Midlife hypertension confers increased risk for cognitive impairment in late life. The sensitive period for risk exposure and extent that risk is mediated through amyloid or vascular-related mechanisms are poorly understood. We aimed to identify if, and when, blood pressure or change in blood pressure during adulthood were associated with late-life brain structure, pathology, and cognition.Participants were from Insight 46, a neuroscience substudy of the ongoing longitudinal Medical Research Council National Survey of Health and Development, a birth cohort that initially comprised 5362 individuals born throughout mainland Britain in one week in 1946. Participants aged 69–71 years received T1 and FLAIR volumetric MRI, florbetapir amyloid-PET imaging, and cognitive assessment at University College London ; all participants were dementia-free. Blood pressure measurements had been collected at ages 36, 43, 53, 60–64, and 69 years. We also calculated blood pressure change variables between ages. Primary outcome measures were white matter hyperintensity volume (WMHV) quantified from multimodal MRI using an automated method, amyloid-β positivity or negativity using a standardised uptake value ratio approach, whole-brain and hippocampal volumes quantified from 3D-T1 MRI, and a composite cognitive score—the Preclinical Alzheimer Cognitive Composite (PACC). We investigated associations between blood pressure and blood pressure changes at and between 36, 43, 53, 60–64, and 69 years of age with WMHV using generalised linear models with a gamma distribution and log link function, amyloid-β status using logistic regression, whole-brain volume and hippocampal volumes using linear regression, and PACC score using linear regression, with adjustment for potential confounders.Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. 465 participants  were included in imaging analyses. Higher systolic blood pressure (SBP) and diastolic blood pressure (DBP) at age 53 years and greater increases in SBP and DBP between 43 and 53 years were positively associated with WMHV at 69–71 years of age . Higher DBP at 43 years of age was associated with smaller whole-brain volume at 69–71 years of age , as were greater increases in DBP between 36 and 43 years of age . Greater increases in SBP between 36 and 43 years of age were associated with smaller hippocampal volumes at 69–71 years of age . Neither absolute blood pressure nor change in blood pressure predicted amyloid-β status or PACC score at 69–71 years of age.High and increasing blood pressure from early adulthood into midlife seems to be associated with increased WMHV and smaller brain volumes at 69–71 years of age. We found no evidence that blood pressure affected cognition or cerebral amyloid-β load at this age. Blood pressure monitoring and interventions might need to start around 40 years of age to maximise late-life brain health.Alzheimer's Research UK, Medical Research Council, Dementias Platform UK, Wellcome Trust, Brain Research UK, Wolfson Foundation, Weston Brain Institute, Avid Radiopharmaceuticals. Evidence before this studyHypertension, particularly in midlife, is associated with late-life dementia risk and with risk of clinically diagnosed Alzheimer's disease. We reviewed previous work on blood pressure and brain health with a focus on white matter hyperintensities, brain volumes, and amyloid pathology. We searched PubMed for all articles published from database inception to Sept 31, 2018, with no language restrictions, for the keywords “blood pressure”, “hypertension”, “brain volume”, “hippocampal volume”, “atrophy”, “white matter hyperintensity”, “cerebral small vessel disease”, “amyloid”, “MRI”, “PET”, and “midlife”. Extensive published literature describes the positive association between hypertension and cerebral small vessel disease. Hypertension has also been associated with smaller brain volumes, with more consistent associations seen with midlife, rather than late life, measures of blood pressure. The association between blood pressure and amyloid burden is less clear. Several small studies found positive cross-sectional associations between higher blood pressure and elevated amyloid burden, whereas two large cohort studies, the Atherosclerosis Risk in Communities and the Mayo Clinic Study of Aging, did not observe an association between midlife hypertension and late-life amyloid burden. Midlife is generally defined as spanning a period between 40 years of age and 65 years of age. Studies to date have primarily investigated associations using a single measure in midlife, with the wide age range at measurement reducing the ability of these studies to determine whether there are specific periods in life when blood pressure, or change in blood pressure, particularly affect late-life brain health. Furthermore, some studies have used retrospective, clinically collected information on hypertension diagnosis, rather than prospectively collected blood pressure measurements from a community-based sample.Added value of this studyOur study presents the first work, to our knowledge, examining the association between blood pressure taken prospectively at multiple timepoints, blood pressure changes, and brain pathologies and volumes measured systematically in a birth cohort in which all participants are of a near-identical age. The study design provides a unique opportunity to examine blood pressure changes in well-defined periods from early adulthood into midlife to late life and to explore their effect on brain pathologies and brain volumes. The use of data from this cohort, whose participants were assessed at the last visit over a 2-year period, enables examination of associations without the confounding effect of age, which is strongly associated with all these measures. We find that early midlife, perhaps extending back into early adulthood, is a particularly sensitive period when elevated blood pressure and rapid blood pressure increases are associated with the development of subsequent white matter hyperintensities and smaller brain volumes. We did not observe an association between blood pressure or blood pressure change and late-life amyloid burden, providing additional evidence that associations observed between midlife hypertension and late-life dementia risk are unlikely to be mediated through amyloidogenic pathways. At the age of 69–71 years, in this cognitively normal cohort, associations between life course measures of blood pressure and cognition were not detected.Implications of all the available evidenceOur results build upon existing evidence regarding the role of blood pressure in the development of subsequent brain pathology. However, although raised blood pressure might be associated with dementia and clinically diagnosed Alzheimer's disease, it does not appear to affect risk for Alzheimer's disease through amyloidogenic pathways at 69–71 years of age. Based on our results, the fourth to sixth decades of life might be a sensitive period when changes in blood pressure are particularly damaging to the brain. Findings suggest that routine and serial blood pressure measurement might need to start earlier than is typically considered , and decisions to start treatment might need to be based not only on absolute blood pressure, but also longitudinal blood pressure change.Dementia affects 44 million people worldwide, a number predicted to triple by 2050.We sought to determine the association between blood pressure and longitudinal blood pressure changes across a period of about 33 years, spanning early adulthood (36 years), midlife (43–64 years), and early late life (69 years), and cerebral small vessel disease, brain volumes, and amyloid pathology in early late life. We hypothesised that blood pressure would be differentially related to markers of different brain pathologies, and that blood pressure and changes in blood pressure in specific periods would affect brain pathology.Participants were from Insight 46, a substudy of the Medical Research Council (MRC) National Survey of Health and Development (NSHD), a birth cohort that initially comprised 5362 individuals born throughout mainland Britain in 1 week in 1946,Ethical approvals for the wider NSHD have been described.18F florbetapir . Amyloid burden was assessed over a 10-min period, around 50 min after injection. Global standardised uptake value ratio was calculated from cortical regions of interest, normalised to eroded subcortical white matter , with simultaneous acquisition of dynamic PET-MRI data, including volumetric (1·1 mm isotropic) T1-weighted and T2-weighted Fluid Attenuated Inversion Recovery (FLAIR) sequences. The full imaging protocol has been described previously.e matter . PositivVolumetric T1-weighted and FLAIR images underwent visual quality control before processing using automated pipelines:Neuropsychology included tests of episodic memory  and diastolic blood pressure (DBP) change for the periods between 36 and 43, 43 and 53, 53 and 60–64, and 60–64 and 69 years of age, conditional on earlier measurements, was calculated as the residual from the regression of each blood pressure measure (from 43 years of age) on the earlier measures for each sex, using individuals with available data at all time-points. Residuals represent changes in blood pressure that differed from changes expected on average given the earlier blood pressure. Residuals were standardised, allowing comparison between periods.APOE genotype. Individuals were categorised as APOE ɛ4 carriers or non-carriers. Adult socioeconomic position was defined as non-manual or manual on the basis of occupation at 53 years of age according to the UK Registrar General's Classification of Occupations. A childhood cognition score was calculated as described previously.Vascular risk factors used in fully adjusted models included smoking status, hypercholesterolaemia, diabetes, and body-mass index (BMI) at time of scanning . GenotypAnalyses were done in Stata version 14.1. Participants were included if they were dementia-free based on expert consensus, informed by clinical history, informant history, and Mini-Mental State Examination score (≥26). For imaging analyses, participants also needed acceptable quality amyloid PET-MRI. For WMHV and brain volume analyses, individuals with white matter pathologies not considered to be of vascular origin  or cortical infarcts inappropriately segmented were excluded. For brain volume analysis, individuals also needed a useable amyloid scan. Otherwise, all participants with available blood pressure measures at any time-point were included in the analysis.Blood pressure at each visit was compared between those in Insight 46 and the whole cohort, using an unadjusted linear mixed effect model for men and women separately, using all available blood pressure measurements. An unstructured residual variance-covariance matrix was used to model correlation between repeated measures in an individual.Owing to the skewed distribution of WMHV, generalised linear models using the gamma distribution with log link were used to investigate associations between blood pressure at each age separately and WMHV at 69–71 years of age. The association between blood pressure and severe WMHV (top quintile of