The HOME BP  trial aimed to test a digital intervention for hypertension management in primary care by combining self-monitoring of blood pressure with guided self-management.Unmasked randomised controlled trial with automated ascertainment of primary endpoint.76 general practices in the United Kingdom.622 people with treated but poorly controlled hypertension (>140/90 mm Hg) and access to the internet.Participants were randomised by using a minimisation algorithm to self-monitoring of blood pressure with a digital intervention (305 participants) or usual care . The digital intervention provided feedback of blood pressure results to patients and professionals with optional lifestyle advice and motivational support. Target blood pressure for hypertension, diabetes, and people aged 80 or older followed UK national guidelines.The primary outcome was the difference in systolic blood pressure (mean of second and third readings) after one year, adjusted for baseline blood pressure, blood pressure target, age, and practice, with multiple imputation for missing values.After one year, data were available from 552 participants (88.6%) with imputation for the remaining 70 participants (11.4%). Mean blood pressure dropped from 151.7/86.4 to 138.4/80.2 mm Hg in the intervention group and from 151.6/85.3 to 141.8/79.8 mm Hg in the usual care group, giving a mean difference in systolic blood pressure of −3.4 mm Hg  and a mean difference in diastolic blood pressure of −0.5 mm Hg (−1.9 to 0.9 mm Hg). Results were comparable in the complete case analysis and adverse effects were similar between groups. Within trial costs showed an incremental cost effectiveness ratio of £11  per mm Hg reduction.The HOME BP digital intervention for the management of hypertension by using self-monitored blood pressure led to better control of systolic blood pressure after one year than usual care, with low incremental costs. Implementation in primary care will require integration into clinical workflows and consideration of people who are digitally excluded.ISRCTN13790648. Hypertension is the major risk factor for cardiovascular disease internationally and evidence from several randomised controlled trials shows that this risk can be reduced by lowering blood pressure.Digital interventions  have the potential to support people in self-management.The HOME BP trial aimed to evaluate whether a digital intervention comprising self-monitoring of blood pressure with reminders and predetermined drug changes combined with lifestyle change support resulted in lower systolic blood pressure in people receiving treatment for hypertension that was poorly controlled, and whether this approach was cost effective.The methods of the HOME BP trial have already been described in detail.Eligible participants were aged 18 or older with treated hypertension, a mean baseline blood pressure reading  of more than 140/90 mm Hg, and were taking no more than three antihypertensive drugs. For the digital intervention, participants needed to be willing to self-monitor and have access to the internet (with support from a family member if needed).Exclusions included blood pressure greater than 180/110 mm Hg, atrial fibrillation, hypertension not managed by their general practitioner, chronic kidney disease stage 4-5, postural hypotension (>20 mm Hg systolic drop), an acute cardiovascular event in the previous three months, terminal disease, or another condition which in the opinion of their general practitioner made participation inappropriate.https://www.nihr.ac.uk/explore-nihr/support/clinical-research-network.htm). Eligible people were identified from clinical codes recorded in the electronic health records of collaborating general practices; these people were invited to attend a baseline clinic to learn about the study. At the clinic, eligibility was established, informed consent was obtained from people who wished to participate, and their baseline clinical data were collected. People who did not want to take part in the trial were given the option to complete a form giving their reasons. Study nurses measured participants’ blood pressure after five minutes’ rest using a standardised technique with a validated electronic automated sphygmomanometer (BP TRU BPM 200).We used practices from the National Institute for Health Research Clinical Research Network (https://www.lifeguideonline.org) in a 1:1 ratio to receive usual care or the HOME BP intervention with optional nurse support. Minimisation factors were participants’ baseline systolic blood pressure, age, diabetes status, and practice. Practice staff were notified of patient group allocation by email.Eligible participants were randomised using an online system . For patients allocated to the intervention group, prescribers were asked to select and agree an individualised drug titration plan .Six and 12 months after randomisation, participants attended follow-up appointments with an independent research nurse where blood pressure and weight were recorded (weight was recorded at 12 months only). Participants then completed follow-up questionnaires online.The HOME BP intervention for the self-management of high blood pressure consisted of an integrated patient and healthcare practitioner online digital intervention, blood pressure self-monitoring, healthcare practitioner directed and supervised titration of antihypertensive drugs, and user selected lifestyle modifications. The intervention was developed using a theory, evidence, and person based approachParticipants were given online instructions on how to correctly undertake self-monitoring (using an Omron M3 monitor), with a demonstration video.Participants were advised, with automated email reminders, to take two morning blood pressure readings for seven days each month and to enter online each second reading (following methods used in the TASMINH2 and TASMIN-SR studies).The following home blood pressure targets were set in line with up-to-date NICE hypertension guidelinesPeople younger than 80 without diabetes: less than 135/85 mm HgPeople aged 80 and over without diabetes: less than 145/85 mm HgPeople with diabetes: less than 135/75 mm Hg.When home blood pressure readings were very high (>180/110 mm Hg) or very low (systolic blood pressure <100 mm Hg), patients were advised to call their general practitioner within three days and HOME BP healthcare practitioners were alerted by email. If mean home blood pressure was controlled for three consecutive months (defined as 100-134/≤84 mm Hg), patients were advised to reduce blood pressure monitoring to once every eight weeks; monitoring reverted back to every month if mean blood pressure subsequently increased above 135/85 mm Hg.The HOME BP intervention included elements designed to motivate and support healthy behaviours. Information was presented about the health related benefits of self-monitoring, about reducing blood pressure through drugs, and addressing common patient concerns about the side effects of drugs. Nine weeks after participants were allocated to the intervention (judged to be sufficient time for self-monitoring habits to have been implemented), an optional tool became available outlining user selected evidence based lifestyle modifications that target healthy eating, physical activity, losing weight (if appropriate), and salt and alcohol reduction.The HOME BP intervention also aimed to build healthcare practitioner motivation, knowledge, and skills to reduce clinical inertia.Optional additional behavioural support for self-monitoring and lifestyle modifications was available to intervention participants through practice nurses or healthcare assistants (referred to as supporters) by using the CARE  approach.Participants allocated to usual care were not provided with self-monitoring equipment or the HOME BP intervention, but had online access to the information provided in a patient leaflet for hypertension . This information comprised definitions of hypertension, causes, and brief guidance on treatment, including lifestyle changes and drugs. These participants received routine hypertension care that typically consisted of clinic blood pressure monitoring to titrate drugs, with appointments and drug changes made at the discretion of the general practitioner. Participants were not prevented from self-monitoring; data on self-monitoring practices were collected at the end of the trial from patients and practitioners.In intervention and usual care groups, decisions about patients’ drugs remained at the prescriber’s discretion at all times.The primary outcome of the trial was the difference in clinic systolic blood pressure (mean of second and third readings) at 12 month follow-up between the intervention and usual care groups, adjusting for baseline blood pressure, practice, blood pressure target levels, and sex. Secondary outcomes  included systolic and diastolic blood pressure at six and 12 months using second and third blood pressure readings, and second to sixth blood pressure readings; weight; modified patient enablement instrument After trial registration, participants and general practitioners were asked about use of self-monitoring in the usual care group. At the end of the trial a medical record review captured prescription of antihypertensive drugs (including any changes) and within trial primary healthcare resource use . Additional outcomes that will be published elsewhere included long term economic modelling and a detailed process evaluation.A sample size of 244 patients for each group was required to have 90% power to detect a difference in systolic blood pressure of 5 mm Hg (standard deviation 17 mm Hg) between the intervention and usual care groups based on the findings from the TASMINH-2 study.The principal analysis used raw and adjusted data, and was agreed in a statistical analysis plan before final data lock (see appendix). The primary analysis used general linear modelling to compare systolic blood pressure in the intervention and usual care groups at follow-up, adjusting for baseline blood pressure, practice (as a random effect to take into account clustering), blood pressure target levels, and sex. Analyses were on an