Cardiovascular diseases are frequently present in chronic obstructive pulmonary disease (COPD). Population-based studies found associations between retinal vessel diameters and cardiovascular health, but it is unknown whether this also applies to COPD patients. Therefore, we measured retinal vessel diameters in COPD patients and aimed to determine the association with cardiovascular risk factors, lung function, and functional outcomes. In addition, we investigated whether an exercise-based pulmonary rehabilitation (PR) program would change retinal vessel diameters, as a proxy for improved microvascular health. Demographics and clinical characteristics, including pulmonary function, exercise capacity, blood pressure, blood measurements and level of systemic inflammation were obtained from 246 patients during routine assessment before and after PR. Retinal vessel diameters were measured from digital retinal images. Older age and higher systolic blood pressure were associated with narrower retinal arterioles . Older age, higher systolic blood pressure and lower level of systemic inflammation were associated with narrower retinal venules . No associations were found between retinal vessel diameters and lung function parameters or functional outcomes. After PR, no significant changes in retinal venular or arteriolar diameter were found. To conclude, retinal vessel diameters of COPD patients were significantly associated with systolic blood pressure and systemic inflammation, whilst there was no evidence for an association with lung function parameters, functional outcomes or other cardiovascular risk factors. Furthermore, an exercise-based PR program did not affect retinal vessel diameter. Although the diagnosis of COPD is based on spirometry, it is well recognized that COPD is associated with a range of systemic extrapulmonary effects1. Indeed, comorbidities are frequently present and contribute to the severity of disease4. Cardiovascular disease  is a common comorbidity in COPD5.Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases7. Indeed, cigarette smoke not only affects the airway epithelium, but also causes vascular endothelial damage and loss of microvascular integrity in several organs, including the heart, brain, and kidney9. In addition, systemic inflammatory processes, oxidative stress, and hypoxia may contribute to microvascular complications in COPD11. Since it has been suggested that changes in the microvasculature may be associated with cardiovascular disease13, monitoring the properties of the microvascular system in COPD could be valuable for additional phenotyping with possible added-value in clinical practice for cardiovascular risk stratification14.Smoking is the most important risk factor for the development of COPD, but it is also a major risk factor for the development of cardiovascular disease15. Findings from large epidemiological studies demonstrated that structural assessment of retinal microvasculature can provide useful information for cardiovascular risk prediction19. Indeed, it has been recognized that changes in the retinal microvasculature may precede the occurrence of hypertension, obesity and diabetes mellitus (DM)20. Earlier population-based studies demonstrated that more narrow retinal arteriolar vessels are associated with hypertension, while wider retinal venular vessels are associated with systemic inflammatory markers, hyperglycaemia, obesity and dyslipidaemia21. Similar findings were observed in patients with type 2 DM, heart failure or rheumatoid arthritis25.Retinal microvasculature can be easily visualized using fundus photography and can serve as a non-invasive proxy to assess the microvascular health status1) and FEV1/forced vital capacity (FVC)27. This would indicate that vascular comorbidities associated with obstructive decrements in lung function may be characterized by defects in the microvascular circulation, as assessed with fundus imaging26.To date, systematic studies characterizing the retinal microvasculature in patients with COPD are scarce. Data from a population study suggest that the width of retinal venules is inversely associated with forced expiratory volume in one second  of 152.5 ± 12.7 µm and mean central retinal venular equivalent (CRVE) of 233.7 ± 21.1 µm. Retinal abnormalities were present in 146 (59%) patients, of which 47 (19%) had multiple abnormalities. Most common abnormalities were increased vessel tortuosity (n = 44), peri-papillary atrophy (n = 42), (suspicion of) cataract (n = 34), and (suspicion of) glaucoma (n = 22) (See Supplementary Table CO %predicted), arterial oxygen saturation at rest (SaO2), systolic blood pressure, diastolic blood pressure, and triglycerides levels , total lung capacity (TLC), diastolic blood pressure, arterial partial pressure of oxygen (PaO2), long-term oxygen therapy, smoking status, smoking pack-years, blood glucose, dyslipidemia, pulmonary and cardiovascular medication, cardiovascular comorbidities and fellow vessel diameter. Higher systolic blood pressure, low level of systemic inflammation and older age were associated with narrower retinal venules; β: −0.229 , p = 0.041; −13.767 , p < 0.001; and −0.654 , p = 0.042; respectively. These associations remained significant after further adjustment for fellow retinal vessel diameter  and cycle endurance time on constant work rate test (CWRT) . 33.5% of the patients achieved a clinically relevant improvement in 6MWT, whilst 51.5% of the patients achieved a clinically relevant improvement in cycle endurance time. No significant differences were found in CRAE  and CRVE  following pulmonary rehabilitation.Non-responders to pulmonary rehabilitation had a significantly worse baseline lung function, and lower BMI and FFMI compared to responders. Baseline retinal vessel diameters and changes in retinal vessel diameters after pulmonary rehabilitation were not significantly different between responders and non-responders Table . In addiThis is the first study measuring retinal vessel diameters in a large group of well-characterized COPD patients. We showed that retinal arteriolar and venular diameters were independently associated with systolic blood pressure, whereas retinal venular diameter was also related to systemic inflammatory status and age. Retinal vessel diameters, as a proxy for microvascular health, did not change after an exercise-based pulmonary rehabilitation program. Retinal vessel diameters were not associated with important functional outcomes of pulmonary rehabilitation. Additionally, we found retinal abnormalities in more than half of the patients with COPD.30. Data from one large population-based study demonstrated that changes in retinal venular diameter were associated with decrements in lung function in healthy individuals (28 mL decrement in FEV1 per SD unit of CRVE), especially in current smokers (93 mL decrement in FEV1 per SD unit of CRVE)26. This association between retinal vessel diameter and lung function was not confirmed by our data from a large group of COPD patients. This might be explained by the compromised lung function with a narrower range of FEV1 values in our population compared to the study of Harris et al.26. In addition, our FEV1 values are at the lower bound of the distribution of values measured in the latter study. Similar to our findings, Chew et al. and Ugurlu et al. did not demonstrate an association between retinal vessel diameter and severity of COPD30.To date, only few studies examined the relation between retinal vascular parameters and lung function18. To date, no studies have evaluated retinal vessel parameters and cardiovascular risk parameters in COPD. Although earlier population-based studies demonstrated that a lower FEV1 is an independent risk factor for cardiovascular morbidity and mortality32, we could not establish an association between lung function parameters and retinal vessel diameter in patients with COPD. Then again, we did find an association between retinal vessel diameter and traditional cardiovascular risk factors, including systolic blood pressure and level of inflammation. Considering the high prevalence and incidence of cardiovascular comorbidity in COPD patients33, and the fact that cardiovascular comorbidities are often undiagnosed35, an easy to obtain fundus image may be an interesting metric for further cardiovascular phenotyping of patients with COPD. However, we emphasize the need for determining the clinical relevance of retinal imaging in cardiovascular risk prediction in patients with COPD.Structural assessment of retinal microvasculature can provide useful information for cardiovascular risk prediction37, and systemic inflammatory processes may have a role in the association between retinal vessel diameter and cardiovascular diseases, including coronary heart disease, DM, hypertension and stroke38. Large population-based studies already demonstrated that systemic inflammation is associated with retinal venular diameter. The Rotterdam study, the multi-ethnic study of atherosclerosis and the Beaver Dam Eye Study reported associations of nonspecific and specific systemic inflammatory markers , interleukin (IL)−6) with larger venular diameter39. Our study is the first to establish an association between systemic inflammation and retinal venular diameter in patients with COPD. Moreover, this association was consistently seen regardless of smoking status, and other cardiovascular risk factors. In addition, we identified an independent association between retinal vessel diameter and systolic blood pressure. The inverse relation between retinal vessel diameter and elevated systolic blood pressure has already been reported in several large population-based studies40, but, to the best of our knowledge, never in patients with COPD. Future longitudinal studies will be needed to demonstrate the usefulness of retinal blood vessel analysis as part of cardiovascular risk screening in patients with COPD.It is increasingly recognized that systemic inflammatory markers are involved in the pathogenesis of cardiovascular diseases and can predict cardiovascular events41, which is further supported by findings from epidemiological studies, showing an association between wider retinal venules and