Acute organophosphorus (OP) poisoning is one of the major causes of mortality among patients presenting to emergency departments in developing countries. Although various predictors of mortality among OP poisoning patients have been identified, the role of repeated measurements of vital signs in determining the risk of mortality is not yet clear.Therefore, the present study examined the relationship between trajectories of vital signs and mortality among OP poisoning patients using latent class growth analysis (LCGA).P-values of < 0.05 were considered statistically significant.This was a retrospective cohort study using data for 449 OP poisoning patients admitted to Civil-Hospital Karachi from Aug’10 to Sep’16. Demographic data and vital signs, including body temperature, blood pressure, heart rate, respiratory rate, and partial-oxygen pressure, were retrieved from medical records. The trajectories of vital signs were formed using LCGA, and these trajectories were applied as independent variables to determine the risk of mortality using Cox-proportional hazards models. n = 60). In trajectory analysis, a low-declining systolic blood pressure, high-declining heart rate trajectory, high-remitting respiratory rate trajectory and normal-remitting partial-oxygen pressure trajectory resulted in the greatest mortality, i.e. 38.9,40.0,50.0, and 60.0%, respectively, compared with other trajectories of the same parameters. Based on multivariable analysis, patients with low-declining systolic blood pressure were three times  more likely to die compared with those who had a normal-stable systolic blood pressure. Moreover, patients with a high-declining heart rate were three times  more likely to die compared with those who had a high-stable heart rate. Patients with a high-remitting respiratory rate were six times  more likely to die than those with a high-stable respiratory rate. Patients with normal-remitting partial oxygen pressure were five times  more likely to die compared with those who had a normal-stable partial-oxygen pressure.Data for 449 patients, with a mean age of 25.4 years (range 13–85 years), were included. Overall mortality was 13.4%(The trajectories of systolic blood pressure, heart rate, respiratory rate and partial-oxygen pressure were significantly associated with an increased risk of mortality among OP poisoning patients. Acute organophosphorus (OP) poisoning is a global public health challenge. Acute OP poisoning cases have high morbidity and mortality, constituting a challenge for hospital practitioners , 2. A sy2 for hypoventilation requiring intubation/ventilation. Vital signs play an important role in the diagnosis of intoxicated patients since they are the key components of toxic syndrome. However, their role in assessing the severity of poisoning and prognosis of these patients remains unclear  to die compared with those who had a normal-stable systolic blood pressure and those in the high-declining heart rate trajectory were three times  more likely to die compared with those who had a high-stable heart rate. Patients in a high-remitting respiratory rate trajectory were six times  more likely to die compared with those who had a high-stable respiratory rate. Patients in the normal-remitting partial oxygen pressure trajectory were five times  more likely to die compared with those who had a normal-stable partial oxygen pressure. (Table According to multivariable analysis after adjustment for age and elapsed time, patients with low-declining systolic blood pressure were three times more likely [HR: 3.0, 95% CI: 1.2–7.1, Among OP poisoning cases, older age and longer elapsed time since ingestion were significantly associated with mortality. Furthermore, individuals in the low-declining systolic blood pressure trajectory and high-declining heart rate trajectory had significantly higher mortality than those in the normal-stable systolic blood pressure trajectory and the high-stable heart trajectory. Similarly, patients in the high-remitting respiratory rate trajectory and those in the normal-remitting partial oxygen pressure trajectory had a nearly sixfold and fivefold increased risk of mortality, respectively, compared with those who were in the high-stable respiratory rate and normal-stable partial oxygen pressure categories. These findings suggest that routine clinical parameters, if observed repeatedly, might be useful clinical tools to identify high-risk groups of patients who might experience considerably high mortality. The mortality in our study is comparable to previously published papers on OP poisoning from different regions, including neighbouring countries , 40–42; 2 [Trajectory analysis showed low-declining systolic blood pressure and high-declining heart rate to be significantly associated with an increased risk of mortality among OP poisoning patients. The result for SBP was in contrast with multiple studies showing that it was not associated with mortality , 27, 42 2 , 50, 51,Vital status parameters and their relationship with mortality among OP poisoning patients were not entirely clear in previous studies , 42, 52.Commonly used scoring systems heavily depend on clinical and laboratory investigational information , 20–26 FThis study has several strengths and limitations, which should be considered when drawing any conclusions. This study was unique because multiple observations of vital status parameters in the first 36 h of admission into intensive care were made and its relationship with mortality among OP poisoning patients was determined. To the best of our knowledge, this is the first study to assess the relationship of vital status parameters with mortality using latent class growth analysis. The current study had a reasonable sample size by including data from several years from the intensive care unit of a tertiary care hospital, which provides generalizable results in our context.In terms of weaknesses, the amount of poison ingested was obtained from medical records, which might not have been correctly estimated by the clinicians. There is some evidence that suggests that the difference in the type of insecticide ingested can influence the outcome , 55 . AsLatent classes of systolic blood pressure, heart rate, respiratory rate and partial oxygen pressure were significant predictors of mortality among acute OP poisoning patients. Large-scale studies with the addition of biomarkers are needed to determine the clinical utility of these trajectories of vital status parameters in determining the prognosis of patients with acute OP poisoning.


Asthma patients experience impairments in health-related quality of life (HRQL). Interventions are available to improve HRQL. EQ-5D-5L is a common generic tool used to evaluate health interventions. However, there is debate over whether the use of this measure is adequate in asthma patients.We used data from 371 asthma patients participating in a pulmonary rehabilitation (PR) program from the EPRA randomized controlled trial. We used four time points: T0 randomization, T1 start PR, T2 end PR, T3 3 months follow-up. We calculated floor and ceiling effects, intra-class correlation (ICC), Cohen’s d, and regression analysis to measure the sensitivity to changes of EQ-5D-5 L ) and the disease-specific Asthma Quality of Life Questionnaire (AQLQ). Furthermore, we estimated the minimally important difference (MID). Based on the Asthma Control Test (ACT) scores, we defined three groups: 1. ACT-A (ACT> 19) controlled asthma, 2. ACT-B (14 < ACT≤19) not well-controlled asthma, and 3. ACT-C (ACT≤14) very poorly controlled asthma.Only the EQ-5D index showed ceiling effects at T2 and T3 (32%). ICC (between T0 and T1) was moderate or good for all measures. Cohen’s d at T2 and T3 was better at differentiating between ACT-A and ACT-B than between ACT-B and ACT-C. The EQ-5D index showed moderate effect sizes (0.63–0.75), while AQLQ showed large effect sizes . VAS was responsive to pronounced positive and negative ACT changes in every period, and AQLQ mostly to the positive changes, whereas the EQ-5D index was less responsive. We estimated a MID of 0.08 for the EQ-5D index, 12.3 for VAS, and 0.65 for AQLQ.All presented HRQL tools had good discriminatory power and good reliability. However, EQ-5D-5 L did not react very sensitively to small changes in asthma control. Therefore, we would suggest using supplementary measures in addition to EQ-5D-5 L to evaluate asthma-specific interventions more comprehensively.https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007740. The registration took place prospectively.German Clinical Trial Register, DRKS00007740 (date of registration: 05/15/2015),  Asthma is a respiratory disease characterized by chronic inflammation of the airways. Asthma patients experience cough, wheeze, and shortness of breath in varying intensity and frequency . This syTwo groups of HRQL assessment tools exist, disease-specific and generic ones. Disease-specific assessment tools are developed for specific diseases. They mainly focus on the impact of disease symptoms and the related consequences, but might also cover aspects of disease-associated impairments in social participation or emotional and general wellbeing. They enable comparisons between patients at different stages of the same disease and help to monitor disease development. In contrast, generic assessment tools can be applied across different diseases because they focus on impairments in general health-related aspects of life. Thus, comparisons between different disease areas or with the general population become possible. However, they might not always fully capture HRQL impairments in the context of disease-specific symptoms, especially in the early stages of a disease .One of the most commonly used generic assessment tools is the EQ-5D-5L from the EuroQol group , which iThere is debate over whether the use of the generic EQ-5D is adequate in asthma patients. Whalley et al. The three-level version has already raised some concerns, e.g., its inefficient ability to differentiate between different levels of asthma control  or that Therefore, our aim is to investigate whether the EQ-5D-5L is suited to measure HRQL in asthma patients in a longitudinal setting, whether it is reliable, and if it is responsive to changes in asthma control, compared with the established