite fitted with a carotid flow sensor showed a sustained 8 cm/s increase in blood velocity48, some unchanged50 and some decreased flow52. The divergence between the previously described measures of CBF and the transcranial Doppler velocity is striking. The original validation studies for TCD showed the correlation between the arterial velocity and the gold standard for CBF (xenon 133 CT) was weak at r = 0.4253. This is because the CBF depends on both the velocity of the blood and the cross-sectional area of the vessel. If the middle cerebral artery is constricted, the CBF will fall but the velocity will increase and in reverse, the velocity will drop but the flow increases when the diameter increases54. The middle cerebral artery lumen can increase in size by 45% by altering carbon dioxide (CO2) levels from low-normal to high-normal55. Theoretically, if the CBF increased purely due to an increase in diameter, then the TCD could underestimate the effect by 45%. Indeed, Coverdale et al. found a change in middle cerebral artery cross-sectional area during acute hypercapnia resulted in a CBF underestimation by TCD of 18%56.The transcranial Doppler of the middle cerebral arterial literature in spaceflight is contradictory. Some studies suggest an increase in cerebral blood velocity57. However, the 84% increase in velocity found would require a 46% reduction in vein diameter to give a normal blood flow volume57. This would require the ICP to approach cerebral perfusion pressure58. This is because as the ICP increases the collapse of veins begins close to their outflow with the more proximal sections (where TCD measures velocity) being increased in size59. Only once the pressure reaches perfusion pressure will the whole vein collapse. No one suggests ICP approaches perfusion pressure in space as this would be lethal. Roberts et al. found some elevation of the brain and crowding of the sulci over the vertex and suggested this could lead to venous narrowing or arachnoid granulation obstruction. However, static pressures are equally distributed throughout a water bath and the reduction in the sulci was mild and unlikely to be water tight58. If the TCD vein diameter is normal then an increase in velocity must indicate an increase in blood flow volume.A recent study has shown a significant increase in the middle cerebral vein velocity on day 150 of spaceflight and ascribed this to a reduction in the vein diameter with a resulting normal venous flow volume60. There appears to be a distinct physiological difference between spaceflight and HDTBR. Thirteen days of space flight in a mouse model led to both a decrease in myogenic vasoconstrictor tone and an increase in arterial distention, leading to a 20% increase in resting cross-sectional area61. This would be consistent with lower vascular resistance and higher CBF during space flight61. This compared to control head-down tilt mice where there was no effect on vasoconstriction, passive pressure-diameter response or maximal diameter61. Using an MRI arterial spin labelling (ASL) technique, 30 days of head-down tilt plus increased CO2, demonstrated the expected decrease in CBF62. However, the five participants who developed optic disc oedema had higher CBF (approaching the baseline levels) compared with the non-oedema group62. This suggests that variations in vasoreactivity and autoregulatory responses to CO2 may play a role in SANS development62. Acute hypercapnia increases the CBF but the effect is short-lived being corrected within a few hours63. However, there is a delayed, more long-lasting vasodilatation occurring with chronic CO2 elevation which appears to be genetically mediated63. In chronic obstructive pulmonary disease, patients retain CO2. A reduction in the CO2 by non-invasive positive pressure ventilation reduced the middle cerebral artery TCD velocity by 23% without affecting the oxygen levels64. It should be noted TCD may have underestimated this effect. In a series of patients undergoing ASL MRI, those found to have an elevated CO2 had a grey matter CBF double the patients with CO2 in the normal range65. The effect was not statistically different between acute and chronic hypercapnia65. Overall, there was a 6.7% increase in CBF per 1-mmHg rise in partial pressure of CO265. Interestingly, women tended to be more resistant to the effect of CO2 than men65 which may point to a reason why men are more prone to develop SANS than women.Similar to the TCD findings, HDTBR studies tend to show a reduced CBF. This is perhaps not surprising as HDTBR also produces a reduction in cardiac stroke volume and CO2 in long-duration spaceflight. Technical constraints maintain carbon dioxide levels at nearly 10 times earth normal levels1. Air convection is also significantly reduced in microgravity and pockets of CO2 may develop around the nose and mouth of astronauts. At an ambient partial pressure of CO2 of 3.8 mmHg during flight, the expired CO2 of a cohort of astronauts was 6.1 mmHg higher than pre-flight levels66. There is a 6–6.7% increase in CBF for each 1-mmHg rise in partial pressure of CO267. This indicates the CBF could be increased by the 41% increase in CO noted by Norsk et al.29. Forty-five per cent of children with IIH have cerebral hyperaemia17. A study in patients with IIH showed a 56% increase in CO2 led to a 166% increase in superior sagittal sinus pressure68 indicating the effect of CO2 on sinus pressure is non-linear. In a modelling study, the increase in blood returning through the venous system significantly increased the pressure drop from the sagittal sinus to the jugular bulbs because the pressure response to CBF of the venous system was quadratic in nature69. The cause of the greater than the linear response of the venous system to blood flow is due to the development of rotational or vortex flow induced by the unusual geometry. Could an increased blood flow in long-term space flight increase the venous pressure is SANS? The normal arterial inflow for a group of average age 43 years is 792 mls/min70. A 40% increase in arterial inflow secondary to the elevated CO2 would lead to a mean arterial inflow of 1110 mls/min. If we were to recruit the 5 normal individuals who had their normal venous outflow modelled with computational fluid dynamics (CFD) in our original paper69, and place them in orbit for 6 months, then we can see from Fig. 17. IIH needs an increase in venous pressure of 7 mmHg to develop. We can see in Fig. 1, perhaps correlating with the 20% of our venous blood flow models which have suggested a large increase in pressure with increased CBF. The fivefold variation in the pressure response to the same increase in blood flow noted suggests that there is a wide variation in response to cerebral hyperaemia in normal individuals. Therefore, there may be some utility