elevated systemic inflammatory markers39. It is therefore possible that the high proportion of patients with increased levels of systemic inflammation in this study might attenuate the association between retinal venular diameter and DM. This is confirmed by the study of Heitmar et al., in which no association was found between retinal vessel diameter and DM in different patients groups with increased levels of inflammation42.In contrast to population-based studies, our findings did not demonstrate an association between retinal venular diameter and blood glucose level or DM. To date, little is known on the exact mechanisms for the association of wider retinal venular diameter with hyperglycemia and DM,. It has been speculated that venular widening may reflect systemic inflammatory processes involved in the pathogenesis of impaired glucose metabolism44. Indeed, a constant oxygen supply is crucial for adequate organ function44., andeven small changes in oxygen supply to the retina can result in tissue hypoxia and retinal changes44. In addition, exposure to corticosteroids may contribute to an increased risk of glaucoma and cataract, though results in patients with COPD are contradictory47. An earlier review demonstrated that structural and functional changes in the retinal microvasculature are more common and severe in patients with COPD compared to non-COPD controls, including increased retinal vessel diameter, lower retinal arterial oxygen saturation, impaired haemodynamics and increased resistive index of the orbital vessels43. Chew et al. also demonstrated that retinal abnormalities were more frequently present in hospital patients with COPD compared to other hospital patients (80% vs. 50%)27. Furthermore, patients with COPD were more likely to report visual impairment compared to subjects without COPD (14.0% vs. 9.6%)48. In line with this, ophthalmological screening in this study identified a high prevalence of retinal abnormalities in patients with COPD. More interestingly, these abnormalities were not recorded in their medical history. As retinal abnormalities can result in a reduced visual acuity49, which is related to a decreased quality of life and physical functioning, and increased risk of falling50, an ophthalmological screening might be valuable in patients with COPD.It has been suggested that hypoxia may be involved in the etiology of some retinal abnormalities in COPD52. In addition, it has been suggested that physical exercise has a positive effect on the structure  and functionality of the microvasculature in subjects with microvascular diseases and physically inactive adults54. To date, only few studies evaluated the effects of different exercise modalities on microvasculature56. In patients with migraine and patients with unipolar depression it has been demonstrated that high-intensity interval training is slightly more effective in improving microvascular structure and function than moderate, continuous exercise56. It remains challenging to determine which exercise modalities are the most optimal for improving microvascular structure and function for different patient groups and disease severities. Indeed, this is the first study in patients with COPD. Our results demonstrate that an exercise-based pulmonary rehabilitation program did not affect static measurements of retinal vessel diameter in patients with COPD. Although exercise training  and duration of the pulmonary rehabilitation program were comparable, or even longer compared to earlier studies, it is possible that this program may not provide optimal stimuli to induce significant effects in retinal vessel diameters56. Moreover, the timing of pulmonary rehabilitation may not be optimal to improve microvascular function. Indeed, it has been recognized that microvascular dysfunction is an early event in the natural history of COPD58, and it is an open issue whether microvascular dysfunction is still reversible in patients with advanced COPD. It is possible that the response to an exercise program can be attenuated in patients with COPD, as endothelial dysfunction and impaired flow-mediated dilation are often present in these patients59. Moreover, the possible effects of exercise training might be influenced by the high prevalence of cardiovascular comorbidities and use of cardiovascular medication. Similar to our findings, it was shown that pulmonary rehabilitation does not appear to be effective in improving arterial stiffness and endothelial dysfunction in patients with COPD61. Future studies should investigate the most suitable timing and exercise regimes for improving microvascular structure and function. In this context, one should also consider a more integral assessment of the microvasculature and include the analysis of biomarkers of endothelial function (e.g. endothelin) and functional markers such as dynamic retinal imaging and Laser-Doppler flowmetry62.Lower levels of physical activity are associated with wider retinal venular diameters30. Furthermore, 20% of the patients in this study had retinal vessel calibers outside the earlier reported age- and sex-specific reference range 63. However, comparison with normative data should be interpreted with caution, as studies used different retinal vessel measurement software systems. It has been demonstrated that there is a poor agreement between different retinal measurement software, indicating that absolute measurements from the different software systems could not be interpreted interchangeably65. Third, static retinal vessel imaging only reflects a snapshot of the retinal microvasculature and provides limited information on functional alterations of the vasculature67. For future studies, we recognize the added-value of dynamic vessel analysis because this test has the potential to assess microvascular reactivity and autoregulation, which are suggested to have diagnostic potential in detecting subclinical endothelial dysfunction in the microvasculature and facilitate early diagnosis of cardiovascular diseases67. Fourth, we only quantified retinal vessel diameter, whilst other retinal vessel parameters, including vessel tortuosity and fractal dimension, may also provide valuable information regarding cardiovascular risk68. Fifth, proportion of patient in GOLD stage I and GOLD A were relatively small, and therefore caution is required when generalizing findings to the whole COPD population. Sixth, we only used hs-CRP as marker of systemic inflammation, and we did not measure other inflammatory markers that may be of interest in COPD, such as IL-6, tumor necrosis factor- α, and fibrinogen. Finally, a high proportion of patients had cardiovascular comorbidities, which may have influenced the findings of this study. However, multivariate analyses did not show an association between retinal vessel diameter and cardiovascular diseases or cardiovascular medication. Furthermore, additional analyses did not show significant differences in retinal vessel diameters between patients with and without cardiovascular diseases.The major strength of this study is the use of a wide array of clinical variables, cardiovascular risk factors, and functional outcomes, allowing a comprehensive analysis of possible variables related to retinal vessel diameter in a large group of well-characterized COPD patients. This study has the following limitations. First, this is an observational study and no causal relations can be established. Furthermore, it is possible that cardiovascular diseases preceded the development of COPD in some patients. Future studies are needed to determine the clinical relevance of retinal vessel parameters for the development of cardiovascular diseases in patients with COPD. Second, we did not include a healthy control group. Then again, it was already documented that patients with COPD have increased retinal arteriolar and venular diameters compared to non-COPD controlsTo conclude, we demonstrated that retinal arteriolar and venular diameters of patients with COPD were significantly associated with systolic blood pressure and level of systemic inflammation, but there was no evidence for an association with lung function parameters, functional outcomes or other cardiovascular risk factors. Furthermore, an exercise-based pulmonary rehabilitation program did not affect retinal vessel diameter. Future studies are needed to evaluate the association between physical activity level and retinal vessel diameters and the possible beneficial effect of increased physical activity level on microvascular health, as assessed by retinal vessel diameters, in patients with COPD.69. The study was approved by the Medical Research Ethics Committees United . The study was performed in accordance with the tenets of the Declaration of Helsinki and Good Clinical Practice and has been registered on www.trialregister.nl (NTR5896) before enrolment of the first volunteering participant. All subjects gave written informed consent.This was a prospective observational study conducted in Ciro 69. Patients were eligible to participate when they were diagnosed with COPD and were clinically stable. Patients with a clinical diagnosis of abnormalities in the lens or cornea, which makes it impossible to image the retina with a fundus camera, were excluded. Additionally, patients with known retinal diseases were excluded. Furthermore, patients who were unable to provide informed consent due to cognitive problems or unable to speak and understand Dutch or English were excluded.Patients referred for clinical assessment and pulmonary rehabilitation to Ciro were screened70. The program consists of 40 sessions and can be inpatient  or outpatient . In addition to progressive physical exercises, such as high-intensity interval and continuous training on a stationary cycle and treadmill, and strengthening exercises, the program also included non-exercising components such as occupational therapy, nutritional counselling, psychosocial counselling, exacerbation management, optimizing medication use, and/or educational sessions.All patients with COPD participated in a comprehensive pulmonary rehabilitation program at Ciro, as defined by the latest international ATS/ERS statement on pulmonary rehabilitation1, FVC, TLC, RV, and