disease-specific Asthma Quality of Life Questionnaire (AQLQ). Furthermore, we aim to provide a MID value for the five-level version for asthma patients, which has not to our knowledge been provided in previous studies.We used data from the EPRA study, a randomized controlled trial (RCT) using a wait-list control group assessing the effectiveness of PR among asthma patients . After approval for rehabilitation (T0), patients were randomized to the intervention group (IG) or control group (CG). The IG started the 3-week PR 4 weeks after randomization , whereas the CG started PR 5 months after randomization (T3). Further details of the study have been published elsewhere . We asseWe assessed disease severity and HRQL using the following measures:The ACT is a self-administered questionnaire to evaluate asthma control . It contThe standardized version of the AQLQ is an asthma-specific HRQL assessment tool containing 32 questions in four domains  , 23. TheThe EQ-5D-5L is a generic HRQL measure from the EuroQol group , which eThe GROC is a rating scale with 15 categories assessing the self-reported change in global health. Patients with improvement and deterioration are symmetrically distributed around zero , 27, witAll analyses were performed with SAS , and p-values of 0.05 or less were considered statistically significant. We looked at floor and ceiling effects at every time point, defined as > 15% of the patients reaching the best/worst HRQL score . FurtherKnown-group validity (Cohen’s d) is used to evaluate the ability of the HRQL tools to differentiate between disease severity groups. Cohen’s d was assessed as the mean adjusted differences in HRQL scales between the ACT groups, divided by their pooled standard deviation at T2 or T3. We adjusted for group (IG/CG), age, sex, smoking status, body mass index (BMI), and employment status before PR (yes/no) to compensate for changes not originating from a change in ACT. Cohen’s d was considered small between 0.2 and 0.5, moderate from 0.5 to 0.8, and large above 0.8 .To estimate the reliability of the HRQL questionnaires, we evaluated ICC   between To estimate the responsiveness of HRQL scales associated with a change in ACT, we conducted different regression analyses for each HRQL scale. The dependent variable was the HRQL change score (ΔHRQL) in three periods . The independent variables were ACT change (ΔACT) in five categories  in the respective period, group (IG/CG), age, sex, BMI, smoking status, employed before PR (yes/no), and previous HRQL at T0, T1, or T2 respectively. ∆ACT = 0 was the reference group. The ACT categories are based on the approach of Sullivan et al. , who anaWe measured the GROC at T2 and T3 and considered a small GROC change as the minimal important change. We calculated the MID separately for improvement and deterioration, as well as combined using the absolute value of the changes. In analogy to Juniper et al. , who anaThe study sample included 371 patients: 199 (53.6%) were in the CG and 172 (46.4%) in the IG. The mean age was 51.4 years (SD: 5.6), and 58.5% of the population was male. Around 50% of the patients were current or previous smokers, and more than 80% were employed before the PR. Baseline HRQL did not differ in the groups, HRQL gains of the IG exceeded that of the CG regarding every measure. The whole development of the HRQL stratified by groups can be seen in Table None of the questionnaires used showed floor effects at any time point. Only the EQ-5D index showed ceiling effects at T2 and T3 with 55 (32%) patients each   and 0.78 CI ); VAS showed moderate ICC (0.62 CI [0.53: 0.70]).At T2, there were 185 (49.9%) patients in ACT-A, 72 (19.4%) in ACT-B, and 114 (30.7%) in ACT-C. At T3, there were 164 (44.2%) patients in ACT-A, 94 (25.3%) in ACT-B, and 113 (30.5%) in ACT-C. Adjusted mean scores for the ACT groups at T2 and T3 can be found in Fig. The overall responsiveness of a change in asthma control (measured in categories) of the HRQL tools was moderate. In most cases, AQLQ and VAS could differentiate between patients staying stable vs. patients reaching the |MID| on the ACT scale. The EQ-5D index was responsive to changes in only one period  Table ; howeverAccording to GROC at two time points, we identified (combining deterioration and improvement) mean MIDs in the pooled analysis of 0.67  for AQLQ, 12.28  for VAS, and 0.09  for the EQ-5D index  and different severity levels (ACT-A|ACT-B vs. ACT-B|ACT-C), but lower. Furthermore, AQLQ and VAS had a higher ability to differentiate between patients with asthma control or notand without asthma control (ACT-A vs. ACT-B) compared with differentiating between not well-controlled and very poorly controlled asthma (ACT-B vs. ACT-C). As the goal is to reach asthma control for most of the interventions, the differentiation between different degrees of uncontrolled not controlled asthma might be considered of secondary value. The results suggest that AQLQ, the EQ-5D index as well as VAS are all suited to detect patient groups with low HRQL and greater need for disease control, e.g., patients eligible for PR. Hernandez et al.  conducte and diffAn important aspect in health economics is the evaluation of health interventions. Therefore, HRQL tools should be reliable and responsive to changes to enable evidence-based recommendations regarding health care interventions. In a longitudinal approach, we assessed reliability (ICC) between T0 and T1, where none of the patients had yet received PR and their ACT score stayed stable. Reliability was moderate for VAS but good for the EQ-5D index and AQLQ. Without interventionA, asthma-related components of HRQL without intervention tend to be more stable than generic health, which might explain the observed higher reliability of the AQLQ. Additionally, AQLQ reflects a time period of 4 weeks, whereas EQ-5D-5 L asks for current health only, which increases the volatility of the measurements. Nevertheless, all instruments are suitable for repeated measurements.We assume that PR improves asthma control and clinical parameters and thus positively affects (at least disease-specific) HRQL. Therefore, in our pooled analysis, we had subgroups experiencing improvement (mostly in the IG) and patient groups staying relatively stable (mostly in the CG). This allowed us to examine HRQL changes in a heterogeneous study population. AQLQ was sensitive to big positive and negative changes (changes ≥|MID|). VAS was also able to differentiate between patients with deteriorating or improving HRQL by more than the MID-ACT, but not between small negative or positive changes. Given that the reference group for all HRQL tools is “no change”, a detection of changes below MID is very challenging because of the slight differences from the reference level. The EQ-5D index in our sample could not differentiate significantly between patients reaching a clinically relevant change on ACT (MID) or not, except for one case. This might be an issue regarding cost–utility studies using QALYs as the primary outcome, as suggested by the National Institute for Health and Care Excellence guidelines because, even if patients reach a clinically relevant increase in ACT (MID) through an intervention, it might be overlooked by the EQ-5D index. Thus, the intervention would not be considered cost effective. Looking at the quantile regression approach, a slightly different pattern emerged, where the EQ-5D index detects changes. However, we believe that the magnitude of the change on the EQ-5D index does not match the change on the ACT (e.g. at quantile 0.5 a MID change on ACT only changes the EQ-5D index by approximately 20% of its estimated MID), and leaves a significant improvement on the ACT undetected. Cost–utility studies should thus consider other secondary outcomes, which can potentially evaluate these changes. Similar results were reported from Sullivan et al. ; howeverUsing the GROC to identify the MID for the AQLQ resulted in a slightly higher MID than previous literature would suggest (0.65 vs. 0.5) . HoweverSzende et al.  used theAlthough the EQ-5D index showed slightly worse properties than the AQLQ, we should be aware of the different approaches behind the questionnaires. Generic questionnaires cover broad life aspects and facilitate comparisons among different disease groups, whereas disease-specific measures are for within-group comparisons. Furthermore, regarding the responsiveness of the tools to an ACT change is easier for the AQLQ, as it measures similar aspects and thus has overlapping content, whereas the EQ-5D index lacks asthma-specific content and can only indirectly measure such a construct , 38.There are some limitations to this study. As the EQ-5D assesses current health, whereas the AQLQ has a timeframe of 2 weeks and the ACT of 4 weeks, there is a potential bias while comparing these measures directly. Because asthma has a varying intensity, depending on the asthma attacks, valuing health on a single day may lead to distorted results.Additionally, there is a chance that HRQL tools behave differently in the control vs intervention CG vs. the IG, and a stratified analysis would be recommended. To achieve a sufficiently high n, we conducted a pooled analysis, but we think that our adjustment for the group variable best possibly accounted for this issue.The generalizability of the results is not necessarily given for patients outside Germany. Furthermore, patients with initially controlled asthma were not included in this analysis; therefore, we might miss important aspects about mild asthma cases. Nevertheless, the number of patients in this randomized controlled setting was high, and we believe our results are still valuable for the examined disease group.In conclusion, all presented HRQL tools had good discriminatory power and good reliability. However, EQ-5D-5L had difficulties in detecting  changes in disease control. Nevertheless, EQ-5D is still an important tool to compare HRQL across disease areas and to facilitate health economic evaluations, also in the field of asthma. Therefore to draw a more comprehensive picture, we would suggest using supplementary measures  to EQ-5D-5L to evaluate asthma-specific interventions. Nevertheless, it is still an important tool to compare HRQL across disease areas and to facilitate health economic evaluations.Additional file 1.


