The Multiple Linear Regression showed non-statistical significance  between the P2/P1 ratio and body mass index, presence of migraine, central sensitization, pain catastrophizing and depression. We found no correlation (p > 0.05) between P2/P1 ratio and migraine frequency, migraine onset, pain intensity, pain intensity at day of examination, disability, allodynia. Migraine patients did not present alterations in the waveform morphology through ICP-NI compared to women without headache and no association with clinical variables was found.This cross-sectional study aimed to compare the waveform morphology through noninvasive intracranial pressure (ICP-NI) measurement between patients with migraine and controls, and to analyze the association with clinical variables. Twenty-nine women with migraine, age 32.4 (11.2) years and headache frequency of 12.6 (7.5) days per month and twenty-nine women without headache, age 32.1 (9.0) years, were evaluated. Pain intensity, migraine disability, allodynia, pain catastrophizing, central sensitization and depression were evaluated. The ICP-NI monitoring was performed by a valid method consisting of an extracranial deformation sensor positioned in the patients’ scalp, which allowed registration of intracranial pressure waveforms. Heart rate and blood pressure measurements were simultaneously recorded during 20 min in the supine position. The analyzed parameter was the P2/P1 ratio based on mean pulse per minute which P1 represents the percussion wave related to the arterial blood pression maximum and P2 the tidal wave, middle point between the P1 maximum and the dicrotic notch. There was no between-groups difference in the P2/P1 ratio (mean difference: 0.04, IC95%: -0.07 to 0.16,  Studies have also suggested a possible association between these symptoms with the increased intracranial pressure (ICP) in conditions such as chronic fatigue syndrome, fibromyalgia, unexplained widespread pain4 and also in migraine5. The hypotheses point to an unknown effect of cerebrospinal fluid pressure dysregulation and ICP that could have harmful effects on the central nervous system, brain and peripheral nerves comparing with the harmful effects of increased blood pressure4.A central nervous system sensitization has been associated with the experience of persistent pain and symptoms such as hyperalgesia, allodynia and hypersensitivity, due to sensory processing changes, neuroplasticity and neuroinflammation7. Migraine is defined as a primary brain disorder and affects about 12% of the population with a peak prevalence between 22 and 55 years, being more prevalent in females (17%) compared to males (6%). The pathophysiology of migraine comprises a complex neurovascular dysfunction involving changes in brain excitability, inflammation of neurogenic origin with consequent vasodilation of cerebral blood vessels, in addition to recurrent activation and sensitization of trigeminovascular system pathways10. Neurogenic inflammation in the blood vessels of the meninges, in the large cerebral arteries and in the sinuses, may be responsible for sending nociceptive afferents, through mechanical, electrical or chemical stimuli, giving rise to a unilateral, pulsatile headache associated with neurological symptoms such as hypersensitivity to light, sound, smell and nausea9. The clinical manifestations of migraine differentiate it from other headaches, and the onset of a migraine crisis is often associated with triggering factors such as stress, hormonal fluctuation , sleep disorders, sensory overload (odors or excessive light)8. In addition, intrinsic triggering factors such as vascular mechanisms are also suggested, however they need to be further investigated9.The role of increased cerebrospinal fluid pressure has already been investigated in patients with migraine6. However, 27% had normal opening pressure and elevated mean cerebrospinal fluid pressure (> 200 mmH20) associated with abnormal waveforms and 18% had elevated opening pressure and elevated mean cerebrospinal fluid pressure (> 200 mmH20) also associated with abnormal waveforms6. The abnormal pressure waveforms during one-hour monitoring were more frequent in patients with chronic migraine and bilateral transverse sinus stenosis diagnosed on cerebral magnetic resonance venography6. However, despite the aforementioned evidence and the recently raised hypotheses of changes in pressure of cerebrospinal and intracranial pressures in migraine patients, these alterations have not been further investigated considering the risks of the invasive methods of the intracranial pressure measurement.An investigation of the cerebrospinal fluid pressure opening pressure in 98 patients with migraine and chronic tension-type headache by an invasive monitoring showed that 55% of patients had normal cerebrospinal fluid pressure (< 200 mmH20) and normal mean waveform pressure over one-hour monitoring11. Some proposed methods consider indirect anatomical or physiological measures that can be influenced by changes in intracranial pressure and include computed tomography, magnetic resonance imaging, transcranial Doppler ultrasound and infrared spectroscopy11. Another non-invasive method was recently developed and validated14. This method considers an extracranial strain gauge sensor that, when positioned in the frontolateral region, detects small variations in cranial deformation induced by intracranial pressure waveforms15. This Food and Drug Administration (FDA)-cleared non-invasive sensor and software to record the variations induced by intracranial pressure waveforms and convert them into numerical values that can be interpreted in real time or analyzed later15. This method was validated in a set of neurocritical patients16, including traumatic brain injury, subarachnoid hemorrhage and stroke, by correlating the biometric amplitude ratio from non-invasive with the ICP waveform morphology from invasive catheter monitoring 14. Also, it has been recently shown a strongly positive correlation of cerebrospinal compliance measurement comparing this noninvasive intracranial pressure (ICP-NI) measurement with a transcranial Doppler blood flow analysis in hydrocephalus patients17.Non-invasive modalities for intracranial pressure monitoring have currently been investigated and proposed in the literature due to the fact that invasive methods, considered as the gold standard, present risks of infection, hemorrhage, require anesthesia, and are expensive18. Under normal physiological conditions, the waveform morphology reveals a pattern in which P1 > P2 > P3. Changes in the waveform morphology may reveal changes in brain compliance, in which P2 > P1 shows reduced brain compliance21. Thus, the aim of this study was to investigate possible alterations in the waveform morphology through ICP-NI measurement in patients with migraine and its correlation with clinical variables. We hypothesized an increased ratio (P2/P1), i.e., P2 higher than P1, in patients with migraine and correlation between the P2/P1 ratio and clinical variables.Intracranial pressure analysis in time domain reveals a waveform morphology with three main peaks: the P1 component (percussion wave) that reflects the ejection of blood from the heart transmitted by the intracranial arteries and the choroid plexus; the P2 component (repercussion wave) that reflects cerebral compliance; and the P3 component (dicrotic wave) that represents the closure of the cardiac aortic valve22. Exclusion criteria were: diabetes mellitus, gestational period, diagnosis of idiopathic intracranial hypertension (according ICHD-III), concomitant primary headaches other than migraine, cardiovascular diseases, habitual use of corticosteroids, history of alcohol abuse in the last 6 months and body mass index higher than 30 kg/m2. The control group was recruited using convenience sampling and the age-matched women were included if they had no current or past diagnosis of any primary headache, no history of recurrent secondary headaches within the last 6 months which required treatment. We included those with an occasional headache, such as headache related with a flu or after alcohol exposure etc. To be included, the control participants also had to have less than 30 points in the Part A of the Central Sensitization Inventory23.This cross-sectional study evaluated 58 participants including women with migraine (n = 29) and headache-free women as a control group (n = 29). The patients with migraine were recruited from a tertiary headache clinic in Ribeirão Preto, Brazil. Inclusion criteria were: women aged 18–50 years, diagnosis of migraine by an experienced neurologist according to the International Classification of Headache Disorders (ICHD-III)24. Participants were asked to avoid drinking caffeine and alcohol and not to perform intense physical activity 24 h before the test. Initially, anthropometric and sociodemographic data and self-reported variables were collected. Then, the noninvasive intracranial pressure measurement (ICP-NI) was continuously and simultaneously collected with the blood pressure by a plethysmography recording equipment during 20 min, after 10 min-resting, in the supine position. The total experimental procedure lasted around 60 min. All methods were performed in accordance with relevant guidelines and regulations.The experimental procedure was performed in one laboratory visit. All participants were evaluated during the afternoon and all women were in the follicular phase of the regular menstrual cycle at the time of evaluation, i.e. up to 14 days after the beginning of the menstrual cycle25 and the 12-item Allodynia Symptom Checklist26 were used to evaluate the pain intensity, disability and allodynia severity. The Pain Catastrophizing Scale27, the Beck Depression Inventory28 and the Central Sensitization Inventory-BR23 were also administrated to characterize the samples.Clinical