WMHV) was also investigated using logistic regression. Linear regression was used to investigate associations between blood pressure and whole-brain volume and mean hippocampal volumes at 69–71 years of age. Model 1 was adjusted for sex, total intracranial volume, and age-at-scan. Model 2 was also adjusted for antihypertensive medication use at time of blood pressure measurement. Model 3 additionally adjusted for blood pressure at 69 years of age to explore associations independently of current blood pressure. Model 4 additionally adjusted for potential cardiovascular confounders: smoking status, BMI, diabetic status, hypercholesterolaemia status, childhood cognition, and adult socioeconomic position. For brain volume analyses, to explore blood pressure influences independently of measurable brain pathologies, model 4 also adjusted for global WMHV and amyloid status.Blood pressure change variables were then treated as the main predictor within generalised linear models or linear regression models. In model 1(c), all SBP or DBP conditional change variables were included and adjusted for sex, total intracranial volume and age-at-scan. In model 2(c), each conditional change variable was assessed individually and adjusted for change in antihypertensive medication status between timepoints under investigation and for other covariates described for model 4.APOE ɛ4 status. Model 3 additionally adjusted for antihypertensive medication use. Model 4 also adjusted for blood pressure (at 69 years of age). Additional vascular risk factors were not included in models due to the limited number of amyloid-positive individuals. Associations between blood pressure change and amyloid status were investigated using three models. Model 1(c) included all conditional change variables (SBP or DBP) within the same model, adjusting for sex. Model 2(c) additionally adjusted for APOE ɛ4 status. Model 3(c) assessed each trajectory separately and adjusted for change in antihypertensive medication status. A differential influence of blood pressure (or change) on amyloid status by APOE ɛ4 status was tested using an interaction term in fully adjusted models.We used logistic regression to test associations between blood pressure at 36–69 years of age and amyloid status at age 69–71 years of age. Model 1 adjusted for sex. Model 2 further adjusted for An exploratory analysis investigated associations between blood pressure and blood pressure change and cognition at 69–71 years of age, using the PACC. The linear regression models that we used are described in the Model assumptions were checked with regression diagnostics, including checks of linearity by examination of residuals. Possible non-linear associations were explored by introducing a quadratic term to fully adjusted models. Any suggestion of a non-linear association (p<0·05) was investigated using linear spline modelling, with introduction of knot points, using standard cutoffs for (pre-)hypertension and hypotension, where appropriate. Statistical significance was set at p<0·05.The funders of the study had no role in study design, data collection, analysis, or interpretation, or report writing. All authors had full access to all the data in the study. The corresponding author had final responsibility for the decision to submit for publication.vs 133·6/74·2 mm Hg), lower BMI (27·6 mm Hg vs 30·4 kg/m2), and lower prevalence of current smoking (3% vs 7%), diabetes (10% vs 17%), and hypercholesterolaemia . There was no evidence of non-linear associations .There was no evidence that blood pressure at any age was associated with amyloid status . Blood pThere was some evidence to suggest that higher SBP across timepoints might be associated with smaller whole-brain volume, with significant effects at 43 years of age  and 53 years of age  and between SBP and hippocampal volume (quadratic p=0·044). Using knot points at 120 mm Hg and 140 mm Hg and a fully adjusted model, no association existed below 140 mm Hg, but a negative association did exist between greater SBP and whole-brain volume at blood pressures greater than 140 mm Hg  smaller hippocampal volume  and smaller whole-brain volume (p=0·0032) than women. Diabetics had smaller whole-brain volume  were both associated with smaller whole-brain volume, independent of white matter hyperintensity load and amyloid burden. These findings are consistent with evidence from the Framingham Heart Study that vascular risk factors at younger ages were most strongly associated with lower brain volume in later life.We did not observe an association between blood pressure and cognition, as reported in other cohorts.Previous studies have produced conflicting findings regarding whether elevated SBP or DBP more strongly affects cerebral small vessel disease and brain volumes.Our findings are particularly relevant considering the findings from the SPRINT MIND study,This study has several strengths. Participants are broadly representative of the population of mainland Britain born in 1946 and were of similar age at assessment. All participants had serial prospective measurements of blood pressure, allowing dynamic changes in blood pressure across the life course to be studied. Limitations inherent in any birth cohort are secular effects. All individuals went through midlife at the same time and are likely to have been exposed to similar hypertension treatments and targets, which might differ from those of individuals born in other periods. Furthermore, although participants have similar blood pressure profiles to the main cohort, we have previously shown that individuals with lower socioeconomic position, lower cognition, and more health problems are under-represented in Insight 46, suggesting that we might underestimate effect sizes compared with the general population.This work shows that the fourth to sixth decade, from early adulthood into midlife, might be a sensitive period when greater blood pressure affects brain pathologies in late life, and that greater increases in blood pressure and, in the case of DBP, decline thereafter might be particularly harmful. These findings suggest that routine serial blood pressure measurement might need to start around 40 years of age (if not before), decisions to start treatment should account for longitudinal blood pressure change, and different approaches to blood pressure management might be needed at different ages. Associations between blood pressure and increased risk for dementia are likely to be mediated through effects on cerebral small vessel disease and brain volumes and not amyloid accumulation.website.A data-sharing policy is available on the NSHD Data Sharing


Electrical impedance tomography (EIT) is a tool to monitor regional ventilation distribution in patient’s lungs under general anesthesia. The objective of this study was to assess the regional ventilation distribution using different driving pressures (DP) during high frequency jet ventilation (HFJV).Prospective, observational, cross-over study. Patients undergoing rigid bronchoscopy were ventilated HFJV with DP 1.5 and 2.5 atm. Hemodynamic and ventilation parameters, as well as ventilation in different regions of the lungs in percentage of total ventilation, assessed by EIT, were recorded.Thirty-six patients scheduled for elective rigid bronchoscopy. The final analysis included thirty patients. There was no significant difference in systolic, diastolic and mean arterial blood pressure, heart rate, and peripheral saturation between the two groups. Peak inspiratory pressure, mean inspiratory pressure, tidal volume, and minute volume significantly increased in the second, compared to the first intervention group. Furthermore, there were no statistically significant differences between each time profiles in all ROI regions in EIT.In our study intraoperative EIT was an effective method of functional monitoring of the lungs during HFJV for rigid bronchoscopy procedure. Lower driving pressure was as effective in providing sufficient ventilation distribution through the lungs as the higher driving pressure but characterized by lower airway pressure.NCT02997072.The study was registered on ClinicalTrials.gov under no.  AdditioElectrical Impedance Tomography (EIT) is a non-invasive, radiation free technology to measure the electrical impedance of the lungs, which corresponds to ventilation. In short, better ventilated parts of the lung are represented by higher electrical impedance. The impedance is measured via 16 surface electrodes attached via an elastic band around the patient’s chest and transmitted to the device. The metrics are processed to colorful images, allowing real-time continuous visualization and observation of regional differences of the ventilated lungs . The EITIncreasing driving pressure (Pplat – PEEP) in intubated and ventilated patients does have an impact on improving regional ventilation, but whether this improvement is also applicable in patients under HFJV is unknown , 15. We We aimed to investigate, if increasing driving pressure causes increased ventilation of dependent lung areas.clincialtrials.gov on .This is a prospective, crossover clinical study. With approval from the institutional review board of the Medical University of Silesia, Katowice, Poland , and written informed consent, we enrolled 36 patients having elective rigid bronchoscopy requiring HJFV. The patients were enrolled at the Medical University of Silesia between July 2014 and December 2016, and the study was registered in 2.Participating patients were between 18 and 60 years, had an American Society of Anesthesiologists (ASA) physical status I-III, and a body mass index (BMI) of 19–30 kg/m2), and cardiac implantable electronic devices .We excluded patients having emergency surgeries, known airway trauma and thoracic wall deformities, obesity  was placed around patient’s thorax under the 5th intercostal space. The reference electrode was placed on patient’s abdomen according to manufacturer’s instructions. Patients were also monitored with continuous 5 lead ECG, non-invasive blood pressure, and peripheral oxygen saturation as clinical routine.Patients were premedicated with oral midazolam 0.1 mg kg-1 one hour prior to arrival to operating room as clinical routine. After arrival in the operating room, the EIT electrode belt  was connected via the side channel of the bronchoscope. Initial ventilation setting included driving pressure of 1.5 atm, inspiratory time of 40%, gas humidifying 40%, and a respiration rate of 180/min (= first intervention group). The proximal end (visor) of the bronchoscope was always open during the complete surgery.After confirmation of complete muscle relaxation by absence of palpable twitches in response to supra-maximal train-of-four stimulation of the ulnar nerve at the wrist, the rigid bronchoscope  was introduced by the surgeon. Once optimal visualization of the vocal cords could be achieved, position of the bronchoscope was fixed, and the HFJV . The fraction of oxygen was 1.0 throughout the complete procedure.Peak Inspiratory Pressure (PIP), Mean Inspiratory Pressure (MIP), Tidal Volume (TV) and Minute Ventilation (MV) were monitored via bronchoscope side channel with jet catheter.General anesthesia was maintained