in performing CFD modelling studies on the venous outflow of prospective long-duration astronauts to try and stratify the risk of developing SANS.Thus, an increase in CO and CBF in long-term space flight may be related to CO69. Some of this data has been previously published69. Informed consent was obtained from all five patients who had their CT venogram data modelled to provide Fig. Initially, a literature search was undertaken in PUBMED looking for all research papers written in the English language with the search criteria “spaceflight associated neuro-ocular syndrome” or “vision impairment intracranial pressure”. Ninety-eight responses were obtained. Papers were chosen for review on the basis of discussing the CSF or blood flow dynamics. After the review, mathematical estimation of venous pressure in long term space flight was undertaken to utilise the computational fluid dynamic modelling undertaken by one of the authors (A.B.). The modelling data consists of 5 computational fluid dynamic models of the cerebral venous outflow from the sagittal sinus to the jugular veins obtained from the CT venogram images of patients who did not have evidence of cerebral disease, please see the original modelling study for further detailsFurther information on research design is available in the Reporting Summary


Background and Objectives: A high body mass index (BMI) is associated with the progression of autosomal dominant polycystic kidney disease (ADPKD). However, body fat (BF), which is another adiposity marker, has not yet been studied. Excessive weight may promote elevation in the endogenous synthesis of organic acid (OA) anions. Accordingly, we aimed to investigate the possible association of the aforementioned markers with kidney volume and renal function in patients with ADPKD. Materials and Methods: We conducted a retrospective cohort study of adult ADPKD outpatients involving clinical, serum, and urinary laboratorial data and body composition assessments retrieved from their medical records. BF was estimated by skinfold thickness (mm) on the non-dominant arm and was considered as normal or high for each sex. Total kidney volume (TKV) and height-adjusted volume (htTKV) were measured by magnetic resonance imaging. The annual estimated glomerular filtration rate (eGFR) slope was analyzed during a median follow-up time of 6 (5.0–7.0) years to calculate rapid progression . Results: A total of 104 patients were included , with 62.5% of the patients classified as high BF. The High BF group presented higher levels of OA, glycosylated hemoglobin (HbA1c), C-reactive protein (CRP), 24 h urinary sodium (UNa), and htTKV, and lower eGFR than those with a normal BF. In the multivariate linear regression, the associated variables with TKV were high BF, OA and BMI . In the binary logistic regression, when adjusted for potential confounders, UNa was the only parameter associated with an increased risk of eGFR decline ≥2.5 mL/min/year . Conclusions: Increased body fat and endogenous production of organic acid anions are associated with larger kidney size in ADPKD but not with a decline in renal function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic nephropathy, characterized by innumerable progressively growing kidney cysts that destroy the renal tissue structure, leading to progressive loss of renal function . The preDespite its genetic origin, several factors, including clinical, epigenetic, laboratorial, radiological, and environmental factors, are considered predictors of disease progression among patients with ADPKD. Male gender, gross hematuria, nephrolithiasis, type of mutation, proteinuria, and inflammation may worsen the progression of the disease ,6. Amongpost hoc analysis of the Halt Progression of Polycystic Kidney Disease (HALT) study showed that overweight and, particularly, obesity were associated with increased kidney volume and loss of renal function in patients with early-stage ADPKD. Subsequently, the same investigators, using data from another cohort , reported that a higher BMI was associated with a greater annual increase in kidney volume, but not with renal function decline [The association between BMI and the progression of ADPKD was recently pointed out by Nowak et al.  whose po decline .Metabolic syndrome, insulin resistance, kidney hyperfiltration, albuminuria, increased vasopressin, and derangements in glucose and lipids metabolism activating pathways that increase cyst growth may all contribute to the connection between obesity and a worse ADPKD prognosis . HoweverTraditionally, BMI is considered a surrogate marker of adiposity; notwithstanding, it cannot discriminate between fat mass and fat-free mass ,18,19,202, with available anthropometric and body composition parameters and biochemistry data, were selected for inclusion. The diagnosis of ADPKD was confirmed by renal ultrasonography, according to the criteria of Pei et al. [This is a retrospective observational study, based on medical records of ADPKD outpatients at the Polycystic Kidney Disease Outpatient Clinic of the Universidade Federal de São Paulo (UNIFESP), between 2012 and 2018. Adult patients (>18 years old) with estimated glomerular filtration rate (eGFR) > 15 mL/min/1.73 mi et al. . Exclusi2). To avoid overestimating the contribution of kidney size to BMI, body weight was adjusted by subtracting kidney weight, estimated by magnetic resonance (MRI) (see below), assuming a tissue density equal to that of water (1 g/cm3) [Weight (kg) and height (m) were measured to calculate body mass index (BMI), defined as body weight in kilograms by height squared in meters (kg/m1 g/cm3) . The percentage of body fat (%BF) was estimated by skinfold thickness (mm) using the equation of Durnin and Womersley . Skinfol2) × 41/1.73; body surface area (BSA) (m2) = 0.007184 × height (cm) 0.725 × weight (kg) 0.425. Sodium chloride (NaCl) daily intake was estimated from 24 h urinary sodium excretion (UNa) according to the formula: NaCl (g/day) = UNa (mEq/24 h)/17 [The body surface area (BSA)-dependent organic acid (OA) anion component, reflecting primarily endogenous acids production, was calculated by the formula of Berkemeyer and Remer : OA (mEq24 h)/17 .Hypertension at admission was defined based on office or clinic levels of systolic pressure ≥ 140 mmHg and diastolic pressure ≥ 90 mmHg  or the uBiochemical parameters considered were serum creatinine, fasting glucose, glycated hemoglobin (HbA1c), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, C-reactive protein (CRP), and 24 h urinary urea, Na, and osmolality. Creatinine serum was determined using a modified Jaffe reaction with a calibration traceable to reference by mass spectrometry with isotopic dilution (ID-MS) .Baseline total kidney volume (TKV) was measured by magnetic resonance imaging (MRI) with renal