characteristics including the frequency of migraine attacks, migraine onset and attack duration (hours) were recorded in the migraine group. Chronic migraine was defined as having attacks more than 15 days per month and episodic and episodic migraine as having at least three migraine attacks per month, according to the IHCD-III. The numeric pain rating scale (range 0–10), the Migraine Disability Assessment (MIDAS)13. The measurements were obtained by a hardware Braincare® 2.0 e by a software (Braincare® 2014.02)  and an electrocardiogram digital recorder  during 20 min in the supine position, after 10 min-resting. The data were recorded by an interface to the microcomputer by using the PowerLab4/35 device (ADinstruments) and a software for data analysis   between groups which resulted in an effect size of 0.66. The power and the alpha level were set at 80% and 5% respectively resulting in a minimum of 29 participants in each group.The sample size was based on a previous study using the same monitoring method proposed in the current studyIndependent samples t-test was used to compare age and body mass index between groups. The Analysis of Covariance was applied to compare the dependent variable P2/P1 ratio between groups by using the body mass index as a covariable. The normal distribution was confirmed by Shapiro–Wilk test. A Multiple Linear Regression was used to investigate the relationship between the P2/P1 ratio (dependent variable) and the following independent variables: body mass index, groups (with and without migraine), central sensitization, pain catastrophizing and depression, respectively in a hierarchical model, which the first block had the body mass index to control a covariable effect. Pearson and Spearman’s correlation coefficient were used to investigate the correlation between P2/P1 ratio and migraine frequency and migraine onset, pain intensity during attacks and pain intensity at day of examination, disability and allodynia in migraine group. The correlation was interpreted as low rs < 0.40), moderate (rs ≥ 0.40 to rs < 0.70), and high (rs ≥ 0.70). A significance level of 0.05 was established, and all analyses were performed using the SPSS software .The Ethics Committee of the Clinics Hospital of Ribeirão Preto Medical School, University of São Paulo approved this study (protocol number: 1278/2019). All participants signed an informed consent form prior to data collection.Informed consent to publish has been obtained to publish the information/image in an online open-access publication.Women in both groups had on average 32 years old, once the control group was age-matched Table . Women wp = 0.03, t = 2.24). The Analysis of Covariance revealed no difference (F (1) = 0.568, p = 0.352) in the P2/P1 ratio comparison between the migraine  and control  groups  adjusted by the covariable body mass index  = 0.881, p = 0.352).All descriptive data are presented at Table p = 0.372; R2 = 0.11)] between the P2/P1 ratio and the presence of migraine, central sensitization, pain catastrophizing and depression, also corrected by the covariable body mass index.The Multiple Linear Regression analysis showed non-statistically significant model [F  = 1.104; p = 0.08), migraine onset , pain intensity , pain intensity at day , disability  and allodynia .We found no correlation between P2/P1 ratio and clinical data measured in migraine group: migraine frequency , mainly in chronic migraine patients with bilateral transverse sinus stenosis diagnosed on cerebral magnetic resonance venography6. Chronic migraine patients have a high prevalence of transverse sinus stenosis, a marker of idiopathic intracranial hypertension5. Although idiopathic intracranial hypertension without papilledema associated with sinus stenosis is also prevalent in asymptomatic individuals, in migraineurs this may be related to migraine progression and chronification, possibly due to sensitization of trigeminovascular system pathways by the sinus congestion7.In the context of existing knowledge, our results develop previous research findings that have investigated the role of ICP in patients with migraine migraine29. Despite the recent advances, the authors highlight the relevance of exploring new biomarkers in order to better understand the migraine pathophysiology and possibly develop new treatment strategies30. Methods of non-invasive measurements of the intra cranial pressure, as the proposed in our study, support and increase the feasibility to better understand the central alterations of migraine patients. Our study reveals that patients with an average frequency of 12.6 attacks per month may not present changes in the intra cranial pressure. However, these findings expand the perspective of future studies considering different subtypes of migraine, which could assist the diagnosis and treatment choices in the future.Recent neuroimaging studies have suggested structural and functional brain alterations such as grey and white matter volume differences and metabolic changes in migraine patients31. Abnormalities in the ICP waveforms, configuration and amplitude, as an increased P2/P1 ratio, are evident in severe traumatic brain injuries19, due to changes in intracranial compliance and cerebral blood flow autoregulation. Recent evidences showed abnormalities in the ICP waveforms in different conditions by using the same non-invasive method as proposed in our study, through assessment of the volume changes in the skull, measured by an electric sensor in millivolts35. Alteration in the P2/P1 ratio were observed in hydrocephalus children32, in renal disease patients before and after dialysis34 and in case studies of children with untreatable headaches and secondary obstructive hydrocephalus33 and idiopathic intracranial hypertension35. On the other hand, no waveform abnormalities were seen in migraineurs in the current study, which represents a less severe disease but still involving a complex neurovascular dysfunction.ICP waveform is determined by a complex interaction among the arterial input, intracranial tissues and the venous outflow4 even considering that about 50% of sample had opening pressure classified as normal (< 200 mmH2O). In this context, the cutoff point of 200 to 250 mmH2O to define the diagnosis of idiopathic intracranial hypertension has been discussed3, since also some pain conditions of unknown origin could be presented with an incomplete form or a variation of idiopathic intracranial hypertension3. Furthermore, high concentrations of anti-inflammatory cytokines as IL-1 receptor antagonist (IL-1ra) and proinflammatory cytokines as monocyte chemoattractant protein-1 (MCP-1)36 and interleukin-837 have been found in the cerebrospinal fluid of fibromyalgia37 and migraine patients36 when compared to asymptomatic patients, although the role of inflammation in migraine is still uncertain39.We also did not find correlation between the P2/P1 ratio and clinical variables, except by a weak positive correlation between increased P2/P1 ratio and higher pain catastrophizing considering women from both groups. Otherwise, previous finds suggest that fibromyalgia patients experienced symptoms relief as reduced headache and back pain, improved mood, concentration, quality of sleep and bowel and bladder function, up to 8 weeks after lumbar puncture16 in patients with traumatic and non-traumatic acute brain injury under invasive ICP monitoring. There was strong correlation for P2/P1 ratio between invasive and non-invasive monitoring and a cut-off 1.2 (P2/P1 ratio) predictive of intracranial hypertension (AUROC 0.9 for ICP > 20 mmHg)14. Our study did not include a cerebral magnetic resonance venography to investigate possible alterations such as transverse sinus stenosis to directly compare with previous literature6. Also, although we tried to control the menstrual cycle period for data collection, there were two women in each group in the perimenstrual period once the control group was age-matched. Furthermore, we did not control the migraine status  in the assessment day and some patients reported mild headache during the measurements. However, since migraine is a cyclic disease, patients might present physiological alterations even in the interictal phase40. Due the exploratory essence of our study – using a pioneer method to assess the intracranial pressure in migraineurs – we recommend that future studies consider not just the migraine phase, but also the migraine subdiagnosis in the evaluation. On the other hand, although our study has limitations, our findings may contribute to the literature on the hypotheses of changes in pressure of cerebrospinal and intracranial pressures in migraine patients by showing the applicability of a new method to extract parameters from ICF waveform. Accordingly, although the gold standard method is the intraventricular catheter system considering accuracy and reliability, other noninvasive ICP monitoring methods including brain imaging methods , indirect ICP estimation , cerebral blood flow evaluation , and also the proposed in our study, represents an easy-to-measure and risk-free procedure41. Advances in new non-invasive methods and evidences of its application in different populations can benefit the applicability in further scientific studies and also in clinical practice of this methods as an alternative to invasive methods.The present study has some weakness, such as the absence of an invasive method of monitoring the pressure in real values to further investigate between-groups differences considering the waveform morphology. On the other hand, the proposed method in our study has been previously validatedMigraine patients did not present alterations in the waveform morphology through noninvasive intracranial pressure compared to women without headache. Also, there were no association between the P2/P1 ratio from this noninvasive measurement and clinical variables.