by continuous infusion of propofol and titrated as clinically appropriate. Continuous deep neuromuscular blockade was confirmed throughout the procedure and boluses of mivacurium were given per clinical judgement. After end to the surgical procedure, the rigid bronchoscope was removed and patients were intubated with a standard single lumen tube. Afterwards patients were transferred to the post-anesthesia care unit (PACU). Mechanical ventilation was maintained and muscle relaxation was reversed. Once patient fully recovered from anesthesia, patients were extubated and remained in the PACU as clinically appropriate.To characterize distribution of regional ventilation, we a priori defined 4 regions of interest (ROI 1–4), which are based on the technical characteristics of the device used. The analyzed ROI divides the lungs into horizontal layers from dorsal-to ventral position. We decided to use this particular ROI, based on the assumption, that dependent lung areas are likely to develop atelectasis during general anesthesia. The use of EIT technology allows to determine the size and location of this atelectasis. During the study, the spread of ROIs were adjusted so that all layers were equal. Interpretation of the functional images relates to distribution of ventilation within the EIT sensitivity region and its changes over time. Numerical values indicate percentage of total ventilation in each region within 15 s time periods.During an EIT examination, minimal alternating electrical currents were applied through pairs of electrodes and the resulting voltages are measured on the remaining electrodes. The most widespread spatial pattern of current applications and voltage measurements is through adjacent electrode pairs. Functional EIT images are generated from series of raw images and the corresponding pixel EIT waveforms, by the use of appropriate mathematical equations. Interpretation of the functional images allows to assess distribution of ventilation within the EIT sensitivity region and its changes over time. Numerical values indicate percentage of total ventilation in each layer within 15 s time periods.p value below 0.05. All tests were two-tailed. Interval data were expressed as mean value ± standard deviation. Distribution of variables was evaluated by the Shapiro-Wilk test and homogeneity of variances was assessed by the Levene test. For comparison of data between driving pressure 1.5 atm and driving pressure 2.5 atm groups, one-way ANOVA analysis with repeated measurement was done with contrast comparison as post-hoc tests. The distance-weighted least squares method was used to illustrate time changes of tidal volumes in four regions of interest separately for each driving pressure group.Statistical analysis was performed using STATISTICA 10.0 PL . Statistical significance was set at a 2), underwent also the second intervention (driving pressure of 2.5 atm) were included in the final analysis . Surgical procedure ended in 2 patients, before the second intervention was started. Consequently 30 patients , group and time interaction (p = 0.29),ROI 1: group influence (p = 0.71), group and time interaction (p = 0.65),ROI 2: group influence (p = 0.41), group and time interaction (p = 0.94),ROI 3: group influence (p = 0.40), group and time interaction  were calculated. There were no statistically significant differences between each time profiles in all ROI regions:The most important finding of this study is, that increased driving pressure did increase overall tidal volumes, but this was mostly based on over-inflation of ventilated lung areas, instead of distributing ventilation to less ventilated lung areas.The EIT was previously reported as an accurate method to detect ventilation inhomogeneity and was validated by several methods including radionuclide scanning, spirometer, and single-photo emission computed tomography –19. Imag2 elimination [During general anesthesia and in supine position, non-dependent parts of patient’s lungs are preferentially ventilated. Consequently, the lung strain is distributed heterogeneously among various regions of lung, with the maximum along the anteroposterior axis , 22. Thimination .We decided to compare the driving pressure of 1.5 atm versus 2.5 atm and hypothesized, that increased driving pressure will improve regional ventilation distribution in dependent regions. Results of our study indicate, that ventilation in all lung areas increased, but non-dependent areas were still much better ventilation compared to dependent areas. Consequently, we did not find any hints, that increased tidal volumes are based on any significant shift of ventilation.Increased driving pressure is applied in the clinical setting in order to provide higher tidal volumes, which is reflected by results of our study. Increased tidal volumes was mostly due increased ventilation of already ventilated non-dependent lung areas (represented as ROI 2 in our study). Dependent lung areas like the ROI 4 in our study were also more ventilated, but tidal volumes were still minimum. Increased tidal volumes and thereby caused stretch of lung tissues is potentially worrisome by causing local inflammation via interleukins  which is known to initiate ventilator induced lung injury . Extra dIntraoperative ventilatory management is definitely not trivial, as this significantly impairs postoperative respiratory course . Specifi2 elimination. Third, this study was designed as a sequential study and although physiologically highly unlikely, previous ventilation with lower driving pressure might have affected subsequent ventilation with higher driving pressure. However, a randomized ventilation strategy might have addressed this potential interference. Fourth, improved ventilation consequently leads to better oxygenation, which was outside of the scope of the current project and consequently, arterial blood analyses were not performed. Finally, although of being of clinical interest, we did not assess atelectasis after the procedure and any clinical complications like pneumothorax.The findings of pour study have some limitations. First, patients in our study tended to be slimmer compared to the general population. Higher BMI affects chest wall compliance due to the mass load effect and secondary causing increased pleural pressure. Airway driving pressures may vary over a wide range in patients according to the BMI. Second, we did not measure arterial oxygenation or COApplying higher driving pressure is commonly used in the clinical setting to increase tidal volumes in order to maintain adequate oxygenation. Increased tidal volumes were achieved by over-inflation of already ventilated non-dependent lung areas, instead of any significant shift to less ventilated dependent lung areas.


Several clinical prediction rules (CPRs) are available for sleep apnoea-hypopnoea syndrome (OSAH), but they are difficult to apply in primary care (PC).Derivation and validation of a CPR using simple measurements available in PC.A prospective study conducted in health centres from the area of influence of three Spanish hospitals.Patients (aged 18–70 years) who attended for any reason; who presented with at least one of the three key symptoms for OSAH ; and who were not undergoing non-invasive ventilation or prior treatment with continuous positive airway pressure (CPAP) were included. Anthropometric data, smoking habit, comorbidities, and Epworth test were collected. Patients were subsequently referred to the sleep unit (SU), where the decision was taken whether or not to instigate treatment. A multivariate logistic model was constructed using a sub-sample and scores assigned based on the regression coefficients; the CPR was validated with the remaining sample. Both receiver operating characteristic (ROC) curves were plotted and the sensitivity, specificity, and predictive values calculated.The derivation sample comprised 352 patients, with 260 in the validation sample. The final factors  were used to develop a rule with scores ranging from 0.00–5.50. The cut-off point that optimises the area under the curve (AUC) is ≥2.50 points . The properties for the validation sample with this cut-off point are as follows: AUC = 0.68; sensitivity = 81%; specificity = 43%; PPV = 61%; NPV = 68%; LR = 0.44.As in similar cases, the specificity is low, meaning that healthy people are referred to a specialist. A negative result rules out the disease in most cases. OSAH is associated with numerous diseases but only 5–9% of the population with severe OSAH is receiving treatment. Although various CPRs have been proposed, none of them is widely used. This CPR presents a lower sensitivity and specificity than other rules, and is more accessible and easier to use, making this rule an ideal tool for use in PC1 Its prevalence increases with age.2 Several studies have found an association between OSAH and numerous diseases, including hypertension,4 and cardiovascular5 and cerebrovascular disease.6 OSAH is associated with a worse quality of life,7 and a higher number of work8 and traffic accidents.10OSAH affects 2–4% of the population.11 Three key symptoms  have been used in standard clinical practice (SCP) to determine the probable presence of OSAH. However, none of these predicts the disease per se, as they are all very common in the general population.Despite the risks associated with OSAH, only 5–9% of the population with severe OSAH is receiving treatment.This situation has outlined the need to develop a tool that discriminates patients presenting a more severe OSAH from those in whom the disease is not present or is unlikely to lead to its complications. Therefore, a tool like a CPR would be most useful for PC physicians, who could apply it to decide whether or not to refer a patient to specialised care.12 Although several attempts have been made to create a CPR,16 none of them is used in SCP. In some cases, this is because they use apnoea–hypopnoea index (AHI) values that are of little clinical interest (AHI = 5 or AHI = 10)17 or, in the case of the neck circumference, due to the collinearity with BMI, which is in the final model as current guidelines indicate the use of CPAP for AHI values >30, or 15 if accompanied by related comorbidity or severe symptomatology.A CPR is considered to be any decision-making instrument prepared from a minimum of three variables obtained from the case history, physical examination, or simple diagnostic tests.et al15reported a high-quality prediction , but this rule is difficult to apply in SCP as the collection of the variables requires meticulous training. Chai-Coetzer et al17 developed the OSA50 screening tool plus overnight oximetry, which shows a very good NPV, with the drawback for its use in PC being that it requires an at-home overnight test.Kushida This study proposes the derivation and validation of a prediction rule, using measurements easy to obtain in PC, in order to distinguish between patients at high and low risk of suffering OSAH.The CPR was developed using a sample of patients recruited prospectively between February 2011 and August 2012. The derivation sample comprised patients who attended the PC departments of two urban health centres and were referred to the SU at the Araba University