TLCO %predicted), SaO2, arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2), peak aerobic capacity (CPET), functional exercise capacity (6MWT and CWRT at 75% of peak work rate), blood pressure, and blood measurements , LDL, triglycerides), and hs-CRP), were obtained during routine assessment prior and after pulmonary rehabilitation, as described before71. Diagnosis of hypertension was based on the use of antihypertensive medication or a systolic blood pressure>140 mmHg and/or diastolic blood pressure>90 mmHg on three separate occasions72. The diagnosis of (pre-) DM was based on a fasting plasma glucose level ≥6.1 mmol/L. Dyslipidemia was defined as total cholesterol  ≥6.4 mmol/L, LDL cholesterol  ≥4.4 mmol/L, HDL cholesterol <0.9 mmol/L, triglycerides ≥1.94 mmol/L, or if receiving lipid-lowering medication. Hs-CRP was used as a marker of systemic inflammation and categorized using the established clinical cutoff points into low (<1 mg/L), borderline (1–3 mg/L), moderately high (3.01–10 mg/L) and markedly high (>10 mg/L)73. Medication use and cardiovascular comorbidities were obtained from patients’ medical records.Demographics and clinical characteristics, including BMI, FFMI, post-bronchodilator pulmonary function  with a field of view of 45° was used to obtain high-resolution, optic disc centred images of the fundus of the right eye of each patient at start and end of pulmonary rehabilitation. Patients had to abstain from exercise in the hour prior to the measurement. A trained grader masked to patient characteristics, analyzed the retinal images using semi-automated vessel analysis software developed at VITO .74. Images were not synchronized on the cardiac cycle, but instead retinal vessel diameters of two images were averaged to minimize random variation in retinal vessel diameter due to different stages of the cardiac cycle75.The six largest arterioles and venules coursing through a zone between 0.5 and 1 disc diameter from the optic disc margin were measured and summarized as CRAE and CRVE, representing the average diameter of arterioles and venules of the eyeIn addition, all images were screened by two ophthalmologist for the following changes: retinal vascular changes , optic disc changes , vitreoretinal or choroidal structural changes . Slightly blurry media was defined as (suspicious of) cataract.A priori, we have calculated the minimum sample size to achieve adequate power. Based on Chew et al.27, demonstrating that microvascular abnormalities were prevalent in 80% of the patients with COPD, we should include 246 participants .76) (Model2). Benjamini-Hochberg corrections were applied to correct for multiple testing. General linear models for repeated measures were used to determine the effect of pulmonary rehabilitation on retinal vessel diameter for all patients with COPD and after stratification for response on pulmonary rehabilitation based on the minimal clinically important difference of the 6MWT and cycle endurance time . All analyses were performed using SPSS 25.0 . Level of significance was set at ≤0.05.Data were tested for normality and are presented as mean and standard deviation (SD) unless noted otherwise. Age- and sex-adjusted stepwise multiple regression models were used to identify the association between retinal vessel diameter and lung function parameters, clinical variables, cardiovascular risk factors and functional outcomes of pulmonary rehabilitation . Variables were selected as possible confounders if they showed a significant association with retinal vascular width on univariate analysis (p ≤ 0.10), or if a variable was reported to be associated with retinal vessel width in previous literature. In case of high collinearity between two variables, the variable with greater clinical significance, based on the judgement of the authors, was chosen. Variables were included in the final model (Model 1) if they were significant (p ≤ 0.05) and/or they modified the estimates of the remaining parameters (>10% change). To account for potential confounding, models were additionally adjusted for fellow vessel diameter (i.e. for CRVE in models of CRAE, and vice versaSupplementary Tables.


We report a 61-year-old female with end-stage renal disease (ESRD) secondary to polycystic kidney disease (PKD) complicated by intradialytic hypertension (IDH). Increased sympathetic drive leading to increased stroke volume and/or vasoconstriction with an inappropriate increase in peripheral vascular resistance (PVR) has been postulated to be the cause of IDH.Attempts to control her blood pressure by reducing her goal weight; increasing dialysis times/ frequency and decreasing her sodium concentrate in the dialysis fluid were unsuccessful. Acting upon literature evidence suggesting renovascular disease as a cause of IDH, we referred her to an interventional radiologist for evaluation of the renal arteries. Selective angiogram of both renal arteries revealed right sided atherosclerotic renal artery stenosis (RAS) treated with insertion of a balloon mounted 6 mm stent and left sided fibromuscular dysplasia (FMD) treated with 5 mm balloon angioplasty.This case highlights the need for interrogating the renal arteries radiologically for a potential cause in difficult to control IDH and comments on the association between PKD and FMD that has not yet been reported. Hypertension on renal replacement therapy (RRT) is best managed by optimizing goal weight, tight fluid control, salt restriction, increased dialysis times/frequency, decreasing sodium in the dialysate and transitioning to home hemodialysis. While ultrafiltration on hemodialysis typically lowers blood pressure, some patients have a paradoxical rise in blood pressure called intradialytic hypertension (IDH).A 61-year-old female was being actively monitored in the hemodialysis unit for intradialytic hypertension (IDH). She was born in Ethiopia and had been diagnosed with autosomal dominant polycystic kidney disease (ADPKD) at the age of 35 and immigrated to Canada at the age of 53. Her mother died in Ethiopia and with no access to medical facilities. Our patient was certain that her mother died of complications of hypertension, but couldn’t remember any specifics. Her brother had successfully received a kidney transplant for ADPKD. Her medical history was also significant for vertically transmitted hepatitis B, rheumatoid arthritis  and latent tuberculosis infection treated with 6 months of isoniazid and rifampin.Ten years prior, she was initiated on a single agent for blood pressure (angiotensin receptor blocker) and 3 years after arrival to Canada progressed to ESRD. She was initiated on hemodialysis (HD) with a left arterio-venous (AV) fistula requiring three antihypertensives. Over the next 4 years, her blood pressure continued to worsen and more so intradialytically and required six agents for control. She weighed 55 kgs and was 172 cm tall with a body mass index (BMI) of 18.4. Her interdialytic weight gain was four kgs at a frequency of 3/week. She was not taking anti-inflammatories for pain relief as her rheumatoid arthritis was quiescent and was on 75 units/kg body weight of erythropoietin, which maintained the hemoglobin between 100 and 110 g/L. Her dialysate (mmol/L) consisted of sodium 135, potassium 2, bicarbonate 35 and calcium 1.25. The average interdialytic 24-h ambulatory blood pressure was 158/78 mmHg. We attempted to treat her with increasing the frequency of dialysis to 4/week, decreasing the dialysate sodium to 130 mmol, increasing the duration to 4.5 h,  but made no impact on her blood pressure. Our attempts to decrease her goal weight further were limited by severe cramps. Aldosterone blockade with spironolactone had no noticeable improvement and she was unable to tolerate the sympatholytic agent clonidine. Due to insufficient control of her blood pressure on six medications the patient was referred to interventional radiology for evaluation of renovascular causes of hypertension. Prior to intervention, she was on hydralazine (100 mg qid), amlodipine (10 mg od), telmisartan (80 mg od), labetalol (200 mg tid), furosemide (80 mg od) and amiloride (5 mg od).Under local anesthesia, percutaneous femoral access was used to introduce the catheter, and selective tight renal artery catheterization was performed. Selective angiogram of both renal arteries revealed right sided atherosclerotic renal artery stenosis (RAS), treated with insertion of a balloon mounted 6 mm stent and left sided fibromuscular dysplasia (FMD), treated with 5 mm balloon angioplasty Figs. , 4 and 5Jula Inrig, in an elegantly written review on IDH  based onPrior investigations of IDH have suggested volume overload may be a key contributor to its pathogenesis. However, the efficacy of aggressive UF during dialysis in patients with IDH is unclear. While there is data to support such a move with normalization of blood pressure , there iAs there was no improvement in blood pressure with conventional measures, we looked at secondary causes of hypertension in dialysis patients . They inThe mechanisms of hypertension in FMD appear to overlap with the proposed pathogenic mechanisms for IDH. FMD is a nonatherosclerotic, noninflammatory vascular disease that may result in arterial stenosis, occlusion, aneurysm, or dissection. Reduction in arterial lumen and the subsequent reduction in perfusion pressure by a unifocally or multifocally stenosed artery leads to activation of the renin–angiotensin–aldosterone system, with volume expansion and hypertension. We hypothesize that ultrafiltration worsens the gradient of renal artery stenosis leading to additional upregulation of the renin angiotensin aldosterone system and subsequent further upsurge in blood pressure. This is the first reported case, to our knowledge, of concurrent FMD in an individual with ESRD from ADPKD. Studies of renal angiograms in potential renal donors revealed a prevalence of asymptomatic FMD at close to 4%  with an Bilateral renal angioplasty in our patient led to impressive reductions in blood pressure and allowed a decrease of 2 drugs. Our case illustrates that in patients with ESRD and difficult to treat IDH, there is value in imaging the renal arteries to evaluate for renal artery stenosis.