intention-to-treat basis and used 100 multiple imputations by chained equations for missing data. The imputation model included all outcome and stratification variables. Sensitivity analyses used complete cases and also a repeated measures technique. Planned subgroup analyses included blood pressure target groups, older versus younger participants (67 as threshold), men versus women, lower index of multiple deprivation scores versus higher scores, and blood pressure better controlled at baseline versus worse controlled at baseline (above or below median systolic blood pressure). Secondary analyses used similar techniques to assess differences between groups. Post hoc we decided to present antihypertensive drugs as the number of dose changes and drug changes rather than as defined daily dose (which combines dose and number of drugs) to show the specific type of changes more clearly.A within trial economic analysis estimated cost per unit reduction in systolic blood pressure—the primary outcome—by using similar adjustments and multiple imputation for missing values as described in the statistical analysis section. UK National Health Service resource use costs included those due to the intervention and those due to changes in drugs and use of other relevant NHS resources. The following items were costed (further details in appendix table A6):Antihypertensive drugs  from NHS drug tariff 2018Primary care contact related to blood pressure  and type of contact Inpatient admission , outpatient visit, or emergency department attendance related to hypertension.We used repeated (1000 times) bootstrapping to estimate the probability of the intervention being cost effective at different levels of willingness to pay per unit reduction in blood pressure.https://doi.org/10.1186/ISRCTN13790648). The original registration was for the development and pilot phase, which ran into the main trial without change. Except for an increase in sample size as documented above, no other substantive changes were made to the protocol after the start of the trial. The trial registration did not specify which blood pressure measurements were to be used in the secondary outcomes, but these were clarified in the statistical analysis plan before data lock as the mean of the second and third measurements, and the mean of the second to sixth measurements. Post hoc analyses are stated.HOME BP is registered as ISRCTN13790648 . At full application stage these contributors were joined by Keith Manship and Shelley Mason. Key aspects contributed to were the development of the intervention, commenting on trial documentation, and taking part in the steering group meetings. Cathy Rice joined as a patient and public contributor during the trial and has remained extensively involved, including optimising many patient facing documents and intervention training content, authorship of this paper and assisting in dissemination. We are immensely grateful for the input of all of our public contributors.Of 11 399 invitation letters sent out, 1389 (12%) potential participants from 76 general practices responded positively and were screened for eligibility. Those who declined to take part could optionally give their reasons, and responses were gained from 2426/10 010 (24%). The mean age of those who gave a reason for declining was 73 years. The most commonly selected responses were not having access to the internet , not wanting to be part of a research trial , not wanting to participate in an internet study , and not wanting to change drugs .Of the 1389 screened, 734 were ineligible and so were excluded . A furthThe groups were well matched, with a mean age of 66 years and mean baseline clinical blood pressure of 151.6/85.3 mm Hg and 151.7/86.4 mm Hg  participants in the intervention group and 282 (89%) in the usual care group . Clinic A post hoc analysis showed that blood pressure dropped by at least 5 mm Hg in 201/270 (74.4%) of the intervention group compared with 170/282 (60.3%) of those receiving usual care: adjusted odds ratio for a 5 mm Hg drop: 1.9 .Exploratory subgroup analyses , but this was not borne out by the objective weight data .Information about possible adverse effects was derived from an extended version of the illness perceptions questionnaire symptoms section and showed no differences between groupsv usual care: 2.0, 95% confidence interval 1.5 to 2.7) and more changes in drugs  participants completing the two core training sessions, 268/305 (88%) completing a week of practice blood pressure readings, and 243/305 (80%) completing at least three weeks of blood pressure entries (table A5). Furthermore, 214/305 (70%) were still monitoring in the last three months of participation (of 12 month study). However, less than one third of participants chose to register on one of the optional lifestyle change modules. Of the subsample of 243 participants with a body mass index greater than 25, 46 (19%) registered on the online weight loss programme.The patient enablement score showed a reduction over time  in the self-management group. This reduction meant that by 12 months a significant difference was found  between the usual care and intervention groups .After 12 months, a post hoc analysis showed that 112/234 (47%) patients in the usual care group reported monitoring their own blood pressure at home at least once per month during the trial; of these, 78 (70%) said that they took their readings to their general practitioner. Of 56/76 (74%) general practitioners who responded, 35 (63%) reported using home readings in their titration decisions for usual care.The within trial analysis for quality of life (EuroQoL-5D-5L) showed no significant difference between the two groups . The difA digital intervention enabling self-management of hypertension, including self-monitoring, titration based on self-monitored blood pressure, lifestyle advice, and behavioural support for patients and healthcare professionals, resulted in a worthwhile reduction of systolic blood pressure achieved at modest cost. This finding was robust in sensitivity analyses, including complete case analysis, and also when the mean of the second to sixth blood pressure readings was used as the outcome. The reduction was achieved through increased titration of antihypertensive drugs with no increase in adverse effects, suggesting that the HOME BP digital intervention reduces clinical inertia and leads to optimisation of treatment. The effect size observed from this intervention could be expected to result in a reduction of 10-15% in patients having a stroke and a reduction of 5-10% in patients having coronary events. Given the low marginal cost, such an effect could make a major difference to the millions of people being treated for hypertension in the UK and worldwide.This was a large trial of a digital intervention in the field of hypertension and with follow-up for a year. Adequate power existed to detect a difference in blood pressure, and over recruitment ensured such an effect was not missed. By recruiting from a large number of general practices, we ensured generalisability in terms of healthcare professionals. However, some evidence was found of preferential recruitment of those with higher socioeconomic status, although we found no evidence that socioeconomic status mediated outcomes. Although white ethnicity (94%) appears over represented in comparison to the population of England and Wales as a whole, this reflects differences in ethnicity by age: 95% of those aged 65-69 have white ethnicity.The mean age of people declining to take part was 73, and the commonest reason cited was lack of internet access, mirroring Ofcom’s latest data showing a reduction in computer access by socioeconomic status and age.The study used minimisation to reduce important baseline imbalance and this has the potential to reduce the effect of randomisation. However, we have no evidence that randomisation concealment was affected. Similarly imputation can influence results, but with high follow-up (89%) and equivalent complete case results this seems unlikely.While prescribing records suggested an increase in drug use, and the questionnaires suggested high rates of drug adherence, data were not available about filling of prescriptions or validated adherence. The best measures of drug adherence use electronic systems, which were not available for this study. However, other work using such methods suggests that self-monitoring improves adherence.v 130 mm Hg) owing to changes in national guidance, and this might have reduced the effect size.The effect size seen in this trial was slightly smaller than, but within the confidence intervals of, our trial that assessed a similar paper based self-management intervention in a similar population. Additionally, the upper confidence interval crosses our prespecified clinically important level of 5 mm Hg.The self-monitoring schedule used here was developed in our previous self-management work, but is different to that recommended in subsequent international recommendations.Subgroup analysis suggested a differential effect by age, which is important given that such interventions have been proposed as particularly relevant to the ageing population.We observed an increase in antihypertensive drug changes in the intervention group, which suggests that the HOME BP intervention led to reduced clinical inertia. This phenomenon has been shown to result in reduced action by clinicians in the face of evidence, in this case of raised blood pressure.The major advantage of a digital intervention is the ability to be deployed at a low marginal cost, and the within trial cost effectiveness analysis supports this assumption. All training for the intervention was delivered online, meaning implementation can also be cost effective. This finding is reflected in the cost of £11/mm Hg reduction, which compares well with £25.66/mm Hg in the HITS trial in Scotland that used a propriety telemonitoring system.Interestingly, the patient enablement instrument showed that patients were enabled to be more active in controlling their hypertension. Many chose to do this through drugs only, whereas a small number chose to include behavioural or lifestyle