Hospital. Patients of the validation sample were recruited at various health centres and referred to the Hospital de Galdakao-Usansolo and the University Hospital in Valdecilla (Santander).All subjects aged 18–70 years and presenting at least one of the three key symptoms for OSAH  were recruited on spontaneous consultation of a PC physician for any reason. Patients with a previous diagnosis of OSAH, prior CPAP treatment or non-invasive mechanic ventilation were excluded. Participants provided consent to participate in the study.After collection of the information in the PC centres, participants were asked to attend the SU at the corresponding hospital. The doctor at the SU, blinded to the information collected in the PC setting, made the diagnostic decisions  as well as the therapeutic decisions , following SCP.The only information obtained in both the PC centre and the SU, the BMI, was used for the inter-observer reliability analysis in order to validate the information collected by the PC physicians.The characteristic to be predicted is the clinical decision of the sleep specialist as regards indication for specific diagnostic tests ; and indication of treatment .The predictive variables taken into consideration were sex, age, weight, height, neck circumference, snoring (five or more times per week), breathing pauses while asleep reported by the partner or companion, daytime hypersomnia, accidents in the past year due to drowsiness, morning tiredness, morning sensation of asphyxia, AHT, heart failure, diabetes mellitus (DM), smoking habit, alcohol consumption, and daytime sleepiness according to the Epworth scale.2 saturation is <90%) were obtained if available from the PSG and/or RP reports.In addition, BMI, neck circumference, and Epworth scale were collected at the SUs. Along with this information, global AHI, supine AHI, and T90  of not less than 0.90, considering a prevalence of 40% for the disease in the study population (data from the SU in Vitoria).According to Flahault Two hundred subjects are required for the validation phase for a power of 90% to confirm the hypothesis that the sensitivity of the CPR in the validation population does not differ from that obtained for the derivation sample by >3%.Means and standard deviations were used to describe continuous variables, and frequencies and percentages for categorical variables.Continuous variables were categorised in order to be applied in a simple manner. Looking at the distribution of results, values close to the median or values close to the tertiles were used as cut-off points.2 test or the student’s t-test for continuous variables.Characteristics of the patients in the derivation and validation samples were compared using the XSPSS (version 22) and R freeware (version 3.1.1) were used for all analyses.et al,19 those variables with <10% lost values were selected as potential predictive variables, which did not exclude any of those from the model. The characteristics of treated patients were compared with those of untreated patients using a univariate logistic regression. A value of P<0.2 indicated that a variable was potentially predictive and should be taken into consideration during the multivariate analysis.According to Kharbanda P≤0.05.Subsequently, the final multivariate logistic regression model was described using a stepwise variable selection method and the LR test to compare two models. The criterion for introducing variables into the model was P>0.05. Both variable selection criteria led to the same final model. The goodness-of-fit was evaluated using the Hosmer–Lemeshow test.A backward stepwise model was also prepared using the LR test in order to ensure the most parsimonious rule possible. The criterion for excluding variables from the model was 19The final scores for the prediction rule were obtained from the logistic regression coefficients using the lowest risk category as reference.The predictive ability of the rule was evaluated for each sample using ROC curves, which present the decision reached with respect to the score. To evaluate the predictive accuracy of the rule for the derivation and validation samples, different cut-off points were established and 2×2 tables were constructed to calculate the following measures: sensitivity, specificity, PPVs, and NPVs . The kappa statistic was calculated to compare the interobserver reliability for measurement of each of the variables included in the CPR. A kappa value >0.60 was considered to be acceptable.P<0.001).Informed consent was obtained from 620 patients. Eight were excluded: five because they were aged >75 years; two because they did not have any of the key symptoms; and one for technical reasons. Full information  was available for 278 of the 352 subjects in the derivation sample (79.0%) and 233 of the 260 subjects (89.6%) in the validation sample . The comP = 0.903), can be seen in The final multivariate model (Hosmer–Lemeshow goodness-of-fit The AUCs for the derivation sample (77.8%) and for the validation sample (68.1%) can be seen plotted in The sensitivity, specificity, PPV, and NPV for the different cut-off points on the scale are provided in For the reliability, the kappa index for this measure is 0.834, although it should be noted that this analysis was performed for a total of 334 out of 612 cases .This study has derived and validated a CPR for identifying patients with suspected OSAH in PC centres. Four independent predictive factors  were selected, and a rule ranging from 0.00 to 5.50 points was generated combining them. Despite being variables 'classically' associated with the presence of OSAH, neck circumference and breathing pauses do not form part of the final model as these variables are confounded by sex and, in the case of the neck circumference, due to the collinearity with BMI, which is in the final model.Although the final goal of a prediction rule is to obtain the highest possible sensitivity, in this study two cut-off points are proposed for two different scenarios. In this case, selecting a cut-off point of ≥1.50 points (highest sensitivity for the rule with the derivation sample) means that sleep tests must be performed in a large number of healthy patients due to the low specificity. This implies the overuse of already limited resources, in addition to the indirect costs and inconveniences generated to the patient.The cut-off point that achieves the best results in terms of sensitivity and specificity for the derivation sample is ≥2.50 points, with a lower sensitivity counterbalanced by a marked increase in specificity.However, selection of this cut-off point for the validation sample leads to markedly different results as both sensitivity and specificity decrease. This nevertheless appears to be the most reasonable option in light of the results. The PPV of the validation sample is also 15–20% higher.This is likely to be mainly due to the fact that the derivation and validation populations sampled differ in terms of baseline risk profile regarding the disease. Thus, the derivation sample includes a higher proportion of males, with a higher BMI and, in general, a higher number of key symptoms for the disease, and therefore a higher pre-test probability.The main limitation of this study is the difference between the derivation and validation groups; the values obtained during validation are markedly lower than those obtained during derivation of this rule. However, this situation merely reflects the study's setting, where access to some healthcare services is unequal and depends on the healthcare organisation.17The present authors also decided to limit the study to population those aged <70 years, with the aim of identifying the disease in a population with a low prior probability of having it. It is doubtful that a rule valid for asymptomatic people works the same way in an aged population, with a higher probability and a greater possibility of confounding due to comorbidity. Similar studies have also chosen this limit, notably the aforementioned work by Chai-Coetzer.17 the present authors believe that the studied rule is easier to apply in PC settings, resulting in a more rational referral to specialised units. This means that the rule is useful despite the drawbacks discussed above.Although the results obtained do not demonstrate as high a sensitivity and specificity as the prediction rules developed previously,20 surveyed PC physicians regarding the use of prediction rules in clinical practice. The results showed that a high percentage of physicians were unaware of and/or did not use prediction rules widely validated in PC, as they considered these rules to be of little use, or preferred their own medical judgement. This could possibly be explained by the complexity of such rules. Therefore, a rule that is easy to use could easily be implemented in already saturated PC centers.A recent study conducted in the UKIn conclusion, this study presents a CPR for diagnosing OSAH which, despite presenting a lower sensitivity and specificity than other such rules, is more accessible and easier to use. This makes it an ideal tool for use in PC, allowing the referral of patients susceptible to presenting the disease to SUs while ensuring a more rational use of the resources available.


The theory that glaucoma patients have a lower intracranial pressure (ICP) than healthy subjects is a controversial one. The aim of this study was to assess ICP noninvasively by determining the relationship between distortion product otoacoustic emission (DPOAE) phase and body position and to compare this relationship between patients with primary open angle glaucoma (POAG), patients with normal tension glaucoma (NTG), and controls. The relationship was also calibrated using published data regarding invasive measurements of ICP versus body position. DPOAEs were measured in 30 controls and 32 glaucoma patients  at the following body positions (assuming 90° as upright): 45, 30, 20, 10, 0 (supine), -10, and -20°. DPOAE phase had a clear, nonlinear relationship with body position. The mean DPOAE phase shifts between the two most extreme body positions (45 to -20°) were 73.6, 80.7, and 66.3° for healthy, POAG, and NTG, respectively (P = 0.73), and the groups showed the same, nonlinear behaviour. This indicates that there is no evidence that glaucoma patients have a reduced ICP. When calibrated with invasive data, ICP and DPOAE phase were linearly related over an ICP of 3 mmHg. This suggests that, more broadly, DPOAEs could be used in the future to monitor changes in ICP in a clinical setting and to measure dynamic changes in ICP such as diurnal fluctuations or changes induced by certain medications. Primary open angle glaucoma (POAG) is a chronic and progressive eye disease characterized by loss of retinal ganglion cells, thinning of the retinal nerve fiber layer, and subsequent visual field loss. If left untreated, it can eventually lead to blindness. Previously, an elevated intraocular pressure (IOP) was deemed to be the key factor in the pathophysiology of glaucoma. However, there is a variant of POAG in which the patients have a normal IOP . One potAlterations in IOP, ICP, or both can lead to a change in the pressure gradient across the lamina cribrosa (LC)—known as the trans lamina cribrosa pressure difference (TLCPD)—and cause it to bulge, therefore damaging the nerve fibers. It has been shown with lumbar punctures (LPs) that patients with glaucoma have a lower ICP than the healthy population and that those with NTG have the lowest –6. As fuLPs are invasive and thus limit a researcher’s ability to conduct experiments with a sufficient number of subjects. In addition, LP opening pressures are only a proxy of the actual ICP as they are measured at the lower part of the spine and typically only in the lateral decubitus position. They are especially not likely to be representative of the pressure behind the LC. This is important because it is possible that NTG is related to an inability to maintain a certain pressure in the upright position, rather than the lateral decubitus position. Interestingly, a recent study by Linden et al.  aimed toOtoacoustic emissions are sounds that originate in the cochlea and can be easily used to measure cochlear function noninvasively ,10. One The aim of this study was to (1) determine the relationship between DPOAEs and body position and to (2) compare this relationship between POAG, NTG, and controls. Finally, we aimed to (3) calibrate this relationship using published data regarding LP-based measurements of ICP versus body position.Subjects with healthy eyes who responded to our advertisement and glaucoma patients who were selected from the Groningen Longitudinal Glaucoma Study database , receiveIn order to be eligible to participate in this study, subjects in all groups had to meet the following inclusion criteria: 50 to 70 years of age and presence of detectable DPOAEs in at least one ear. Additionally, for healthy controls: IOP of 21 mmHg or lower, no eye disease, and no family history of glaucoma (determined by a questionnaire). To exclude eye disease, we performed optical coherence tomography , frequency doubling technology , and a measurement of visual acuity . For POAG: diagnosed glaucoma and IOP over 21 mmHg before the onset of IOP lowering treatment. For NTG: diagnosed glaucoma and IOP of 21 mmHg or lower before the onset of IOP lowering treatment and at any time during follow-up. Glaucoma was defined according to Heeg et al . We requf1-f2 emission, a fixed rate of f2/f1 = 1.20 with tones at frequencies f1 = 1000 Hz and f2 = 1200 Hz and levels L1 = L2 = 72 dB SPL were used. All DPOAE measurements were completed in a sound-isolated audiometric room in the otorhinolaryngology clinic.DPOAEs were measured using hardware (Elios) and software (Echosoft version 2.4.2) developed by Echodia . To ensure the highest magnitude responses at the 2Blood pressure  and upright IOP  were measured. Subjects were then secured onto the tilt table . Body mass index (BMI) was determined using self-reported height and weight.DPOAEs were measured at the following body positions (assuming 90° as upright): 45, 30, 20, 10, 0 (supine), -10, and -20°. At each position, 30 seconds were allowed for normalization of the emission, and presumably the ICP ,19. ThisGroups were described with mean and standard deviation (SD) for normally distributed variables; means were compared using one-way analysis of variance (ANOVA). For variables with a skewed distribution, we used median and interquartile range (IQR) for descriptive statistics and the Kruskal-Wallis test for comparing medians of groups. Proportions were compared using a chi-square test.The stimulus and data collection protocols are already described in detail by Avan et al . At eachDue to the subject specific offset of the DPOAEs, normalization of the data was required. For each subject, an average phase over all body positions was calculated and the individuals’ data were normalized using this value. Individual measurements with a signal to noise ratio (SNR) of less than 3 dB were excluded. If fewer than 2 measurements with a SNR over 3 dB were available at more than one body position (out of 5 measurements per body position), those subjects were removed entirely. All analyses were performed using R . A p-value of 0.05 or less was considered statistically significant.Of the 35 healthy subjects who agreed to participate, 1 was excluded because of an abnormal eye exam and 1 because of lack of emissions. Of the 43 glaucoma patients who agreed to participate, 7 were excluded because of lack of emissions. Due to signals below the noise floor, we could not analyze the data of 3 of 35 controls, 1 of 22 POAG patients, and 3 of 21 NTG patients. Therefore a total of 62 participants were included in the analysis . The observed relationship between DPOAE phase and body position was also shown in POAG and NTG . The meaIn order to be able to interpret the DPOAE phase data, we merged our data of phase as a function of body position presented in As previously mentioned, the ear probe was removed between the first and second test to examine the test-retest variability of the device. There is a nonlinear relationship between DPOAE phase and body position that is similar in healthy subjects and patients with POAG and NTG. Above an ICP of approximately 3 mmHg, there is a linear relationship between DPOAE phase and ICP with a slope of 4 degree/mmHg; below 3 mmHg, there is no clear relationship between phase and ICP.Previous studies have demonstrated that DPOAE phase shifts can accurately represent changes in ICP. As one step of a larger experiment, Büki et al.  measuredFor many of the subjects there was a noticeable increase in phase that occurs toward the upright position, so that the minimum phase occurred at 30° and not at 45° see Figs  and 2. TThere were some limitations in the current study: First, DPOAEs were not measured at the upright position which was due to a limitation of the tilt table. However, within the range of body positions included in this study, the nonlinear relationship between phase and body position could clearly be uncovered. It is also important to note that 3 NTG subjects could not complete the second part of the test due to nausea and dizziness. No other subjects had any problems with the test. Interestingly, this supports the concept that vascular factors and impairment of ocular blood flow might play a role in the pathogenesis of NTG . Indeed What information regarding ICP can be obtained from the DPOAE measurements? Importantly, due to a subject-specific offset, there is no one-to-one relationship between DPOAE phase and ICP. For an ICP above 3 mmHg, there is a linear relationship between DPOAE phase and ICP, which implies that a change in phase can be converted into a change in ICP, where 4° corresponds to 1 mmHg . This suThere are many theories as to why glaucoma may occur in patients with a normal eye pressure. One theory is that NTG patients simply have thin corneas, yielding erroneously low IOP measurements. In this study, however, the corneal thickness for POAG and NTG were similar , signifying that another explanation is necessary. What do our results suggest regarding ICP in NTG? The overall phase shift seemed smaller in the NTG patients than in the healthy subjects or POAG patients , but theIn conclusion, we did not find evidence that NTG patients have a reduced ICP. Beyond glaucoma, however, DPOAEs can be used to monitor ICP changes noninvasively, which may further clinical care and the understanding of ICP variation and regulation tremendously. First, however, future research should focus on a robust and reproducible probe placement in order to minimize variability.S1 TableThis is the underlying information for the current study.(XLSX)Click here for additional data file.


Background: Cerebral small vessel disease (CSVD) is frequent in patients with cardiovascular risk factors including arterial hypertension, and it is associated with vascular damage in other organs and the risk of stroke, cognitive impairment, and dementia. Early diagnosis of CSVD could prevent deleterious consequences. Objective: To characterize CSVD associated with indicators of subclinical vascular damage in asymptomatic hypertensive patients. Materials and Methods: Participants were hypertensive (HT) and non-hypertensive (non-HT) individuals; without signs of cerebrovascular disease, dementia, and chronic renal failure. For CSVD, white matter hyperintensities (WMH), enlarged Virchow–Robin perivascular spaces (EVRPS), lacunar infarcts, and microbleeds were investigated. Subclinical vascular damage was evaluated  and atheroma plaque). Results: CSVD MRI findings were more frequent in HT; as well as greater intimal thickening. The IMT and/or plaque was significantly associated with all MRI variables; but retinopathy was correlated with EVRPS and lacunar infarcts. Only microalbuminuria was related to the greater severity of WMH in HT. Multivariate analysis evidenced that CSVD was independently associated with the combination of indicators of vascular damage and systolic blood pressure. Conclusions: Combining indicators of subclinical vascular damage, such as carotid morphological variables, microalbuminuria, and hypertensive retinopathy for early detection of CSVD in asymptomatic hypertensive patients could prove to be useful to take actions for the prevention of irreversible brain damage, which could lead to cognitive impairment, dementia and stroke. Arterial hypertension (HT) is the most prevalent non-communicable disease worldwide, and has long been recognized as a major risk factor for cardiovascular diseases. It has a long-term unfavorable impact on target organs ,2,3, worThe prevalence rate of HT in Cuba in 2009 was 202.7 per 1000 inhabitants, a value that has gradually increased to 219.4 in 2016 and 225.2 in 2017 , and thiAdditionally, cardio and cerebrovascular diseases occupy the first and third causes of death respectively. In 2017, the mortality rates and the years of potentially lost life for these diseases increased. Heart conditions lead to 24,423 deaths in 2016 , increasing to 27,176  in 2017; of these, 64.9% were of ischemic causes, and 45.3% of them due to AMI. On the other hand, 9 456 deaths due to CVD were reported in 2016 and 9913 in 2017, with rates of 84.2 and 88.1 per 100,000 inhabitants, respectively 2. Smokers and former smokers (until five years ago): subjects who smoked one or more cigarettes per day during at least one year prior to inclusion. Age over 55 years, according to the European guidelines arterial hypertension [Vascular risk factors were recorded in all subjects as follow: arterial hypertension when blood pressure (BP) readings ≥ 140/90 and/or with antihypertensive treatment. Diabetes mellitus (DM): subjects with one fasting glycemia ≥ 11.1 mmol/L, or two consecutive fasting glucose readings ≥ 7 mmol/L, or those receiving hypoglycemic medication . Dyslipidemia: subjects with total cholesterol ≥ 5.5 mmol/L, or triglycerides ≥ 1.7 mmol/L, or receiving statin treatment. Obesity: subjects with a body mass index (BMI) greater than 30 kg/mrtension . FinallyPeripheral venous blood was extracted (10 mL) and collected in a dry tube for blood chemistry and a urine sample (4 mL) was obtained from the first morning urination. Microalbuminuria was determined employing a sandwich immunoenzymatic quantitative assay, with a cutoff value of <20 mg/mL .The variable “indicator of subclinical vascular damage” comprised the following variables: intima media complex (IMC) thickening and/or plaque, degree of retinopathy and microalbuminuria, and was dichotomized as follows: Slight damage (minor): patients without retinopathy or grade I retinopathy, and/or IMC thickening and/or plaques, microalbuminuria ≤ 20 mg/L. More severe damage (major): grades II or III retinopathy, IMC thickening and/or presence of plaques and microalbuminuria > 20 mg/L. Individuals with at least two altered parameters were included.Data analyses:2 test and t-student test were used to evaluate the associations between categorical variables, and to compare continuous variables respectively. A multiple regression analysis was performed to determine the association of MRI variables with indicators of vascular damage in HT. Statistical processing was carried out with the STATISTICA 10.0 program for Windows and the level of significance was estimated at p <0.05.