volumetrics performed by obtaining length, width, and depth using the ellipsoid equation. Values were combined from both kidneys, corrected for height (htTKV) . Age and2) over 5 years. Our analysis was restricted to patients exhibiting three to seven measurements of eGFR from baseline determinations. Rapid progression was considered when the eGFR slope was greater than or equal to 2.5 mL/min/year over 5 years [The Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI)  was used 5 years .p < 0.05 was considered significant. The variables’ distribution was evaluated by the Kolmogorov–Smirnov test. Categorical variables are presented as n (%), normally distributed variables as mean ± standard deviation (SD), and non-normally distributed variables as median (interquartile range (IQR)). Residuals were checked for normality, and variables were natural log-transformed when appropriate. Patients were divided into two groups according to normal or high body fat percentage, and differences between them were tested by Student’s t-test or Mann-Whitney, as appropriate. Pearson’s chi-squared or Fisher’s exact tests were applied between categorical variables. The slope was calculated individually based on the least squares method, which consists of an estimator that minimizes the sum of squares of the linear regression residuals. Linear regression analysis was performed to study possible determinants of TKV and binary logistic regression to assess potential factors associated with an eGFR decline ≥ 2.5 mL/min/year. All variables with a p-value < 0.20 in the univariate analysis were subsequently included in the multivariate model, adjusted for age, sex, presence of hypertension, and baseline eGFR.Statistical analysis was performed using IBM SPSS version 23.0 . In all analyses, 2. A total of 104 subjects met the inclusion criteria . Clinical and laboratorial parameters of all patients were obtained. Hypertension was significantly higher among high BF patients (81.3 vs. 64.1%). As shown in p = 0.09). The high BF group presented with higher levels of OA, HbA1c, and CRP, and lower eGFR than the normal BF group, with no significant differences between groups regarding diabetes, metabolic syndrome, mean values of fasting glucose, blood lipids, and urine osmolality. The percentage of patients with abnormal serum levels of glucose, HDL, and triglyceride also did not differ. Patients in the high BF group consumed more NaCl  than those in the normal BF group. Protein intake assessed by PNA did not differ between the groups. Of 104 patients, 76 had available data for TKV calculation. A total of 235 medical records of ADPKD patients were reviewed, of whom 59 had incomplete parameters of body composition data, 48 did not have all available biochemistry data, and 24 had an eGFR ≤ 15 mL/min/1.73 mp = 0.01). According to the Mayo imaging classification, 63.2% were rapid progressors (1C-1D-1E) but there was no significant difference with respect to body fat percentage between these slow and rapid progressors  (data not shown in tables). The results of binary logistic regression using rapid progression (eGFR decline ≥ 2.5 mL/min/year over 5 years) as the dependent variable are shown in Increased body mass has been recently shown to be independently associated with the rate of TKV growth in other cohorts ,13. Bodyper se or to the concomitant metabolic syndrome. In the current study, the prevalence of metabolic syndrome was low (around 17%) and did not differ between patients with high or normal body fat. It is worth mentioning that waist circumference was not included in the metabolic syndrome criteria to avoid bias by increased kidney size. We did not observe statistical differences between the groups regarding the percentage of patients with high triglyceride or low HDL levels, the latter being a known parameter of progression [The link between excessive body fat and increased kidney volume is not well-established yet, but some hypotheses have been raised. Obese individuals with metabolic syndrome present high plasma levels of copeptin , a markegression . The perObesity may cause inflammation  and it m2. Furthermore, metabolic acidosis is a common complication of moderate to severe CKD and has been shown to increase the risk of CKD progression; as eGFR decreases, there is less excretion of ammonia and alkalis [Unmeasured anion accumulation and retention and increased acid synthesis are hallmarks of obesity, and higher BMI has been associated with an increased risk of developing anion gap metabolic acidosis ,46. Here alkalis ,49. Inte alkalis  reported alkalis ,52, even alkalis . Among A alkalis ,54, alth alkalis  proposed alkalis  recently alkalis , and hyp alkalis ,54, sugg alkalis . TherefoA direct and independent association between urinary sodium (a marker of high NaCl intake) and a decline in eGFR ≥ 2.5 mL/min/year over 5 years, suggesting progression was evident in the present analysis. These findings are in line with other studies carried out in ADPKD patients, in which increased sodium excretion was associated with a decline in renal function ,58. The In the current series, there was no association between body adiposity, represented by high BF, organic acids, and BMI with the eGFR decline during the analyzed period of over 5 years. Although observed in a small sample, our results are similar to findings reported by Nowak et al.  in a mucLimitations of the present study include the retrospective observational nature of the study, not being able to establish a cause–effect relationship, and the possible selection bias in the sampling. The availability of data as just one TKV measure, performed at the beginning of the study, without the possibility of studying the influence of this measure over time, is also a limiting factor. The absence of urinary pH, citrate, and serum bicarbonate data precluded further analysis of the acid-base status and its relationship with obesity and adiposity. In addition, the level of physical activity could not be assessed. Finally, the relatively small number of patients can also be viewed as a limiting factor in our analysis. Our study also has strengths. Although body composition data were not obtained by a gold standard method such as DEXA , skinfolCurrent data encourage future studies with a larger sample and longer follow-up to validate our findings, in addition to the inclusion of other body composition methods such as DEXA or computed tomography, which allow for the evaluation of the effect of muscle mass on these outcomes.The present study suggests that increased body fat and endogenous production of organic acid anions are associated with greater kidney size in ADPKD, irrespective of the presence of fully established metabolic syndrome, but they are not independent risk factors for the decline in renal function.