We investigated the commonly prescribed antihypertensive drugs and their association with blood pressure (BP) control in adult Cameroonians.we consecutively recruited hypertensive outpatients attending the Buea and Limbe Regional Hospitals (southwest region of Cameroon). Controlled BP was defined as BP < 140/90mmHg in hypertensive patients aged 60 years or younger, diabetics or patients with chronic kidney disease or a BP < 150/90mmHg in non-diabetic hypertensive patients older than 60 years of age (JNC8).of the 408 participants included (mean age 61.1 years), 67% were female. The median duration of hypertension was 6 years and the median duration of the current treatment was 22 weeks. Commonly prescribed antihypertensives were calcium channel blockers , thiazide/thiazide-like diuretics  and angiotensin-converting enzyme inhibitors . The median monthly cost of antihypertensive was 10279.6 CFA . Seventy percent (70%) of participants were receiving at least 2 drugs, with ACEI+TD/TLD, CCB+TD/TLD, and ACEI+CCB+TD/TLD being the most frequent combination. The rate of BP control was 52% overall, and 60% in participants on monotherapy.CCBs were the most prescribed single antihypertensive drugs in this setting while ACEI+TD/TLD was the most common combination. About half of patients were at target BP control levels Improving availability and affordability of these medications may improve hypertension management and control. Hypertension is a major global public health problem  and the Worldwide, treatment strategies have changed and gradually moved from monotherapy to low dose combination therapy . Recent Study design, setting, and sampling: we conducted a hospital-based cross-sectional study, with data collected over a period of four months (January-April 2018) at two secondary referral hospitals of the Southwest Region (SWR) of Cameroon . The Buea Regional Hospital (BRH) has a catchment population of over 200,000 inhabitants 2.was used . InformaDefinitions: hypertension diagnosis was retained when a participant reported having been on BP-lowering medications over the last 15 consecutive days or an elevated BP value with systolic blood pressure (SBP) ≥140mmHg and/or diastolic blood pressure (DBP) ≥90mmHg obtained from 3 different consultations, documented in the participant´s medical records. The severity of hypertension was defined as SBP of 140-159mmHg or a DBP 90-99mmHg for stage 1 and SBP ≥160mmHg or diastolic blood pressure (DBP) ≥100mmHg for stage 2 JNC 7 [ 2 JNC 7 . MonotheData analysis: categorical variables are expressed as frequencies and percentages while quantitative variables are expressed as mean and standard deviation for normally distributed variables and median and 25th-75th percentiles for skewed variables. The chi-square and Fischer exact test were used to compare categorical variables as appropriate in the univariate analysis. Variables that were statistically significant in the univariate model were used for analysis in the multivariate analysis. Logistic regressions adjusted for age, gender and center were used to determine the significant predictors of prescription of antihypertensive medications and BP control. For the prescription of antihypertensive medications, the predictor variables were; the age, duration of hypertension, duration of practice, the severity of hypertension, average monthly income, prescriber, presence of comorbidities and the dependent variable was the different treatment regimen. When assessing factors that influence BP control, predictor variables were; age, gender, marital status, occupation, physical activity, smoking, BMI and treatment regimen while the dependent variable was the level of BP control. All statistical analyses were performed using SPSS version 23 IBM and p-value ≤0.05 was taken to indicate significance.Ethical consideration: ethical clearance was obtained from the Institutional Review Board of the Faculty of Health Sciences, the University of Buea and the study conformed to the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from each eligible participant before inclusion.General characteristic of the study population: a total of 408 participants were included in the study  of participants paid for their drugs from out of pocket money while only 4 (1.0%) benefitted from insurance coverage. In all, 93.1% of patients were prescribed a once-daily drug regimen. Of the 408 prescriptions, 44% were bitherapy, 31% monotherapy and 26% contained three or more drugs  were the most prescribed antihypertensive in 35.1% of the participants either as single or combination therapy with the most frequent molecule been amlodipine (30.5%). Thiazide/thiazide-like diuretic (TD/TLD) in 26.1% was the second most prescribed therapeutic class, with the most frequently used molecule being hydrochlorothiazide ; while angiotensin-converting enzyme inhibitors (ACEI) in 19.5% was the third leading class, with the most frequently used molecule been perindopril (7.0%); . Among pBlood pressure control: in all, 211 (51.7%) participants had a controlled level of BP; with no gender difference in proportions of controlled hypertension (50% in men Vs 52.6% in women p=0.70). By treatment regimens, the proportion of controlled hypertension was 60% for monotherapy, 50.3% for bitherapy, 48.3% for tritherapy and 23.5% for quadritherapy (p=0.024). The control rate was higher in participants aged ≥60 years than in those aged <60 years , and varied by BMI status (p=0.046). In age, sex and center adjusted logistic regression, BMI <25 , been on monotherapy  and Bitherapy  were significant predictors of BP control.et al. in a study in urban Cameroon in 2016 [et al. and Busari et al. in Nigeria who found that diuretics were the commonly prescribed antihypertensive medications [Our study revealed that, calcium channel blockers (CCB) were the most commonly prescribed antihypertensive in a third of participants, followed by thiazide/thiazide-like diuretic (TD/TLD) and angiotensin-converting enzyme inhibitor (ACEI). About two-thirds of participants were on combination therapy, with the severity of hypertension and duration of hypertension being the predictor of prescription. About half of treated patients were at target BP control level with the age of patients, BMI and treatment regimen being important correlates of BP control. The patterns of prescription in our study were similar to those found by Menanga  in 2016 . They ar in 2016 . Howeverications , 27. Thiications .et al. in Nigeria (79%) [et al. in Ethiopia (50%). A higher proportion of participants in our study had comorbidities just like participants in Adedapo et al. study (77% and 88% respectively) whereas only 28% of participants in Menanga et al. study had associated comorbidities [et al. in Cameroon and Adejumo et al. in Nigeria and are both in accordance with the JNC 8 guidelines [The percentage of participants on combination therapy (70%) was similar to that reported by Adedapo ia (79%)  but highbidities . The JNCbidities . Studiesbidities . The mosidelines , 25, 26.et al. (37.4%) [In our setting, the only available fixed drug combination as tritherapy was either ACEI+CCB+TD/TLD or ARB+CCB+TD/TLD which was relatively expensive when compared to a similar combination containing separate pills. Controlling hypertension is very challenging in SSA with only 7% of people with hypertension having their BP below targeted values . In a pr (37.4%) . This coet al. [et al. in Ethiopia [et al. (64%) but however much higher than that obtained by Busari et al. who (34%) [et al. Most studies have shown that patients will require 2 or more antihypertensive to achieve BP control [However, the control rate of participants was much similar to that of Adejumo et al.  in NigerEthiopia . PreviouEthiopia -37. The Ethiopia . Up to 6ho (34%) , 27. The control -41.Study limitations: blood pressure control was assessed using office BP reading which may tend to underestimate the BP control rate. Also, this study was a hospital-based study done in a secondary care setting, so may not reflect the situation in the primary health care setting. Adherence to antihypertensive medication wasn´t assessed in this study.Contemporary antihypertensive prescription patterns in our study were dominated by CCB, diuretics and ACEI with 7 of every 10 patients receiving at least 2 drugs. Half of the patients had their BP controlled which is still below optimal but far better than previous reports. The need to intensify all efforts geared towards BP control to reduce the morbidity, mortality and cost burden associated with hypertension cannot be overemphasized. As such, providing clinicians with simple, clear and concise local hypertension guidelines with peculiarities on first-line medications and combination pharmacotherapy is critical. Also, health policymakers need to improve the availability and affordability of required medications so as to design more effective interventions that improve hypertension control and management.Uncontrolled hypertension is a major health issue in sub-Saharan Africa with only 7% of hypertensive patients on treatment have their BP under control;Prescription of antihypertensive drugs prevents adverse complications of hypertension such as stroke, myocardial infarction and heart failure;Several international guidelines recommend a combination of 2 or more drugs from different classes in order to achieve optimal BP control with little or no place for monotherapy.There is the absence of local guidelines to treat hypertension in several African countries and furthermore, little was known on the prescription of pharmacotherapy and its effectiveness on BP control among hypertensive blacks leaving in SSA; in our study, CCBs were the most prescribed single antihypertensive drugs;Monotherapy was effective in controlling BP in over 60% of our patients with uncomplicated and non-severe hypertension. Hence there is still a place for a single-drug regimen in controlling uncomplicated hypertension; clinicians in our setting tend to prescribe more combination therapy as recommended by most contemporary guidelines, especially in the presence of comorbidities;Although 70% of patients were treated with a combination of 2 or more drugs, BP control of hypertension could be achieved in only 50% of our participants; this study emphasizes the need for early detection, treatment and control of hypertension using combination therapy. Providing clinicians with local guidelines to support their practice in a bit to help reduce the burden of uncontrolled hypertension.