χEthical aspects:The ethical principles for medical research in humans of the Declaration of Helsinki of the World Medical Association 2013  were fulp = 0.00). Meanwhile, the percentage of individuals with more than 3 risk factors was significantly higher in HT (54.2%) compared with non-HT subjects (10.8%).We studied 157 patients between 28 and 74 years of age, 120 were HT and 37 were non-HT . PatientIn relation to the MRI variables, the majority of the findings related to CSVD were more frequent in HT patients . In geneYears of evolution of HT and SBP were significantly associated with CSVD severity; the means were higher in patients with more severe CSVD (severity 2–4 group) . Carotid morphological variables, specifically IMT and/or the presence of plaques, were statistically associated with CSVD severity in HT patients. Most of the patients without intimal thickening had a lower CSVD severity, but even in these cases, more severe CSVD may be present in a small proportion of subjects. Also, the highest severity of retinopathy (grades II–III) and the presence of microalbuminuria were more frequent in patients with more severe CSVD .p = 0.00, p = 0.01, p= 0.00, respectively). There was a significant increase of HT patients with more severe retinopathy (II–III) who had WMH , EVRPS , and lacunar infarct . Only HT patients with lacunar infarct were statistically associated with microalbuminuria  (The presence of WMH (88%), EVRPS (86%), and lacunar infarcts (15%) were related statistically with greater thickness of the IMC and/or plaque  (p = 0.0 = 0.03) .2 = 0.93 (p = 0.33); RF ≤ 3/>3: χ2 = 0.89 (p = 0.34); IMT and/or Plaque: χ2 = 0.03 (p = 0.85).Microbleeds were not significantly related with any of the indicators of vascular damage. This analysis was also performed with the non-HT group (excluding retinopathy severity), and the association of the indicators of vascular damage with the presence of hyperintensities and Virchow–Robin spaces was not significant   were considered as independent categorical variables, whereas SBP was a continuous independent variable. The model and intercept were significant. CSVD score was independently associated with the combination of vascular damage indicators, SBP and the interrelation between age groups ≤ 55/>55 years with vascular damage indicators ( = 0.02) . The senIn contrast, In this study, neuroimaging findings corresponding to CSVD were identified in asymptomatic hypertensive patients, which showed associations with the combination of subclinical vascular damage indicators . Lacunar infarctions, microbleeds, and WMH  were only present in hypertensive patients. More severe CSVD score was observed in both groups (HT and non-HT), but in greater proportion in hypertensive patients. Associations between these cerebral parenchymal changes and intimal thickening and/or the presence of carotid plaques, retinopathy severity, microalbuminuria, SBP, years of evolution of HT, and the presence of cardiovascular risk factors were found. Additionally, CSVD score was associated with the combination of vascular damage indicators, which had a good sensitivity for the detection of CSVD in asymptomatic hypertensive patients.The detection of white matter changes in neurologically asymptomatic hypertensive patients has distinctive characteristics: they appear earlier and more severely in these individuals compared with non HT subjects of similar age . In thisHigh BP causes vasoconstriction and sclerotic changes in the retinal vessels, such as hyaline degeneration and intimal thickening, which causes arteriolar stiffness . These cThe multivariate model allowed us to observe associations between indicators of vascular damage related to HT and CSVD. Other analyses, such as that of Yakushiji et al. , in whicThe results suggest that indicators of subclinical vascular damage may be associated with CSVD, independently of other risk factors. Considering that microalbuminuria, intimal thickening, and retinopathy are markers of vascular damage as a common mechanism, changes in arterial resistance of hypertensive patients  have repercussions on global hemodynamics . This stThe combination of carotid morphological variables, microalbuminuria, and hypertensive retinopathy seems to be an acceptable parameter to perform early screening and detect CSVD in asymptomatic hypertensive patients. It could be an inexpensive and available option to select those patients at higher risk, in order to treat them more intensely and prevent irreversible brain damage, which could lead to cognitive impairment, dementia, and stroke. This would be very important to preserve the quality of life and avoid the heavy financial burden on their families and society.


Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N‐oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora. The content in the proximal ileum and jejunum is less, only 102‐3 cells/g.‘Gut microbiota’ is the umbrella term for the large number of microorganisms that are dependent on the human gut and help the host complete multiple physiological and biochemical functions accompanied by their metabolites. As previously reported, the gastrointestinal tract is known to be home to more bacteria than any other part of the human body.33.1Enterobacteriaceae and Streptococcus spp, was higher in atherosclerotic CVD than in the healthy controls.Collinsella, while the gender‐ and age‐matched controls had an increased abundance of Eubacterium and Roseburia.The composition and functions of the gut microbiome are affected by external factors that are associated with increased CVD risks, including aging, obesity, a sedentary lifestyle and dietary patterns. In turn, the composition of the gut microbiome may affect the development of CVD.Lactobacillus rhamnosus GG (LGG) or telmisartan (TLM).Eubacteria, Anaeroplasma, Roseburia, Oscillospira and Dehalobacteria) have been shown to be effective in preventing atherosclerosis. Similarly, experiments performed by Stepankova et al demonstrated the protective effects of intestinal bacteria on the progression of atherosclerotic lesions.Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, have been validated to be associated with the acceleration of atherosclerosis in animal models after dietary intervention or intravenous infusion.In addition to these studies in humans, there are a series of animal studies. Chan et al established atherosclerotic models by feeding apolipoprotein E knockout (ApoE−/−) mice a high‐fat diet for 12 weeks supplemented with In the light of these findings, some types of gut bacteria have been identified as novel contributors to the progression of atherosclerosis, while others can protect against atherosclerotic plaque lesions. It is still unknown how the microbes that reside within our bodies can drive or initiate the development of atherosclerosis. It is unclear which species play a leading role in contributing to CVD and the detailed mechanisms involved require further investigation.One microbial metabolite, trimethylamine N‐oxide (TMAO), has gained considerable attention as a major influencing factor in CVD. The composition of the gut microbiota is altered when dietary patterns change. Trimethylamine (TMA) is generated by the altered microbiota through metabolizing choline,Recently, a series of clinical trials showed the relationship between gut microbiota and CVD events. A study by Li et al revealed that the TMAO level in acute coronary syndromes was an independent predictor of both short‐term (30 days and 6 months) and long‐term (7‐year) major adverse cardiac events.3.2Klebsiella spp, Streptococcus spp and Parabacteroides merdae) involved in the pathogenesis of hypertension and that these were related to the severity of disease.The gut microbiota consists of four major phyla: Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria. Firmicutes and Bacteroidetes account for a large part of the intestinal microflora. The ratio of Firmicutes (F) and Bacteroidetes (B) (F/B) is considered a biomarker for gut dysbiosis.˗/˗ and wild‐type mice with antibiotics for a set time period to determine whether metabolites from the microbiota mediate blood pressure via Olfr78.‐/‐ mice after antibiotic treatment, but no effect was seen in the control mice. This indicated that Olfr78 contributes to the hypertensive effects by means of SCFAs. Pluznick et al indicated that GPR41 and Olfr78 had opposing functions in the modulation of blood pressure after responding to propionate (a type of SCFA).The mechanisms of hypertension are complex and multifactorial. The gut microbiota is considered a risk factor for a variety of diseases including atherosclerosis,Thus, blood pressure is closely linked to the diversity, richness and evenness of the microbiome living in the gut and it is affected by the F/B ratio. The hypertensive and hypotensive effects of SCFAs are mediated by binding to Olfr78 and GPR41 respectively. The discovery that drug intervention has an influence on blood pressure modulation by changing the species as well as the metabolites of the gut microbiota may provide new ideas for the treatment of hypertension. Moreover, how the intestinal microflora influences blood pressure deserves further exploration.3.3Heart failure (HF) encompasses a group of complex clinical syndromes that result in damage to the structure or function of the heart. HF is the end stage of many CVDs. Although pharmacological and non‐pharmacological therapies can delay the progression of HF, the short‐ and long‐term mortality rates remain high.Candida, Campylobacter and Shigella species were proven to be positively correlated with the severity of disease. Compared with healthy controls, intestinal permeability (IP) increased for 78.3% of the patients with CHF. The gut was more permeable in patients with moderate and severe CHF than patients with mild CHF. Right atrial pressure was positively correlated with IP. In another animal experiment, the abundance of 10 types of faecal flora was changed in HF guinea pigs with pressure overload.Pasini et al compared the bacteria and fungi in the faeces of HF patients with those of healthy controls.Collectively, changes in the intestinal microflora exist in patients with HF. The aforementioned metabolite TMAO generated by the gut microbiota has a certain significance in HF patients. Two cohort studies, which enrolled hundreds of participants, demonstrated that elevated TMAO levels were predictive of the long‐term mortality risk in patients suffering from not only CHF,In addition to gut microbiota metabolites mentioned above, p‐cresyl sulfate (PCS) and phenylacetylglutamine (PAG) are involved in CVDs as well.4Recent studies have shown that intestinal microbiota is critically involved in cardiovascular health and diseases.4.1Broad‐spectrum antibiotics are commonly used in cardiovascular experiments targeting the gut microbiota. Galla et al administered three types of oral antibiotics  to Dahl salt‐sensitive (S) rats and spontaneously hypertensive rats (SHR) to investigate any changes in blood pressure. They found alterations in the intestinal microflora accompanied by increased systolic blood pressure in the S rats and decreased systolic blood pressure in the SHR after minocycline and vancomycin intervention, but not neomycin intervention.4.2Clostridium difficile infection,Faecal microbiota transplantation (FMT) is capable of contributing nutrients, inhibiting the growth of pathogenic bacteria and regulating the immune system of the host through transplanting functional bacteria from healthy individuals into the gastrointestinal tract of patients, thereby helping patients reconstruct the normal functions of the gut microbiota.4.3Lactobacillus, Bifidobacterium, Lactococcus, Streptococcus and Enterococcus.