Because pressure in the thorax and abdomen are expected to be similar during a cough, we hypothesized that measurement at other thoracic or abdominal locations might also be similar as well as useful in clinical scenarios. This study aimed to compare cough pressures measured at thoracic and abdominal sites that could serve as alternatives to esophageal pressures (Pes (the gold standard) as well as gastric, central venous, bladder and rectal pressures  were measured simultaneously. The intraclass correlation coefficient (ICC) was used to evaluate the repeatability of the measurements in each patient at each site and evaluate agreement between alternative sites  and Pes. Bland–Altman plots were used to compare Pes and the measurements at the other sites.Nine patients scheduled for laparotomy were asked to cough as forcefully as possible from total lung capacity in supine position. Three cough maneuvers were performed while Pes 112 , Pga 105 , Pcv 102 , Pbl 118 , and Prec 103  cmH2O. The ICCs showed excellent within-site repeatability of the measurements (p < 0.001) and excellent agreement between alternative sites and Pes (p < 0.004). The Bland–Altman plots showed minimal differences between Pes, Pga, Pcv, and Prec. However, Pbl was higher than the other pressures in most patients, and the difference between Pes and Pbl was slightly larger.Median  maximum pressures were as follows: PCough pressure can be measured in the esophagus, stomach, superior vena cava or rectum, since their values are similar. It can also be measured in the bladder, although the value will be slightly higher. These results potentially facilitate the assessment of dynamic expiratory muscle strength with fewer invasive catheter placements in most hospitalized patients, thus providing an option that will be particularly useful in those undergoing thoracic or abdominal surgery.NCT02957045 registered at November 7, 2016. Retrospectively registered. Cough is a physiological response whose purpose is to eliminate secretions from the airway tract. Thus, the inability to cough forcefully enough to be effective would increase the risk of pulmonary complications such as atelectasis or pneumonia. This inability is observed in neuromuscular or respiratory diseases and is particularly likely after abdominal or thoracic surgery, when pain, surgical injury and/or the residual effect of anesthetics come into play –3.ga, Pes) [cv), which has been used as an alternative to Pes [bl), which has been compared to Pga [rec), which has been used to measure intra-abdominal pressure as an alternative to Pbl [Because a cough maneuver can be made voluntarily and easily by a patient without training, cough pressure measurements at various sites can be obtained readily in clinical situations, in contrast to the often used maximum mouth expiratory pressure recorded during a static artificial maneuver , 5, whicga, Pes) –6. It isga, Pes) , 7. Furte to Pes ; bladderd to Pga , 9; and e to Pbl . Howevercv, Pbl, and Prec as alternatives to Pes or Pga for the measurement of cough pressure.We hypothesized that these catheters could be suitable for measuring cough pressure without compromising patient comfort, as occurs with the placement of a gastric or esophageal balloon. We also reasoned that placement of a rectal balloon catheter, which does not cause the nausea associated with esophageal or gastric balloons, could also measure cough pressure comfortably. If these hypotheses are correct, wider clinical use of cough pressure to reflect respiratory muscle strength and possible risk of respiratory compromise might be facilitated. The aim of this study was to evaluate the use of PAdult patients scheduled for open-midline laparotomy for colon cancer surgery, which required placement of central venous and bladder catheters, were enrolled prospectively. Exclusion criteria included rectal surgery, chronic obstructive pulmonary disease , neuromuThe study was approved by the clinical research ethics committee of Parc de Salut Mar  and by the Spanish Agency for Medicines and Health Products (AEMPS). All patients signed an informed consent form before entering the study, and we provided each with an insurance policy to cover care in the event of adverse events related to the procedures.All patients underwent forced spirometry measurement  the day before surgery. Reference values were those for a Mediterranean population .es and Pga were measured with compliance balloon catheters  as previously described [Pescribed . The catcv was measured from the distal port of a double-lumen catheter  placed through the subclavian or internal jugular veins [cv waveform [Par veins . Correctwaveform .bl was measured with a transurethral (Foley) catheter inserted after the bladder was drained and 50 mL of a 0.9% saline solution was instilled [Pnstilled , 14, 15.rec was measured with a compliance balloon inserted 10 cm inside the rectum and filled with 5 mL of air [PPressures were measured with catheters placed in the esophagus, stomach, superior vena cava, bladder and rectum as follows:All the pressure curves were displayed on a screen and recorded with a data acquisition system  for off-line analysis. Patients lay in supine position and all the pressure transducers were calibrated and aligned with the axillary midline.The correct placement of all catheters was assessed by asking the patient to perform a sharp sniff and a cough maneuver while the researcher monitored the signal on the computer screen . Once alCough pressure was then measured at all points. Patients were asked, always by the same researcher (L.G.A.), to cough as forcefully as possible  from totSoon after the end of the protocol, the patients were asked to indicate which catheters caused the least and the most discomfort.es. Bland–Altman plots of mean differences were used to compare Pga, Pcv, Pbl and Prec with the gold-standard (Pes) [es rather than Pga was chosen as the gold standard because the former is measured in the chest, where a cough effort becomes effective. Maneuvers that generated the maximum Pes were chosen for comparison between sites. That maximum value was then compared to the pressures generated by the patient during the same maneuver at each of the other sites.The sample size was calculated to allow us to detect an intraclass correlation coefficient (ICC) value defined as excellent  with a srd (Pes) . Pes ratp value of < 0.05 was considered statistically significant in the ICC analysis. Statistical analysis was performed using IBM SPSS  and STATA  software.A Eleven patients initially consented to participate in the study, but one withdrew consent as catheters were about to be inserted. Data from one patient were lost because of technical problems. Thus, we analyzed data for nine patients. Their characteristics are summarized in Table The cough pressure curves for all sites were congruent. Figure es values for the nine patients was 112  cmH2O. The other median cough pressures recorded at the same time as the maximum Pes values were as follows: Pga 105 , Pcv 102 , Pbl 118 , and Prec 103  cmH2O.The median  for the maximum Pes.Individual measurements recorded for patients at each site are shown in Table p < 0.001) and excellent agreement between alternative sites and Pes (p < 0.004) (Table The ICCs showed excellent repeatability between the three pressures recorded for each patient at each site (within-site repeatability) (4) Table .Table 3AES and pressures at other sites were as follows: Pga 0.7 , Pcv − 2.1 , Pbl 5.8 , and Prec − 2.5  cmH2O. Bland–Altman plots of the differences between Pes and each of the other pressures are shown in Fig. cv and Prec were the alternative-site pressures that showed the best agreement . The average differences between Pbl and Pes were slightly larger, Pbl usually registering higher values than Pes.The median  differences between maximum PThe rectal catheter was the least unpleasant for all the patients, whereas the ones introduced nasally into the esophagus and stomach were the most uncomfortable for seven patients (4 men and 3 women). The bladder catheter was the most uncomfortable for 2 men.bl values were systematically slightly higher than the gold-standard Pes values.This study demonstrates that cough pressure can be measured with central venous or rectal catheters as alternatives to conventional esophageal balloon catheters. Bladder catheters could also be used although recorded PThe ICC analysis indicated excellent repeatability between measurements at the same site, evidence of the precision of cough pressure measurements. In a few patients, cough pressures were slightly lower and differences among repeated maneuvers higher than for the other subjects, but in a series of continuous non-selected patients this minimal variability can be expected. In fact, 5–10% of adult outpatients cannot achieve reproducible pulmonary function results when repeated maneuvers are performed with coaching . The lares, and the Bland–Altman plots showed small differences lacking clinical significance between Pes and Pga, Pcv and Prec. These data therefore suggest that the alternative measurements are reliably accurate. Thus, Pcv or Prec would be valid candidates to choose as surrogates for Pes. The greater difference between Pbl and Pes, on the other hand, shows that pressure behaves somewhat differently at the bladder, something the clinician would need to bear in mind. Furthermore, given that Pbl was usually higher than Pes, we can conclude that Pbl was precise but less accurate than pressure measurements at the other alternative sites. This slight but systematic difference between Pes and Pbl would mean that the bladder catheter would be the last-choice alternative to the esophageal