Renal function impairment related to type 2 diabetes (T2DM) presents serious threat to public health. Previous studies suggest that vascular endothelial growth factor-B (VEGF-B) might contribute to renal injury. Therefore, this study investigated the association of serum VEGF-B level with the risk of renal function impairment in T2DM patients.2 and 101 participants with eGFR≥ 90 mL/min/1.73m2. Clinical data were collected, and a binary logistic regression model was employed to test the association between potential predictors and eGFR.Serum VEGF-B levels were measured in 213 patients with type 2 diabetes and 31 healthy participants. Participants with type 2 diabetes were further divided into a group of 112 participants with eGFR<90 mL/min/1.73m2.Serum VEGF-B levels evaluated in type 2 diabetes patients compared with healthy controls. In patients with type 2 diabetes, serum VEGF-B level was positively correlated with triglyceride, serum creatinine and cystatin C while negatively correlated with HDL-C and eGFR. Binary logistic regression showed that serum VEGF-B level was an independent risk factor of eGFR<90 mL/min/1.73mSerum VEGF-B level is associated with renal function impairment in patients with type 2 diabetes and may be a potential drug target for diabetic kidney disease. With the global prevalence of type 2 diabetes mellitus (T2DM), diabetic kidney disease (DKD) has become the leading cause of end stage renal disease (ESRD), and poses a great burden to diabetes patients and the health care system . Progresin vivo, which triggers a widespread speculation of VEGF-B playing its angiogenic role mainly through its recruitment of other VEGFs (via membrane receptors neuropilin-1(NRP-1) or vascular endothelial growth factor receptor-1 (VEGFR-1), and an improvement of insulin sensitivity along with blood lipid profiles was observed in VEGF-B deficient mice fed with high-fat diet  is a member of the vascular endothelial growth factor (VEGF) family expressing in multiple organs, such as heart, adipose, muscle, brain, and kidney . Differeer VEGFs , 6. Howefat diet , 7. Morefat diet , 9. Seeifat diet , 11. FurAlthough evidences from animal experiments suggest the vital role of VEGF-B in DKD occurrence, the relationship between circulating VEGF-B level and renal function impairment in T2DM patients still remains unclear. In this study, we tested the serum VEGF-B levels of 213 T2DM patients as well as 31 healthy participants, and analyzed the potential link between serum VEGF-B levels and renal function of patients with T2DM. Our results would provide a better insight into the role of VEGF-B in the pathogenesis of diabetic renal impairment as well as the intervention of diabetic kidney disease.31 healthy participants were recruited from the health examination center of the affiliated hospital of Nanjing university of Chinese medicine. None of the healthy participants had known metabolic disorders, kidney injury or other kind of diseases. 213 T2DM patients were recruited from the department of endocrinology of the affiliated hospital of Nanjing university of Chinese medicine. All participants with T2DM satisfied the world health organization 1999 criteria when diagnosed . This st2). Homeostasis model of assessment for insulin resistance (HOMA-IR) = fasting glucose (mmol/L)╳fasting insulin (mU/L)/22.5. Estimated glomerular filtration rate (eGFR) was calculated according to CKD-EPI2012scr-cys.All participants were admitted to the department of endocrinology. Detailed medical history and physical examination data, including gender, age, medicine usage, resting blood pressure, weight and height were obtained upon admission. Venous blood and midstream urine samples were collected at 6:00 a.m. from participants after 12 hours of fasting. The examination of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), fasting blood-glucose (FBG), fasting C peptide (FCP), glycosylated hemoglobin (HbA1c), serum creatinine (SCr), blood urea nitrogen (BUN), Cystatin C (CysC), urine albumin-to-creatinine ratio (UACR) and 24-hour urine total protein (UTP) were performed at laboratory center of the affiliated hospital of Nanjing university of Chinese medicine. Body mass index (BMI) = body weight (kg)/the square of body height (mFresh blood samples were stood at room temperature (22°C) for 30min and then centrifuged at 3000rpm for 10 min. The supernatant were collected as serum samples and stored at -80°C. Serum VEGF-B values were determined by human enzyme-linked immunosorbent assay (ELISA) kits .χ2) was employed for comparisons of categorical variables. The relationships between clinical indicators were examined using Pearson correlation, Spearman correlation or partial correlation. Binary logistic regression analysis was used to test the association between potential predictors and eGFR. A p-value of <0.05 was indicated statistically significant.Statistical analyses were performed using SPSS 25.0. All data were represented as mean ± standard deviation (SD), median with interquartile range (IQR) or percentage, as appropriate. Data that were not normally distributed, including Diabetes duration, FBG, HbA1c, HOMA-IR, Triglyceride, Total cholesterol, HDL-C, LDL-C, Serum creatinine, Blood urea nitrogen, Cystatin C, UACR, UTP, eGFR, Serum VEGF-B were logarithmically transformed before analysis. ANOVA and Mann-Whitney U tests were used for continuous variables distributed normally and asymmetrically, respectively. Chisquared test (p<0.001).The study recruited 244 eligible participants, including 213 patients explicitly diagnosed with T2DM at baseline and 31 healthy subjects seeking for routine examination. Fasting blood samples were collected from all participants and serum VEGF-B levels were tested. As shown in 2), we further divided the enrolled T2DM patients into a group of 112 participants with eGFR<90 mL/min/1.73m2 and 101 participants with eGFR≥ 90 mL/min/1.73m2 (p>0.05). However, the eGFR<90 mL/min/1.73m2 group had older age (p<0.001), longer diabetes duration (p=0.004), lower DBP (p=0.003), as well as worse renal dysfunction characterized by higher levels of SCr (p<0.001), BUN (p<0.001), CysC (p<0.001) and UACR (p=0.005). Most importantly, eGFR<90 mL/min/1.73m2 group also showed a significantly increased level of serum VEGF-B (p=0.002) (p>0.05). But, a higher percentage of patients using beta-blockers (p=0.007) and Calcium channel blockers (p=0.039) in eGFR<90 mL/min/1.73m2 group was showed by Chisquared test  Table 1.p=0.013), serum creatinine  and cystatin C  while inversely correlated with HDL-C  and eGFR  after adjusting gender, age, smoking history, drinking history, diabetes duration and BMI. However, although partial correlation confirmed that VEGF-B level significantly associates with several renal function indicators (p>0.05).As shown in 2. We found that serum VEGF-B level (p=0.002) was significant in predicting eGFR<90 mL/min/1.73m2, even after controlling age, UACR, diabetes duration and diastolic pressure (based on the results from p<0.001) showed a significant, positive relationship with eGFR<90 mL/min/1.73m2 as well . This could be partially explained by the limited sample size, but also, the phenomenon was consistent with the epidemic of NADKD in T2DM. Moreover, traditionally, albuminuria and diabetic retinopathy are important components of early DKD prediction and diagnosis. But increasing studies point out that substantial numbers of T2DM patients with DKD do not have retinopathy nor abnormal albuminuria, and normoalbuminuria T2DM patients with low GFR (<60 mL/min/1.73m2) are more likely to show diffuse lesions, nodular lesions, tubulointerstitial lesions or vascular lesions compared to those with preserved GFR (≥60 mL/min/1.73m2)  . Our dat/1.73m2) , 23. And2 in patients with type 2 diabetes and it was irrelevant to albuminuria. However, certain limitations of this study should be noted. Firstly, owing to the difficulty in obtaining renal samples from T2DM patients, VEGF-B levels in serum were tested only, thus we are unable to trace the accurate source of the increasing VEGF-B. Secondly, the persuasion as well as the reproducibility of our findings might be blunted by the limited sample size. Current chronic kidney disease nomenclature used by KDIGO is based on eGFR (G1-G5) along with albuminuria (A1-A3), but most of our cases were restricted at G1 and G2 stage, which made it far too difficult to further stage the patients by KDIGO standard. 90 mL/min/1.73m2 is an eGFR cutoff value widely accepted by guidelines .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.


Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be an adjunct treatment to cardiopulmonary resuscitation (CPR). Aortic occlusion may increase aortic pressure and increase the coronary perfusion pressure and the cerebral blood flow. Peripheral arterial blood pressure is often measured during or after CPR, however, changes in peripheral blood pressure after aortic occlusion is insufficiently described. This study aimed to assess changes in peripheral arterial blood pressure after REBOA in patients with out of hospital cardiac arrest.2 (EtCO2) was measured before and after aortic occlusion. Differences in arterial blood pressures and EtCO2 before and after occlusion was analysed with Wilcoxon Signed Rank test.A prospective observational study performed at the helicopter emergency medical service in Trondheim (Norway). Eligible patients received REBOA as adjunct treatment to advanced cardiac life support. Peripheral invasive arterial blood pressure and end-tidal CO2 increased significantly 60 s after occlusion, by a mean of 1.16 kPa (p = 0.043). Before occlusion the arterial pressure in the compression phase were 43.2 (range 12–112) mmHg, the mean pressure 18.6 (range 4–27) mmHg and pressure in the relaxation phase 7.8 (range − 7 – 22) mmHg. After aortic occlusion the corresponding pressures were 114.8 (range 23–241) mmHg, 44.6 (range 15–87) mmHg and 14.8 (range 0–29) mmHg. The arterial pressures were significant different in the compression phase and as mean pressure  and not significant in the relaxation phase (p = 0.223).Five patients were included to the study. The median REBOA procedural time was 11 min and median time from dispatch to aortic occlusion was 50 min. Two patients achieved return of spontaneous circulation. EtCOThis study is, to our knowledge, the first to assess the peripheral invasive arterial blood pressure response to aortic