The median disease duration was 14 (IQR 5–18) years. Heart rate increased, and stroke volume index and end-tidal CO2 decreased significantly during the test (p ranging from <0.001 to <0.0001). The cardiac index decreased by 26(7)%: p < 0.0001. CBF decreased from 617(72) to 452(63) mL/min, a 27(5)% decline. All 19 severely affected ME/CFS patients met the criteria for an abnormal CBF reduction. Conclusions: Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS.Introduction: In a study of 429 adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), we demonstrated that 86% had symptoms of orthostatic intolerance in daily life. Using extracranial Doppler measurements of the internal carotid and vertebral arteries during a 30-min head-up tilt to 70 degrees, 90% had an abnormal reduction in cerebral blood flow (CBF). A standard head-up tilt test of this duration might not be tolerated by the most severely affected bed-ridden ME/CFS patients. This study examined whether a shorter 15-min test at a lower 20 degree tilt angle would be sufficient to provoke reductions in cerebral blood flow in severe ME/CFS patients. Methods and results: Nineteen severe ME/CFS patients with orthostatic intolerance complaints in daily life were studied: 18 females. The mean (SD) age was 35(14) years, body surface area (BSA) was 1.8(0.2) m Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients have a high prevalence of orthostatic intolerance ,2. In a Documenting an abnormal cerebral blood flow is helpful in guiding therapy for orthostatic intolerance (OI). As described in the IOM report: “Orthostatic intolerance is defined as a clinical condition in which symptoms worsen upon assuming and maintaining upright posture and are ameliorated  by recumbency” . SymptomA limitation of the extracranial Doppler measurements is that image acquisition lasts between 2 and 7 min . Due to Assuming that severe ME/CFS patients cannot tolerate prolonged standing during tilt testing and may have more hemodynamic abnormalities including a rapid decline of blood pressure, the aim of the current study was to test the hypothesis that reduced cerebral blood flow and reduced stroke volume index/cardiac index could also be confirmed in severe ME/CFS patients during 15 min of low-grade (20 degree) head-up tilt testing.From June 2019 to April 2020, 139 patients visited the outpatient clinic of the Stichting CardioZorg, Hoofddorp, the Netherlands, because of a suspicion of ME/CFS. This cardiology clinic specializes in diagnosing and treating adults with ME/CFS. All patients were evaluated by the same clinician (FVC). During the first visit, it was determined whether patients satisfied the criteria for CFS and ME, taking the exclusion criteria into account. Patients were classified as having CFS, chronic fatigue or no chronic fatigue as defined by Fukuda and colleagues  and as h2 (PetCO2) was monitored using a Lifesense device .Measurements were performed as described previously , with thInternal carotid artery and vertebral artery Doppler flow velocity frames were acquired by one operator (FCV), using a Vivid-I system  equipped with a 6–13 MHz linear transducer. Flow data of the internal carotid artery (ICA) on the right and on the left side were obtained ~1.0–1.5 cm distal to the carotid bifurcation and of the vertebral artery (VA) on the right and on the left side, data were obtained at the C3–C5 level. Care was taken to ensure the insonation angle was less than 60 degrees, that the sample volume was positioned in the center of the vessel and that it covered the width of the vessel. High-resolution B mode images, color Doppler images and the Doppler velocity spectrum (pulsed wave mode) were recorded in one frame. The order of imaging was fixed: left internal carotid artery (ICA), left vertebral artery (VA), right internal carotid artery (ICA) and right vertebral artery (VA). At least two consecutive series of six frames per artery were recorded. The recording time intervals of the first and last imaged artery were noted and these times were corrected to the times of a radio clock, setting the start of tilt at 0 min. Heart rate and blood pressures of the echo recording time intervals were averaged. In the supine position, image acquisition started 8 2) min prior to tilting (supine data) and during the upright position acquisition started at 10 (4) min. Based on data from healthy controls during a 30-min 70 degree head-up tilt, we defined an abnormal reduction in CBF as a >13% decline during the tilt compared to the supine values [ min prioTo determine stroke volume, velocity time integral (VTI) frames were obtained in the resting supine position and the upright position as previously described . The aorThe changes in heart rate and blood pressure during the head-up tilt test were classified according to the consensus statements ,6: normaBlood flows of the internal carotid and vertebral arteries were calculated offline by an investigator (CMCvC) who was unaware of the patient severity status and unaware of the hemodynamic outcome of the head-up tilt test. Vessel diameters were manually traced by CMCvC on B-mode images, from the intima to the opposite intima. Surface area was calculated: the peak systolic and end diastolic diameters were measured, and the mean diameter was calculated as: mean diameter = (peak systolic diameter × 1/3) + (end diastolic diameter × 2/3) . Blood f2). SVIs of the separate cycles were averaged. Cardiac index was calculated by the equation: SVI × heart rate/1000 (L/min/m2).To determine stroke volumes, the velocity time integral was measured offline by manual tracing of at least 6 cardiac cycles, using the GE EchoPac post-processing software, by one operator (CMCvC). Stroke volumes were calculated from the corrected VTI and the LVOT cross-sectional area, as described previously ,13. Strot-tests were used for comparison, when appropriate. Linear regression analysis was performed correlating the percent cardiac index change with the percent cerebral blood flow change. A p value of <0.05 was considered significant.Data were analyzed using Graphpad Prism version 6.05 . All continuous data were tested for normal distribution using the D’Agostino–Pearson omnibus normality test, and presented as mean (SD) or as median with the IQR, where appropriate. For continuous data, paired and non-paired 2 and BMI 24.0 (5.4) kg/m2. The median disease duration was 14 (IQR 5–18) years. All patients met the Fukuda criteria for CFS, and all met the ICC criteria for ME. Daily life orthostatic intolerance symptoms were reported by all 19 ME/CFS patients. At the time of the test, no patients were being treated with drugs influencing heart rate or blood pressure and none were being treated with selective serotonin reuptake inhibitors (SSRI). Of the 19 ME/CFS patients, four met the criteria for POTS at 20 degrees. None of the patients developed orthostatic hypotension or vasovagal syncope at 20 degrees.Nineteen patients with a severe grade of ME/CFS were studied . Baseline characteristics were as follows: mean age 35 (14) years, height 171 (4) cm, weight 70 (17) kg, BSA 1.8 (0.2) mp < 0.0001), and end-tidal CO2 decreased from 38 (3) to 29 (6) mmHg (p < 0.001). Cerebral blood flow supine was 619 (68) mL and at the end of study was 453 (63) mL, a decline of 27 (5)%, with a decrease ranging between 21% and 37%. All 19 patients met criteria for an abnormal reduction in cerebral blood flow, being a more than 13% reduction. Stroke volume index decreased from 36 (6) to 25 (5) mL/m2, a decline of 31 (8)%. Cardiac index fell from 2.9 (0.5) to 2.1 (0.4) L/min/m2, a decline of 27 (7%).p < 0.0001). p < 0.0001). p < 0.005).p < 0.05). All other data were not significantly different between the two groups. The main finding of this exploratory study is that in severe ME/CFS patients, a significant reduction in cerebral blood flow can be provoked during a brief 20 degree head-up tilt test. The combination of low-grade head-up tilt testing and extracranial Doppler echography has not been described before. The 27% reduction in cerebral blood flow after 15 min compares to the 26% reduction observed after 30 min of 70 degree head-up tilt in a less severely affected population of ME/CFS patients [A previous study with 20 degree head-up tilt testing for 15 min in adolescent CFS patients showed a significantly higher heart rate and lower stroke volume index early after tilting (0.5–2.5 min after onset of tilt) in CFS patients compared with controls . The preIt is generally assumed that part of the OI symptomatology is related to cerebral hypoperfusion ,5,15,16.Several points about the study findings deserve emphasis. First, in our earlier study using a 70 degree tilt test, the decrease in stroke volume index was 31% at 15 min post tilt with no differences between mild, moderately and severely affected ME/CFS patients . The str2 values were lower in CFS patients compared with controls, at all tilt angles. Previous studies have shown that hypocapnia can reduce intracranial vessel diameters, thereby altering the relation between flow velocity changes and hemodynamic changes [2-related vasoconstriction of the middle cerebral artery in CFS patients. Vasoconstriction leads to increases in cerebral flow velocities, resulting in non-significant differences in the TCD measurement between CFS patients and controls. The more direct measurement using extracranial Doppler identifies the global reduction in CBF that can be missed with transcranial Doppler. The similarity of cerebral blood flow reduction in the present study and our previous study despite the lower degree of orthostatic stress and the shorter tilt is most likely related to the more severe disease status of patients in the present study [Second, in a previous study, we found that cerebral blood flow reduction was 26% during a 70 degree tilt test . However changes ,39,40. TThird, as seen in our previous study and other recent studies using transcranial Doppler, we again demonstrated that an orthostatic intolerance/abnormal cerebral blood flow reduction may be present without heart rate and blood pressure abnormalities ,34,35,362 reductions also support the observation that 20 degrees is sufficient to provoke similar cerebral blood flow changes in severe ME/CFS patients compared with a less severely diseased group of ME/CFS. When hypocapnia is observed, a focus on respiration depth and speed has the potential to be one of the therapeutic guidance options for these patients to lessen orthostatic intolerance complaints. Another possible factor besides vasculature, autonomic nervous system and end-tidal CO2 might be altered blood cell behavior, especially red blood cell [Fourth, the data of this study extend the observation that hypocapnia is significant in ME/CFS patients and is a likely contributor to reductions in cerebral blood flow ,34,41. Tood cell ,43.2 in the present study will need to be determined in future and larger studies.Fifth, in a previous review on the relation between acute cardiac output changes and cerebral blood flow changes, Meng et al. found in healthy volunteers that a 30% reduction in cardiac output resulted in a 10% reduction in cerebral blood flow . In the Finally, even during a brief 20 degree tilt, four (21%) patients developed POTS. This has not been described before and might be a reflection of the severity of the disease. It also implies that the diagnosis of POTS cannot be dismissed when patients have complaints suggestive of POTS in non-standing positions like sitting or lying down with a slight head-up position.Patients are advised to lie down when they experience orthostatic intolerance complaints. Our findings of a clinically significant cerebral blood flow reduction at just 20 degrees suggest that a slight head-up position may not be adequate enough to resolve symptoms of orthostatic intolerance in some patients. Furthermore, the European Society of Cardiology syncope guidelines and other papers advocate the use of a nocturnal head-up position of more than 10 degrees to prevent nocturnal polyuria and the consequent circulatory underfilling ,46,47,48This study only included ME/CFS patients who were bedbound, and we caution that the 20 degree head-up tilt angle needs further study before it can replace longer 70 degree tilt angles for assessing less severely impaired ME/CFS patients. Comparisons of the hemodynamic and cerebral blood flow abnormalities of 20 and 70 degrees of tilting are needed. We also did not include healthy controls for comparison. It is possible that healthy controls would have little or no perturbation in response to a 20 degree head-up angle, which would have the effect of widening the physiologic differences between ME/CFS patients and controls. Whether disease severity differences lead to differences in cerebral blood flow reduction needs to be studied in the future. Finally, while it is reasonable to expect that the 20 degree abbreviated tilt test would be less taxing than a longer 70 degree tilt test, and therefore less likely to provoke post-exertional malaise, this hypothesis remains to be tested.2, stroke volume and cardiac index.This study demonstrates that a short 15-min tilt using a mild 20 degree head-up angle is sufficient to provoke a clinically significant reduction in cerebral blood flow in patients with severe ME/CFS. This method of orthostatic testing has the potential to improve the assessment of the prevalence of orthostatic intolerance in severely affected ME/CFS patients who are reluctant to undergo a 70 degree tilt. In this patient population, a milder orthostatic stress was able to confirm the following: cerebral blood flow abnormalities in the absence of heart rate and blood pressure abnormalities; POTS is a small subset; and associated reductions in end-tidal CO