catheter. Pbl could nevertheless be useful in hospitalized patients who already have a bladder catheter in place, so as to avoid disturbing the patient by placing an additional one. The clinician must always take into account this fixed bias in relation to Pes when interpreting the pressures.The ICC analysis also demonstrated excellent agreement between alternative sites and Pga has been used widely to reflect cough pressure in studies of respiratory muscle strength [es in this study, we designated Pes as the gold standard in the Bland–Altman analysis because it is recorded in the chest, where cough effort takes place. Cough pressures have fluctuated in previous studies of expiratory muscle strength measured with Pes or Pga [Although Pstrength –6, 20 ans or Pga  because Our study was performed under conditions relevant to clinical situations. Patients were in supine position, in which the pressure transducers were all at the same approximate level, favoring reliable comparison between measurement sites. Patients carrying central venous or Foley (bladder) catheters are usually confined to a bed. The cough maneuver was performed from TLC in order to achieve a standardized test measurement  and becabl and Pes discussed above. If no catheter has been inserted, a good choice would be a rectal catheter, which our patients found to be the least uncomfortable. Pes remains the gold standard, but its main disadvantage, that the insertion of a balloon catheter through the nose causes discomfort [The practical implication of our study is that cough pressure can be measured using the technique that best fits the clinical condition of an individual patient. A central venous catheter would be the first choice if one has been inserted. A bladder catheter could also be used provided the clinician bears in mind the larger difference between Pscomfort , was conscomfort . For theThis study has limitations. The results probably cannot be extrapolated to patients with chronic cough, in whom voluntary cough pressure can be higher than in healthy individuals . In addiOur results facilitate further investigation and patient management in many settings. An important scenario is the postoperative period after abdominal or thoracic surgery, where cough effort is reduced –3 and whes. These results support assessing expiratory muscle strength for clinical or research purposes without using an additional invasive catheter in most hospitalized patients. If no invasive catheter has already been placed for clinical purposes, a minimally invasive catheter can be chosen for assessing cough pressure.Pressure generated with a cough maneuver from TLC in supine position can be measured in the esophagus, stomach, superior vena cava, or rectum indistinctly. Bladder catheters could also be used, although the recorded pressures would usually be slightly higher than P


The study aimed to establish how granulocytes, monocytes and macrophages contribute to the development of bronchopulmonary dysplasia (BPD).Study A: samples of blood and tracheal aspirates (TAs) collected from preterm newborn infants during the first 3 days of life were investigated by flow cytometry, and testing for white blood cells (WBCs), neutrophils and neutrophil extracellular traps (NETs). Maternal blood samples were also collected. Study B: data from previously-tested samples of TAs collected from preterm newborn infants were re-analyzed in the light of the findings in the new cohort.Study A: 39 preterm newborn infants were studied. A moderate correlation emerged between maternal WBCs and neutrophils and those of their newborn in the first 3 days of life. WBCs and neutrophils correlated in the newborn during the first 8 days of life. Decision rules based on birth weight (BW) and gestational age (GA) can be used to predict bronchopulmonary dysplasia (BPD). Neutrophil levels were lower in the TAs from the newborn with the lowest GAs and BWs. Study B: after removing the effect of GA on BPD development, previously-tested newborn were matched by GA. Monocyte phenotype 1 (Mon1) levels were lower in the blood of newborn with BPD, associated with a higher ratio of Monocyte phenotype 3 (Mon3) to Mon1. Newborn infants from mothers with histological chorioamnionitis (HCA) had lower levels of classically-activated macrophages (M1) and higher levels of alternatively-activated macrophages (M2) in their TAs than newborn infants from healthy mothers.Immune cell behavior in preterm newborn infants was examined in detail. Surprisingly, neutrophil levels were lower in TAs from the newborn with the lowest GA and BW, and no correlation emerged between the neutrophil and NET levels in TAs and the other variables measured. Interestingly, monocyte phenotype seemed to influence the onset of BPD. The rise in the ratio of Mon 3 to Mon 1 could contribute to endothelial dysfunction in BPD. Among the pathophysiological factors implicated in bronchopulmonary dysplasia (BPD), the inflammasome and immunity have been attracting the interest of investigators in the field of preterm newborn research. Maternal choriodecidual membranes and lung inflammatory response both seem to play a part as well, judging from findings in tracheal aspirates (TAs) from preterm newborn infants .The human immune system originates from the yolk sac and then develops in a process that continues throughout pregnancy and is completed after birth . NeutropIntra-amniotic infection and histological chorioamnionitis (HCA) are inflammation-related conditions characterized by a rise in white blood cells (WBCs) and neutrophils in the choriodecidual membranes and blood of the affected newborn –11. NeutThe aim of the present study was to investigate the role of the main cells of innate immunity in the development of BPD. The study is divided into two parts. First, a cohort of preterm newborn infants was enrolled to investigate the relationships between their blood and tracheal aspirates and their white blood cells, neutrophils, neutrophil extracellular traps and maternal data (study A). Then data collected in our previous study  were re-The study was conducted with the approval of the Ethics Committee of Padova University General Hospital, first granted on 12 November 2012, and updated on 22 September 2016 (Prot. n. 2724P). Signed informed consent forms were obtained from all participating parents. The research was conducted according to the principles expressed in the Declaration of Helsinki.Study A was a prospective observational study designed to examine the relationship between WBC counts in the bloodstream and TAs from newborn, and to correlate their levels with maternal variables  and neonatal variables including GA, birthweight (BW), BPD, early sepsis, and levels of cells (neutrophils and granulocytes), and enzymes in TAs. Newborn infants admitted to the NICU at the Department of Women’s and Children’s Health at the University of Padova from January 2016 to December 2017 were identified from a prospectively-managed database. Infants with major congenital malformations were not considered eligible for enrollment.Study B investigated the relationships between blood and TA flow cytometric data and outcomes in terms of BPD, HCA and patent ductus arteriosus (PDA), without the confounding effect of GA. Data obtained from previously-tested newborn infants were re-examined considering groups of patients matched by GA. More details about the data collection and analytical methods can be found in Milan et al. .Blood samples were routinely collected from the umbilical catheter on admission to the NICU or within 3 days to obtain baseline hematological parameters, and then non-invasively as part of routine newborn clinical surveillance and/or hematological data monitoring.To obtain the TAs the airways were suctioned with 0.5 mL of 0.9% saline injected through a tracheal tube. Neonates were ventilated and their secretions were collected in a closed cuvette, which was immediately placed in ice and sent to the lab for analysis. The TA samples were centrifuged (400 rpm for 5 min).Seeded cells were marked and placed in the flow cytometer to assess overall cell lineages, the percentage of dead cells and neutrophils, and NETosis. www.abcam.com). Similarly, urea was assayed using colorimetry with the KA 1652 kit from Abnova. (www.abnova.com).Two commercial kits  were used to examine NE and MPO concentrations in TAs. A 96-well plate was covered with anti-NE or MPO antibodies. Controls and samples were added to the wells and incubated at room temperature. After lavage, a second avidin-conjugated antibody was added to the wells and incubated at room temperature for 1 h. The same procedure was used with streptavidin-HRP conjugate. Tetramethylbenzidine was added as the HRP substrate. A yellow stain changing from blue color was seen after adding the acid solution, and the yellow stain is proportional to the level of NE. (info@vygon.it) connected to a Babylog VN500  or heated and humidified high-flow nasal cannula (HHHNC) . N-CPAP pressure was adjusted routinely to 5–7 cmH2O, and the largest prongs that could fit easily into the nostrils were used in each infant. The N-CPAP treatment criteria were clinical signs of increased breathing effort  with a preserved respiratory function, and a FiO2 request no higher than 0.30, a PaCO2 no higher than 54 mm Hg  or 58 mm Hg (capillary blood), and a pH > 7.2. Most patients with an increased oxygenation demand may have needed a dose of surfactant. A Babylog VN500 was used for synchronized mechanical ventilation (SIMV) or high-frequency ventilation (HFV). Expiratory tidal volumes of 4–6 mL/kg of BW were allowed. End expiratory pressure began at 5–6 cmH2O, depending on the FiO2 and lung inflation. Inspiratory times of 