occlusion during CPR in the pre-hospital setting. REBOA application during CPR is associated with a significantly increase in peripheral artery pressures. This likely indicates improved central aortic blood pressure and warrants studies with simultaneous peripheral and central blood pressure measurement during aortic occlusion.ClinicalTrials.gov (NCT03534011).The study is registered in  Resuscitative endovascular balloon occlusion of the aorta (REBOA) may increase the aortic pressure during cardiopulmonary resuscitation (CPR) and can possibly be an adjunct treatment in non-traumatic cardiac arrest patients. The use in preclinical and human studies has recently been reviewed , 2 and tThe central aortic BP is the main determinant for the CPP during resuscitation. Increase in CPP is associated with return of spontaneous circulation (ROSC) in humans . The REBThe newly commenced REBOARREST trial is a randomised controlled trial (RCT) that aims to investigate the efficacy of REBOA as an adjunct treatment to advanced cardiovascular life support (ACLS) . The curClinicalTrials.gov-reference, which reported on the use of REBOA in 10 patients [This was a prospective observational study, performed by the physician-staffed helicopter emergency medical service (HEMS) in Trondheim, Norway, with a catchment population of approximately 700,000. The personnel at the HEMS base has previously been educated in the use of the REBOA technique during ACLS . This cupatients . EthicalAll patients that met inclusion/exclusion criteria were resuscitated on scene according to the current ACLS guideline published by the Norwegian Resuscitation Council .Patients between 18 and 75 years of age, with non-traumatic cardiac arrest and by-stander CPR commenced within 10 min were included. Exclusion criteria were suspected or known pregnancy, known terminal illness, accidental hypothermia, drowning, strangulation and suspected intracerebral haemorrhage.www.reboarrest.com.Patients were endotracheally intubated, manually ventilated and received mechanical chest compressions . Invasive arterial BP were measured via the left radial or brachial artery and registered at one-minute intervals. If the physician failed to achieve peripheral arterial access in the left radial or brachial artery, the patient was excluded and did not receive REBOA as an adjunct treatment, and standard ACLS was provided as per routine. The REBOA procedure was performed in sterile conditions under ultrasound guidance  via the femoral artery. A catheter  was inserted to a length of 50 cm for an aortic zone 1 occlusion. The balloon was inflated with the amount of 0,9% saline specified by the producer or to resistance was felt, to ensure full aortic occlusion. The detailed procedure has previously been reported  and is aDemographic and cardiac arrest variables were obtained through a semi-structured interview with the performing physician and by the Utstein template for CPR related variables . Time of2 (EtCO2) values were obtained  and measured before balloon inflation, directly after inflation, 30, 60 and 90 s after inflation, and after ROSC of any duration. This was performed similar as to the pilot study [End-tidal CO2 before and after occlusion was analysed with Wilcoxon Signed Rank test. A p value of < 0.05 was regarded as statistically significant.Data was analysed with IBM SPSS Statistics 27 and R version 3.6.0. The R package ‘ggplot2’ was applied for visualization. Continuous variables are reported as mean with standard error or median with range, as appropriate. Categorical variables are described as count and/or proportion. Differences in arterial BP and EtCODuring the study period, HEMS was dispatched 88 times due to OHCA. Of these, 22 were older than 75 years and 14 had obtained ROSC before the arrival of the HEMS crew. Thirty-five patients were not eligible for REBOA due to other exclusion criteria . Two of the five patients achieved ROSC and one patient was admitted to hospital. No patients survived to day 30.p = 0.104) 30 s after occlusion. From before start of aortic occlusion to 60 s after occlusion, the EtCO2 increased by a mean of 1.16 kPa (p = 0.043).The mean EtCO2 value before start of aortic occlusion was 3.00 kPa and increased by a mean of 1.08 kPa (The peripheral artery pressures changes after aortic occlusion are demonstrated in Fig. One patient showed signs of CPR-induced consciousness after aortic occlusion, to the extent that sedation was needed. The tertiary hospital was consulted for possible extracorporeal membrane oxygenation treatment, but it was declined due to long duration of cardiac arrest. The resuscitation efforts were then abandoned.To our knowledge, this is the first study to report changes in peripheral arterial pressure due to aortic occlusion in humans suffering from OHCA. Our findings demonstrate that aortic occlusion during ACLS is associated with increase in peripheral arterial pressure. The REBOA catheter in use is not approved to perform aortic pressure recordings, hence we were not able to measure the central aortic blood pressure. However, we find it likely that an increase in the radial or brachial arterial pressures during CPR also indicate an increase in central aortic blood pressure.Blood pressure can differ significantly between the central and peripheral arteries , but fewAdditionally, few studies, and with small sample sizes, report intra-arterial BP differences between the brachial and radial artery . It is rFinally, of the 17 potentially eligible patients, only seven patients received REBOA and it is difficult in retrospect to determine the reason for this lack of compliance to protocol. However, it is likely due to some of the expected and challenging pre-hospital environmental factors considered to complicate the procedure, such as low temperature, light conditions, wind, rain, and unsafe location.First, this data must be regarded as preliminary findings due to a limited number of patients. Second, it was a single-centre study, with few physicians and paramedics involved. Third, all the physicians were board-certified anaesthesiologist with considerable experience with the use of ultrasound and Seldinger technique, and the results may not be relevant to other settings. Fourth, the arterial pressures are measured with one-minute sampling rate. The BP may vary during this time interval, hence further studies may benefit from the use of higher sampling rate, or continuous sampling. Finally, this study primarily increase knowledge on the hemodynamic changes caused by REBOA during CPR and cannot conclude about the potential clinical benefit from a REBOA intervention.To our knowledge, this is the first study to investigate the peripheral invasive arterial blood pressure response to aortic occlusion during non-traumatic OHCA patients. REBOA as an adjunct treatment during resuscitation may significantly increase the peripheral artery pressures and it is likely that this indicates improved central aortic blood pressure. Our findings warrant studies with simultaneous peripheral and central blood pressure measurement during aortic occlusion.


Secondary aims included: the evaluation of the effect of PEEP on respiratory mechanics, arterial partial pressure of carbon dioxide (PaCO2) and hemodynamics; the correlation between changes in ICP and LUS as well as respiratory parameters; the identification of factors at baseline as potential predictors of ICP response to higher PEEP.The effects of positive end-expiratory pressure (PEEP) on lung ultrasound (LUS) patterns, and their relationship with intracranial pressure (ICP) in brain injured patients have not been completely clarified. The primary aim of this study was to assess the effect of two levels of PEEP . Changes in ICP were significantly correlated with changes in LUStot , LUSp , respiratory system compliance , mean arterial pressure  and PaCO2 . Baseline LUStot score predicted the increase of ICP with PEEP.Thirty patients were included; 19 of them (63.3%) were male, with median age of 65 years [interquartile range (IQR) = 66.7–76.0]. PEEP from 5 to 15 cmHLUS-together with the evaluation of respiratory and clinical variables-can assist the clinicians in the bedside assessment and prediction of the effect of PEEP on ICP in patients with acute brain injury.The online version contains supplementary material available at 10.1186/s13054-022-03903-7. ConcernAs increased ICP is associated with poor outcome , it is fIn a small physiological study using quantitative Computed Tomography (qCT) , we show2O and 15 cmH2O—on global and regional LUS scores and their correlation with the changes of ICP, with the aim to evaluate if LUS can provide similar information as qCT about the effects of PEEP on lung densities and ICP.Therefore, we conducted a prospective observational study on a population of mechanically ventilated brain injured patients to assess the effect of two levels of PEEP – 5 cmH2 and hemodynamics; the correlation between changes in ICP and LUS; the identification of factors at baseline as potential predictors of ICP response at higher PEEP.Secondary aims included the assessment of the effect of PEEP on respiratory mechanics, PaCOThis study is reported according to the “Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)” statement guidelines for observational cohort studies . Patients were excluded in case of absence of invasive ICP monitoring or informed consent, or if they did not receive LUS or PEEP test from 5 to 15 cmH20.Patients were screened for inclusion from August 1st 2020 to September 1st 2021, and considered eligible if they were > 18 years old, required mechanical ventilation and were admitted to the ICU of San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genoa, Italy, after acute brain injury  requiring invasive ICP monitoring, and if underwent LUS evaluation based on clinical indications at two different levels of PEEP ], pre-injury comorbidities , type of acute brain injury , Glasgow Coma Scale (GCS) at ICU admission, type of ICP monitoring inserted , the occurrence of pulmonary and extrapulmonary ICU complications , and patients’ outcome, such as ICU length of stay, mortality and neurological status  at ICU discharge.2O.In the ICU, patients were sedated with propofol and/or midazolam and fentanyl, were intubated and mechanically ventilated in pressure or volume-controlled ventilation. Tidal volume was targeted to 6–8 mL per kg of predicted body weight (PBW); however, higher values of tidal volume were tolerated, if driving pressure was maintained below 15 cmH2O every minute), from 5 to 15 cmH2O, and evaluating step by step the changes in respiratory mechanics and cerebral hemodynamics to set the optimal values of PEEP. Previous evidence and our clinical experience suggest that these values of PEEP are safe in brain injured patients [The decision to perform a PEEP test was based on the clinician’s evaluation if optimization of mechanical ventilation was required, according to local protocols. PEEP test was performed in volume-controlled ventilation in all patients, under strict monitoring of ICP, without neuromuscular blockade. So far, no specific indications are available on the optimal levels of PEEP to be applied in brain injured patients . A recenpatients , 7, 14.2O after allowing 5 min for stabilization. We used this relatively short time for high PEEP exposure before repetition of the cerebral and respiratory measurements, as previous studies showed that the majority of changes in volume and recruitment occurs in this timeframe and that most respiratory units recruit below 30 cmH2O [2O) represent the standard levels of PEEP used to estimate response to PEEP in ARDS patients [Data were obtained at PEEP 15 cmH30 cmH2O . The chopatients .2O included regional and global LUS score, as well as neuromonitoring parameters , systolic (FVs), mean (FVm), and diastolic Flow Velocities (FVd); respiratory mechanics and arterial blood gases parameters including arterial partial pressure of oxygen (PaO2)/inspired fraction of oxygen (FiO2) ratio, tidal volume (VT), plateau pressure (Pplat), Crs, respiratory rate (RR), arterial saturation of oxygen (SaO2), arterial pH (pHa) and PaCO2.Data collected at PEEP 5 and PEEP 15 cmH2O; therefore, a reduction in lung ultrasound and negative values of ΔLUS will correspond to an increase in lung aeration at higher PEEP levels. On the contrary, an increase in LUS score and positive values of ΔLUS will correspond to a reduction in lung aeration at PEEP 15 cmH2O. The presence of air bronchogram and its characteristics (static/dynamic/punctiform/arborescent) was also reported.LUS was performed using a linear 12 MHz) or phased-array probe (2.5 MHz) for the visualization of pleural line or tissue-like pattern, respectively  MHz or p, 19. ForTCD) was calculated using a previously validated formula [Invasive ICP monitoring was inserted according to our local policies and clinical practice, and following the latest Brain Trauma Foundation Guidelines . Ultraso formula .2O—value at PEEP 5 cmH2O). Correlations were sought using the Spearman’s rho. We further modeled ΔICP using linear regression as function of clinically sound covariates, adopting a variance inflation factor threshold of 5 as acceptable limit for multi-collinearity. All statistical analyses were performed in SPSS Statistics, Version 25.0 . Significance was assumed at two-tailed p < 0.05.We were not able to perform an a priori sample size calculation as no studies on the effect of PEEP on LUS characteristics and ICP in brain injured patients are available. However, our sample size was higher compared to previous physiologic studies regarding PEEP augmentation in ARDS or in brain injured patients , and of Over the described period, 42 patients were considered for inclusion. Among these, 11 were not monitored with invasive ICP, and one patient had no consent signed and was not included. A total of 30 patients were included in the final analysis. Four of them were also enrolled in our previous study . Among tp = 0.069) (Table p = 0.002) while no differences were found in LUSl and LUSa . Considering LUStot, the percentages of score 0 pattern were increased (p = 0.005), while in score 3 pattern were reduced (p = 0.007) after PEEP augmentation . In the posterior areas, scores 0 and 1 were increased after PEEP augmentation  while score 3 was reduced (p = 0.006). Dynamic punctiform air bronchogram was observed in ten patients. Punctiform static air bronchogram and arborescent static bronchogram were detected in two and six cases, respectively. Dynamic punctiform air bronchogram was present only in patients who did not experience increased ICP after PEEP augmentation.After PEEP augmentation, total LUS score did not change significantly , and PaO2/FiO2 improved , whereas no effect on PaCO2 and Crs was observed   and ΔLUSp , but not with ΔLUSa and ΔLUSl  , ΔPplat  ΔMAP , and ΔPaCO2  , whereas ΔLUSl and ΔLUSa were not . Finally, ΔICP was correlated with ΔONSD , but not with ΔICPTCD.ΔICP was correlated with ΔLUStot . We did not observe any significant correlation between the basal values (at PEEP = 5 cmH2O) of ICP, ONSD, ICPTCD, Crs, MAP, PaCO2, and the changes of ICP at PEEP 15 cmH2O.At linear regression analysis, basal LUStot was correlated with the changes in ICP after PEEP increase  the improvement in LUS score occurs mainly in the posterior areas and is correlated with a decrease or no changes of ICP; (2) decreased respiratory system compliance and mean arterial pressure as well as increased PaCO2 are correlated with greater ICP augmentation; (3) basal LUStot can predict ICP increase after PEEP application. In particular, the higher is the basal LUStot, the smaller is the change of ICP after PEEP application.In a cohort of mechanically ventilated brain injured patients undergoing a PEEP test from 5 to 15 cmHThis is the first study describing the use of LUS in brain injured patients for the definition of lung echographic patterns, and which assesses the effect of PEEP increase on ICP variation.2), and hemodynamic stability is maintained [Little is known about the optimal levels of PEEP to be applied in mechanically ventilated brain injured patients . The useintained , 28, 29.2. This is also in line with the current recommendations in this population of patients, which suggest to apply the same level of PEEP as for the general ICU population [In a recent study, we demonstrated that alveolar recruitment evaluated through qCT was correlated with increased ICP . Althougpulation . Althougpulation , the neepulation , 31. Compulation . Howeverpulation , 33.Our study suggests that LUS can be used as surrogate of qCT to evaluate lung recruitment after PEEP increase and its effect on ICP, and that when PEEP increases lung volume by alveolar recruitment, the increase in plateau pressure is limited. This phenomenon is particularly relevant in the posterior areas of the lung, where we observed the highest percentage of pathologic LUS pattern and in particular lung densities (score 3), potentially able to respond to recruitment. A possible explanation in these cases is that, independently from individual variations in the chest wall compliance, the transmission of airway pressure to the thoracic compartment is reduced, thus minimally affecting increases in ICP. On the other side, if PEEP overinflates aerated lung without alveolar recruitment, Crs decreases, yielding greater increase in Pplat. In this case, the transmission of airway pressure to the thoracic compartment is increased, thus promoting an increase in ICP.LUS scores in the anterior and the lateral areas of the lung did not importantly change after PEEP application and were not correlated with ICP changes.This is a new finding, when compared to the available literature on the use of lung ultrasound for PEEP titration, which reports in fact the interest in the loss of aeration of mainly the anterior fields to identify PEEP responders . This caMoreover, in our population, we observed median lower LUS scores than what reported by previous literature on patients with acute respiratory failure ; this suIn the present study, none of the respiratory and neuromonitoring derived parameters evaluated at baseline PEEP was predictive for ICP increase with PEEP. However, a higher LUS score at baseline was associated with a reduced risk of changes in ICP, thus suggesting that in patients with greater severity of lung injury and pulmonary morphology (with higher incidence of consolidations), PEEP can cause recruitment without causing important effects on cerebral hemodynamics. A signal on the consolidations features is also present, with higher potential for PEEP responsiveness in consolidations with dynamic punctiform air-bronchogram, corresponding to patent airways with airflow during inspiration.We also found a significant correlation between changes of ONSD and ICP, thus confirming our previous findings , and sugIn summary, in this study we demonstrated that LUS can be used as a surrogate of qCT to evaluate the effect of PEEP on ICP and can be used at patient’s bedside to predict the effect of PEEP on ICP. Despite our sample size is limited, this represents a great novelty as LUS can become an important clinical tool for neuro-ICU physicians. By performing serial bedside LUS, they would be able to safely titrate PEEP and assess/predict the effect of PEEP on intracranial pressure, minimizing the risk of intracranial hypertension and secondary brain damage. LUS is a radiation free, non-invasive, safe and easily available tool; however, it can present some limitations compared to qCT  , 37.2/FiO2 is < 300 at PEEP of 5 cmH2O.  In addition, we included patients with different types of brain damage, thus resulting in a heterogeneous population for both cerebral and respiratory characteristics. Second, although we standardized mechanical ventilator settings, respiratory mechanics evaluation and arterial blood gases measurement during PEEP test, we cannot exclude that different ventilator setting may have led to different results [This study has several limitations that need to be mentioned. First, in our ICU, the PEEP test is a routine procedure that is normally performed but only in selected patients with acute brain injured patients, and when the PaO results , 38. Thi results , 39, 40.LUS, together with the evaluation of respiratory variables, can assist the clinicians in the bedside assessment and prediction of the effect of PEEP on ICP in mechanically ventilated patients with acute brain injury.Further larger studies are warranted to assess the role of LUS for the titration of PEEP in this cohort of patients, and to create a statistical model with selected independent variables aimed to improve the accuracy of the prediction of ICP response to PEEP.Additional file 1. STROBE, additional information on data analysis, methods, and additional results.