Patients with adrenal insufficiency (AI) have excess mortality and morbidity, mainly due to cardiovascular (CV) diseases. The mechanisms for this is unclear.To assess CV structure and function in AI patients on conventional replacement therapy and after switching to once-daily, modified-release hydrocortisone (OD-HC) in comparison with healthy matched controls.This was a retrospective analysis of 17 adult AI patients  on stable replacement with cortisone acetate [median  33.5 (12.5–50) mg] and, if needed, fludrocortisone [0.1 (0.05–0.2) mg], and 17 healthy matched controls. Ten patients were switched to an equivalent dose of OD-HC. Data from echocardiography, 24 h Holter-ECG and 24 h blood pressure monitoring were collected at baseline and 6 months after the switch to OD-HC.P = 0.001) and left atrial diameter , and a higher ejection fraction  than controls. AI patients had lower nocturnal systolic and diastolic blood pressure than controls . After the switch to OD-HC, nocturnal diastolic blood pressure normalised. No significant changes were observed in echocardiographic and Holter-ECG parameters following the switch.At baseline, AI patients had smaller left ventricular diastolic diameter (47.1 ± 4.2 vs. 51.6 ± 2.3 mm; AI patients on conventional treatment display cardiovascular abnormalities that could be related to hypovolemia. Switch to OD-HC seems to have beneficial effect on blood pressure profile, but no effect on cardiovascular structure and function. Adrenal insufficiency (AI) is a life-threatening disease characterised by impaired secretion of glucocorticoids (GC), with or without mineralocorticoid (MC) deficiency . The mosLong-term outcome in patients with AI was for a long time considered to be similar to that of the general population , 6. HoweIncreased CV morbidity and mortality in patients with AI have been traditionally related to higher cortisol exposure and a GC replacement therapy that fails to mimic the physiological diurnal variation in serum cortisol. Inadequate GC replacement has been associated to adverse lipid profile, increased body weight and diabetes mellitus , 12–14. It is well known that CG and MC receptors are widely expressed in the circulatory system. However, the effects of either adrenal steroid deficiency (e.g. from disease onset until diagnosis and/or under-treatment during stress-related situation) or cortisol overexposure on CV system have not been fully elucidated. In addition, no study has so far investigated whether switching to the novel replacement treatment with once daily modified-release hydrocortisone (OD-HC) may affect structure and function of the CV system.In this case-control study, we aimed to assess echocardiographic and hemodynamic parameters in patients with AI on stable conventional GC replacement therapy. The secondary aim was to investigate the impact of a switch from conventional GC replacement to OD-HC on the CV system.This was a retrospective analysis on data collected from patients with primary and secondary AI followed at the Endocrinology Unit at University of Campania “Luigi Vanvitelli” in Naples between January 28, 2015 and July 28, 2016. Fifty patients with AI were screened and 17  were included in the study ; 4. Active malignancies; 5. Pregnancy; 6. Any other disease requiring medical therapy with GCs. Seventeen healthy subjects among hospital employees, matched for age, gender, smoking habits and body mass index (BMI) served as controls. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Second University of Naples.Anthropometric variables including weight, height, arterial blood pressure and heart rate (HR) were collected from a baseline visit for all patients and controls. In addition, data on echocardiography, 24 h Holter recording (Holter-ECG), and 24 h ambulatory blood pressure monitoring (BPM) were collected from a baseline visit in both groups. Out of 17 patients with AI, 10 (7 patients with primary and 3 with secondary AI) switched to an equivalent dose of OD-HC .Transthoracic echocardiograms were performed with a two dimensional transthoracic echocardiography , phased-array transducers at frequencies of 7–12 MHz and analysed for surrogate markers of CV disease, including left atrial diameter (LAD), interventricular septum thickness at diastole (IVSTDd), left ventricle end-diastolic diameter (LVEDd), and left ventricular ejection fraction (LVEF). The presence of valvular disease was assessed according to recommendations of the American Society of Echocardiography .A 24 h Holter-ECG recording was performed with an Evo device . During this examination, the patients followed their usual daily routines and activities. The following parameters were recorded in both groups: mean daily and nocturnal HR [HR day and HR night], presence of supraventricular tachycardia (SVT), ventricular premature complexes (VPCs), and presence of ventricular tachycardia (VT).The blood pressure was monitored using an ambulatory BPM provided by Omron Electronics S.p.A. (Sphygmomanometer Bracelet Intelli Wrap M-L Hem-FL31-E). In this study, 8:00–23:00 was set as daytime, and 23:00–8:00 was set as night-time. The blood pressure was monitored once every 30 min during the day and night for at least 23 h and interpreted according to authoritative literature . The meat-tests for normally distributed data and the Mann–Whitney U test for non-parametric data. Comparisons between related samples were performed with the Wilcoxon Signed Rank test. All tests were two-tailed and P values < 0.05 were considered statistically significant.Data are presented as means and standard deviations (±SD), median (range), numbers and percentages. Statistical analyses were performed with SPSS 25.0 statistical software packages . Comparisons between groups were performed with unpaired Sample size was assessed based on a previous case-control study that analysed echocardiographic characteristics in seven patients with primary AI, before and after GC replacement treatment, and ten healthy controls . To our P = 0.727)  and 17 matched healthy controls were included in the study. Clinical and demographic characteristics of the study population are presented in Table P = 0.039) whereas no differences were observed in triglyceride levels. Electrolyte levels as well as fasting plasma glucose did not differ between the groups  as well as smaller LAD  compared with healthy subjects  and secondary AI (n = 6), median LVEDd was 45.9 (42.1–53.0) mm vs. 49.8 (43.3–56.0) mm and LAD was 34.0 (30.0–37.0) mm vs. 38.0 (23.0–44.0) mm, respectively (Table P = 0.003) (Table n = 11) were compared to a sub-group of matched controls (n = 11), same findings were recorded , and the mean diastolic blood pressure (MAP-D night) was 65 ± 9 vs. 73 ± 7 mmHg (P = 0.008). Conversely, no difference was recorded in mean blood pressure during daytime (Table n = 11) was compared to controls, a significantly lower mean diurnal systolic blood pressure was recorded (Supplementary Table n = 11) and secondary AI (n = 6) are shown in Table A significantly lower nocturnal blood pressure was found in AI patients compared with controls Table ; Fig. 2bHolter-ECG analyses displayed similar HR in patients and controls, as was the number of VPCs. Two patients and two controls presented with asymptomatic SVT whereas no episode of VT was recorded Table .P = 0.028], reaching a similar level to the healthy controls  were switched to an equivalent dose of OD-HC. After a 6-month period on stable treatment, total and LDL-cholesterol decreased whereas fasting plasma glucose was unaffected Table . An incrls Table ; Fig. 3.In the present study, echocardiographic abnormalities were recorded in patients with AI on replacement therapy with cortisone acetate twice or thrice daily compared with matched healthy controls. Despite both groups exhibited left ventricular function and architecture in the normal range, patients with AI displayed a smaller LVEDd as well as LAD than healthy subjects, suggesting a status of hypovolemia.Patients with AI usually present with dehydration and hypovolemia at diagnosis. Hypotension as well as a loss of circadian variation in blood pressure has also been described , 23. To Cardiac abnormalities, characterised by small left ventricular chamber size and high prevalence of mitral valve prolapse, were recorded in seven patients with primary AI at diagnosis, and normalised after 4–8 months of adequate replacement therapy . SomewhaPublished data on myocardial function in patients with AI are scanty and somewhat controversial, showing a left ventricular dysfunction in some studies but not in others –26. ReduAccording to several pre-clinical and clinical studies, cardiac ultrasound has an important role in the assessment of fluid status by providing information on ventricular diastolic and systolic function and loading condition , 31. ShoHypovolemia and hypotension are tightly related. Indeed, several evidences have showed that reduction of extracellular fluid in the body results in decreased mean arterial pressure –35. In oThe role of GC deficiency on cardiac electrical activity has not been fully elucidated. Preclinical studies in primary AI models have suggested that GC signalling plays an important role in the regulation of left ventricular function, whereas MC signalling has a preponderant effect in the modulation of cardiac electrical activity . InteresTo our knowledge, this is the first study to analyse CV structure and function in patients with AI on conventional replacement therapy and after switching to OD-HC. After a 6-month period on stable treatment with OD-HC, lipid profile improved and diastolic nocturnal blood pressure increased to a similar level seen in healthy controls Table ; Fig. 3.The main strengths of this study rely in the strict inclusion and exclusion criteria used to select the study population. However, its limitations are the relative short follow-up period (6 months after the switch to OD-HC) and the heterogeneity of the study group, including patients with both primary and secondary AI. Finally, a selection bias should be considered due to the limited number of subjects included.In conclusion, our study shows echocardiographic signs of mild dehydration and a reduced nocturnal blood pressure in patients with AI on conventional therapy. These findings may suggest that hypovolemic status, typical of patients with AI at diagnosis, is not resolved by conventional GC replacement treatment. The switch to OD-HC seems to have a beneficial effect on blood pressure profile, but no effect on cardiac structure and function.Supplementary Table 1