Home blood pressure measurements have equal or even greater predictive value than clinic blood pressure measurements regarding cardiovascular outcomes. With advances in home blood pressure monitors, we face an imminent flood of home measurements, but current electronic health record systems lack the functionality to allow us to use this data to its fullest. We designed a data visualization display for blood pressure measurements to be used for shared decision making around hypertension.We used an iterative, rapid-prototyping, user-centred design approach to determine the most appropriate designs for this data display. We relied on visual cognition and human factors principles when designing our display. Feedback was provided by expert members of our multidisciplinary research team and through a series of end-user focus groups, comprised of either hypertensive patients or their healthcare providers required from eight academic, community-based practices in the Midwest of the United States.A total of 40 participants were recruited to participate in patient (N = 16) and provider (N = 24) focus groups. We describe the conceptualization and development of data display for shared decision making around hypertension. We designed and received feedback from both patients and healthcare providers on a number of design elements that were reported to be helpful in understanding blood pressure measurements.We developed a data display for substantial amounts of blood pressure measurements that is both simple to understand for patients, but powerful enough to inform clinical decision making. The display used a line graph format for ease of understanding, a LOWESS function for smoothing data to reduce the weight users placed on outlier measurements, colored goal range bands to allow users to quickly determine if measurements were in range, a medication timeline to help link recorded blood pressure measurements with the medications a patient was taking. A data display such as this, specifically designed to encourage shared decision making between hypertensive patients and their healthcare providers, could help us overcome the clinical inertia that often results in a lack of treatment intensification, leading to better care for the 35 million Americans with uncontrolled hypertension. Blood pressure (BP) control in the US is a public health problem. Hypertension is uncontrolled in about half of the 70 million US adults diagnosed with the disease –3 despitRecent research has identified the important role of home BP measurements, considered equal—or even superior—to clinic BP measurements in their value in predicting cardiac risk , 11. HomCurrently, for patients who monitor their BP at home, the data they collect may not be utilized to its potential. Understanding tabular presentations of numerical data often requires significant cognitive resources, the format often hides context, and trends are more difficult to detect. Data visualizations are a highly effective way to communicate both quantitative and probabilistic information to patients, with a variety of formats being effective –14. HoweDespite the power of data visualization as a technique to communicate quantitative information, graphing capabilities in current EHR systems are limited . Graphs Previously, we reported our efforts to determine the informational needs of patients and physicians to engage in shared decision making around hypertension using a single data display . In thatIn this paper, we present the design and refinement of such a data display to be used by a patient and their healthcare provider simultaneously, during an office visit, to improve shared decision making around hypertension management. We aimed to address several problems currently plaguing patients and physicians about the display of blood pressure measurements: (1) patients lack clarity about goal BP values; (2) patients are concerned by outlier values despite the average BP being in the goal range and considered “controlled”; (3) patients’ overdependence on the most recent BP values; and (4) patients not understanding the temporal connection between medication changes and BP response, as BP and medications are typically not on the same screen, and onset of action delay is different for each medication. We used an iterative, rapid-prototyping, user-centred design methodology, involving both our core research team and the focus groups reported in the previous work . We focuOur research and design team was assembled to develop an optimized BP data display to support clinical decision-making by patients and physicians. The team includes practicing family physicians; a physician member of Joint National Commission on Hypertension (JNC-8) and former chair of the United States Preventive Services Task Force (USPSTF) ; a data Inherent in our approach was our mission to design for shared physician and patient use to inform shared decision making around hypertension. We conducted a total of five focus groups dedicated to reviewing prototype displays and iterating on their design, alternating between hypertensive patients, and family physicians and internal medicine physicians—focus groups 1, 3, and 5 were with patients, and focus groups 2 and 4 were with physicians. Analysis of focus group qualitative data took place in three phases: a team debrief, a rapid preliminary analysis immediately following each focus group, and final analysis of compiled data. Patient and physician participants returned for three confirmatory focus groups to view and comment on the final prototype.The preliminary qualitative analysis following each focus group helped us identify participant responses to our designs and to allow for rapid iteration of our prototypes . A more The University of Missouri Health Sciences Institutional Review Board reviewed and approved this study and its human subjects’ participation and consent process. We recruited Family and Community Medicine (FCM) and General Internal Medicine (GIM) physicians from eight academic, community-based practices in the Midwest of the United States. We contacted their patients—aged 18 years or older, with a diagnosis of hypertension, and identified by their physicians as appropriate to participate in this study—by a mailed letter, signed by their physician. During each focus group, prototype displays were presented to all participants with minimal briefing to gauge the intuitiveness of each design. Participant demographics are presented in Table Graphing blood pressure carries