It has been shown that blood pressure (BP) values measured in obese subjects are higher than the individuals with normal weight, even in normotensive limits. However, data concerning the Ambulatory Arterial Stiffness Index (AASI) and blood pressure load in normotensive obese subjects is lacking. This study was aimed to compare the ambulatory arterial stiffness index and blood pressure load in normotensive obese and healthy controls.One hundred normotensive obese and one hundred normal weight subjects were included in this study. All subjects underwent 24-hour ambulatory blood pressure monitoring. Ambulatory arterial stiffness index was calculated from 24-hour ambulatory blood pressure monitoring records. Ambulatory arterial stiffness index was defined as one minus the regression slope of unedited 24-h diastolic on systolic blood pressures. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) load values were calculated from 24-hour ambulatory blood pressure monitoring analysis.Ambulatory arterial stiffness index of the obese subjects was significantly higher than the healthy controls . 24-hours systolic blood pressure and diastolic blood pressure loads were significantly higher in obese subjects. Logistic regression analysis revealed that body mass index (BMI) was an independent predictor for an abnormal ambulatory arterial stiffness ındex (≥0.50) .Blood pressure load and ambulatory arterial stiffness index are increased in normotensive obese patients. Moreover, body mass index is an independent predictor for an abnormal ambulatory arterial stiffness index. Our results indicate that obese subjects are at higher risk for future cardiovascular events despite normal office BP levels. Obesity, which may give rise to the development of various diseases, is currently one of the most important health problems globally. The prevention and early diagnosis of the elevated blood pressure (BP) may help reducing the complications associated with hypertension. The relationship between obesity and hypertension has been well established. The blood pressure values measured in obese patients are higher than normal weight subjects even in the normotensive rangeThe aim of our study was to evaluate the AASI and BP load in obese patients who were diagnosed as having normal BP on office BP measurements.Obese patients (BMI≥30) aged >18 years, without overt hypertension, and whose office blood pressure lower than 140/80 mmHg were underwent ABPM at TOBB Economics and Technology University Hospital and Kecioren Teaching and Research Hospital, Ankara. ABPM results were evaluated according to European Society of Cardiology (ESC) hypertension guidelinesAll subjects underwent transthoracic echocardiography as a part of the routine cardiovascular examination. The office blood pressure of each patient in the study was measured by manual sphygmomanometers on the left arm after 5 minutes of rest. Three consecutive blood pressure measurement averages were obtained for participants with systolic below 140 mmHg and diastolic below 90 mmHg. ABPM monitoring was performed with a commercially available ABPM device . Automatic BP recordings were obtained regularly every 30 minutes during the 24-hour ABPM period. Patients with mean 24-hour systolic BP (SBP) ≥ 130 mmHg and/or diastolic BP (DBP) ≥80 mmHg, mean daytime SBP≥135 mmHg and/or DBP≥85 mmHg and mean nighttime SBP>120 mmHg, and nighttime DBP≥70 mmHg on ABPM were diagnosed as hypertensive, and below this values were defined as normotensive2. Obesity is classified as a BMI ≥30 kg/m2Body mass indexes (BMI) were calculated using the formula BMI: kg/mDemographic, clinical and laboratory parameters including glucose, creatinine, lipid profile and complete blood count parameters were recorded in all patients. Informed consent was obtained from each patient and the study was approved by the institutional ethics committee.The differences in AASI and BP load between the obese subjects and healthy controls were the primary outcome measure of the study. The predictive role of BMI on AASI was the secondary outcome measure.All statistical analyses were performed using the SPSS 25 . Categorical variables were expressed as frequencies and continuous variables as mean ± standard deviation. The independent samples t test was used to compare continuous variables and chi-square test was used to compare categorical variables between the groups. Correlation analysis was performed to assess the association between the interventricular septum thickness (IVS) and AASI and BP load. Logistic regression analysis was performed to identify the contributors of an abnormal AASI (≥ 50). Variables demonstrating a statistical significance of <0.01 on univarate analysis were included in the logistic regression model. A p value <0.05 was considered statistically significant.Baseline clinical and laboratory data of the groups are shown in Logistic regression analysis revealed that BMI was an independent predictor for an abnormal AASI (≥0.50) . AASI was significantly correlated with the IVS  or lack of data about sleep quality or sleep disorders could be other limitations. There is strong and well known association between sleep disorders, hypertension and obesity. Both obesity and sleep disorders like obstructive sleep apnea (OSA) are risk factors for the development hypetension.22Blood pressure load and AASI are increased in normotensive obese patients compared to healthy controls. Moreover, BMI is an independent predictor for an abnormal AASI. Given the critical predictive role of AASI on future cardiovascular events, our findings may suggest that the risk for developing hypertension and cardiovascular events is increased in obese subjects with normal office blood pressure measurements.


Background: Mean corpuscular volume (MCV) is major used as an indicator for the differential diagnosis of anemia. Macrocytic anemia in decompensated cirrhosis is common. However, the relationship between macrocytic anemia and decompensated hepatitis B virus (HBV) associated cirrhosis has not been fully addressed.Methods: In this cross-sectional study, a total of 457 patients diagnosed decompensated HBV associated cirrhosis who met all inclusion criteria from 2011 to 2018 were analyzed. Association between macrocytic anemia and the liver damaged (Model for End Stage Liver Disease (MELD) score) were examined using multiple logistic regression analyses and identified using smooth curve fitting.Results: Compared with normocytic anemia, MCV and MELD are significantly positively correlated in macrocytic anemia (p < 0.001). A non-linear relationship of MCV and MELD association was found though the piecewise linear spline models in patients with decompensated HBV associated cirrhosis. MCV positive correlated with MELD when the MCV was greater than 98.2 fl .Conclusion: Macrocytic anemia may be a reliable predictor for mortality because it is closely related to the degree of liver damage in patients with decompensated HBV associated cirrhosis. Liver cirrhosis is a frequent end stage of liver disease, which itself results from a long-term process of fibrosis and sustained inflammation and leads to chronic liver disease . HepatitAnemia is now identified as an important predictor of adverse outcomes in liver cirrhosis patients, such as the development of acute-on-chronic liver failure (ACLF) in outpatients with cirrhosis and hepatocellular carcinoma mortality rates . Mean coPrevious a study showed that the relationship between MCV and MELD , howeverThis is a retrospective study from the Big Data Platform of the First affiliated hospital of Dalian Medical university from May 2011 to April 2018, our data consists of 1732 patients with decompensated HBV associated decompensated cirrhosis. Our research used the International Classification of Diseases codes to identify decompensation cirrhosis with HBV hospitalized patients. Decompensated Cirrhosis in Patients with hepatitis B according to the China’s Guidelines for the Prevention and Treatment of Chronic Hepatitis B , 1) HBsAThe research protocol was reviewed and approved with a waiver of written informed consent by the Ethics Committee of the First affiliated hospital of Dalian Medical university, informed consent by telephone was obtained from each participant. All the methods were performed in accordance with relevant guidelines and regulations.Demographic characteristics were obtained from face-to-face communication with patients or their families when the patient was admitted to our hospital. Blood samples were taken from the patients on an empty stomach for more than 10 h after the whole night and fast sent to the laboratory assessments. Having more than one cigarette per day is considered as smoking and alcohol intaking more than 20 g per day for at least a year is considered as drinking . EstimatUsing the following formula to calculate the MELD score: 9.57 × loge (creatinine mg/dl) + 3.78 × loge (bilirubin mg/dl) + 11.2 × loge (INR) + 6.43, where INR is the international normalized ratio and 6.43 is the constant of the etiology of liver disease .p-value < 0.05 in the univariate analyses were planned to be included in the multivariate model. The possible linear and nonlinear models were used to assess the relationship between MELD and MCV by multiple linear regression models and two-piece piecewise regression models adjusted for sex, age, smoking, drinking, SBP, DBP. We then performed stratified analyses in order to further explore potential modifier on the MELD-MCV association.Categorical variables were described in counts (percentages) and continuous variables as means ± standard deviation (SD). Patients were distributed into 3 groups by mean corpuscular volume (MCV) classification. The variables were followed normal distribution and homogeneous in variance. The levels within 3 groups of the continuous variables were analyzed using one-way ANOVA. categorical variables were analyzed using Chi-square test. To evaluate the relationship between the MELD score and macrocytic anemia were analyzed using univariate and multivariate linear regression analyses. Only variables with a http://www.R-project.org, The R Foundation) and Empower (R) . The results data were considered statistically significant When p-value was <0.05.All data analysis and form generation were produced using the statistical package R (n = 72) and microcytic anemia (n = 55). The cohort was 74.2% male, had a mean age of 65.5 (SD = 12.9). In addition, we found significantly higher expression levels of serum bilirubin, international normalized ratio (INR) and MELD score in macrocytic anemia when compared to normocytic or microcytic anemia. However, no significant differences were found in age, gender, smoking, drinking, diabetes, hypertension, systolic blood pressure, diastolic blood pressure, creatinine, eGFR, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltranspeptidase (γ-GT).The baseline characteristics of subjects with anemia were divided into three groups . Among tβ = 2.20, 95% CI: 0.99–3.41, p < 0.001), normocytic group was used as a normalization control  after adjustment for sex and age in Model I  after adjustment for sex, age, smoking, drinking, SBP, DBP in Model II in multivariate analysis . There was a strong positive correlation if MCV greater than 98.2 fl  ; Table 4In this study the analysis was done retrospectively, we suggested that macrocytic anemia (MCV >100 fl) related to the degree of liver damage in decompensated HBV associated cirrhosis patients. This variability persists even after adjusting for age, gender, smoking, drinking, SBP and DBP.Positive association between MCV and MELD was found among HBV-associated decompensated cirrhosis. Our findings by the two-piece piece-wise regression model to display the relationship between MCV and MELD as non-linear relationship. Positive correlation was observed when the MCV was higher than 98.2 fl, while negative correlation occurred when the MCV was lower than 98.2 fl.Macrocytosis, which is also known as MCV >100 fl, is not necessarily corelated with anemia. Moreover, in most of the cases it is unattached to anemia . We seleThe significance of macrocytosis remains an underestimated issue in the past. Only a small number of studies had relevant reports . An artiMacrocytosis is considered a structural and functional abnormality of the erythrocyte membrane. Several potential pathological mechanisms may explain our observations. First, irrespective of the etiology vitamin deficits is common in patients with cirrhosis, such as vitamin B12 and folate deficiency , macrocyThe MELD score is approved for assessing the degree of liver diseases. These variables include prothrombin time, INR, serum bilirubin and creatinine level. MELD score changes with variations in these variables. Higher MELD scores associate with increased risks of death and hepatic events in cirrhosis. In our study, among the parameters of MELD score, bilirubin and INR showed an increase on patients with macrocytic anemia. However, there was no remarkable difference with creatinine and eGFR. Therefore, macrocytic anemia may not be relevant to renal injury in patients with decompensated HBV associated cirrhosis.Several study limitations are noted. First, the main limitation of this study lies in its retrospective observational nature, the cross-sectional nature of our study does not permit the determination of causality between MCV and MELD. Second, this study included only Chinese participants, and therefore these findings may not be generalizable to other biogeographic ethnic groups. Third, we did not perform an analysis on the data of folate, serum vitamin B12 and reticulocyte count, which could provide a better understanding of macrocytic anemia in cirrhotic patients.Macrocytic anemia was highly correlated with the degree of hepatic dysfunction and may be a reliable predictor for mortality in patients with decompensated HBV associated cirrhosis. We found a non-linear relationship between MCV and MELD. Moreover, further large-scale, well-designed and multicenter studies need to be conducted to confirm our conclusions, it is important to evaluate and investigate this association and to gain insight the underlying mechanisms.