modifications as part of blood pressure management. The small proportions choosing behavioural support might seem counterintuitive, but as has been pointed out before, enabled patients do not always make the decisions that clinicians or public health physicians would like them to.Trials of self-monitoring blood pressure appear to work best with relatively intensive cointerventions  and the current study fits with that literature.Surveys suggest that most general practitioners are drawing on self-monitoring in their hypertension management, and that at least one third of patients with hypertension are self-monitoring.Overall, this digital intervention for the management of hypertension that uses self-monitored blood pressure and behavioural techniques has led to better control of blood pressure than usual care. The HOME BP digital intervention, combined with self-monitoring, has the potential to provide cost effective support for patients and professionals in lowering blood pressure. The next step is an implementation strategy to realise such benefits for the whole population.Previous trials of self-monitoring and self-management have shown effectiveness in reducing blood pressure, but have often relied on relatively expensive technology or time consuming training packages to realise any benefitShort term trials of digital interventions have shown potential to improve blood pressure control, but have not provided sufficient evidence for widespread implementationHome and Online Management and Evaluation of Blood Pressure (HOME BP) is a digital intervention comprising self-monitoring of blood pressure with reminders and predetermined drug changes combined with lifestyle change support for the self-management of high blood pressure HOME BP resulted in better control of systolic blood pressure after one year than usual care and at low incremental cost; adverse events were similar to usual careDigital interventions such as HOME BP have the potential to be implemented at scale in a cost effective manner


Uricemia dramatically rises with the stage of chronic kidney disease (CKD) and correlates with its mortality. Hemodialysis (HD) being the most used treatment at the end stage in sub-Saharan Africa, we sought to evaluate its efficacy on the clearance of uric acid (UAc) when used alone and twice per week.A cross-sectional study of all consenting patients with CKD stage 5 recruited at random during HD sessions in a reference Centre in Cameroon from January to April 2017. We collected socio-demographic data, relevant clinical information, HD related variables, and measured serum uric acid (SUA) levels before and after the dialysis to assess the uric acid clearance. A clearance between 65 and 80% and above 80% was considered as low and good efficacy of HD respectively. Statistical analysis was performed using SPSS version 21.0. Factors associated with HD efficacy were assessed using Fisher’s exact test and are presented with their odds ratios (OR) and 95% confidence levels.One hundred four patients  were included. The mean age was 49.9 ± 13.3 years. Hypertension (25%) and chronic glomerulonephritis (16%) were the main suspected etiologies of CKD. The median time on renal replacement therapy by HD was 3 years . The prevalence of hyperuricemia was 81.9%. The means of SUA levels were 78.8 ± 13.8 mg/L and 26.4 ± 6.6 mg/L respectively before and after dialysis. Mean SUA clearance was 66% ± 10%. The efficacy of HD on UAc was moderate in 92 (63.9%) and good in 2 (1.4%) patients. Excess weight  and Kt/Vurea < 1.2  significantly reduces the efficacy of HD.HD used alone for 2 sessions per week has a moderate efficacy on uric acid clearance in CKD. Therefore, we should improve the Kt/V (> 1.2), and combine HD to uric acid lowering drugs and diet modifications to increase its efficacy. Chronic Kidney Disease (CKD) is a global health problem that affects more than 200 million people around the world . Africa Of the various strategies in place for the management of hyperuricemia during ESKD, HD alone has been shown to be the most effective , 15. HowThe methods section was presented according to the STROBE recommendations for observational studies .We carried out a prospective cross-sectional study at the Hemodialysis Centre of the Douala General Hospital (DGH). It is a tertiary and referral hospital in the urban city of Douala, equipped with 18 dialyzers branded Fresenius® 4008S generator , with a polysulfone synthetic dialysis membrane and bicarbonate dialysates. It is the largest dialysis center in the country, caring for 225 patients by the end of the year 2016. Study participants were recruited from the 1st January to 31st April 2017 (4 months). Eighty percent of the patients received two dialysis sessions per week.We included all consenting adults ≥21 years), at the end-stage kidney disease according to the KDIGO 2012 , while qualitative variables were expressed as counts and proportions. The comparison of means of paired quantitative variables was done using the paired Student’s T-test. Factors modifying UAc were determined using Fisher’s exact test. The odds ratio (OR) and its 95% confidence interval were used to quantify the degree of association. The threshold of significance was set at 0.05 for all the statistical tests used.Overall 144 patients  were involved in the study. The mean age of participants was 49.2 ± 14.1 years. Underlying nephropathies included hypertensive nephropathy (25%), chronic glomerulonephritis (16%), diabetic nephropathy (15.3%), and were unknown in 27 patients (18.8%). At the time of the study, 128 (88.9%) patients were reported to have hypertension, 47 (32.6%) had excess weight, and 33 (22.9%) had diabetes. 124 (86.1%) patients had an arterio-venous fistula (86.1%), and 105 (72.9%) had a kidney size about FX10.Hyperuricemia was found in 118 patients (81.9%) and 16 (11.1%) had a documented gout crisis in their past history since the initiation of hemodialysis. Ninety-one (63.2%) patients reported less than 100 mL urine output in 24 h. The baseline characteristics of the population are presented in Table p = 0.02), but the mean of the diastolic blood pressure remained unchanged (p = 0.10)  participants. The mean Kt/Vurea was 1.3 ± 0.2 and could only be calculated for 34 participants   and an excess weight  were found to be significantly associated to HD efficacy , but, this reduction was moderate (mean UAc of 66 ± 10%). A few participants (1.4%) had more than 80% clearance, which corresponds to those undergoing 3 sessions of HD per week. This result is similar to those of Alaraj et al. in Saudi Arabia . The dialysis adequacy assessed by Kt/Vurea measures how much urea is removed during dialysis and has been adopted to 1.2 as standard value for dialysis adequacy by the Kidney Disease Outcomes Quality Initiative (KDOQI) . A Kt/V bove 80% . These rterature , was notp = 0.03, OR 0.4 . The weight of participants defines the size of the dialysis membrane and weight influences the volume of distribution and thus the plasma clearance of the dialyzed substances. Age (p = 0.8), sex (p = 0.2), and comorbidities like hypertension (p = 0.8), diabetes (p = 0.5) and gout (p = 0.1) were not associated to a better clearance. These results are similar to those of Alaraj et al. and Soriano et al. [Apart from HD related variables, the participant’s characteristics were tested for association with UAc. We found that excess weight significantly reduces uric acid clearance  and combine HD to uric acid lowering drugs and diet modifications.


Although mild hypercapnia is generally well tolerated in patients with asthma, there is accumulating evidence that elevated levels of CO2 can act as a gaso-signaling molecule, triggering deleterious effects in various organs such as the lung, skeletal muscles and the innate immune system. Here, we review recent advances on pathophysiological response to hypercapnia and discuss potential detrimental effects of hypercapnia in patients with asthma.Asthma is a common chronic respiratory disorder with relatively good outcomes in the majority of patients with appropriate maintenance therapy. However, in a small minority, patients can experience severe asthma with respiratory failure and hypercapnia, necessitating intensive care unit admission. Hypercapnia occurs due to alveolar hypoventilation and insufficient removal of carbon dioxide (CO Asthma is a chronic disease characterized by reversible airway obstruction caused by bronchial smooth muscle contraction, airway inflammation and increased secretions, and is currently estimated that more than 330 million people are afflicted with this disease worldwide ,2. The n2) tension, is a complication of inadequate alveolar gas exchange in patients with severe acute and chronic lung diseases [2 acts as a gaso-signaling molecule, resulting in deleterious effects in various organs such as the lung [2 activate specific gene expression [2 sensing, CO2-dependent regulation of respiration and signaling events initiated by hypercapnia, and discuss the relevance of these data to patients with asthma and hypercapnia.Hypercapnia, an elevation in the arterial carbon dioxide  [2 is thought to traverse biological cell membranes via passive diffusion, depending upon the transmembrane concentration gradient of CO2 and the lipid/water partition behavior of the gas [2 permeability and of protein channels used by CO2 to cross membranes such as aquaporins (AQPs) [2 [2 very rapidly equilibrates with its hydrated form, H2CO3, which in turn dissociates into H+ and HCO3− catalyzed by carbonic anhydrases [Cells possess the ability to sense and respond to changes in concentration of gaseous molecules through evolutionarily conserved pathways . CO2 is es (~5%)  are signes (~5%) ,52. CO2  the gas . Howevers (AQPs) ,55 and rs (AQPs)  has chalAQPs) [2 . Once inhydrases .CO2 + H2 (pCO2) in the blood, which occurs due to insufficient removal of CO2 , can give rise to elevated pCO2 in the cerebrospinal fluid and result in elevated H+ concentrations, cerebrospinal fluid acidification. Multiple sites within the central nervous system are capable of sensing and eliciting rapid adaptive responses to these changes, which