0.30–0.40 s were allowed, with rates not to exceed 50 breaths/min. The NICU protocol establishes that arterial oxygen saturation, as measured by pulse oximetry, be maintained between 92% and 96%, with an arterial pH of at least 7.20, and moderate permissive hypercapnia with a partial pressure of carbon dioxide (PaCO2) of 40–55 mm Hg.WBC counts were obtained using standard laboratory techniques with a Siemens ADVIA 2120 counter (when urgent) or a Sysmex XE-2100 (for scheduled tests), including absolute segmented neutrophil, eosinophil, and basophil counts, together with lymphocyte and monocyte differential counts. Antibiotics were administered prophylactically to all NICU newborn and stopped when sepsis-screening results were negative . Newborn infants were diagnosed with early-onset sepsis if a culture yielded pathogenic bacteria or increased C-reactive protein levels. As a standard nasal continuous positive airway pressure (N-CPAP) system, we used the circuit made with Hudson prongs  or a Vygon cannula  were used because the variables being measured were not independent, a strong correlation applied to the data. In PLS, the measured variables are linearly combined into so-called latent variables that can be investigated to ascertain the relationships existing between the data collected. Both regression and classification problems can be solved, depending on whether the outcome of interest is continuous or categorical. In the case of categorical outcomes, PLS becomes PLS-Discriminant Analysis (PLS-DA). More details on the use of PLS in data analysis can be found in Stocchero et al. . DecisioThirty-nine newborn infants were involved in this prospective observational study. They were all intubated and on mechanical ventilation. Their neonatal data are summarized in The relationships between the newborn’s clinical features and their blood/TA data were investigated using heatmaps based on Spearman's correlation and the Mann-Whitney test. The threshold used for assessing significance was set to 0.15 on the basis of the false discovery rate. The heatmap is shown in The relationships between the maternal and neonatal WBC and neutrophil levels, at the various time points, and NETosis were investigated using heatmaps based on Spearman’s correlations . We only2, HCO3, base excess (BE), max C reactive protein levels from days 1 to 8, surfactant doses, severity of respiratory distress syndrome (RDS), delivery, premature pre-labor rupture of membranes (PPROM), pre-eclampsia, sex, medically-induced pregnancy, PDA, fetal growth restriction. No direct correlation was found between blood or TA neutrophils, or NETosis and BPD. A set of decision rules based on three variables—BW, antenatal steroids, and surfactant doses—was obtained using the RIPPER algorithm. The classification error calculated from the 5-fold coefficient of variation (CV) was 14%. Excluding antenatal steroids and surfactant doses, the rule “a BW of less than 1100 g is associated with the onset of BPD” was obtained, with a classification error in 5-fold CV of 20%. It is worth noting that GA and BW correlated strongly , and GA could substitute BW in the decision rule, obtaining similar results (the rule “a GA of less than 203 days is associated with the onset of BPD” produced a classification error in 5-fold CV of 20%).The variables considered were BW, GA, antenatal steroids, pH, pCO+1/7d (SD = 3 wk +1/7 d), a mean BW of 1274.1 g (SD = 648.6 g), antenatal steroids in 71.3% of cases, and RDS in 97.2%, HCA in 22.3%, and BPD in 22%.The study groups and the methods for measuring monocytes and macrophages were as reported in Milan et al. . BrieflyA subset of 32 newborn infants extracted from the whole dataset included 16 who developed BPD and 16 matched for GA (from 25 to 32 weeks) who did not. A PLS-DA model  was able to distinguish between these two groups, with a 28% classification error in 5-fold CV, and a receiver operating characteristic (ROC) curve showing an area under the curve (AUC) of 0.68 in 5-fold CV. Box plots of the predictors are shown in Another subset extracted from the whole dataset consisted of 29 newborn forming two groups matched for GA (from 23 to 32 weeks), 9 with and 20 without maternal HCA. A PLS-DA model  was able to distinguish between the two groups with a classification error of 21% in 5-fold CV, and a ROC curve with an AUC of 0.78 in 5-fold CV. The latent variable did not correlate with GA. Box plots of the predictors are shown in Our studies aimed to identify prematurity-related changes in cellular innate immunity in blood and TAs, and to identify any association with the onset of BPD. The results of Study A confirmed previous findings regarding the immaturity of the preterm-born infant’s immune system, with a reduced pool of monocytes and more neutrophils. The latter differences are greater for higher GAs and BWs of the newborn , 20. NeuOn the other hand, lower WBC levels were found associated with pre-eclampsia, which is a known cause of leukopenia and neutropenia , 23. It As previously reported, higher WBC counts were identified in newborn infants after vaginal delivery . InteresThe lack of any correlation between NETs and neutrophils in TAs probably stems from the balance between suicidal  and vitaOur search for an early WBC imbalance as a marker of the development of BPD was unsuccessful: no direct correlations emerged between blood or TA neutrophil counts, or NETosis and BPD.We could nonetheless identify some known risk factors of BPD development in our population: a BW of less than 1100 gr, or a GA of less than 203 days correlated strongly with the onset of BPD. This underscores how preventing preterm delivery should be the main objective for the prevention of BPD.http://dx.doi.org/10.1016/S2352-4642(18)30181-0 The reduction of Mon1 noted in HCA patients also points to a pathogenic hypothesis for the relationship between HCA and BPD. These data warrant further investigation.On the other hand, the retrospective part of this study (study B) revealed some promising details regarding lower Mon1 levels and a higher Mon3/Mon1 ratio as possible factors involved in BPD development, or as markers of its onset. Although extremely preliminary, these findings suggest that an early polarization of monocytes towards a classical activation may help to protect against BPD. A higher Mon3/Mon1 ratio in the blood presumably led to an altered endothelial function involving the migration of monocytes into the intima , where tLastly, PDA appears to be involved in BPD development without modifying inflammatory cell levels, and duct patency does not seem to be predictable from blood and TA monocyte-macrophage profiles studied here.A limitation of our work lies in the revalidation of our metadata because the whole group of patients had already been partially studied (with no results contrasting with those reported here). The relationship found here in the prospectively-studied sample mainly concerns the “effect” of GA on WBC and neutrophil levels in the blood or TAs. This could also justify differences relating to delivery mode  and pre-eclampsia compared with normal pregnancy.In conclusion, studying the innate and adaptive immune system has potential as a forward-looking approach to BPD , especiaS1 Data(XLSX)Click here for additional data file.


Gender differences in asthma perception and control have been reported. The PROXIMA observational study assessed these outcomes in a cohort of Italian severe allergic asthma (SAA) patients. This post hoc analysis of the PROXIMA results was aimed at assessing gender differences in SAA in a real-world setting, focusing on disease perception and impact on quality of life (QoL).The PROXIMA study was an observational, multicenter study, consisting of a cross-sectional and a prospective longitudinal phase, including adult outpatients diagnosed with SAA at step 4 requiring a therapeutic step-up. Patients on omalizumab treatment at baseline were included in the 12-month longitudinal phase. Disease control was assessed by the Asthma Control Questionnaire (ACQ) score, patients’ disease perception by the Brief Illness Perception Questionnaire (BIPQ), and QoL by the EuroQoL five-dimensional three-level questionnaire (EQ-5D-3 L) at baseline and after 6 and 12 months. Two regression models were used to evaluate the association between gender and BIPQ total score and EQ-5D-3L score, respectively.T test p-value  < 0.05). Statistically significant gender differences were observed for some specific items, with males reporting less symptom experience, concern about the disease, and emotional impact at 12-months. The results of the multivariate regression model for repeated measures showed that overall treatment with omalizumab improved disease perception overtime regardless from gender. Males reported a significantly better QoL compared to females at both 6 and 12 months.357 patients  were analyzed for the cross-sectional phase and 99  for the longitudinal phase. The prevalence of perennial and seasonal aeroallergens was similar between genders. ACQ score decreased similarly during omalizumab treatment at 6 and 12 months in both genders; no gender differences were observed in control rates. Asthma perception was worse among females at all study visits reaching statistical significance at 12 months (mean (SD) B-IPQ total score 41.8 (9.4) vs 35.6 (12.0); In this real-world setting, females confirmed to have a worse perception of asthma, feel it as more symptomatic and suffer a greater impact on their QoL, even though having similar baseline severity and obtaining similar level of control. Among adults, the incidence and severity of asthma are higher in females than in males, particularly between the 4th and 6th decade [Asthma is a chronic disease that affects more than 300 million people of all ages and ethnic groups worldwide and represents a major health care burden . Furtherh decade ; over thh decade  and in th decade . Although decade , others h decade , 11. Difh decade , 13, andh decade , 15.