Gdue is a nutraceutical obtained from the association of two marine algae, Ascophyllum nodosum and Fucus vesiculosus, in addition to chromium picolinate, which could be useful for the treatment of dysglycemia, overweight, and the other components of the metabolic syndrome. The aim of the study was to assess the real-world effectiveness and safety of Gdue when administered to subjects with one or more components of the metabolic syndrome.  A longitudinal, retrospective, observational study, conducted among primary care physicians, nutritionists, and specialists from various disciplines. The impact of 180 days of administration of Gdue was assessed on body weight, waist circumference, fasting blood glucose, HbA1c, lipid profile, and blood pressure levels. The likelihood of experiencing a first major cardiovascular event over ten years was estimated using Italian risk charts. General linear models for repeated measures were applied to assess changes in the parameters of interest during the follow-up. Results are expressed as estimated marginal means with their 95% confidence interval.  Overall, 505 patients were enrolled by 282 physicians. After 6 months of treatment with Gdue, body weight was reduced on average by 7.3 kg , waist circumference by 7.5 cm , fasting blood glucose by 16.3 mg/dL , HbA1c by 0.55% , systolic and diastolic blood pressure by 7.1 mmHg  and 4.2 mmHg , respectively, LDL cholesterol by 18.2 mg/dL , and triglycerides by 39 mg/dL . HDL cholesterol was significantly increased by 2.9 mg/dL . The 10-year risk of cardiovascular events significantly decreased by 1.8%, corresponding to a relative risk reduction of 27.7%.  Our real-world study shows that 6 months of treatment with Gdue have an impact on all the components of the metabolic syndrome, thus offering the potential for decreasing the cardiovascular risk associated with metabolic syndrome. Metabolic syndrome has become a major health problem in most of the modern world and is characterized by abdominal obesity, insulin resistance, dysglycemia, hypertension, and hyperlipidemia , 2. The α-amylase and α-glucosidase enzymes in the intestine, causing a slowdown in the absorption and digestion of carbohydrates and demonstrating an important antihyperglycemic action in vivo, in particular on postprandial hyperglycemia [Two marine algae, Ascophyllum nodosum and Fucus vesiculosus, could be useful for the treatment of dysglycemia, overweight, and the other components of the metabolic syndrome –5. Ascopglycemia –17. In aglycemia . Furtherglycemia .Chromium is an essential trace element involved in the metabolism of carbohydrates, lipids, and proteins and is a necessary cofactor for many insulin functions, promoting the binding to its receptor in muscle cells, adipocytes, and hepatocytes and also promoting the phosphorylation of receptors –21.In streptozotocin-induced diabetic animals, administration of chromium picolinate decreased plasma glucose levels, normalized glycogen content in the liver, increased the activity of glycolytic enzymes , and suppressed the activity of gluconeogenic enzymes (glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) in the liver . The inhβ-cell exhaustion.At the oral dose of 250-500 mg, Gdue reaches levels 25-50 times higher in intestinal fluids than in vitro inhibitory concentrations, completely, uncompetitively, and reversibly inhibiting carbohydrate-degrading enzymes. Preclinical studies have confirmed this mechanism of action , 8, respAnimal studies also suggest a positive effect of Ascophyllum nodosum and Fucus vesiculosus on liver steatosis, frequently associated with the metabolic syndrome .α levels, evaluated as endothelial damage markers [Open-label or double-blind controlled trials have shown how Gdue reduces the glycemic index of ingested foods, postprandial glycemic peaks, and the consequent insulin response , 9–11. W markers . Further markers , 11.Assessing whether the results of these clinical trials are applicable to the broader range of patient populations treated under routine clinical practice conditions and in different settings is of importance to determine the magnitude of effectiveness of Gdue use.The aim of the study was to assess the real-world effectiveness and safety of Gdue when administered to subjects with one or more components of the metabolic syndrome. The impact of 180 days of administration of Gdue was assessed on fasting blood glucose, HbA1c, body weight, waist circumference, lipid profile, and blood pressure levels.This is a longitudinal, retrospective, observational study, conducted among primary care physicians, nutritionists, and specialists from various disciplines.Male or female patients aged ≥18 yearsPresence of one or more components of the metabolic syndrome, according to the IDF definition , includiPatients treated with Gdue. The decision to prescribe Gdue was based on clinical judgment and was independent of study participationPatients were included if they fulfilled the following eligibility criteria:Gdue was generally administered at the recommended dose of 2-3 tablets per day at meals as integration of a dietary prescription.At baseline (start of Gdue) and after 90 days and 180 days of treatment, the following information was collected from clinical records on an ad hoc form: age, gender, body weight, waist circumference, fasting blood glucose, HbA1c, blood pressure, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Information on comorbidities and concomitant treatments was also collected. Participating physicians were requested to report any adverse event registered during the follow-up.In a subgroup of 89 patients, information on fasting insulin levels was also available at baseline and during the follow-up. In these patients, HOMA-IR was also calculated as an index of insulin resistance. Data collected were those available in medical records and prescribed according to routine clinical practice, and no laboratory test was performed specifically for the study.Descriptive data were summarized as mean and standard deviation (continuous variables) or counts and percentages .U-test for continuous variables and the chi-square test for categorical variables.Patient characteristics at baseline were compared by gender using the Mann-Whitney P value < 0.05 was considered for statistical significance.General linear models for repeated measures were applied to assess changes in the parameters of interest during the follow-up. Results are expressed as estimated marginal means with their 95% confidence interval (95% CI). Mean changes of each parameter were also estimated by tertile of the parameter at baseline. All tests are two-sided, and a The likelihood of experiencing a first major cardiovascular event  over the following ten years was estimated using the Progetto Cuore Italian risk charts .Statistical analyses were performed using the SPSS software ver. 23.0 .Overall, 505 patients were enrolled by 282 physicians (range 1-8). Among participating physicians, 65.5% were general practitioners, 10.9% were nutritionists, 8.1% were endocrinologists, and 15.5% were from other specialties . The characteristics of the patients enrolled by gender are reported in P = 0.03) and more likely to have hypertension . No other statistically significant differences emerged for all the other variables investigated.The proportion of patients with availability of information at baseline varied between 98.6% for body weight and 49.9% for total cholesterol; the availability of information relative to 180 days ranged from 88.9% for body weight to 41.8% for total cholesterol (supplementary table P < 0.0001).The analysis was also performed by gender  of the patients; moderate gastrointestinal side effects  were referred by 0.6% (N = 3) of the patients.Mild gastrointestinal side effects  were reported by 3.4%  [The beneficial effects of Gdue on waist circumference were also previously documented in a single-arm, 6-month study involving 50 overweight or obese patients , which s < 0.05) . In our  < 0.05) .P < 0.001), LDL cholesterol , and triglyceride levels  and a significant increase in HDL cholesterol levels . In our study, we found a statistically significant effect on all the parameters of the lipid profile, with an average reduction of 18.2 mg/dL for LDL cholesterol and 39.0 mg/dL for triglycerides, while HDL cholesterol was significantly increased by 5.2 mg/dL in men.The impact of Gdue therapy on lipid profile was assessed in a randomized, double-blind placebo-controlled trial involving 175 individuals with T2DM . In thisTo our knowledge, no previous studies have assessed the impact of Gdue therapy on blood pressure. We documented a significant reduction in systolic and diastolic blood pressure, evident after three months and even larger after six months, with an average reduction of 7.1 mmHg for systolic blood pressure and 4.2 mmHg for diastolic blood pressure. The effect on blood pressure can represent the consequence of weight loss; in fact, it is well established that weight loss is associated with a parallel decrease in systolic and diastolic blood pressure .Finally, a reduction vs. baseline in fasting insulin levels and HOMA index after 6 months of treatment with Gdue was described in the study by De Martin et al. , while aThe study has strengths and limitations. Among the strengths, the large number of patients and healthcare professionals involved provides a realistic picture of the effectiveness of Gdue under routine clinical practice conditions. Also, the study allowed to assess the impact of the treatment on a large array of different parameters of the metabolic syndrome.Among the limitations, it should be emphasized that follow-up data were not available for all patients. Also, BMI could not be calculated given the lack of information on height in most of the patients. However, it should also be noted that the degree of missingness was modest for some key variables such as FBG, body weight, and waist circumference. Furthermore, baseline characteristics of individuals with full data and those with missing data were largely superimposable, with the only exception of an older age and a higher prevalence of hypertension among those with all the information available. Another limitation is represented by the lack of a control group; in addition to the therapy with Gdue, additional aspects of care may have influenced the study results. In this respect, it is worth mentioning that study results were not affected when data were analyzed according to the dietary prescription made to the patients .In conclusion, our real-world study shows that 6 months of treatment with Gdue have an impact on all the components of the metabolic syndrome, thus offering the potential for decreasing the cardiovascular risk associated with metabolic syndrome. A significant reduction in the levels of key risk factors was documented even in patients in the lower tertile of the distribution of each variable, suggesting that also individuals with initial, mild elevation of FBG, blood pressure, or lipid parameters can benefit from this therapeutic approach.