additional demands compared to a single-number measurement such as body weight. A single blood pressure measurement is a pair of numbers and considered as such by both clinicians and patients. We considered two potential models currently in use. First, anesthesiology professionals have graphed blood pressure with pen and paper using an inverted caret and caret to mark the systolic BP (SBP) and diastolic BP (DBP) values, respectively Fig. . This al“I have them come in with the cuff to see how well their cuff works with my cuff. I would think confirmed versus unconfirmed would be confirmed with the nurse runs through the machine, writes down some numbers from, you know, hard data, versus unconfirmed would be patients calling us in with some numbers, ‘cause they could make those up.”Round 4, GIM Physician 7— The raw data in the EHR should reveal the source of measurement . We explored separate symbols to represent each of these sources. Additionally, we explored distinct symbols to differentiate confirmed/validated (thus more trustworthy) home BP measurements versus unconfirmed/unvalidated home measurements. “Home confirmed” refers to having clinical staff validate the accuracy of a patient’s cuff and measurement technique. Data trustworthiness depends on accurate and complete recordkeeping by the patient, the use of proper technique, and confirmation of that technique and results by office staff using the same equipment.“I’m not sure that differentiation matters to me that much.”— Round 2, FCM Physician 19However, we discovered in our focus groups that using a different visual symbol for each distinct data source added more complexity than needed for the task at hand: management of hypertension in the ambulatory setting giving priority to home BP values over office BP values. For example, inpatient or operative BP values were already recognizable by their markedly higher density—due to frequent measurement—and thus did not need symbols distinct from other non-home  BP measurements. Each new symbol gave the impression of importance; however, when everything is important, nothing stands out.Currently, most BP records are primarily made up of office BP measurements, gathered during regular visits. We expect this to change in the future as internet-connected home BP cuffs become integrated with patient portals and EHRs. Additionally, it is likely that passive BP monitoring is in our future as the personal health device  market is exploding in size . We explThe reader of the graph should be able to perceive at a glance whether the BP is in control or not. In existing EHRs, goal ranges may not be displayed at all Fig. A or may “The shading allows us to quickly see if we’re below 140 and below 90 […] Do I get to adjust my shading for the risk of my patient?”— Round 4, GIM Physician 7Recommendations for goal ranges can vary for special adult populations  and may differ among guideline-issuing organizations, which also revise their guidelines every few years. Goal ranges may also need to be personalized for patients who have symptoms (dizziness from low BP), certain disease states (diabetes), organ dysfunction , or when BP varies so widely that it fluctuates beyond both upper and lower bounds. The numeric range covered by the goal range bands was pre-set the same for all patients at 90–140 SBP and 60–90 DBP. The focus group participants expressed a strong desire for the ability to personalize the BP goal ranges on a per patient basis. Later designs added those controls.“Right. It [orange squares] doesn’t seem to have a purpose. It doesn’t seem to clarify anything; it doesn’t seem to add anything to me.”“… I can see that [orange fill means out of range]. I don’t need the orange.”— Round 1, Patient 17A variety of methods were considered to provide visual emphasis to values out of range, including using larger Fig. D or colo“There’s no color in the chart. It, the normal range of the graph is small and hard to read. It should be enlarged and blown up since those are the normal ranges.”— Round 1, Patient 16Initial designs used an all greyscale color palette Fig. G. This alike-with-like paradigm—if the data points and connecting line are within the goal range band of matching color then the BP is in a healthy range; otherwise the BP is too high/low.“Yes, the color is helpful. I think it’s gonna help, I think it would help patients to understand the difference between the diastolic range and the systolic range, and also you’re tying the blood pressure readings to the color of your target range. I think that is helpful.”— Round 2, FCM Physician 10We switched to pastel colors , with orange for SBP and blue for DBP, both colorblind safe Fig. H. To avo“I would probably almost want to put the numbers up there with the lines, you know, displaying, you know, what the numbers are…”— Round 1, Patient 13Our original prototype designs did not include an associated data table as data tables are a universal component of EHR designs. However, at our focus groups, a proportion of both patients and physicians preferred to see the data table in addition to the graphical displays. For the data table, we adopted our host EHR color scheme and bold text  to denote out of range values. In the context of visually adjacent data tables and graphical displays, we initially assumed that for each data point, there should be a one-to-one correspondence between a table value and a graph data point. We encountered several considerations that caused us to question that assumption, namely issues with data density and missing data.data dearth—BP measurements were taken only during clinical visits in the office, or during hospitalization . Today we are in a period of data nascence—while a fraction of patients are able and willing to monitor their BP at home, their ability to upload those measurements to an EHR is not without technological barriers. We are rapidly approaching a period of data abundance—both wearable and non-wearable BP monitors become more ubiquitous and data standards evolve to allow for automatic and seamless uploading of regularly collected patient BPs directly in the EHRs of healthcare providers.We believe we are currently in a transitional period for home BP measurements. In the past, we inhabited a period of The potential for high density home BP measurements limits the numeric values that could be presented in the line graph and accompanying data table for any given length of time—very dense data will require aggregation. To address this, we designed a system