Despite advances in acute management and prevention of cerebrovascular disease, stroke and vascular cognitive impairment together remain the world’s leading cause of death and neurological disability. Hypertension and its consequences are associated with over 50% of ischaemic and 70% of haemorrhagic strokes but despite good control of blood pressure there remains a 10% risk of recurrent cerebrovascular events and there is no proven strategy to prevent vascular cognitive impairment.Hypertension evolves over the life-span, from predominant sympathetically-driven hypertension with elevated mean blood pressure (BP) in early and mid-life to a late-life phenotype of increasing systolic and falling diastolic pressures, associated with increased arterial stiffness and aortic pulsatility. This pattern may partially explain both the increasing incidence of stroke in younger adults as well as late-onset, chronic cerebrovascular injury associated with concurrent systolic hypertension and historic midlife diastolic hypertension. With increasing arterial stiffness and autonomic dysfunction, blood pressure variability increases, independently predicting the risk of ischaemic and intracerebral haemorrhage, and is potentially modifiable beyond control of mean blood pressure.However, the interaction between hypertension and control of cerebral blood flow remains poorly understood. Cerebral small vessel disease is associated with increased pulsatility in large cerebral vessels and reduced reactivity to carbon dioxide, both of which are being targeted in early-phase clinical trials. Cerebral arterial pulsatility is mainly dependent upon increased transmission of aortic pulsatility via stiff vessels to the brain whilst cerebrovascular reactivity reflects endothelial dysfunction. In contrast, although cerebral autoregulation is critical to adapt cerebral tone to blood pressure fluctuations to maintain cerebral blood flow, its role as a modifiable risk factor for cerebrovascular disease is uncertain.New insights into hypertension-associated cerebrovascular pathophysiology may provide key targets to prevent chronic cerebrovascular disease, acute events and vascular cognitive impairment. These aetiologies depend upon intermediate disease phenotypes which can be treated, such as carotid endarterectomy for atherosclerosis16 or anticoagulation for AF.17 However, the intracranial physiological effects of hypertension are less well understood even though they may explain some of the residual risk of recurrent stroke despite effective BP lowering. In the PROGRESS study, a 12mmHg reduction in blood pressure with combination treatment reduced recurrent stroke by up to 43%,18 whilst any treatment reduced intracerebral haemorrhage by 50%, with similar efficacy in all secondary prevention trials,19 but there was still a 10% risk of recurrent events. In the multi-centre TIARegistry, there was a 14.3% risk of recurrent major vascular events (MACE) at 5 years with a 9.5% risk of recurrent stroke,20 despite high-quality secondary prevention.Hypertension is associated with all ischaemic stroke subtypes, whether cardioembolic stroke related to atrial fibrillation (AF),9 These represent further intermediate phenotypes linking hypertension with cerebrovascular outcomes, and are responsible for 30% of ischaemic strokes, 80% of intracerebral haemorrhage22 and 45% of dementia, as well as late-onset refractory depression and significant global functional impairment at older ages.24 SVD is evident on brain imaging in >50% of people over 65 years of age and nearly all people over 80 years of age25. However, no specific treatments exist to target its progression.The principal manifestation of chronic cerebrovascular injury is cerebral small vessel disease. Originally defined by pathological changes including vessel lipohyalinosis, fibrinoid necrosis and vessel rarefaction, cSVD is now primarily defined by imaging characteristics on MRI  for bothAny original data that support the conclusions of this study are available from the authors upon reasonable request.26 Randomised controlled trials then confirmed that a reduction in mean blood pressure reduced the risk of recurrent events by the predicted degree,7 irrespective of baseline cerebrovascular risk18 and at minimally increased baseline blood pressure levels.28 However, hypertension research for primary prevention has lacked a nuanced focus on stroke, with limited stroke phenotyping in large randomized controlled trials (RCTs), whilst stroke research has lacked a nuanced understanding of hypertensive physiology and its effect on the cerebral circulation.Derivation of the statistical measure ‘usual’ blood pressure in the early 1990s allowed precise estimation of the blood pressure related vascular risk by adjusting for variation between clinic visits, to remove the resulting bias that caused underestimation of the effect of average blood pressure (‘regression dilution bias’).10 As preventative strategies including antihypertensive treatment and reduced salt intake have become more effective the incidence of stroke has reduced in older age groups.29 However, due to the aging population there is a marked overall increase in the prevalence of stroke and vascular cognitive impairment. Furthermore, in younger patients under 50 years, particularly women, age-standardised stroke incidence is increasing, associated with increasing rates of obesity and hypertension.31At all ages, elevated mean blood pressure is associated with an increased risk of stroke.32In late life, stroke, SVD and vascular cognitive impairment reflect the cumulative cerebrovascular effect of hypertension over the whole life-span . Althoug25 driven by aging and hypertension and with a strong, genetic contribution.33 White matter hyperintensities (WMH) and concurrent systolic blood pressure are strongly associated at all ages,34 but there is a stronger relationship with midlife blood pressures,36 whilst the strength of the relationship increases the earlier in life the blood pressure is measured.37 Early microstructural brain imaging changes on diffusion tensor imaging in midlife participants in the UK Biobank study are cross-sectionally associated predominantly with mean arterial pressure, independent of age, whilst the association with pulse pressure attenuates significantly after adjustment for age. However, this interaction is synergistic such that increased pulse pressure accentuates the age-related deterioration in cerebral microstructure.36Similarly, SVD is uncommon before 55 years of age but then increases at an increasing rate,38 and acute ischaemic stroke due to small vessel occlusion,39 implying a potentially causative interaction between increasing blood pressure levels over a timescale of a year or less, and both rupture or occlusion of small cerebral vessels. This relationship is particularly strong for stroke subtypes most closely related to hypertension, including deep parenchymal vs lobar haemorrhage and lacunar versus non-lacunar stroke, and provides a strong rationale for early, consistent blood pressure control, particularly after intracerebral haemorrhage, as is being tested with telemetric home monitoring in PROHIBIT-ICH (NCT03863665).In contrast to the long-term association with chronic SVD, recent blood pressure elevations are more strongly associated with both acute intracerebral haemorrhage40 However, there were age-dependent differences between genetically determined drivers of mean versus pulsatile blood pressure. Both were associated with late-life large artery athero-thrombo-embolism, but elevated mean pressure was dominant across ages for other aetiological subtypes.41 Similar analyses have confirmed likely causative relationships between hypertension and the risk of incident all-cause dementia.42Mendelian randomisation has also demonstrated an age-dependent evolution of the relationship between blood pressure and cerebrovascular outcomes, with a likely causative association between high blood pressure and all stroke subtypes, except for lobar intracerebral haemorrhage.43 but vascular risk factors remain dominant after childhood.44 In particular, overactivity of the sympathetic nervous system is a key driver of hypertension, with increased muscle sympathetic nerve activity (MSNA) associated with obesity and blood pressure.45 This implies a potential treatment target with early, unblinded trials of renal sympathetic denervation (RDN) suggesting large reductions in systolic blood pressure (up to 40mmHg). Unfortunately, the properly blinded, sham-controlled Symplicity HTN-346 study failed to replicate this. However, more recent trials ,47 with newer devices and 4-quadrant denervation, have suggested that a more rigorous interventional approach can achieve significant blood pressure reductions. However, the achieved BP reductions are equivalent only to the addition of one new drug, whilst the application of RDN to patients with stroke is yet to be tested.Early-life risk factors for late life cerebrovascular disease include low birth weight and pre-eclampsia,48Baroreceptor activation therapy is an alternative, whereby an implanted stimulator increases the parasympathetic:sympathetic balance, with a resulting reduction in blood pressure. Lagging behind RDN, uncontrolled studies have been prone to bias but a sustained blood pressure reduction was achieved in the sole RCT in resistant hypertension (RHEOS PIVOTAL).51 and its progression is hypertension-dependent, with a 20mmHg elevation of SBP associated with a 1.14m/s progression in PWV per decade.52 Furthermore, there are strong associations between aortic PWV and specific cerebrovascular phenotypes including acute lacunar stroke,53 deep intracerebral haemorrhage (by contrast with lobar),54 cerebral SVD and cognitive impairment 56, with a similar odds ratio of 1.25-1.3 per SD increase in PWV associated with an increase in severity of white matter hyperintensities on the Fazekas scale.Late-life hypertensive phenotypes are characterized by increasing arterial stiffness, with a reduction in elastin and increase in collagen in the aorta reducing vascular compliance and increasing speed of travel of the aortic pressure wave from the heart to the carotid and femoral arteries . This marker of ‘vascular aging’ has a hazard ratio of 1.54 per standard deviation increase for stroke and 1.42 for all vascular events,57 Following reflection, the ‘reverse’ travelling wave then returns towards the heart to meet the forward travelling wave before it has dissipated. With increasing arterial stiffness, there is thus greater ‘augmentation’ of the peak of the waveform, increasing the aortic systolic pressure. Aortic BP is even more strongly associated with the risk of recurrent events than brachial pressure,58 since low resistance vascular beds  are more directly exposed to aortic pressures. Thus, a greater reduction in aortic pressure with an amlodipine-based regimen compared to an atenolol-based regimen potentially explained differences in vascular outcomes in the ASCOT-BPLA trial.59Increased arterial stiffness is also associated with increased wave reflection, whereby the pressure-wave generated with each cardiac impulse ‘reflects’ from points of increased impedance, either at the junction of large and medium vessels or between medium arteries and arterioles.4 However, the statistical adjustment used to calculate ‘usual’ blood pressure depends upon adjusting for the variation in BP between assessments. The greater the variability in blood pressure (BPV) the greater the adjustment and the stronger the estimated relationship between mean blood pressure and subsequent risk. However, blood pressure is highly variable between clinic visits,60 and across five cohorts, the top decile of visit-to-visit BP variability was associated with 2.2-3.8 times the risk of recurrent stroke compared to the bottom decile.61 Variability was reduced in patients randomized to a calcium-channel blocker based regimen compared to an atenolol-based regimen, explaining the difference between treatment regimens that was not explained by mean blood pressure62 and consistent with effects of calcium channel blockers or thiazide-like diuretics in all large randomized controlled trials BPV and the risk of stroke.63Mean blood pressure level over the lifespan is the strongest predictor of cerebrovascular disease.64 on both visit-to-visit and home day-to-day variability,65 and worse outcome after both ischaemic66 and haemorrhagic stroke67 with increasing BPV. The association between BPV and cognitive impairment is greater than that for mean BP, although associations are highly heterogeneous between studies and may reflect reverse causation.68 Variability is predictive from visit-to-visit, day-to-day69 or beat-to-beat,70 is associated with arterial stiffness, baroreceptor dysfunction and increased reactivity to stress71 and progresses over the age of 5572 in parallel with progression of arterial stiffness and aortic pulsatility  by antagonism of the angiotensin-aldosterone system. Other potential targets include PPARy receptors, with reduced remodeling of large cerebral vessels in rat models under the influence of rosiglitazone or pioglitazone,77 with could explain the reduction in cerebrovascular events with pioglitazone in the IRIS trial.78Chronic hypertension is associated with characteristic changes in small vessels throughout the body. Shear stress promotes intracranial atherosclerosis and intracranial stenoses, whilst in smaller vessels it induces smooth muscle hypertrophy, reorganization (or disorganization) of smooth muscle