Aspergillus fumigatus. It complicates and aggravates asthma. Despite their potential associations, the underlying mechanisms of asthma developing into ABPA remain obscure. Here we performed an integrative transcriptome analysis based on three types of human peripheral blood, which derived from ABPA patients, asthmatic patients and health controls, aiming to identify crucial lncRNAs implicated in ABPA and asthma. Initially, a high-confidence dataset of lncRNAs was identified using a stringent filtering pipeline. A comparative mutational analysis revealed no significant difference among these samples. Differential expression analysis disclosed several immune-related mRNAs and lncRNAs differentially expressed in ABPA and asthma. For each disease, three sub-networks were established using differential network analysis. Many key lncRNAs implicated in ABPA and asthma were identified, respectively, i.e., AL139423.1-201, AC106028.4-201, HNRNPUL1-210, PUF60-218 and SREBF1-208. Our analysis indicated that these lncRNAs exhibits in the loss-of-function networks, and the expression of which were repressed in the occurrences of both diseases, implying their important roles in the immune-related processes in response to the occurrence of both diseases. Above all, our analysis proposed a new point of view to explore the relationship between ABPA and asthma, which might provide new clues to unveil the pathogenic mechanisms for both diseases.Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity lung disease caused by a fungus known as  Aspergillus fumigatus in the bronchial mucosa. The first case was described by Aspergillus fumigatus is the most common fungi causing fungal sensitization (Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity disease response to the presence of tization , suggestIn spite of the fact that the correlation between asthma and ABPA has been well elucidated, the detailed causality between two entities, particularly the pathogenesis of ABPA is not fully understood yet. For instance, only a small proportion of severe asthmatic patients develop ABPA. Both diseases are characterized by extremely high serum level of IgE (Immunoglobulin E) but a small proportion of ABPA patients has less high serum IgE level . ApproxiA. fumigatus . However, the polymorphisms of TLR9 are reported to have no associations with the patients with severe asthma who are also associated with Aspergillus sensitivity . It was This study was approved by the Medical Ethics Committee of First Affiliated Hospital of Guangzhou Medical University . All experiments were performed in accordance with relevant guidelines and regulations of the Ethics Committee of First Affiliated Hospital of Guangzhou Medical University. All participants provided written informed consent prior to the publication of clinical and sequencing data. Briefly, a total of 27 unique male individuals were enrolled for our study, including 7 asthma patients , 12 ABPA patients and 8 healthy individuals considered as control group . The diahttps://trace.ncbi.nlm.nih.gov/Traces/sra/) and are assigned the accession number PRJNA582337.For each enrolled subject, the peripheral whole blood was extracted and the peripheral blood mononuclear cell (PBMC) was separated immediately by ficoll-paque. The total RNA was extracted using trizol (invitrogen) method and the library for RNA sequencing was prepared based on a standard protocol established by RiboBio Company in Guangzhou and sequenced on Illumina. All the raw RNA-seq data used in the present study are deposited at Short Read Archive (SRA) database of NCBI (The raw data was trimmed by Trimmomatic v0.36 (ILLUMINACLIP: TruSeq3-PE.fa:2:30:10:8:true SLIDINGWINDOW:4:15 LEADING:3 TRAILING:3 MINLEN:50)  and the Homo sapiens from Ensembl database  with default parameters. Statistical hypotheses were used to investigate whether there were significant differences in the observed proportion of SNPs, INDELs and SSRs among populations of ABPA, asthma and healthy control. The detailed process sees For single nucleotide variants, i.e., SNPs and small insertion and deletion (INDEL) detection, we applied Genome Analysis Toolkit (GATK) analysis pipeline  for varip-value ≤ 0.05)  . Functio ≤ 0.05)  plugin i ≤ 0.05) , which cGSE35571, GSE473, GSE31773, GSE2125) from NCBI GEO database were downloaded and analyzed  of cytoHubba  plugin ianalyzed .P < 0.05 was considered as statistically significant.For the basic statistics of clinical data , all theP < 0.05). There was no significant difference in eosinophil or neutrophil counts of peripheral blood in the three groups. Regarding the percentages of inflammatory cells in induced sputum, no statistical difference was found in any type of inflammatory cells between asthma and ABPA. There was also no statistical difference in the results of lung function between the two patient groups. In the comparison of IgE levels, patients with ABPA had higher total IgE levels (P < 0.05), higher positive rate of specific IgE (P < 0.05), in particular A. fumigatus specific IgE (P < 0.01) than patients with asthma. In addition, use of glucocorticoids  did not differ significantly between asthma and ABPA.As shown in RNA-seq via Illumina sequencing platform yielded on average 130 million reads per sample . After qA total of 4,521,799 SNPs and 671,669 INDELs were identified across 27 samples via GATK analysis pipeline . MajoritFor SSRs analysis, a total of 4,740,915 different types of SSRs were identified  . No signA total of 2,481 differentially expressed transcripts  were found in the comparison of ABPA vs healthy controls –3D, and Additionally, hierarchical cluster analysis via R language based on DETs revealed three main expression patterns of DETs cross these samples . ConcretThe aforementioned analysis has revealed several lncRNAs and mRNAs differentially expressed in ABPA and asthma patients. Next to investigate the possible roles of these lncRNAs implicated in the pathogenesis of ABPA and asthma, we proposed a differential network analysis. Initially, we built an RNA–RNA interaction network based on the expression profile data of eight healthy controls using the Pearson Correlation Coefficient (PCC) method. Then the interactions of these RNAs in the networks were re-assessed based on the expression profiles of 12 ABPA patients and 7 asthmatic patients. To assess the changes of network from healthy status to disease status, three different filtering criteria  are found in health controls, whereas these interactions are shown having weak correlation  in ABPA patients. It is suggested these RNA–RNA interactions might be disrupted by the occurrence of ABPA. 243,399 RNA–RNA interactions exhibit similar situation in asthma. For each disease, the immune-related RNA–RNA interactions in two loss-of-function networks were extracted to establish the loss-of-immune-related-function network, respectively  were used. The results indicated that the expression level of the selected hub nodes are consistent with the result of GEO datasets  and two lncRNAs  from the two networks were selected for validation. The expression profiles of four GEO datasets  exhibited distinct mutations across those samples . Although more than half of century has passed since ABPA was first described, its exact pathogenesis as well as potential relationship with asthma is still unknown. The clinical data of the collected subjects in the present study do not show significant difference between ABPA and asthmatic patients, except that ABPA have higher IgE level . We ther samples . Regardit asthma .nd hub node in rd hub node in Next, we tried to find some clues from the comparison of gene expression among those groups, particularly in lncRNAs. In addition to traditional differential expression analysis, we proposed a differential network analysis to detect the dynamic changes of transcriptome across those different groups. Differential network analysis based on three different filtering criteria figured out several key lncRNAs and mRNAs. The reason that we applied different filtering criteria for three different groups is that three networks exhibit extremely distinct threshold value of pearson correlation coefficient, and different criteria would yield a similar number of RNA–RNA interactions in different groups. Notably, we applied 12 different algorithms of topological network analysis to make sure our predictions more reliable and convincing. Our analysis indicated that the interactions involved in 82 key transcripts (hub nodes in network) were dramatically disrupted by the occurrence of ABPA, and some interactions were repressed by ABPA and some were gained in response to ABPA . For insth hub node in By integrating two networks, we could find several common key mRNAs and lncRNAs. Permutation test shows the reliability of this analysis. Some of them have already been demonstrated to be correlated to asthma or ABPA. For example, PARP14 was found to play a role in transcription of interleukin-4 (IL4)-responsive genes, which controls cell survival, metabolism and proliferation . InhibitOur analysis discloses many lncRNAs associated to immune-related mRNAs, which suggests these lncRNAs might participate regulation of immune-related processes in response to the occurrence of both diseases. Further investigation on the interactions among them might provide some clues to access underlying mechanisms of pathogenesis for both diseases. Certainly, more ingenious experimental design and validation is required to conclude the concrete roles of these lncRNAs in both diseases. In short, our analysis describes a rough transcriptome landscape of ABPA and asthma, and benefits understanding the pathogenesis of both diseases.10.7717/peerj.11453/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.11453/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.11453/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.11453/supp-4Supplemental Information 4Click here for additional data file.