results in alteration in the rate and depth of breathing.Increased partial pressure CO2 is a complex process involving integration of multiple brain regions, effector channels and molecules. Neurons detect changes in CO2/H+ and modulate the CO2-chemosensory regulation of respiration. Several regions in the brain, particularly medulla oblongata, medullary raphe and cerebellum in the brain stem, have been described as potential area of interest [2 level [2 chemosensitivity to elicit the change in respiratory rate.Acute chemosensing of COinterest ,60,61,62[2 level . Much of[2 level . Here, w2 levels occurs via a physiological adaptation to reflect acid/base balance in the blood. The pH is a major effector of CO2-dependent signaling in the brain. The Twik-related acid-sensing potassium (K+) (TASK) channels are members of the background K2P channel family that facilitate selective K+ leak and contribute to the negative resting membrane potential in cells [2-dependent regulation of breathing. TASK-1 and -3 channels display acid sensitivity and are widely expressed in known chemosensing regions in the brain [The ability to acutely sense and respond to elevated COin cells . TASK-1,he brain . Catechohe brain . Specifi2 levels, independently of extracellular acidification [+ channels [2-dependent inhibition during hypercapnia. A recent study reported that the chemo-sensitivity of connexin 26 linked directly to a CO2-dependent posttranslational modification of the channel, independently of pH changes [2 can bind to Lys125 on connexin 26 forming a carbamate bridge between Lys125 and a neighboring residue, Arg104. The CO2-dependent modification causes a structural change in the gap junction, which facilitates altered connexin-dependent signaling . This study identified central chemo-sensitivity to elevated CO2 mediated not only by indirect changes in pH but directly by high CO2-dependent modifications.Huckstepp et al., reported adenosine triphosphate (ATP) released from brain slices derived from the ventral surface of the medulla oblongata in response to elevated COfication . Connexichannels , partici changes . Molecul2, resulting in acute respiratory acidosis (pH < 7.35). Levels of partial pressure of CO2 in arterial blood (PaCO2) among asthmatic patients experiencing severe exacerbations varies considerably. Scala reported that hypercapnia occurred in 10 to 26% of cases presenting to the emergency department with greater airway obstruction, higher respiratory rate and pulsus paradoxus [2 reaching 202 and 218 mmHg  in two 24 and 28 year-old women during severe status asthmaticus [2 values of 293 mmHg (pH = 6.77) [The pH-modulating effects of hypercapnia can be attenuated via bicarbonate reabsorption by the kidneys . Howevers pH < 7.5. Levelshmaticus , 208 mmHhmaticus  and 175  = 6.77) , a two y = 6.77)  and an e = 6.77) .2 value, 53.6 mmHg) were more likely to require maintenance therapy with β-adrenergic agents and corticosteroids, and were less likely to have been discharged from an emergency room visit [2 level, but no difference of arterial oxygen tension, than those who did survive  [2 on the first day of mechanical ventilation with the “permissive” hypercapnia averaged 67 mm Hg and exceeded 100 mmHg in 12% of cases  [In patients with asthma, the presence of hypercapnia reflects more severe airflow obstruction and more severe chronic asthma conditions ,11. Moun.3 mmHg) ,10,70,7159 mmHg) . With th2 on the lung airways, innate immunity and adipogenesis, which could contribute to the disease pathogenesis and progression of asthma.The symptoms and physiologic consequences of hypercapnia are significant. A series of adaptive mechanisms are activated in vital organs such as brain and heart to preserve tissue oxygenation and perfusion, in particular by preservation and defense of intracellular pH. The injurious effects of hypercapnia on the central nervous and cardiovascular systems are well documented . Hyperca2 levels are reported to modulate the tone of lung airways, which is in a dynamic equilibrium between excitatory and inhibitory mechanisms. Lung airway cells sense and respond to changes in CO2 levels via specific mechanisms of the vagus reflexes, molecular CO2 and pH effects. The effects of hypercapnia on the airways and airway smooth muscle is complicated. There are reports attesting to it causing increased airway contractility [2 conditions modulate the airway tone, focusing on the effects of hypercapnia and respiratory acidosis.The predominant feature of asthma is shortness of breath or dyspnea due to the excessive constriction of the airway smooth muscles. As such, relieving airway smooth muscle constriction is a therapeutic target of asthma management. Elevated COactility ,83,84,85actility ,95,96,972 levels in the blood affect the airway tone was first reported in 1892 [2-rich mixtures) caused bronchoconstriction in dogs, which was confirmed in various models of normoxic hypercapnia-exposed dogs [2 concentrations decreases specific airway or pulmonary conductance [2 exposure were initially interpreted as extrathoracic airway narrowing [1/β2 adrenergic receptor agonists. However, the direct studies of laryngeal resistance during high CO2 exposure indicated no change in animal models [2 exposure, suggesting that other mechanisms contribute to the hypercapnia-mediated airway constriction. More recently, we have reported that high CO2 acts as a signaling molecule to increase smooth muscle contraction in mouse and human airway smooth muscle cells [2, independently of hypoxia and extracellular pH, increased acetylcholine-induced cell contraction dependent on CO2 dose and exposure time in cell culture systems. In a murine model, the exposure to normoxic hypercapnia increased acetylcholine-induced airway contraction in precision lung cut slices as well as airway resistance. Furthermore, we found that, in a small cohort of patients with chronic obstructive pulmonary disease (COPD), patients with hypercapnia (PaCO2 > 45 mmHg) had higher airway resistance, which improved after correction of hypercapnia , leads to downregulation of the microRNA-133a (miR-133a) and consequent upregulation of Ras homolog family member (Rho) A and myosin light-chain (MLC) phosphorylation. Our data suggest that elevated CO2 levels activate specific signal transduction pathways in airway smooth muscle cells, which results in deleterious effects on the airway tone, leading to bronchoconstriction. Taken together, these more recent reports suggest that hypercapnia promotes airway constriction by activating the vagus nerve and high CO2-responsive signal transduction pathways to worsen airway obstruction in patients with severe asthma.Our study also provided insights into the molecular mechanisms by which high CO2 concentrations initially decreased airway constriction as well as the isolated bronchial ring tension caused by drugs such as 5-hydroxytryptamine [2 relaxed the constriction of airways in a patient with unilateral pulmonary artery occlusion [2+) [2+ levels through voltage-dependent Ca2+ channels in the K+-induced contractile model, thereby inhibiting airway smooth muscle cell contraction [2 levels may have a transient relaxing effect on contracted airways due to the decrease in pH, i.e., respiratory acidosis. There are no reports describing that hypercapnia and acute respiratory acidosis improved airway contractility or obstruction during acute exacerbation in patients with severe asthma.Hypercapnia has been also reported to lead to airway relaxation ,95,96,97yptamine ,89,90. Iyptamine ,88. In hcclusion  and youncclusion  or exerccclusion ,92. Thescclusion ,94. Extrion [2+) . Intracetraction . As suchCaenorhabditis elegans [Drosophila melanogaster [Drosophila S2 cell line, hypercapnia suppressed induction of genes involved in specific antimicrobial peptides such as diptericin that are regulated by Relish, an orthologue of the mammalian transcription factor NF-κB [2-induced inhibitions of cytokine gene expression, phagocytosis, autophagy and NF-κB signaling was independent of pH effects. Contrastingly, acidosis is known to impair the function of immune cells [2 levels decreased IL-6 and TNF expression in the lung during the early phase of Pseudomonas aeruginosa infection, and inhibited the phagocytosis of bacteria and generation of reactive oxygen species by lung neutrophils, resulting in increased burden of Pseudomonas aeruginosa in the lungs and other organs and higher mortality [2 levels increased influenza A virus replication and inhibited antiviral gene and protein expression in macrophages. Interestingly, both in vivo studies showed similar reversibility of hypercapnia-induced defects in antiviral and antibacterial immunity [2 level should be taken into consideration as a potential risk factor to cause and worsen any infections in patients with severe asthma.Respiratory infection is one of the risk factors for development and exacerbation in patients with asthma ,106,107. elegans  and Drosnogaster . In adulor NF-κB . Transcror NF-κB ,39. It dor NF-κB . In humaor NF-κB . Fitzpator NF-κB . Hypercaor NF-κB . Furtheror NF-κB ,35,113. ne cells , includine cells . Thus, hortality . More reortality . They obimmunity ,29. Therimmunity ,117,118,2 increase in BMI above the mean for age and sex translated to a 12% increase in risk of OSA [Asthma and obstructive sleep apnea (OSA) have been reported to coexist and contribute to an overlap syndrome where a bidirectional relationship may negatively affect the other condition ,120,121.k of OSA , suggestk of OSA ,125,126.k of OSA . Obesityk of OSA ,129. Reck of OSA . The meck of OSA . In animk of OSA ,133. In k of OSA , suggestk of OSA . Collect2 levels are rapidly sensed by chemosensing regions of the brain that regulate the respiratory drive, however, there are many reports suggesting that hypercapnia is also sensed by non-excitable cells and has significant effects on cellular and tissue functions. Recent discoveries suggest that hypercapnia increases airway contractility, impairs the innate immune response, and promotes adipogenesis, which likely underlies, at least in part, the negative effects of elevated CO2 in patients with asthma (2 values has been shown to be beneficial in patients with obstructive lung diseases and hypercapnia [Hypercapnic respiratory failure is a hallmark of severe asthma. As reviewed above, elevated COh asthma . Mechaniercapnia ,138,139.ercapnia ,136,137.ercapnia . There i