of data aggregation to deal with dense measurements Table . Users sThe potential for missing data is substantial currently, due to a combination of infrequency in office visits where measurements can be taken and the variable frequency of home measurements both within and between individual patients. We propose the following affordances to help account for missing data over a particular timeframe in the display: if < 10% of consecutive data points would be missing, we simply do not plot any points, connect the remaining points as we normally would, and leave gaps in the data table; if > 10% of consecutive data points are missing, we still leave gaps in the data table but we connect remaining points in the line graph with a dashed line. Thus, no points are plotted but the amount of missing data can be inferred from style of the line on the display (solid vs. dashed). This can be seen in Fig. There is evidence that the variability of BP measurements has much less clinical significance than the mean BP . Additio“Well, I’m trying to figure out how I would use it and the only thing I could see would be if there were some other intervention besides medication that occurred at that point. So you said this is where we started a restricted sodium diet or, you know, something like that.”— Round 2, FCM Physician 18We had discussed, and participants agreed, that recording behavioral changes  on the display, as well as metrics related to BP goals , would be helpful.“…when you’re down in the grey area [goal range], which appears to be the range that you’re shooting for, well, you don’t really need the bubble to tell you you’re in there because you’re in there. So I just think, I don’t know that that adds anything to the body of the display.”— Round 1, Patient 17Participants were less receptive to the idea of the annotation presenting an analysis of the information that appeared obvious through the graphical representation  but analysis such as average BP over time was attractive.We experimented with two approaches to display user-generated annotations. First, we explored a free-floating-bubble design where annotations were displayed as floating bubbles that would hover over the various parts of the display. Two schemes were used: (1) a color-coded variant, in which different colors of annotation bubbles denoted different topics Fig. A; and 2B. It wasHowever, a potential concern of the free-floating-bubble design was if annotations became popular, they would overwhelm the screen. Additionally, this design introduced certain problems: Where do you put the bubble? Does the bubble have to be manually placed by the person making the annotation or is there some internal logic that is used?To avoid these issues, an annotation timeline was introduced Fig. C. Annota“I mean, yeah, it looks like when they started the Lisinopril that, you know, the blood pressure started going down and stuff from the 10, low dose of a 10 to a 20, so they had to increase it to keep it down.”— Round 3, Patient 1We previously designed a medication timeline to help visualize polypharmacy, which was found to improve physician performance in routine medication management , compared to more traditional tabular displays of medication lists . We inco“I like it, because when you move the mouse it then shows you at this point, this is your blood pressure, this is the medicine you were on or a combination of medications.”— Round 1, Patient 17In many modern EHRs cross-categorical displays—which show all these elements in a single display—are rare and there is a need to switch between displays, which increases cognitive load. Our display presents the graphical display, data table, and medication timeline in a single display. We introduced a colored, vertical scrubber bar to help both patient and physician users link these elements together Fig. . As a usOur goal was to design a graphical display to visualize temporal trends for an individual patient's blood pressure, to support shared decision making between the patient and their healthcare provider with the aim of improving BP control across the population. The primary audience for this display is the patient-provider dyad (or caregiver-provider dyad) whose shared goal is to achieve the long-term goal of improved hypertension control. The display needed to clearly show whether BP was controlled compared to a goal range, to make recent trends in the BP apparent, to support judgments to improve control, and to foster action to achieve control. Design decisions were made with the intent of minimizing cognitive load by using principles that leverage fast visual cognition . Table 3https://smarthealthit.org) harnesses the FHIR  from HL7  to create open solutions and tools for innovators to build applications that can connect to systems using the FHIR platform. Using this platform or FHIR standards, non-commercial or commercial developers could deploy the design into other EHRs or Personal Health Record platforms.We partnered with the Tiger Institute, a technology collaborative between the University of Missouri and Cerner Corporation, to produce and deploy this as a separate display view in our local EHR implementation using the SMART on FIHR platform. The SMART  project  where the working prototype is deployed in a single EHR. However, this tool has promise for scaling across the non-commercial or commercial EHR environment as the designs could be integrated given the right technical supports. Second, we took a primary care perspective during the design process as the majority of hypertension care is provided in the primary care setting . HoweverFurther efforts should include adding the ability to modify the goal range for special patient categories (diabetes or chronic kidney disease), for different age groups (pediatric and geriatric), and to individualize for patients who have symptoms (dizziness from low BP) or other special characteristics. We recommend further work to include provider or patient annotations within the timeline, and to develop machine language linguistic summary annotations that would foster action to improve BP control .We iteratively developed a data display specifically designed to encourage shared decision making between hypertensive patients and their healthcare providers. This could help us overcome the clinical inertia that often results in a lack of treatment intensification, thus leading to better care for the 35 million Americans who have hypertension but do not have their blood pressure under control.


Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, small vessel, necrotizing vasculitis. The disease is mainly characterized by hypereosinophilia and asthma with frequent sinonasal involvement, although multiple organs can be affected, including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. IL-5 production is pathogenetically central for the development of the disease by promoting proliferation, transvascular migration and functional activation of eosinophils. The degree of blood and tissue eosinophilia appears to be associated with disease pathogenesis and eosinophil depletion represents a promising treatment approach for EGPA. We prospectively evaluated the efficacy and safety of a low dose (100 mg q4w), 12-month course of mepolizumab, an anti-IL-5 monoclonal antibody, in eight patients with severe asthma and active EGPA. Patients were recruited by the tertiary care center of Clinical Immunology and Allergy, University of Naples Federico II. The following outcomes were assessed before (T0), and after 6 (T6) and 12 months (T12) of mepolizumab treatment: Birmingham Vasculitis Activity Score (BVAS), prednisone intake, Sino-Nasal Outcome Test (SNOT-22), Total Endoscopic Polyp Score (TENPS), Asthma Control Test (ACT), Forced Expiratory Volume one second (FEV1)%, blood eosinophilia. BVAS score significantly decreased showing a sharp reduction in disease activity score. Clinical improvements in terms of sinonasal scores and asthma symptoms were observed, in parallel with a drastic drop in eosinophil blood count. Prednisone intake was significantly reduced. In two patients, asthma exacerbations led to discontinuation in mepolizumab therapy after 6 and 12 months despite BVAS reduction. Mepolizumab treatment was well tolerated, and no severe adverse drug effects were registered. In conclusion, our 12-month real-life study suggests that mepolizumab may be beneficial and safe in active EGPA patients by improving disease activity score, sinonasal and asthma outcomes while reducing the burden of prednisone intake. Eosinophilic granulomatosis with polyangiitis (EGPA), formerly Churg-Strauss syndrome, is a rare disease characterized by potentially life-threatening systemic, small vessel, eosinophilic vasculitis , 2. PrevEGPA pathophysiology remains only partly understood; it is associated with anti-neutrophilic cytoplasmic antibodies (ANCAs), usually directed against myeloperoxidase (MPO) or proteinase 3 (PR3) in approximately 40% of the patients , 10. ANCInterleukin 5 (IL-5) is a major hematopoietin regulating the life cycle of eosinophils , 13. CirEGPA management is based on reducing active inflammation, modulating the immune response and managing disease-specific and/or treatment-related complications. In a proportion of patients, remission may be achieved with systemic corticosteroid therapy, alone or in combination with more potent immunosuppressant therapies  but a relapse rate of 30–40% is reported . MoreoveMepolizumab is a fully humanized monoclonal antibody that binds to free IL-5 with high specificity and affinity, thus preventing the interaction to the alpha chain of IL-5 receptor (IL-5R) on the eosinophilic cell surface. The drug is approved as add on treatment of patients with severe eosinophilic asthma (SEA) accordingly to the GINA guidelines and it is administered subcutaneously (s.c.) every four weeks with a dosage of 100 mg (100 mg q4w) , 21.Previous studies demonstrated efficacy and safety of higher dosages of mepolizumab (300 mg q4w) in the induction and maintenance of remission of relapsing or refractory EGPA , 22–24. The aim of this study was to investigate the effects of low-dose mepolizumab  in EGPA patients in terms of disease control [evaluated by the Birmingham Vasculitis Activity Score (BVAS)], sinonasal control [by using the Sino-Nasal Outcome Test (SNOT-22) score and Total Endoscopic Polyp Score (TENPS)], and asthma control [by Asthma Control Test (ACT) and Forced Expiratory Volume at 1 s % (%FEV1: FEV1/FEV1 predicted)], after 6 (T6) and 12 (T12) months of treatment. In addition, reduction of eosinophil blood count and oral prednisone intake were also evaluated at T6 and T12.Strongyloides stercoralis infection.The study involved the Division of Clinical Immunology and Allergy, a tertiary care center of the University of Naples Federico II. Patients recruited in the study were in follow-up in the outpatient clinic for EGPA and comorbid SEA. Head and neck consultation was performed by an Ear, Nose and Throat (ENT) specialist and a maxillo-facial surgeon. Inclusion criteria were diagnosis of EGPA according to the American College of Rheumatology 1990 criteria  and/or t2-agonists (LABA)/corticosteroids (ICS) associations, plus long-acting anti-antimuscarinic drugs (LAMA) as stated by step 5 GINA guidelines for severe asthma, and intranasal corticosteroids (mometasone 50 μg spray: one spray in the morning and one spray in the evening for each nostril) for rhinosinusitis with or without nasal polyposis. For one out of eight patients of the study not receiving prednisone at baseline, mepolizumab was added to immunosuppressor treatment. As mepolizumab is not yet approved for EGPA in Italy, the drug was prescribed for treatment of severe eosinophilic asthma, according to the recommendations of the Italian Drug Agency (AIFA) at a dosage of 100 mg q4w s.c. for a 12-month course.Patients were treated with mepolizumab as add-on therapy to oral corticosteroids (OCS), inhaled long-acting betaThe parameters used to verify the efficacy of mepolizumab were: BVAS, SNOT-22, TENPS, ACT, FEV1%, blood eosinophils and prednisone dosage, performed at baseline (T0) and after 6 (T6) and 12 months (T12) of mepolizumab treatment.The BVAS is designed to document clinical features that are directly due to active vasculitis. It rates 10 areas of interest  . DiseaseSNOT-22, the most commonly used instrument for patients reported outcomes , 32 was ACT is a validated five-item questionnaire for assessing asthma control. Each item is scored on a five-point scale from 1 to 5 , with a total score of 5–19 and 20–25 points describing uncontrolled and well-controlled asthma, respectively.Spirometry  before and after salbutamol 400 mcg, was performed according to the guidelines of the American Thoracic Society/European Respiratory Society (ATS/ERS) . FEV1, FAsthma exacerbations were registered as an acute or subacute worsening in symptoms and lung function from the patient’s usual status .Pulmonary involvement was assessed by high-resolution tomographic chest examination based on the presence of ground-glass opacities, areas of consolidation with thinning of the bronchial wall, and the presence of small centrilobular nodulations or pleural effusion. Cardiac involvement, a negative prognostic factor for EGPA, was assessed by electrocardiographic and echocardiographic study. The presence of neurological interest (mononeuropathy and polyneuropathy) was confirmed with clinical examination and electromyography. Kidney and liver were evaluated through laboratory