−/− mice different types of inulin (a kind of prebiotic) to observe the relationship between inulin and atherosclerosis. The results showed that atherosclerotic lesions decreased by 35% and 25% after long‐chain inulin intervention and oligofructose‐enriched inulin supplementation, respectively, compared with mice fed a control diet. A number of studies have shown that both probiotics and prebiotics have beneficial effects on lipid modulation,Proper supplementation with probiotics is able to interfere with the functions and composition of intestinal microflora, resulting in activation of the immune system and control of inflammation. Common probiotics include 4.4Several studies have examined the effects of diet on the gut flora and disease by administering mice a high‐salt diet (HSD).5Some research has been conducted on protecting cardiovascular system with chemicals that inhibit microbial metabolic processes. For example, 3, 3‐dimethyl‐1‐butanol, a non‐lethal inhibitor of TMA formation, reduced atherosclerotic lesions by decreasing the levels of TMAO that were converted from TMA in ApoE−/− mice.6Trillions of bacteria reside in the human gut, mainly divided into probiotics, neutral bacteria and pathogenic bacteria. Among them, the Firmicutes and Bacteroidetes families occupy the highest proportion and the F/B ratio is a vital parameter reflecting intestinal disorders. Factors such as lifestyle, drug application and intestinal environment disorders may contribute to gut dysbiosis, promoting the occurrence and development of CVD. Changes in the gut microbiota of individuals with coronary artery disease, hypertension and HF have been observed in both human and animal experiments, but the specific mechanisms are still under study Figure . ResearcBecause the gut microbiota is closely related to CVD, new ways to treat CVD based on the gut microbiota are emerging. For patients with CVD, reasonable adjustment of diet structure and optimization of diet composition are particularly important for maintaining physical health. Prebiotics can promote the growth of probiotics and inhibit the growth of pathogen. Supplement of prebiotics and/or probiotics may be effective and feasible in the treatment of CVD. FMT is limited mainly because it causes great changes in the intestinal microflora of the patients, and at the same time, it brings both beneficial and harmful bacteria to the patients, which may lead to adverse complications.In the future, more experiments will be conducted to investigate the correlation between the gut microbiota and CVD. The direction will focus on the exploration of intestinal bacteria directly related to the occurrence and development of CVD. The pathogenesis of intestinal flora and its metabolites is not fully understood and the relevant basic and clinical studies need to be further carried out. Some new microecological preparation can ameliorate CVD through improvement of gut microbiota,The authors declare that there are no conflicts of interest.


Kidney transplant patients suffer from vascular abnormalities and high cardiovascular event rates, despite initial improvements post-transplantation. The nature of the progression of vascular abnormalities in the longer term is unknown. This pilot study investigated changes in vascular abnormalities over time in stable kidney transplant patients long after transplantation.Brachial artery flow-mediated dilation (FMD), nitroglycerin-mediated dilation, carotid-femoral pulse wave velocity (cf-PWV), ankle-brachial pressure index, and common carotid artery intima-media thickness (CCA-IMT) were assessed in 18 kidney transplant patients and 17 controls at baseline and 3–6 months after.P = 0.19), body mass index , serum cholesterol , systolic blood pressure (BP) , diastolic BP , or diabetes status  between transplant patients and controls. No difference existed in vascular markers between patients and controls at baseline. In transplant patients, FMD decreased , cf-PWV increased , and CCA-IMT increased . No changes were observed in controls.There was no difference in age (51 ± 13 vs. 46 ± 11; Markers of vascular structure and function worsen in the post-transplant period on long-term follow-up, which may explain the continued high cardiovascular event rates in this population. Patients with chronic kidney disease (CKD) have a higher burden of cardiovascular disease (CVD), including kidney transplant recipients . AlthougEndothelial dysfunction, arterial stiffness, and accelerated atherosclerosis are common in stable kidney transplant patients and may contribute to the high cardiovascular event rate , 5, 6. EThe nature of the changes in these vascular abnormalities in kidney transplant recipients is unknown. Previous studies mostly examined changes in the vascular properties of transplant patients pre-transplantation and immediately post-transplantation. They were not examined in stable transplant recipients long after transplantation. If these changes are adverse, they may be the result of novel risk factors post-transplantation and may be a cause of the high cardiovascular event rate. This pilot study investigated the changes in endothelial dysfunction, arterial stiffness, and atherosclerosis in stable kidney transplant recipients long into the post-transplant period.2) and have been transplanted for ≥6 months with or without previous dialysis. Exclusion criteria included a history of malignancy, heart failure, vasculitis, lupus, myocardial infarction or cerebrovascular event within 6 months or recent hospitalisation within 3 months prior to starting the study. The study was approved by the London South East Research Ethics Committee. All participants gave informed consent prior to their inclusion in the study. Vascular parameters were measured in a quiet vascular laboratory with a controlled temperature of 22–24 °C at recruitment (baseline visit) and 3–6 months after recruitment (second visit). Figure Participants included patients recruited from the transplantation clinic, patient relatives, and staff volunteers. Patients were eligible if they were between 18 to 80 years of age with stable kidney function for ≥3 months  measurements were taken. Body mass index (BMI) and waist to hip ratio (WHR) were calculated.Brachial FMD, NMD, and CCA-IMT were performed as described in previous studies by our group . Cf-PWV Ankle-brachial pressure index (ABPI) was assessed with a continuous wave Doppler instrument (8–10 MHz). The ABPI of each leg was calculated by dividing the highest systolic BP in the desired leg between the measurement of the dorsalis pedis and posterior tibial artery divided by the highest systolic BP between the two arms. The mean ABPI value for each participant was derived from the average between the ABPI of the right and left leg.Blood and urine samples were collected for biochemical analysis at the South West London Pathology (SWLP) services. The internal quality assurance of the SWLP service is guaranteed by strict adherence to analytical protocols and a comprehensive internal quality control programme. The SWLP service subscribes to all national external quality assessment schemes for the tests they provide and their laboratories are also registered with the Clinical Pathology Accreditation of the United Kingdom Accreditation Service, which ensures that the services meet the stringent requirements expected from a pathology service. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation .pb) was used to determine correlations between binary and continuous variables. A two-sided P-value of < 0.05 was used to determine statistical significance. Analyses were performed using SPSS version 25.0 .Continuous variables were analysed with an independent samples t-test, categorical variables using a chi-squared test, and within-group comparisons using a paired t-test. Bivariate correlations between continuous variables were calculated using Pearson’s correlation coefficient (r). Point-Biserial correlation  before transplantation was 29 ± 14 months . The median time since transplantation at recruitment was 86 months with an IQR of 123 months. Transplant patients were taking up to 3 of 6 different immunosuppressants at recruitment. The immunosuppressants used were Tacrolimus (89%), Mycophenolate Mofetil (39%), Prednisolone (44%), Azathioprine (22%) and Sirolimus (6%). The aetiology of CKD in our transplant patients were the following: autosomal dominant polycystic kidney disease (4), IgA nephropathy (4), hypertension (2), pyelonephritis (1), focal segmental glomerulosclerosis (1), gout nephropathy (1), and type 2 diabetes mellitus (1). Four transplant patients had an unclear aetiology to their CKD.Table P = 0.03), while cf-PWV  and CCA-IMT increased  , cf-PWV , or CIMT . Changes in FMD was associated with baseline haemoglobin , corrected calcium , and transferrin . Changes in FMD were not associated with age , BMI , WHR , gender , DM , SBP , diastolic BP (DBP) , or smoking . Changes in FMD were not associated with any other lab values in Table P > 0.05). Changes in PWV was associated with baseline transferrin . Changes in cf-PWV were not associated with age , BMI , WHR , gender , DM , SBP , or DBP . Changes in cf-PWV were not associated with any other lab values in Table P > 0.05). Changes in CCA-IMT was associated with baseline phosphate . Changes in CCA-IMT were not associated with age , BMI , WHR , gender , DM , SBP , or DBP . Changes in CCA-IMT were not associated with any other lab values in Table P > 0.05).No significant correlation existed between the decline in eGFR and changes in FMD (This study shows the worsening of vascular structure and function in stable kidney transplant patients, where FMD decreased while cf-PWV and CCA-IMT increased. Change in eGFR was