Studies from both humans and animals experiments have offered abundant evidence supporting that mountain sickness is associated with changes in autonomic nervous function (ANF), which can be measured by heart rate variability (HRV).We aimed to assess changes of ANF in chronic mountain disease by measuring HRV in patients with high altitude pulmonary hypertension (HAPH).From November 2018 to March 2019, 120 patients in the cardiac care unit of the People's Hospital of Tibet Autonomous Region were selected as the observation group, and 50 patients without organic heart disease served as the control group. Pulmonary artery systolic pressure was evaluated by echocardiography in patients with HAPH, divided into three groups: mild (30‐49 mm Hg), moderate (50‐69 mm Hg) and severity (≥70 mm Hg) groups. A 24‐hour dynamic electrocardiogram (DCG) was obtained for each patient. HRV  indexes were measured and compared.Compared with the control group, time domain parameters including SDNN, SDANN, RMSSD, PNN50, and HRVTI were reduced, as well as frequency domain indexes such as TP, VLF, LF, and HF. LF/HF was highest in mild HAPH group and lowest in the moderate HAPH group, and the difference between the two groups was statistically significant.The HRV of patients with chronic HAPH in high altitude areas in Tibet is significantly reduced relative to healthy controls, and significantly negatively correlated with the severity of pulmonary artery hypertension. High‐altitude‐pulmonary hypertension (HAPH) is a specific disease affecting individuals at altitudes above 2500 m. The VI World Congress on Mountain Medicine & High Altitude Physiology unified it as high altitude pulmonary hypertension (HAPH).22.1The current survey was officially implemented after approval from the Medical Ethics Committee of the People's Hospital of Tibet Autonomous Region, China . All subjects or their families fully understood the purpose and methods of the study, and provided signed informed consent. There were no health interventions involving the subjects. All individual data were anonymous prior to analysis.2.22) levels were measured by hand‐held oxygen meter  in the second left finger. The control group consisted of 50 patients with no definite cardiopulmonary disease and no signs of pulmonary hypertension on echocardiography. The subjects were all Tibetans living at altitudes >3000 m. The baseline data of each group of subjects are shown in Table From November 2018 to May 2019, 120 patients with HAPH were admitted to the Cardiac Care Unit of the People's Hospital of Tibet Autonomous Region, including 64 males, aged 22‐84 (63.78 ± 1.56) years, and 56 females, aged 28‐84 (63.34 ± 1.33) years. Those taking calcium antagonists and β blockers affecting HRV were excluded. All participants provided written informed consent. All subjects were questioned about ethnicity, occupation, living altitude and detailed medical history after hospitalization, and underwent physical examination. Hemoglobin measurement, electrocardiography, 24‐hour dynamic electrocardiography (DCG), and echocardiography were performed within 48 hours of admission. Also, finger oxygen saturation  in June 2005, based on the European Heart Association and the European Respiratory Diseases Association and approved by the International Cardiopulmonary Transplant Association. The Guidelines for the Diagnosis and Treatment of High Pressures define the standard for pulmonary hypertension as the mean pulmonary artery pressure > 25 mm Hg2.4A Phillips EPIQ 7C (coPHILIPS) echocardiographic diagnostic system with probe frequencies ranging from 1 to 5 MHz was used to measure tricuspid regurgitation flow to calculate pulmonary systolic pressure (PASP). The grouping of the included subjects was determined by the measured values, and HAPH was classified into mild (30 to 49 mm Hg [1 mm Hg = 0.133 kPa]), moderate (50 to 69 mm Hg) and severe (≥70 mm Hg).Left ventricular ejection fraction (LVEF) was derived as follows: LVEF = (EDV‐ESV/EDV) × 100, where EDV and ESV are end diastolic volume and end systolic volume, respectively.2.5am and rest for 15 minutes before inspection. The DCG was recorded and replayed on a computer, excluding ventricular/supraventricular premature or other arrhythmias. The 24‐hour continuous DCG was recorded, and the ventricular/supraventricular premature contraction and interference were automatically eliminated by the software.Subject information was collected using a 12‐lead 24‐hour full information DCG system . Sampling requirements were: starting point at 9‐11 2.5.1Time‐domain indicators for 24‐hour long‐range analysis included SD of normal RR intervals (SDNN), SD of 5 minutes average normal RR intervals (SDANN), root mean square of successive difference in RR interval (RMSSD), percentage of RR intervals differing more than 50 ms from the preceding one (PNN50) and HRVTI, also called triangle index.am to 11:00 am, and frequency domain analysis was performed. The fast Fourier transform method (FFT) was employed. Frequency domain included total power (TP), very low frequency , low frequency , and high frequency .The frequency domain index was evaluated in a short time interval of 5 minutes. The subjects were arranged in a quiet time position from 9:00 2.6t test was performed to compare group pairs, and ANOVA was carried out to compare multiple groups. The LSD‐ or SNK‐q test was performed for data with homogeneous variance, and nonparametric tests for those with heterogeneous variance. Generalized linear model (GLM) analysis was used to adjust the confounders. The Kruskal‐Wallis test was performed for analysis. Multiple comparisons were performed by the Mann‐Whitney U test. For all tests, P values < .05 were considered statistically significant.Analyses were performed using SPSS (version 25.0). Parameters with normal distribution were expressed as mean ± SD (SD), and count data as percentage or number of cases. Independent samples 33.12 at the fingertip was decreased significantly in the HAPH group compared with control patients (P < .01). Hemoglobin were increased significantly in the HAPH group compared with control cases (P < .01). The HAPH course was 5.00 ± 0.65 years. It is worth noting that the average heart rate decreased progressively in with increasing HAPH severity (P < .05). At the same time, left ventricular ejection fraction decreased progressively with increasing pulmonary artery pressure (P < .05) , time domain indexes such as SDNN, SDANN, RMSSD, PNN50, and HRVTI progressively decreased from mild to severe groups of HAPH patients compared with control values, with statistically significant differences (P ≤ .001). Similarly, after adjustment for SaO2, frequency domain indexes such as TP, VLF, LF, and HF progressively decreased from mild to severe groups of HAPH patients compared with control values, and the differences were statistically significant (P ≤ .001). In patients with mild pulmonary hypertension, the LF/HF ratio was slightly elevated compared with controls (P = .03). Meanwhile, this ratio was lowest in patients with moderate pulmonary arterial pressure followed by the severe diseased patients; both groups showed significantly lower LF/HF ratios compared with control values (P < .001). These data are detailed in Table After adjustment for oxygen saturation SaO, time do3.2.1P < .01)  Table .4Individuals living at high altitudes for a long time could have a series of physiological or pathological changes due to low pressure, low oxygen concentration, dry and cold weather, elevated solar radiation and ultraviolet radiation, which affect pulmonary artery pressure. At present, the important role of autonomic nervous regulation in its development is not clear.HRV is currently the most widely used method for the evaluation of ANF. As a noninvasive quantitative indicator for judging cardiac autonomic nervous activity, HRV has been confirmed by many clinical trials.In the time domain of HRV, HRVTI represents the overall change of heart rate. SDNN and SDANN represent enhanced sympathetic activity. RMSSD and PNN50 represent weakened vagal activity, while RMSSD is more often used to evaluate vagal nerve function because of its good stability. The time domain analysis in this study was performed on a 24‐hour time course, so assessment of long‐term ANF in patients with HAPH is more accurate.In this study, with the increase of pulmonary artery pressure, all time domain indexes of patients with HAPH were significantly reduced. We observed a significant decrease in ANF in patients with chronic HAPH. HRV frequency domain analysis often uses short‐term studies, so it is more suitable for short‐term evaluation of ANF in patients with HAPH. The TP in the frequency domain represents the sum of high frequency, very low frequency, and ultralow frequency. LF was once used as a very important indicator of HRV to reflect the functional status of the sympathetic nerve. However, with further research, LF is no more considered an effective marker of autonomic nervous activity itself, because besides autonomic nervous system, it is also affected by baroreceptor activity.In addition, studies in China have shown that the incidence of sinus tachycardia in patients with type I pulmonary hypertension mainly including idiopathic pulmonary hypertension, congenital heart disease‐related pulmonary hypertension and connective tissue disease‐related pulmonary hypertension can reach 26%.4.12. Further validation studies are needed to verify these findings.We used noninvasive methods to assess pulmonary artery pressure and cardiac function in this study. These methods tend to underestimate the level of pulmonary arterial pressure, which is not as accurate as invasive measurement methods.The authors have declared that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.Figures S1‐10 The box charts of the average values of various HRV indexes.Click here for additional data file.