cells, a reduction in the wall:lumen ratio, reduced vascular compliance and, over time, rarefaction of vessels. This increases intracranial cerebrovascular resistance, balancing increased perfusion pressures, but is associated with impaired resting perfusion is evident in the white matter of patients with severe cSVD.79 Furthermore, break down of the blood brain barrier (BBB) in cerebral small vessel disease is seen both in white matter hyperintensities and in areas of normal appearing white matter in patients with either lacunar stroke or established white matter hyperintensities elsewhere in the brain.80 BBB dysfunction may be induced directly by chronic hypertension as a potential mechanism for development of SVD or cognitive decline, either through haemodynamic effects or through the induction of oxidative stress and low-grade inflammation81 or through Amyloid beta-mediated pathways.82Endothelium derived nitric oxide (NO) is a key driver of vasodilatation, with reduced functional hyperaemia in older hypertensive patients, reduced vascular reactivity in cerebral small vessel disease and increased circulating markers of endothelial cell dysfunction in patients with cSVD and hypertension.39 Recurrent stroke was reduced in patients with lacunar events in the SPS3 trial, whilst haemorrhagic stroke was reduced by 63%. Moreover, intensive blood pressure lowering was associated with a reduction in progression of white matter hyperintensities , with a dose-response relationship between blood pressure reduction and rate of progression. However, there was also increased cerebral atrophy, and in the majority of these trials baseline white matter hyperintensities were not severe, limiting generalizability to patients with advanced cerebral SVD. However, reassuringly, there was no evidence of impairment of MRI-measured cerebral perfusion with intensive treatment in the more severely affected participants in the PRESERVE trial.83Cerebral small vessel disease is associated with 30% of ischaemic stroke, 80% of intracerebral haemorrhage and 45% of dementia.85 The pattern of distribution of microbleeds is indicative of the underlying pathology, with a strictly lobar distribution associated with cerebral amyloid angiopathy, reflecting deposition of β-amyloid in small cortical and leptomeningeal vessels. In contrast, deep microbleeds in the basal ganglia and brainstem are associated with hypertension, left ventricular hypertrophy, arterial stiffening and pulse pressure with a dose-response relationship between hypertension and severity of microbleeds.86 Although hypertension may trigger symptomatic lobar haemorrhage in CAA, there is a weaker overall association with hypertension, suggesting hypertension may aggravate CAA but not cause it. Studies to intensively control blood pressure after haemorrhage, either by intensive monitoring (PROHIBIT-ICH) or early triple, combination therapy (TRIDENT), may help to determine the effects of improved hypertension control.Cerebral microbleeds are the most prevalent haemorrhagic radiological manifestation of cerebral SVD. These areas of ‘blooming’ artefact most often reflect deposition of paramagnetic material, usually microscopic areas of subclinical blood extravasation (haemorrhage), though a range of lesions from haemosiderin deposition to intact erythrocytes to vessel wall calcification have been demonstrated.87 This distribution of SVD markers associated with hypertension reflects brain regions most exposed to intraarterial pressures and pulsatility,88 and vulnerability to these factors is at least partially genetically determined, with a heritability of basal ganglia PVS of up to 0.6 and significant shared heritability with white matter hyperintensities and shared genetic associations in large scale genome-wide association studies.89 This indicates a common hypertension-associated genetic predisposition across different manifestations of cSVD, and may also contribute to observed associations between PVS and both ischaemic90 and intracerebral haemorrhage.91Similar to cerebral microbleeds, there is a stronger association between hypertension and dilated perivascular spaces in the basal ganglia than with PVS in the centrum semiovale.92 or by high temporal-resolution multiband imaging.93 Cerebral pulsatility is strongly associated with severity of white matter hyperintensities,94 acute lacunar infarcts, cerebral microbleeds95 and dilated perivascular spaces.96 It increases with age and is tightly associated with aortic stiffness and aortic pulsatility,97 reflecting increased transmission of the aortic waveform to the brain, modified by dampening of the waveform at points of tortuosity and impedance and by the distal resistance of smaller cerebral vessels. It is highly reproducible, progresses over the age of 65 and independently predicts the risk of recurrent cerebrovascular events. However, methods to modify it independent of mean blood pressure are not clear. In the ECLIPSE study a phosphodiesterase 3 inhibitor (cilostazol)98 reduced cerebral pulsatility, potentially explaining beneficial effects of cilostazol in clinical trials beyond its known antiplatelet activity.11Cerebral vessels modify the blood pressure to maintain perfusion of the brain throughout the cardiac cycle , from beat-to-beat and hour-to-hour  and in response to endogenous and exogenous stimuli (via reactivity). Cerebral artery pulsatility is measured on transcranial ultrasound (Gosling’s pulsatility index), 4d-phase contrast MRI sequences,99 exiting via newly identified meningeal lymphatic vessels.100 This pathyway has been linked to drainage of amyloid β and other solutes. Despite limitations in experimental techniques101, 2-photon imaging tracer studies and ligation studies of the carotid102 indicate that arterial pulsatility provides motive force for perivascular drainage in healthy animals. However, it is unclear whether hypertension-associated increases in pulsatility and vascular stiffness affect perivascular drainage in humans, given a lack of in vivo glymphatic imaging techniques that do not require intrathecal injection of contrast.103Arterial pulsatility may also be key to drainage of interstitial fluid from the brain along perivascular spaces, sometimes called ‘glymphatics’. This recently identified pathway challenged the axiom that CSF reabsorption only happened via the arachnoid granulations, with intracisternal injection of radiolabeled tracers appearing in the CSF filled perivascular spaces around arteries, and then around veins,The endothelium controls the cerebrovascular response to stimuli, regulating smooth muscle tone via balanced vasodilator and vasoconstrictor pathways. The archetypal, eNOS vasodilator pathway induces smooth muscle cGMP upregulation and cell relaxation to increase local CBF, which antagonises vasoconstrictor pathways such as endothelin-mediated vasocontriction.104 CVR is an attractive therapeutic target, being simple to measure, modifiable by established medications, and with a biologically plausible relationship to disease. It is associated with severity of white matter hyperintensities, dilated perivascular spaces105 and microbleeds, and progresses in parallel with progression of SVD. Recent studies have also demonstrated impaired CVR in the basal ganglia in patients with deep intracerebral haemorrhages.106Cerebrovascular reactivity (CVR) is most commonly measured in vivo by altering carbon dioxide levels,  and measuring the vascular response .However, studies of the relationship between hypertension and CVR, independent of established cerebrovascular injury remain sparse with inconsistencies in methods of measurement of CVR, limited data in different cerebrovascular manifestations and uncertainty regarding the temporal order of the components of the phenotypes. This critical question may be answered by large collaborative studies such the MarkVCID and SVDs@TARGET consortia, and by interventional studies targeting improvements in CVR: TREAT-SVDs (NCT03082014), OxHARP (NCT03855332), LACI-2 (NCT03451591).Cerebral autoregulation maintains cerebral blood flow despite changes in blood pressure, with sustained BP elevation inducing vasoconstriction and increased resistance to blood flow. Hypertension is associated with a rise in the ‘set-point’ of this curve to compensate for elevations in blood pressure, although the dynamic range achieved may still be less than the upper limit of blood pressure variability.107 dCA is measured either by induced blood pressure changes  or by resting-state relationships between spontaneous fluctuations in blood pressure and cerebral blood flow in time-domain (‘Mx’), or frequency-domain transfer function analysis to estimate the magnitude (gain), delay (phase) and strength of the relationship (coherence), or by modeling the response to an acute step change . The underlying changes in vascular tone depend upon myogenic, metabolic and autonomic/neurogenic responses to maintain stable CBF.With technical advances to measure beat-to-beat blood pressure and cerebral blood flow, dynamic cerebral autoregulation (dCA) reflects rapid adaptation to changes in blood pressure.108 is associated with an increased risk of early neurological deterioration109 and haemorrhage110 and can predict a poor response to reperfusion therapies despite recanalisation,111 but studies have been small with inconsistent findings, partly due to difficulties in consistent measurement of dCA, although international collaborations (INFOMATAS) seek to better define its role. 112Despite the critical biological importance of cerebral autoregulation, evidence for its role in the aetiology of stroke is limited. Autoregulation is commonly impaired in the ipsilateral hemisphere in severe ischaemic stroke,In comparison, the population-based effect of hypertension and age on dCA are even less well documented. Limited studies have not demonstrated a consistent decline in autoregulation with age, although with conflicting results. Similarly, there is limited evidence of the effects of chronic hypertension on dCA and its relevance to development of cerebrovascular pathology, despite significant potential for new interventional targets.113Hypertension-related secondary prevention of cerebrovascular disease will be the focus of subsequent articles in this series, including intracerebral haemorrhage, recurrent ischaemic events and cognitive impairment. These intermediate pathophysiological targets between hypertension and clinical events provide new potential treatment targets. For example, calcium channel blockers and thiazide-like diuretics appear to reduce BP variability, but effects at different baseline blood pressure levels and by stroke aetiology are needed and there remains a need to define which antihypertensive medications are optimal in the secondary prevention of stroke.114 CSPS115) with cilostazol reducing ischaemic stroke to an extent greater than expected from its antiplatelet effects, with no increased risk of haemorrhage. Finally, XILO-FIST has recently reported a null effect of allopurinol on progression of white matter hyperintensities, despite a small reduction in blood pressure.116 However, no trial has yet identified a reliable intervention that has lead on to definitive trials showing efficacy.A number of trials are currently testing repurposed interventions to target specific aspects of these phenotypes. TREAT-SVDs is comparing the effects of amlodipine versus atenolol and losartan on cerebrovascular reactivity to inhaled carbon dioxide on MRI, and is expected to report in 2022/2023. OxHARP is testing phosphodiesterase inhibitors (sildenafil and cilostazol) on cerebral pulsatility and reactivity to carbon dioxide, using both transcranial ultrasound and MRI, with dCA as a secondary outcome. The completed but unreported PASTIS study (NCT02450253)assessed the effect of a single dose of tadalafil on white matter perfusion in the early phase after a lacunar stroke. LACI-1 tested implied improved cerebrovascular reactivity on MRI with either cilostazol or isosorbide mononitrate in lacunar stroke, leading to LACI 2 to test the same agents to prevent recurrent lacunar strokes and progression of white matter hyperintensities. This follows suggested benefits in larger clinical trials (PICASSO,The relationship between hypertension and stroke, and its reduction by appropriate blood pressure control, has significantly reduced its incidence. However, our developing understanding of the complex physiological effects of hypertension on the cerebral circulation, particularly in the context of cerebral SVD and its consequences, promises new treatment paradigms for the future.