not associated with changes in FMD, CCA-IMT, or cf-PWV. Traditional risk factors including age, BMI, WHR, gender, DM, SBP, and DBP did not correlate with the changes seen. Baseline haemoglobin, corrected calcium, and transferrin was associated with changes in FMD. Baseline transferrin was associated with changes in cf-PWV while baseline phosphate was associated with changes in CCA-IMT.CKD patients exhibit endothelial dysfunction as measured by FMD , 5. In pCKD patients demonstrate accelerated atherosclerosis as evidenced by high CCA-IMT , 6. The Cf-PWV is a marker of arterial stiffness and predicts the appearance of CVD in CKD, including in transplant patients , 18, 19.Most studies evaluating changes in FMD, CCA-IMT, and cf-PWV in transplant patients do so in immediately post-transplanted subjects. Improvements or non-progression in these parameters shortly after transplantation does not exclude a reversal in recovery. Unlike these studies, our patients were recruited long into the post-transplant period at a median of 86 months post-transplantation. Different pathophysiological mechanisms exist in the development of endothelial dysfunction, accelerated atherosclerosis, and arterial stiffness. Successful kidney transplantation can eliminate important factors that contribute to the progression of these vascular aberrations. However, during long-term follow-up, cardiovascular risk factors often remain and some even worsen, which may explain the progression seen. Additionally, immunosuppression may prevent further improvement and eventual deterioration.2 to 85.8 ± 13.7 mL/min/1.73 m2 in patients from Yilmaz’ group [2 upon follow-up. Correlations between CCA-IMT and eGFR may only be seen with substantial changes in eGFR.Failure in graft function can explain the progression of endothelial dysfunction in the late post-transplant period. Elimination of ureamic milieu may be particularly important in the restoration of vascular structure and function immediately after transplantation. Interestingly, we found baseline corrected calcium to be associated with changes in FMD and baseline phosphate to be associated with changes in CCA-IMT. Studies have described progressively decreasing FMD with greater renal impairment , 5. Imprz’ group . WhereasIt is important to consider the role of immunosuppressants in enabling the progression seen. Calcineurin inhibitors increase endothelin levels and abrogate nitric oxide-induced vasodilation, making them potent vasoconstrictors , 30. AddAnother factor that warrants consideration is the dyslipidaemia seen in our transplant patients. Metabolic syndrome is a novel multiplex CVD risk factor that includes dyslipidaemia, central obesity, dysglycaemia, and hypertension. It is common in those with CKD, evidenced by reports of prevalence ranging from 30% in stage 3–4 CKD to 69% in incident haemodialysis patients , 32. OurAnaemia is common in CKD and its aetiology is multifactorial in nature. However, erythropoietin deficiency seems to be the major factor for explaining low haemoglobin in CKD patients. We found that baseline haemoglobin predicted change in FMD in our transplant patients, while baseline transferrin predicted change in FMD and cf-PWV. Indeed, previously it has been reported that haemoglobin is inversely related to FMD in CKD patients with or without diabetes , 35. In Ultimately, our study had a small sample size, hence it was difficult to reveal correlations between traditional and non-traditional risk factors with the changes observed, including uraemia, and aspects of metabolic syndrome.Our study demonstrates that progressive worsening in surrogate markers of vascular structure and function occur in the post-transplant period upon long-term follow-up. Although transplantation initially alleviates the cardiovascular burden, the vascular disease progresses in the long-term beyond the initial ‘honeymoon’ period. Since cardiovascular mortality is the commonest cause of mortality amongst transplant patients, the nephrology community has long sought for interventions that could improve the adverse cardiovascular picture in such patients. Thus, it is important to further characterise the nature of the changes in vascular abnormalities in kidney transplant recipients, which this pilot study achieves. The ultimate goal of this study is to determine the power needed to demonstrate a difference with an intervention on FMD, cf-PWV, and CCA-IMT in kidney transplant patients.


The detrimental effects of intracranial hypertension  are well documented , 2. HICPHICP has been classically defined as an ICP > 20 mmHg, and this threshold has been considered the trigger for treatment . Recent Figure Head-up positioning (15–30°),Hemodynamic stability aimed to maintain an appropriate cerebral perfusion pressure ,Sedation and analgesia  ,2 at 35 mmHg, and oxygen saturation ≥ 94%),Mechanical ventilation to prevent hypercapnia and hypoxia , I start Diclofenac infusion [Normothermia; if the temperature is > 37.5 infusion .Crystalloids as preferred maintenance fluids  to maintWhen I decide to administer ICP-lowering therapies, I use a “staircase” approach  with escIf HICP persists, I subsequently escalate to osmotic agents, mannitol (up to 0.5–1 g/kg every 4–6 h) or hypertonic saline . They have several transient mechanisms (lasting 4–6 h) mainly due to osmotic effects but also hemodilution, increased cardiac output and increased blood pressure. I prefer testing both of them (using an equimolar bolus) for evaluating their efficacy in the individual patient. Their efficacy is higher if started at an ICP > 25 mmHg .I generally reserve to patients with refractory intracranial hypertension ICP-lowering strategies associated with significant side effects and potential complications as hyperventilation, metabolic suppression and decompressive craniectomy , 12.2 ~ 30–32 mmHg, only in patients in whom ICP remains abnormally elevated despite first- and second-line treatments, considering adding for safety a brain oxygenation monitor. I use more aggressive hyperventilation only in life-threatening cases with the risk of cerebral herniation and death.Hyperventilation produces a reduction of HICP by inducing cerebral vasoconstriction and reducing cerebral blood volume . The effBarbiturates have been historically used for decreasing brain metabolism and consequently cerebral blood flow/volume and therefore HICP at the cost of serious side effects including hypotension and infections. I avoid long-term administration, and I generally administer thiopentone  as temporary “bridge” to decompressive craniectomy (DC) in refractory cases. I prefer, as third tier therapy, DC that has a long-lasting effect on the control of refractory HICP. DC performed without severe refractory HICP increases the rate of unfavourable neurologic outcome and should be avoided . On the In conclusion, my approach to ICP-lowering strategies has a stepwise fashion associated with a continuous check of the efficacy of the therapies. This will allow me to deescalate ICP-lowering strategies as soon as possible (ICP control > 24 h). Tapering therapies (as hyperventilation and osmotic) might produce a rebound effect, and it needs to be done slowly and under ICP monitoring.Alternatively, if the therapies are ineffective, I intensify treatments until the patients are judged salvable. When, in more severe unsalvageable cases, everything is ineffective and DC is not an option, a wise limitation of the therapies has to be evaluated.Additional file 1:Summary of the remediable causes of intracranial hypertension. (DOCX 15 kb)


NET) mentioned in the paper by Murugan et al. in a recent issue of Critical Care does not equate to the real UFNET in patients with renal replacement therapy initiation. Furthermore, the baseline blood pressure among the groups had a statistically significant difference. Both of these two factors may affect the final results. Thus, we should be cautious interpreting the conclusions.The concept of net ultrafiltration (UF Critical Care, Murugan and colleagues drew the conclusion that, among critically ill patients with ≥ 5% fluid overload, the patients with net ultrafiltration (UFNET) exceeding 25 ml/kg/day compared with those below 20 ml/kg/day had a lower 1-year risk-adjusted mortality [NET in their paper was calculated as the difference between the volume of ultrafiltration and substitution fluids. Furthermore, for patients receiving continuous venovenous hemodiafiltration and slow continuous ultrafiltration, UFNET corresponded to the volume removed. However, for patients on renal replacement therapy, spontaneous urine output (UO) and intravenous fluid via the peripheral vein (Fiv) should also be taken into account for the estimation of total UFNET. Thus, the total net ultrafiltration should be adjusted by UFNET + UO – Fiv. We believe that this adjustment achieves a more accurate parameter to reflect the hemodynamic status of patients in clinical practice.In a recent issue of NET intensity in all the patients receiving renal replacement therapy and the subset of patients receiving continuous renal replacement therapy (P < 0.001). It is well recognized that low blood pressure is a common complication during renal replacement therapy and is strongly associated with illness severity [NET intensity and mortality by categorized blood pressure levels to provide stronger evidence.In addition, as shown in their study, the imbalance was observed for the mean arterial pressure among three different levels of UFseverity . Low blo NET volume. However, we would like to clarify that the purpose of our study was to examine whether there was an independent association between the process of care variable, UFNET intensity, and risk-adjusted 1-year mortality. Thus, we specifically did not include the urine output and the intravenous fluids in the calculation of UFNET (exposure variable) as it would confound the assessment of the relative contribution of UFNET intensity on the outcome.We would like to thank Dr. Li and colleagues for their thoughtful letter regarding our article . They prIn our study, all intravenous fluids administered, as well as fluid losses including the urine output, were part of the input and output equation to calculate the severity of fluid overload before initiation of renal replacement therapy as well as the cumulative fluid balance during renal replacement therapy  and further research is required to determine the relative contribution of these variables on UFNET intensity and outcomes.Nevertheless, we would like to acknowledge that in clinical practice there are variety of factors that are likely to influence the clinical decision to determine the target UFNET intensity and outcomes. Although we could certainly perform a stratified analysis by mean arterial pressure, it would be difficult to fit models that account for continuous variation in blood pressure throughout the duration of renal replacement therapy and disentangle its association with UFNET intensity and the outcome.We completely agree with Dr. Li and colleagues that even though we adjusted for mean arterial pressure as well as the vasopressor dose in the models, we cannot exclude the possibility of residual confounding by hemodynamics on UF