tests and abdomen ultrasound. Peripheral blood eosinophil counts were measured using an automated hematology analyzer. Prednisone intake (mg/day) was registered during scheduled visits.Treatment with immunosuppressors and /or prednisone was managed by the same physicians that prescribed mepolizumab. From week 4 post baseline onward, in those patients who showed improvement in respiratory symptoms and lack of manifestations attributable to active vasculitis, prednisone was tapered downwards according to the standard of care practice .Safety was clinically monitored on the basis of the frequency and severity of adverse events .All procedures complied with the Helsinki Declaration of 1964, subsequently revised in 2013. The study protocol was approved by the ethical committee of the University of Naples Federico II. Informed consent was obtained from all patients who agreed to participate to this study.Data as demographic, clinical, and other disease-related variables were statistically described with the use of frequencies (percentages when appropriate) for categorical variables, and the mean and SD for quantitative variables. The comparison between the sample means at T0 vs. T6, T6 vs. T12, and T0 vs. T12, for the variables of the continuous type, was performed by means of Student’s t-test, by calculating the 95% confidence interval. All p values were two-sided, and values less than 0.01 were considered significant. The calculations were performed using IBM SPSS Statistics, v.20.0 software .8 patients  mean age 55.75 years, were included in the study. Table Measurements were performed according to study protocol at 6 and 12 months of mepolizumab treatment. Interestingly, BVAS significantly decreased to 3.6 ± 1.3 at T6 and 3.0 ± 1.9 at T12 (T0 to T12 p < 0.01)  during the study, while he was on mepolizumab treatment (after T6). This patient was excluded from SNOT-22 and TENPS evaluation at T12.Another patient recruited for the study had severe recalcitrant nasal polyposis with a large left frontal sinus mucocele at T0 (TENPS 8). At the Magnetic Resonance Imaging (MRI) and computer tomography scan there was evidence of a mucocele protruding from the left frontal sinus to the left frontal region causing an extensive erosion of the posterior wall of the frontal sinus Fig. a–d. The An overall clinical improvement in terms of asthma control was measured: mean ACT was 18.4 ± 8.9 at T6 and 20.4 ± 5.8 at T12 (T0- T12 p ≤ 0.01)  , upper respiratory tract infection (3/8), worsening of asthma (2/8). As arthralgia may be secondary to adrenal suppression axis during OCS tapering, we performed assessment of hypothalamic–pituitary–adrenal axis integrity in all patients, according to the standard of care in order to exclude such correlation .Therapeutic approach of EGPA is challenging for clinicians, as the standard of care treatments  are hardly effective, and long-term remission is difficult to achieve in many patients. As EGPA is a rare disease, only a small number of randomized control trials (RCT) is available and there is a large need for real-life evidence. EGPA and SEA exhibit some similarities in their pathogenesis and therefore mepolizumab has been effectively used as the first targeted treatment in EGPA patients. However, it is still not clear whether the efficacy of the drug in the treatment of EGPA is due to its ability to control respiratory  symptoms or if it effectively plays a role in systemic vasculitis manifestations. As eosinophilia is central to the physio-pathogenesis of the disease, it is hypothesized that direct or indirect depletion of eosinophils may be beneficial for EGPA treatment. IL-5, is increased in patients with active EGPA and mediates different pathogenetic pathways leading to eosinophilic inflammation and tissue injury by promoting eosinophil adhesion to vascular endothelium and CC chemokine receptor 3 dependent migration of eosinophils from the vasculature . TherefoIn our study, the mean BVAS at the time of mepolizumab initiation was 21 ± 8, reflecting an active disease. As BVAS is designed to document clinical features directly due to active vasculitis a significant BVAS reduction at T6 and T12 suggests an overall clinical improvement of the disease during mepolizumab treatment.ENT involvement in EGPA is very frequent: rhinosinusitis, epistaxis, and neurosensory hearing loss are common features. Moreover, nasal polyposis may require recurrent surgical revisions . There iThe efficacy of mepolizumab in SEA has been demonstrated in several studies: the drug induces reduction of asthma exacerbations and improvements in lung function   both in Blood eosinophilia was sharply reduced. Apparently, this result is directly associated to the blocking effect of mepolizumab on circulating IL-5. The first clinical evidence of successful use of mepolizumab in EGPA was reported in 2010 by two different studies treating EGPA patients with 750 mg of monthly mepolizumab infusions , 41. TheExperts suggest that the definition of complete response during EGPA treatment should include a prednisone dosage ≤ 7.5 mg/day to control systemic manifestations . In thisThe most important target in the treatment of EGPA is to induce long-term remission and reduce the burden of systemic glucocorticoids and immunosuppressive therapies. In our study, 4 out of 8 patients had previously received or were on immunosuppressive drugs for disease control, and 7 patients were on prednisone at T0. Mepolizumab allowed corticosteroid tapering, exerting a corticosteroid-sparing effect. Given the side effects of systemic corticosteroid treatment in EGPA patients , we suggest that reduction of prednisone intake in our patients may represent a main clinical benefit of mepolizumab treatment. In addition, during the observation period, patients remained clinically stable from the cutaneous, cardiologic, renal, and neurologic point of view. Mepolizumab treatment was safe, and no severe adverse events were registered. Upper respiratory tract infections or worsening of asthma could be part of the EGPA clinical picture and therefore could be considered as hallmarks of incomplete response to low-dose mepolizumab.Recent real-life studies report evidence that low-dose mepolizumab can induce clinically relevant benefits in patients with non-active EGPA, especially on asthma symptoms and exacerbation rates, reduce the use of OCS and immunosuppressive drugs, and even prevent EGPA relapse for extrapulmonary manifestations –27. MoreThe study has some limitations: the open-label design, the absence of a control arm and the small number of participants make it difficult to extend our results to EGPA patients overall. Moreover, we prescribed low-dose (100 mg q4w) mepolizumab for severe eosinophilic asthma in our EGPA patients as high dose mepolizumab (300 mg q4w) is not yet approved for EGPA in Italy. However, these preliminary results can be a starting point for larger real-life studies, to define the most suitable, disease-severity tailored dosages of mepolizumab in EGPA patients.