Atrial fibrillation (AF) is the most prevalent sustained arrhythmia worldwide and it aggravates cardiovascular morbidity and mortality; however, this is largely under-diagnosed. Moreover, among end-stage renal disease patients on haemodialysis, AF is substantially more common and serious. The researchers conducted this study to assess the prevalence of, and the factors correlated with AF in Jordanian haemodialysis patients.In a cross-sectional analysis conducted from October 2018 to February 2019 in four tertiary hospitals, the researchers enrolled all consenting patients aged 18 years or older who were on haemodialysis for at least three months prior to the study. We screened for AF clinically by pulse palpation, precordial auscultation, by an automated blood pressure monitor and an electrocardiogram. The researchers reported qualitative variables as counts and frequencies, while continuous variables were summarised using the mean or median where necessary. We used multiple logistic regression with backward selection to identify independent risk factors of AF.p = 0.031), history of ischaemic heart disease , history of smoking , and low interdialytic weight gain  were independently correlated to AF.A total of 231 patients were enrolled; mean age was 54.8 ± 15.6 years (from 20 to 86), and 44.3% of them were women. The prevalence of AF was found to be 7.8% , with no gender disparity. Age (adjusted odds ratio [AOR] = 1.05; 95% CI, 1.01–1.10; The prevalence of AF among patients on maintenance haemodialysis is high, but largely undiagnosed. AF is generally associated with advancing age, history of ischaemic heart disease, lower interdialytic weight gain, and history of smoking. We suggest routine check-up of AF in this high-risk group of patients as anticoagulant therapy if indicated may prevent serious complications. However, there is a need for large-scale cohort studies and for the creation of regional chronic kidney disease and dialysis registries in the Middle East region. Atrial fibrillation (AF) is the commonest cardiac arrhythmia, and a global public health problem associated with high rates of hospitalisation, disability, and complications such as heart failure, cardiomyopathy, and cardio-embolic events like stroke –4. The iIt is estimated that between 11 and 13% of the world’s population is affected by chronic kidney disease (CKD); with the prevalence of stage 5 CKD estimated at about 0.1% . WorseniThis study sought to evaluate the prevalence and factors associated with previously undiagnosed AF among patients with ESRD on maintenance haemodialysis. The information from the study is vital to enlighten practice in the Middle East and add to the limited literature on topic globally.This was a cross-sectional analysis conducted from October 2018 to February 2019, in four haemodialysis centres in Amman. Each dialysis unit serves about 50 to 150 patients and is managed by a nephrologist.All patients with ESRD undergoing haemodialysis were screened for eligibility and then invited to take part in the study. The researchers enrolled all consenting participants aged 18 years or older, diagnosed with ESRD and had received haemodialysis for at least three months prior to the study. We excluded patients with a previous diagnosis of arrhythmia or AF, and any psychiatric, psychological, or debilitating disorder which could prevent the patients from either being interviewed or understanding the questions.Using the Cochrane’s formula below, we calculated a minimum acceptable sample size (n) of 167 participants. = 0.124 ; and d =Participants were consecutively enrolled in the study.The study protocol was approved by the ethical review boards (IRB) of the participating hospitals. All patients signed an informed written consent form after being explained the details of the research, its procedure, the potential benefits and harm, and their questions were satisfactorily answered.Patients were interviewed by trained final year medical students using a pre-designed questionnaire to collect information on the general demographic information , past medical history , and dialysis related information . Information on the patient’s drugs and results of the laboratory tests were also collected from the patient’s medical file. The patient’s body mass index was computed using the patient’s weight (measured in the nearest 10 g) and height (in centimetres). An automated blood pressure (BP) monitor with irregular heartbeat detector  was used to detect the presence of irregular heartbeat during BP recording. This device has been clinically validated for detecting AF during blood pressure recording with a sensitivity of 98.7% .At baseline, prior to haemodialysis, we screened all patients for AF by palpating their pulse and auscultating their heart to check for irregularities using the automated BP monitor and a 12-lead electrocardiogram (ECG). The patients’ BP and pulse were also monitored during dialysis using the automated BP monitor. An irregular heartbeat sign on the device screen would flash if an irregular heartbeat was detected. If the sign flashed, the BP was remeasured after five minutes to confirm the presence of the sign. A second ECG was obtained if the sign persisted. Only patients with an episode of AF on 12-lead ECG were confirmed to have AF. All ECGs were performed by trained final year medical students, and the ECG findings were interpreted blindly by a consultant cardiologist in two separate sessions.p-values less than 0.1 on bivariate analysis, with the exception of gender, were evaluated using backward elimination method and based on the Akaike information criterion (AIC) for final inclusion in the multiple regression model [p-values below 0.05 were considered statistically significant.We used Microsoft Excel 2010 spreadsheets for data entry and curation, and the statistical software R  for data analysis. We reported qualitative variables as counts and proportions while we summarized quantitative variables as means and medians with their corresponding standard deviation (SD) and interquartile range (IQR), respectively. Histograms and probability distribution plots were used to visually assess continuous variables for normality and presence of outliers. The Fisher’s exact test was used to compare categorical variables, while the student t-test or Mann-Whitney U test was used to compare continuous and categorical variables as appropriate. We determined independent factors correlated with AF using multiple logistic regression analysis utilizing backward elimination method . Only vaon model . Lower Ap < 0.001), Table Collectively, we enrolled 231 participants in this study. Only one candidate was excluded because of previous diagnosis of AF. The mean age of the participants was 54.8 years (SD = 15.6) and participants who developed atrial fibrillation were significantly older than their counterparts without atrial fibrillation , Table Eighteen out of the 231 participants were diagnosed with atrial fibrillation giving a prevalence of 7.8%  with no gender disparity (p = 0.031), ischaemic heart disease , history of smoking , and low interdialytic weight gain  as independent factors associated with the occurrence of atrial fibrillation with a very good accuracy (C statistics = 82.2%), Table The final multiple regression model predicted age , Table The model was also a good fit for our data as was revealed by a non-significant Hosmer-Lemeshow test (Chi-square = 3.31, We sought to evaluate the prevalence and factors associated with atrial fibrillation among ESRD on maintenance chronic haemodialysis. The high prevalence of 7.8% was linked to increasing age, history of smoking, history of ischaemic heart disease and lower interdialytic weight gain with a very good accuracy.Very few studies have evaluated the prevalence of subclinical AF among ERSD patients on maintenance haemodialysis. The prevalence of AF in this study is similar to rates of 7.7 and 8.0% reported by Konigsbrugge et al., 2017 . The lowIn the current study, age, history of smoking, history of ischaemic heart disease, and low interdialytic weight gain explained up to 25.4% of the total variability in the outcome. Age has been consistently reported in literature to be a strong predictor of AF , 20, 24.Additionally, ischaemic heart failure is a well-established risk factor for AF . A previThe association between cigarette smoking and AF is controversial. Although a link has been demonstrated between smoking, mostly current smoking and AF in most part of literature, most studies conducted on ESRD patients on haemodialysis have failed to identify any associations , 25, 28.Finally, in our study, lower interdialytic weight gain was associated with the occurrence of AF. Traditionally, higher interdialytic weight gain is linked to adverse morbidity and all-cause mortality and has been a growing area of interest in dialysis medicine –33. HoweAlthough we attained the minimum acceptable required sample size for this study, a larger sample size would have enabled us to detect smaller effects. Smaller sample sizes seem to be a major challenge for studies where data was collected prospectively using a cross-sectional design . Most laThe prevalence of subclinical atrial fibrillation among ESRD patients on maintenance dialysis was found to be high and this was mainly driven by advancing age, history of ischaemic heart disease, history of smoking, and lower interdialytic weight gain. ESRD is distinctive in Jordan because it affects mostly younger individuals at the prime of their economic productivity, thereby posing a significant socioeconomic burden. We suggest checking routinely for AF in patients on haemodialysis and if present to consider anticoagulant therapy as this may prevent serious complications. Finally, more large-scale studies are required on the national territory and the Middle East region, with the creation of national and regional registries for prospective observations.