LVMI and diabetes mellitus were significant influencing factors for cardiovascular events : diabetes mellitus, 2.84 ; LVMI > 156 g/m2, 2.86 ). Pre-HDBP, post-HDBP, and WABP were independently associated with higher LVMI in the follow-up periods. Hemoglobin and human atrial natriuretic peptide (hANP) levels were associated with LVMI beyond 12 months after HD initiation. Treatment of hypertension, overhydration based on hANP, and anemia may reduce the progression of LVMI and help identify HD patients at high risk for cardiovascular events.This study aimed to identify the ideal timing and setting for measuring blood pressure (BP) and determine whether the left ventricular mass index (LVMI) is an independent risk factor associated with increased cardiovascular events in hemodialysis (HD) patients. BP and LVMI were measured at baseline and at 6 and 12 months after HD initiation. BP was monitored and recorded at nine different time points, including before and after HD over a one-week period (HDBP). The mean BP measurement was calculated as the weekly averaged BP (WABP). LVMI was significantly correlated with home BP, in-office BP, HDBP, and WABP. Receiver operating characteristic analysis indicated that the cutoff LVMI value for cardiovascular events was 156 g/m Cardiovascular (CV) disease is a leading cause of morbidity and mortality in hemodialysis (HD) patients. The US Renal Data System 2014 Annual Data Report stated that, between 2011 and 2013, cardiac arrest was the primary cause of two-thirds of CV-related deaths in HD patients  to past CV events were calculated. In model 4, high LVMI and end of week after HD-BP were found to be associated with past CV events. In other words, high LVMI showed an increase in the incidence of past CV events, and low blood pressure after weekend dialysis showed an increase in past CV events (The univariate regression analysis showed that LVMI was significantly correlated with start- and end-of-week waking systolic HBP, systolic VBP, pre-HD systolic BP, post-HD systolic BP, WABP, and hemoglobin levels at 12 months after HD initiation . hANP waV events .2 with DM after performing multivariate regression analysis. End-of-week post-HD systolic BP significantly decreased 12 months after HD initiation. We also found that pre-HDBP at the start of the week, post-HDBP at the end of the week, and WABP were independently associated with LVMI on univariate regression analysis of follow-up. Multiple BP measurements taken before and after dialysis and during dialysis were reconfirmed to be the most accurate assessment format. With regard to monitoring BP, the time point at which the BP is measured should be defined clearly. Moreover, because the BP of HD patients varies with each HD session as a result of loss of excess fluid, BP fluctuation should be considered. It is important not to limit BP evaluation to only one measurement, such as before dialysis or after dialysis; rather, multiple measurements of BP should be performed and then averaged. In this study, the number of DM cases was significantly higher in patients with CVE than in those without CVE. VBP was significantly higher in patients with LVMI > 156 g/m2 than in those with LVMI < 156 g/m2. The results of this study indicated that patients with low blood pressure after weekend dialysis showed an increase in past CV events. A previous study reported that systolic blood pressure < 110 mmHg and DBP < 70 mmHg were independent risk factors of CV events and all-cause mortality [In this prospective observational study, we found an association between increased CV events and LVMI > 156 g/mortality , which sortality . In thisortality .We observed that hemoglobin levels differed at 12 months after initiating HD, but hemoglobin was not an independently associated factor with LVMI. A further analysis indicated that hemoglobin levels were correlated with end-of-week post-HD systolic BP. A previous study on the independent effect of BMI reported a greater effect on LVH in women than in men . There aIn our study, albumin was one of the factors associated with LVMI 12 months after HD initiation. This finding is consistent with other studies showing that serum albumin is negatively correlated with LVMI . hsCRP, Our study has some limitations. First, it was not double-blinded, and there was no control group in this study. Second, as an observational study, the findings established an association rather than a causal relationship among systolic BP, hemoglobin, and LVH. Third, the study did not evaluate patients’ compliance with home ambulatory BP monitoring or compliance with antihypertensive medication regimens. Furthermore, we did not apply highly precise and reliable cardiac magnetic resonance imaging, the new gold standard for measuring LVMI .Nevertheless, the findings of our study clearly defined the relative role of LVM with diabetic kidney disease in the risk assessment of patients with ESKD. Echocardiography may aid in the identification of a group at higher risk of developing CV events in HD patients. While assessing LVMI after the initiation of HD may be difficult, the treatment of hypertension, overhydration based on hANP, and anemia after dialysis initiation may reduce the progression of LVH and help identify patients at high risk for cardiovascular events before and after HD initiation.


People at increased risk of developing diabetic foot ulcers often wear therapeutic footwear less frequently than is desirable. The aims were to identify patient groups prone to nonadherence to wearing therapeutic footwear and modifiable factors associated with adherence.A questionnaire was mailed to 1230 people with diabetes who had been fitted with therapeutic footwear. Independent variables were categorized into five domains. For each domain, variables that were associated with adherence in a univariate regression analysis were entered into a multiple regression analysis.p < 0.05) between higher adherence and paid employment, current foot ulcer, previous foot ulcer, satisfaction with follow-up, self-efficacy, understanding of lost/reduced sensation as a risk factor for foot ulcerations, visible storage of therapeutic footwear at home, storage of conventional footwear out of sight, consistent choices about which footwear type to wear, and a belief that therapeutic footwear promotes ulcer healing. The five multivariate models explained 2–28% of the variance in adherence, with the strategies for footwear use domain explaining the most.A total of 429 (34.9%) questionnaires were analyzed. Multiple regression analyses showed significant associations (Patients without paid employment or without foot ulcer experience are more prone to nonadherence. To improve adherence, clinicians should advise patients to store therapeutic footwear in a visible place at home and put conventional footwear away and encourage patients’ self-efficacy and habitual use of therapeutic footwear. Future studies should investigate this topic further and explore ways to promote changes in habits. A study limitation was that all variables were self-reported. Diabetic foot ulcers affect 19–34% of people with diabetes during their lifetimes and are associated with increased mortality and risk of amputation , 3, but n = 1230) fulfilling the criteria for inclusion in the study in May and June 2017. The inclusion criteria were that the person should be at least 18 years old , have diabetes mellitus, have been prescribed therapeutic footwear at some point and have visited one of the two participating prosthetic and orthotic clinics from January–December 2016. Bilateral major amputation was the only exclusion criterion. For those who had not responded to the questionnaire 1 month later, a reminder letter was sent. The study was approved by the Regional Ethics Committee Review Board of Uppsala (reference number 2016/528).A questionnaire was constructed based on the Health Belief Model, which includes perceived seriousness of the health condition, perceived susceptibility of developing the condition, perceived benefits and barriers to engaging in the health behavior, cues to action, and self-efficacy . The mod2-test, respectively, with p < 0.05 indicating a statistically significant difference. The dependent variable, adherence to wearing therapeutic footwear, was measured with two questions adapted from the Questionnaire for Persons with a Transfemoral Amputation [The respondents’ age and sex distributions were compared to those of the rest of the sample, using a two-sided t-test and χputation . The quep-value < 0.10 were entered into a forward linear multiple regression analysis, in which p-values < 0.05 were considered statistically significant. In addition, explorative secondary analyses were conducted on variables in the domain that explained most of the variance in adherence. In these analyses, adherence levels were compared between response categories for each item using one-way analysis of variance (ANOVA) with Fisher’s least significant difference (LSD) test as a post hoc test. P-values < 0.05 were considered statistically significant. IBM SPSS Statistics for Windows, version 25.0  was used for all statistical analyses.The independent variables were grouped into five domains. The first domain consisted of variables related to demographics, health and social support with the aim of identifying patient groups prone to nonadherence. The second to fifth domains consisted of variables related to health care services, attitudes towards foot ulcers, strategies for footwear use and attitudes towards footwear. For the variables in these domains, the aim was to identify modifiable factors that were associated with adherence. Linear regression was used to test the associations between each variable and therapeutic footwear adherence. For each domain, variables with a n = 429) and the rest of the sample (n = 801) were not significantly different . Mean age also did not significantly differ between respondents  and the rest of the sample . The majority of the respondents were men, retired, had type 2 diabetes, were ulcer-free at the time of the survey and had a history of foot ulcers . Thus, 429 questionnaires were included in the analysis, for a response rate of 34.9%. The sex distributions of the respondents . The model explained 6% of the variance in adherence.In the univariate regression analyses, being retired, having paid employment, having type 1 diabetes, having type 2 diabetes, having a current foot ulcer, having a previous foot ulcer, having a partial foot amputation, and having an amputation through or above the ankle had p-values less than 0.10  had 10 Table . Only sap-values less than 0.10 in the univariate regression analyses, but only the former was significant (p < 0.05) in the multiple regression analysis  to wear it and increase the effort to choose it by needing to go and get it from somewhere else. Second, patients should be advised to keep their therapeutic footwear visible at home to provide a visual cue (reminder) to wear it and reduce the effort to choose it. Third, clinicians should discuss with patients how to form new footwear habits, that is, how therapeutic footwear can become the new default option that is chosen without conscious effort. Strategies to create such new habits is an important avenue for future research and may include advice on how to store footwear and patient education to support self-efficacy , which wThis is the largest study on therapeutic footwear adherence to date, and the results revealed that adherence was explained to the largest extent by variables that have not previously been investigated. Thus, a strength of the study was that a wide range of potential predictors were included. Some limitations of the study were that it was observational and cross-sectional, which limited the possibility of inferring causality. For example, certain ways to store footwear, high self-efficacy and the habitual use of therapeutic footwear may improve adherence, but it is possible that these variables reflect adherence rather than cause it. Thus, future studies should use interventions to modify these variables to investigate whether they actually are causes of adherence and potential targets for clinical interventions to improve adherence. In addition, studies should be conducted in other countries to test the generalizability of the results. Other limitations were that we only had data on sex and age for the non-respondents, which means that we cannot know if the sample was representative of the full population. Furthermore, all data were self-reported, and the questionnaire’s content validity and psychometric properties were not investigated.Patients without paid employment or without experience of foot ulcers are more prone to nonadherence than those with employment or with foot ulcer experience. To improve adherence, clinicians should advise patients to store therapeutic footwear in a visible place at home and put conventional footwear away and encourage patients’ self-efficacy and habitual use of therapeutic footwear.