® In the Management of Asthma) study was an observational, non-controlled, multicenter, two-phase study in Italian severe allergic asthma (SAA) patients, aimed at assessing the prevalence of perennial environmental allergies  and the rate of disease control after up to 12 months of omalizumab treatment . The secondary objectives of the study included the assessment of patients’ disease perception and level of asthma control during both the cross-sectional and longitudinal phases and patients’ compliance to and persistence with omalizumab, rate of exacerbations and patients’ QoL during the longitudinal phase [The PROXIMA  the association between gender and presence of perennial or seasonal allergies at baseline and, in patients on omalizumab treatment included in the longitudinal phase, the effect of gender on (ii) asthma control, (iii) asthma perception and (iv) QoL during 12 months of follow up.The PROXIMA study was an observational, non-controlled, multicenter cohort study, conducted from December 27, 2013 to June 21, 2016 at 25 Italian centers specialized in asthma treatment, consisting of two phases, a cross-sectional and a prospective longitudinal phase. Outpatients aged ≥ 18 years, diagnosed with SAA at step 4 according to GINA 2012 guidelines and requiring a therapeutic step-up , were inThose who were on treatment with omalizumab at baseline visit were included in the 12-month longitudinal phase, provided that they had started omalizumab as per clinician judgement (according to AIFA criteria) not earlier than 15 days before enrolment and within 30 days after enrolment.In the PROXIMA study, the level of disease control had been assessed by the Asthma Control Questionnaire (ACQ) score, a validated tool with a 7-point scale, where 0 means well-controlled and 6 extremely poorly controlled asthma . AccordiPatient’s disease perception had been assessed by means of the Brief Illness Perception Questionnaire (B-IPQ), a validated 9-item questionnaire designed to rapidly assess cognitive and emotional representations of illness . Five ofThe patients’ QoL had been measured by the EuroQoL five-dimensional three-level questionnaire (EQ-5D-3L), a validated and standardized measure of health status developed by EuroQol Group to provide a simple generic measure of health status for clinical and economic evaluation , 24. AllBeing this a post hoc analysis, all patients evaluated in the cross-sectional and longitudinal phases of the PROXIMA study were considered in the gender analysis, with no formal a priori hypothesis about gender distribution of patients. For the cross-sectional phase, all patients fulfilling inclusion/exclusion criteria were analyzed; for the longitudinal phase patients treated with at least one dose of omalizumab at study entry (from 15 days before to 30 days after enrolment) who completed the longitudinal phase on treatment with omalizumab  and with available ACQ assessment at baseline and during the follow-up period were considered.The continuous, normally distributed variables were expressed as a mean ± SD and comparisons between groups were performed with the parametric Student’s t test. In case of not normally distributed parameters, median and interquartile range (IQR) were provided and males were compared to females by means of the non-parametric Wilcoxon rank sum test. Absolute and relative frequencies were calculated for qualitative data and differences between categorical variables were tested by Chi square or Fisher exact test. The significance threshold was set as 0.05 . MissinEight bivariate logistic regression models were used to assess the association between perennial asthma and gender, keeping constant the effect of the following clinically relevant covariates: age, duration of asthma, age at diagnosis and serum IgE level (included in the model as continuous variable), presence of comorbidities , number of exacerbations during the last year , smoking , and ACQ score .Two regression models for repeated measures—since outcomes were assessed at baseline and follow-up visits—were used to evaluate the effect of gender on (1st model) patients’ disease perception  and (2nd model) QoL (EuroQoL score), keeping constant the effect of other clinically relevant covariates. As covariates the following were included: age and duration of asthma (as continuous variable), presence of comorbidities at baseline visit , smoking at baseline , number of exacerbations in the year before baseline , total omalizumab dose taken during follow-up (as continuous variable), concomitant medications with ICS, ICS + LABA, oral corticosteroids (OCS) . We were also interested in estimating the effect of time on patients’ disease perception and QoL, holding gender and all the other variables included in the model constant. For this reason, the visit  was also included as covariate in the two models.Statistical analysis was performed using SAS v9.4 and Enterprise Guide v7.1. Project management including data banking, quality control and statistical analysis, was performed by Medineos Observational Research .The analyzed population included 357 patients in the cross-sectional phase—232 (65.0%) females—and 99 patients in the longitudinal phase—62 (62.6%) females. Median (IQR) age at study inclusion was 52.3 40.2–61.9) years in females and 50.2 (38.1–64.5) years in males. Demographic and baseline clinical characteristics by gender and study phase are summarized in Table .9 years In the original PROXIMA study the mean (SD) compliance rate to omalizumab  was 96.9 (7.8)% during the 12-month follow-up. In the longitudinal phase, the mean (SD) total dose of omalizumab—whose posology depends on serum IgE level and body weight—injected during the follow-up period was 6309.3 (3820.1) mg in females and 6934.5 (4148.4) mg in males. Asthma medications taken concomitantly to omalizumab are summarized in Table Median ACQ score, expressing the level of asthma control , decreased from baseline both at 6 and 12 months in males and females Table . ConsideThe B-IPQ scores at all time points by gender for all items and total score are reported in Table Gender differences were observed in EuroQoL score at study visits, with males reporting a better QoL that reached statistical significance in comparison to females at 6 and 12 months . In our by-gender analysis, no significant difference was found in the prevalence of perennial vs seasonal allergies between males and females. Our results show that in the PROXIMA patient population, defined by the requirement of step-up therapy at enrolment, males and females obtained similar level and rates of asthma control with add-on omalizumab, as measured by the ACQ. However, the overall perception of the disease, assessed by the B-IPQ, though improving on omalizumab treatment, was significantly worse in females compared to males at 12-month follow-up visit. In particular, some aspects of the disease were perceived significantly worse in females, i.e. symptom experience, concern about asthma, and emotional impact. We were not able to find in the literature whether these differences in the B-IPQ score translates into a clinically relevant difference and this can be considered a limitation of the B-IPQ score. However, our results are consistent with previous observations in patient populations of different countries, reporting that females tend to complain more bothersome day- and night-time asthma symptoms than males and have a worse perception of such symptoms and of disease control, despite having similar pulmonary function and asthma medications , 26, 27.One peculiar aspect of the PROXIMA study was precisely the evaluation, as secondary objectives, of the perceived burden of disease by means of patient reported outcomes (PROs) . Indeed,This study has the important limitation of being a post hoc analysis of a study that had not originally been designed with the aim of detecting gender differences. It also carries the limitation of the original PROXIMA study of a higher numerical imbalance between sexes than reported in the literature. Furthermore, the use of questionnaire in the PROXIMA study may have implied a potential risk of selection bias owing to exclusion of patients who were considered unable to complete them. Another limitation is that, despite the choice of standardized questionnaires, several PROXIMA findings were based on self-report and thus subject to recall bias. On the other hand, our post hoc gender analysis has the merit of providing real-world information about the differences in PROs from males and females with severe asthma. The absence of spirometry data at the 6 and 12 months, that would have allowed to correlate objective measures of respiratory function of our SAA patients to their ACQ and QoL scores, is another limitation due to the post hoc nature of our study.In this real-world setting, females confirmed to have a worse perception of the disease, feel the disease as more symptomatic and suffer a greater impact on their daily activities and QoL, even though having similar baseline severity and obtaining similar level of disease control. As emerged from other MetaGeM post hoc analyses, the impact of conditions and therapies on males and females may be significantly different. We believe that better understanding gender differences in diseases in general, and in asthma in particular, is of major importance in order to provide personalized education and management across the life course.