Hypertension is a disease with significant clinical and socio-economic consequences. The reduction in cardiovascular mortality and morbidity in patients treated for hypertension is directly related to the magnitude of blood pressure reduction. Diuretics have proven useful for the prevention of cardiovascular complications in addition to a long history of safety and efficacy. The main aim for this meta-analysis is to compare the efficacy of the combination of angiotensin receptor blocker (ARB) and chlorthalidone (CTLD) to the combination of ARB and hydrochlorothiazide (HCTZ) in patients with hypertension.http://ClinicalTrials.gov and http://www.clinicaltrialsregister.eu in July 2020 to identify studies that investigate the effect of the combination of angiotensin receptor blocker with chlorthalidone or hydrochlorothiazide on the systolic and diastolic blood pressure in patients with hypertension. Changes in systolic and diastolic blood pressure (BP) expressed as a weighted mean difference (WMD) were our primary outcomes. The random-effects method was chosen as the primary analysis and results were presented with a 95% confidence interval (CI). Sensitivity analysis was performed and bias was assessed.A comprehensive literature search was conducted through electronic databases PubMed, MEDLINE, Scopus, PsyInfo, Cochrane, eLIBRARY.ru, Our search returned 2745 titles. Of them, 51 full-text articles remained to be subjected to assessment. Comparisons of ARB/HCTZ versus ARB showed changes in BP of −6.89  mmHg for systolic BP and − 3.67  mmHg for diastolic BP. For the ARB/CTLD versus ARB/HCTZ comparison changes were − 6.30  mmHg for systolic BP and − 3.57  mmHg for diastolic BP.Our analysis suggests a small but significant favor for CTLD in blood pressure control when compared to HCTZ. We believe it should be considered as a valuable alternative for HCTZ and an option for fixed dose combinations with an ARB although further research is required. Hypertension is a major global public-health challenge affecting approximately 1 billion individuals worldwide, with a projection to increase to 1.56 billion by 2025 given the increasingly aging population . The sevThe reduction in cardiovascular mortality and morbidity in patients treated for hypertension is directly related to the magnitude of blood pressure reduction. The utility of diuretics in the prevention of cardiovascular complications has been shown in major clinical trials , and theHowever, many treated hypertensive patients have inadequate blood pressure control and do not attain treatment goal , 13. AltCombination therapy with a renin-angiotensin system (RAS) inhibitor (either an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker [ARB]) plus a diuretic is a widely used and effective approach that has become an established component of evidence-based hypertension treatment guidelines –18. The The main aim for this meta-analysis is to compare the efficacy of the combination of angiotensin receptor blocker and chlorthalidone to the effect of the combined use of angiotensin receptor blocker and hydrochlorothiazide in adult patients with hypertension.http://ClinicalTrials.gov and http://www.clinicaltrialsregister.eu) in September 2018 to identify studies that investigate the effect of the combination of angiotensin receptor blocker with chlorthalidone or hydrochlorothiazide on the systolic and diastolic blood pressure in patients with hypertension. The following keywords and various combinations were used in the search: hydrochlorothiazide, chlorthalidone, diuretics, ARB, angiotensin receptor blocker, hypertension, blood pressure, clinical trial, controlled, randomi*, double blind. Results were not limited only to those in English. Similar key words and their combinations were used in Cyrillic: гидрохлортиазид, хлорталидон, диуретики, AR блокеры, ARB, повышеное давление, артериальная гипертензия, кровяное давление, артериальное давление, клиническое испытание, клиническое исследование, контролированное, рандомизированное, двойное слепое. Unfortunately, results in Cyrillic were not found. Full-text articles and abstracts were checked for relevance to the topic and were assessed. Generally, we did not restrict the search period but relevant articles were mainly published in the 1980-2020 period.A comprehensive literature search was conducted through electronic databases: Cochrane, eLIBRARY.ru, MEDLINE, PsyInfo, PubMed, Scopus, and registries for data of clinical trials (Search results were assessed for relevance on the basis of the following inclusion criteria: (1) type of study/trial—epidemiologic, controlled, and randomized; (2) investigation of the effect the combination of angiotensin receptor blocker with chlorthalidone or hydrochlorothiazide on the systolic and diastolic blood pressure; (3) type of subjects included—representatives of the whole population or a specific stratum; (4) patients with essential hypertension; (5) access to raw data; (6) eligibility for statistical analysis. If any clarification of results or conclusions was needed, authors were contacted for additional information. We have not limited our search to a particular angiotensin receptor blocker but have attempted to review the group as a whole. Sources were excluded if they represented trials in which the principle arm reported other outcomes different from changed in systolic and diastolic blood pressure; other conditions apart from hypertension; other combinations of CTLD and HCTZ .Effective public health practice project was utilized to assess study quality. This tool includes assessment of different characteristics like selection bias, study design, blinding, data collection method, confounders, and drop outs in order to help raters form an opinion of quality based upon information contained in the study. Studies that correspond to the aforementioned inclusion criteria are subjected to a quality estimation and general ratings are taken into account when results from the study are interpreted. Overall quality of evidence for the two primary outcomes was assessed according to Grade methodology.All relevant studies identified were carefully reviewed, sorted, and assessed. Figure Q and the I2 statistics, where p values of less than 0.10 were used as an indication of the presence of heterogeneity and an I2 parameter greater than 50% was considered indicative of substantial heterogeneity [Because of the significant heterogeneity of the individual studies, we chose the random-effects method as the primary analysis. To assess the aforementioned heterogeneity of treatment effect among trials, we used the Cochran ogeneity . The thrOur search returned 2745 titles. Once duplicate reports and studies not relevant to the analysis were excluded, 51 full text articles remained to be subjected to assessment. After evaluation based on the inclusion criteria described in the methods, only 15 studies presenting data for 28 separate dose regimens remained to be included in the analysis comparing the efficacy of the combination of angiotensin receptor blocker and chlorthalidone to the effect of the combined use of angiotensin receptor blocker and hydrochlorothiazide in patients with hypertension . I2 and Q values signify a moderate heterogeneity of results. Bias has been assessed . They also comment that the incremental reduction in blood pressure for the combination containing 25 mg CTLD is significantly greater than what has previously been seen with an FDC containing 25 mg of HCTZ [Only one article was found that compared the effect of the combination of ARB/CTLD on the systolic blood pressure to the effect of monotherapy with ARB. Sica et al. compared treatment with azilsartan medoxomil (AZL-M) 20 mg, 40 mg, or 80 mg; CTLD 12.5 or 25 mg; or 1 of the 6 combinations of these doses . Their primary endpoint was the change in systolic blood pressure determined by an ambulatory blood pressure measurement. The authors conclude that for the pooled AZL-M/CLD 40/25-mg and 80/25-mg FDC groups, SBP reduction by ABPM was 28.9 mmHg and exceeded AZL-M 80 mg and CLD 25 mg monotherapies by 13.8 mmHg and 13 mmHg, respectively  reduction in stroke for all trials, 46% (35-55 %) in primary prevention trials, 44% (21-44 %) in secondary prevention trials, and 35% (20-47 %) in trials including subjects with a history of coronary heart disease . Other aOur analysis suggest as many have before us , 47–52 tIt should be noted that a certain degree of heterogeneity exists in the studies which were deemed eligible and were included in the analysis. This can be attributed to multiple factors such as variety of study design and outcomes; differences in the inclusion and exclusion criteria; the way of measuring BP; different ARBs used; and varying doses of diuretics. We have, however, attempted to determine the significance of those differences by performing sensitivity analysis.p = 0.0016) [Interest in CTLD was renewed of late. MRFIT is the first trial to suggest superiority of CTLD. Results from MRFIT show that replacement of HCTZ with CTLD might lead to lower coronary heart disease mortality . Dorsch  0.0016) . This es 0.0016) . At the  0.0016) . We have 0.0016) , 36 repoThere are several studies investigating the effect of CTLD and HCTZ on blood pressure. Greater reduction in SBP was recorded in a small randomized, single-blinded, crossover study comparing CTLD 12.5 mg/day (force-titrated to 25 mg/day) and HCTZ 25 mg/day (force-titrated to 50 mg/day)  and in aWe evaluated a large number of sources in our attempt to examine the interchangeability of HCTZ and CTLD when they are used in combination with an ARB by assessing their effect on systolic and diastolic blood pressure. We tried to draw conclusions only by referring to trials we deemed to be of satisfactory quality see . Even thThere are a number of limitations intrinsic to the analysis. First of all, high quality trials investigating the efficacy of CTLD combined with ARB are scarce. Secondly, we have evaluated the effects of HCTZ and CTLD using data for combined doses. Almost all studies included in our statistical analysis were conducted relatively recently and all but two were funded by industry. Additionally, we did not take into consideration any existing comorbidities of the patients.The combination of an ARB with a diuretic is a widely used method for addressing hypertension as a first or subsequent line of treatment. The most commonly used diuretic seems to be HCTZ. Our analysis suggests that CTLD should be considered as a valuable alternative for HCTZ and an option for fixed dose combinations with an ARB due to its tentative prevalence in blood pressure control when compared to HCTZ.Additional file 1: Table S1. Quality assessment results. Figure S1. Funnel plot for systolic blood pressure ARB/HCTZ versus ARB. Figure S2. Funnel plot for diastolic blood pressure ARB/HCTZ versus ARB. Figure S3. Funnel plot for systolic blood pressure ARB/CTLD vs ARB/HCTZ. Figure S4. Funnel plot for diastolic blood pressure ARB/CTLD vs ARB/HCTZ. Table S2. Sensitivity analysis SBP and DBP ARB/HCTZ vs ARB. Table S3. Sensitivity analysis SBP and DBP ARB/CTLD vs ARB/HCTZ. Table S4. Quality of the evidence according to the GRADE methodology for the 2 outcomes.