Pulse wave analysis is an emerging approach that analyzes parameters comprising strong predictors of cardiovascular (CV) events and all-cause mortality, especially in patients with high CV risk based on established risk factors. This study used the oscillometric method, provided by the Mobil-o-Graph  device, to compare data regarding the pulse wave analysis parameters in hypertensive nondiabetic and diabetic patients.In this cross-sectional study, 276 individuals were examined in the academic hypertension outpatient care unit of the Federal University of the Triângulo, in Mineiro, Brazil, from January to December 2016. The pulse wave analysis was performed by oscillometry, and its parameters were acquired from all patients.P = .008 and.0003, respectively). The mean peripheral systolic blood pressure and pulse pressure were also significantly higher in the diabetic group . The average pulse wave velocity  was 9.4 ± 1.6 and 8.8 ± 1.6 in the diabetic and nondiabetic groups, respectively (P = .003).Of the 276 patients, 99 were diabetic and 177 nondiabetic. The mean systolic and pulse central blood pressure were significantly higher in diabetic patients than in nondiabetic patients (The group of hypertensive diabetic patients had significantly higher central blood pressure, peripheral blood pressure, and PWV than the hypertensive nondiabetic patients. The patients with overlapping established CV risk factors presented values of the pulse wave analysis parameters consistent with higher central pressure and greater arterial stiffness. Increasing importance has been attributed to arterial components, namely, endothelial dysfunction and arterial stiffness.,8The most reliable parameter in determining arterial stiffness is pulse wave velocity (PWV), which is the major component of pulse wave analysis. A pulse wave is generated at each systole, and its components depend on left ventricular function and arterial characteristics. Thus, the analysis of the pulse wave by a reliable, noninvasive, reproducible, and inexpensive technique constitutes a useful method in predicting CV risk and mitigating CV events. This new approach to access pulse wave parameters is feasible for outpatient use and therefore is a simple and useful equipment for primary care units. Validation studies suggest a strong correlation with invasive intra-aortic catheter measurements, which is the gold standard.–12Recently, a new oscillometric method that is noninvasive and reproducible has been developed. This method allows the measurement of peripheral and central blood pressure and pulse wave analysis parameters, notably the PWV, through the transformation of the brachial pulse waveform.Currently, the aortic PWV is a known strong predictor of CV events and all cause mortality, especially in patients who already have high CV risk based on established risk factors.Hypertension is a pathologic condition with concerning prevalence worldwide.The increase in blood pressure levels has a wide range of effects in the body, and the arteries are frequently involved. Hypertension is already considered an important cause of arterial stiffness and is related to high PWV values and other components of pulse wave analysis such as the augmentation index (AugI) and augmentation pressure (AugP).,15Diabetes is also a morbid condition regarding its effects to the arteries. Individuals with diabetes have greater PWV compared with the general population even when adjusted for age, blood pressure, and heart rate. Diabetes is also described as an independent marker of CV disease in patients with diabetes.,16,17 by comparing hypertensive patients with and without diabetes.Hypertension is an important and powerful modifiable risk factor of CV diseases in patients with type 2 diabetes. The rate of hypertension among diabetic individuals is up to 75%, which points to an important association regarding CV physiopathology alterations in these 2 conditions. This suggests an additive effect in the arterial stiffness process, evaluated mainly by the PWV. The purpose of this study was to evaluate the importance of diabetes and hypertension, as well as its coexistence, in the behavior of arterial pulse wave analysis parameters22.1This prospective cross-sectional study included 276 hypertensive individuals undergoing regular follow-up at the academic hypertension outpatient care unit of the Federal University of Triângulo Mineiro (FUTM) and Diagnostic Cardiac Center (DCC), located in Uberaba, Minas Gerais, Brazil. Informed consent was obtained and documented. The patients were examined from January to December 2016. Patients with hypertension and diabetes who were attending regular follow-up at our outpatient care were included. Patients younger than 18 years, with underlying condition(s) that required recent hospitalization, heart failure functional class 3 or 4 of the New York Heat Association, and end-stage kidney disease were excluded. The protocol of the study followed the principles of the Declaration of Helsinki and was approved by the institutional ethics committee. Written informed consent was obtained from all participants.2.2,18,19 and also registers the peripheral and central blood pressure levels. A common cuff was centered to the left upper arm. Cuff size was chosen according to the circumference of the mid upper arm. Generation of central aortic blood pressure curves based on brachial pulse waves is based on a previously published algorithm that integrates arterial impedance and aortic hemodynamics into a mathematical model. After digitalization, the signal processing is performed using a 3-level algorithm. In a first step, the single pressure waves are verified for their plausibility by testing the position of minima and the corresponding wavelengths. During the second stage, all single pressure waves are compared with each other to recognize artifacts. Thereafter, an aortic pulse wave is generated by the means of a generalized transfer function. The idea behind a transfer function is the modification of a certain frequency range within the acquired pulse signal to get the aortic pressure wave.,20After a rest period of at least 30 minutes, the oscillometric method of pulse wave analysis was performed in an appropriate room, between 9:00 AM and 3:00 PM, during peak period of antihypertensive medication. The device used, Mobil-O-Graph , is a commercially available brachial oscillometric ambulatory blood pressure monitor that has been validated according to the recommendations of the European Society of HypertensionFour consecutive measurements were taken every 2 minutes according to general recommendations for clinical studies.All individuals answered questions about personal and clinical data . Patients also underwent conventional sphygmomanometer arterial blood pressure measurement according to the guidelines of the Brazilian Hypertension Society. The diagnosis of hypertension was based on the same guidelines. and were attending regular follow-up at the diabetes outpatient care of the FUTM. We did not select any specific subgroup of diabetic patients.The hypertensive diabetic patients were diagnosed according to the American Diabetes Association recommendations2.3t test signed rank test continuous variables. Given unequal sample sizes of our data, multivariate analyses (ANOVA) with D’Agostino–Pearson test was used to compare pulse wave analysis parameters and performed adjustment for age, smoking, mean antihypertensive agents per patient, mean body mass index, mean abdominal circumference (cm). For PWV adjustment we add peripheral systolic blood pressure (pSBP), peripheral mean blood pressure (pMBP), peripheral pulse pressure (pPP), central systolic blood pressure (cSBP), central pulse pressure (cPP), and AugP.We built a database using the Excel program and performed the statistical analysis using the GraphPad Prism  and MedCalc software. All results are expressed as mean ± standard deviation. Chi-squared test was applied to compare proportions and Student 33.1± 11.9 and 59 ± 11 years, respectively. A total of 272 (98.5%) patients were taking antihypertensive medication. The population characteristics are given in Table Among the 276 hypertensive patients, 177 were nondiabetic and 99 were diabetic. There were 173 women (62.6%), and the average age of the patients in the nondiabetic and diabetic groups was 58 3.2P = .008 and .0003, respectively) . The average PWV was 9.4 ± 1.6 and 8.8 ± 1.6 in the diabetic and nondiabetic groups, respectively (P = .003).The mean cSBP and pulse pressure were significantly higher in the diabetic group in comparison with the nondiabetic group (y) Table . We obtaP = .002), pSBP 143 ± 1.9 vs 138 ± 1.4 (P = .0003), pPP 56 ± 1.3 vs 50 ± 0.9 (P = .0001), cPP 42 ± 1.1 vs 39 ± 0.9 (P = .01). And missed significant values for: pMBP 112 ± 1.6 vs 110 ± 1.2 (P = .38), cSBP 131 ± 1.8 vs 128 ± 1.3 (P = .18), and AugP 14 ± 0.8 vs 12 ± 0.6 (P = .10).After adjustment for diabetic vs nondiabetic comparisons, these differences remained significant for the following variables: PWV 9.1 ± 0.05 vs 8.9 ± 0.03 . There was no statistical difference between the average AugI and the diastolic central or peripheral blood pressure .The AugP was also higher in patients with diabetes  than nondiabetic patients (n = 203). Compared with our study, the patients on DESIR had higher systolic blood pressure values (158 ± 29 vs 160 ± 28) than our study (137 ± 17.6 vs 145 ± 22.5). Surely the differences in PWV between the studies at least in part could be explained by a difference in blood pressure. Using a new method to measure arterial stiffness, equally, we found significant differences in arterial stiffness between diabetic and nondiabetic patients, which reinforce our results.In a review based on data obtained from the French cohort, DESIR (Data from an Epidemiologic Study), diabetic patients (n = 126) showed significant higher PWV values (11. 5 vs 13.9; ,4Our study had some limitations. The stratification of the study subjects could have been performed according to the time of diagnosis and control of the underlying disease. There was no control group of healthy individuals, which could estimate the real impact of hypertension and diabetes in the pulse wave parameters. In the diabetic group there was a higher prevalence of smoking patients; however, we could not find data about the association between the smoking habit and the PWV. An important aspect of the sample analysis was that the PWV was higher in the hypertensive diabetic patients regardless of age variation. Age is a factor that presents an independent association with increased arterial stiffness and could be a confounding variable in the analysis.The development and application of technologies that are simple, routine, cheap, and relevant are great value, especially in developing countries like Brazil where CV and metabolic diseases are important public health problems. In this context, the establishment of approaches that allow the early identification of risk factors become essential in the promotion of health in its primary level of care and prevention.Furthermore, our study raised the need for approaches that take into account the diagnostic time of diabetic patients and their glycemic control. The drug used in the treatment of hypertension is also a relevant aspect to be considered. The comparison between different glycemic levels and the CV repercussion on pulse wave parameter should motivate more studies.In conclusion, in this study, hypertensive diabetic patients had significantly higher central and peripheral systolic pressure and pulse pressure compared with hypertensive nondiabetic patients. The AugP was also statistically higher in hypertensive diabetic patients. Furthermore, diabetic patients had higher PWV regardless of age variation, and the difference was statistically significant. This study demonstrated that patients with overlapping established risk factors for CV disease had altered pulse wave analysis parameters consistent with arterial stiffness and central hemodynamic disorders.Conceptualization: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Elisabete Aparecida Mantovani Rodrigues Resende, Valdo Jose Dias Silva, Dalmo Correia.Data curation: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Formal analysis: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende.Investigation: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Methodology: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Valdo Jose Dias Silva, Dalmo Correia.Project administration: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Resources: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Software: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Supervision: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Validation: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Visualization: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Dalmo Correia.Writing - Original Draft: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Elisabete Aparecida Mantovani Rodrigues Resende, Valdo Jose Dias Silva, Dalmo Correia.Writing - Review & Editing: Luiz Antonio Pertili Rodrigues Resende, Marco Antonio Vieira Silva, Jose Augusto Mantovani Resende, Elisabete Aparecida Mantovani Rodrigues Resende, Valdo Jose Dias Silva, Dalmo Correia.