Increased blood pressure (BP) variability may worsen the prognosis of stroke. This study aimed at investigating the association between BP variability and early functional prognosis in patients with pontine infarction.  According to types of pontine infarction, all the 137 patients were divided into two groups: 70 patients with paramedian pontine infarction (PPI) and 67 patients with deep pontine infarction (DPI). Common risk factors, 24-hour continuous blood pressure monitoring data, and the coefficient of variation were collected after admission in the hospital. Functional outcomes were evaluated with modified Rankin scale (mRS) at 3 months after discharge . P=0.003; OR = 1.08, 95% CI = 1.002–1.166, P=0.04; OR = 1.58, 95% CI = 1.164–2.159, P=0.003; OR = 9.87, 95% CI = 1.045–32.193, P=0.04).  The level of Glu, HbA1c, LDL, and NIHSS scores in the PPI group was significantly higher than that in the DPI group, and the concentration of blood uric acid was lower in the PPI group. Diastolic pressure in the PPI group is significantly higher than that in the DPI group, and coefficient of variation (CV) of systolic pressure in PPI is higher when compared with DPI ((88.77 ± 1.71) mmHg vs. (80.74 ± 1.31) mmHg; (11.54 ± 0.35) vs. (10.24 ± 0.25)). In multivariate analyses, the CV of systolic pressure, diastolic pressure, NIHSS scores, and the paramedian pontine infarction was independently associated with 3-month clinical outcome  variability, NIHSS scores, and paramedian pontine were associated with early poor prognosis in patients with acute pontine infarction. Stroke, the third leading cause of death behind heart disease and cancer with its morbidity, disability, mortality, and high recurrence rate, has become one of the most serious diseases threatening human neurological health . 85% of Hypertension is a serious risk factor for stroke  and may By impairing the structure of vascular endothelial function, unsteadiness of BP variability could lead to atherosclerosis, and the formation of atherosclerotic plaques, BP variability, in turn, leads to vascular atherosclerosis or other vascular diseases –12. BP vWe hypothesized that BP variability and localization of pontine infarction would contribute to poor neurological outcomes in acute pontine infarction. The aim of this study was to evaluate the influence of BP variability on pontine infarction and early prognosis based on the infarct location in the pontine infarction.The study included clinical data of 137 consecutive patients admitted for acute pontine infarction and hospitalized between December 2016 and September 2018 in Kaifeng Central Hospital. Patients were enrolled in this study when they fulfilled the following criteria: (1) nonatherosclerotic factors such as cardiogenic cerebral embolism, vasculitis and dissection, and other unknown etiologies, and (2) no history of malignancy, brain tumor, intracerebral hemorrhage, severe cardiac failure, severe hepatic failure, severe renal failure, renal hypertension, or endocrine diseases, such as primary hyperaldosteronism or pheochromocytoma. Clinical early outcomes were evaluated using the modified Rankin Scale (mRS) at 3 months after admission. This study was approved by the Ethics Committee of the Kaifeng Central Hospital. Written informed consent was obtained from all patients prior to their enrolment in this study. Each patient was evaluated by at least one neurologist. The diagnosis was based on clinical presentation and confirmed by magnetic resonance imaging (MRI) findings of the brain and carried out during the first 48 h after admission. Neurologists, unaware of the patient's blood pressure (BP), reviewed the MRI scans to characterize the pontine infarction type. All the cases were divided into two groups according to stroke location: paramedian pontine infarction (PPI)  and deep pontine infarction (DPI) . Demographic data and medical history were recorded, as well as whether the patient had hypertension prior to the stroke.The BP was measured by the ambulatory blood pressure monitoring  , which wCerebral infarctions and their locations were evaluated using a 1.5 T MRI scanner  on the day of admission. Acute ischemic stroke was diagnosed on diffusion-weighed imaging .U test was performed for continuous variables, and the χ2 test or Fisher's exact test was performed for categorical variables. Binary logistic regression models were established to investigate risk factors contributing to poor outcome at 3 months after discharge. Values of P < 0.05 were considered significant. SPSS statistical software version 23  was used for statistical analysis.All variables were expressed as means, or numbers (percentage). Analysis of variance or the Mann–Whitney A total of 137 patients were included in the study, and no patients died during the follow-up period. The medical characteristics of all the patients are shown in P < 0.05), whereas, in contrast with PPI group, the concentration of blood uric acid was lower than that in the DPI group (P < 0.05). There was no significant difference in HDL, cholesterol, urea, creatinine, and homocysteine between the two groups (P > 0.05). All patients received basic therapy including antiplatelets, lipid-lowering medications, and improving the function of mitochondria, and nearly 10% of them received thrombolytic therapy, but we did not find significant difference in the therapies between the two groups (P > 0.05).The common risk factors are shown in In order to study the blood pressure variability between different groups of patients, 24-hour dynamic blood pressure monitoring was performed. Our study showed that diastolic pressure in the PPI group is significantly higher than that in the DPI group. CV of systolic pressure in PPI is higher when compared with DPI. However, we could not find any difference in SD of systolic and diastolic BP between the two groups .In our study, we observed the relationship between the location of pontine infarction and BA stenosis by magnetic resonance angiography (MRA). There were 51 patients having BA stenosis in PPI, only 9 in the DPI group. We found that the stenosis rate of BA in PPI was significantly higher than that in DPI by chi-squared test .P < 0.1). Our finding suggested that CV of systolic pressure, diastolic pressure, infarction location, and NIHSS scores was directly associated with the poor outcome at 3 months (The OR and 95% CI were calculated after adjusting for the following variables: glycated hemoglobin, LDL, CV of systolic pressure, diastolic pressure, uric acid, infarction location, and NIHSS scores, for they have difference between the two groups (3 months .The present study demonstrated that the systolic BP variability and diastolic BP were associated with 3-month clinical outcome. And the effect was independent of common risk factors such as LDL, age, and gender. Further analysis showed that the patients in the PPI group had poor outcome, suggesting lesion location is most strongly correlated with neurological outcomes of patients with pontine infarction. It has been suggested that BP variability plays an important role in the development of vascular events and may result in poor outcome –17; to oIt has been previously reported that age, history of diabetes mellitus, arterial stenosis, and high serum urea have been associated with prognosis –21. AmonPrevious studies have reported that systolic BP variability in the acute phase of ischemic stroke is associated with neurological lesion, poor outcome, and even early death , 23. HowPrevious studies have reported the location of pontine infarctions is associated with the poor outcomes –28, and Some limitations need to be noted in the present study. Firstly, being a single-center study, the universality of the study may be limited. This is an observational study, so the results may not clearly state the causal relationship between BP variability and early neurological outcome. Secondly, the associations between BP variability and the neurological outcome may differ according to different cause of each case, the sample size of our study was insufficient, and we cannot examine heterogeneity among the potential causes for the insufficient of the sample size in our study. In addition, we did not measure infarct volume and did not calculate the circadian rhythm of BP in this study, and further study is needed to verify our findings.Despite the above limitations, our results suggested that there has a relationship between BP variability and early prognosis in acute pontine infarction for the first time. These results provided a potential modifiable risk factor for the therapy of pontine infarction. Further research was needed to investigate the causal relation between BP variability and early prognosis.


In obstructive sleep apnea (OSA), there are brief episodes of partial or total upper airway obstruction during sleep, which leads to apnea or hypopneas. Much attention is required to understand OSA's effects on the human body, owing to how common but under-diagnosed this disorder remains. Though the role of OSA in cardiovascular (CV) disease is commonly discussed, it remains unclear how it induces changes in the human body. The intermittent and recurrent hypoxia occurring at the cellular level in this condition is critical for the dramatic changes observed. Vascular endothelial cell (VEC) injury and other mechanisms seen in OSA lead to changes in the CV system. OSA can take a toll on a person's overall functioning, especially with so much importance in today's time on preventing and treating cardiac-related deaths. A total of 31 published articles were included from the PubMed database for our literature review. Most of the studies showed a strong association of OSA with hypertension, especially resistant hypertension. Findings were consistent with OSA's independent role in causing CV diseases, included heart failure, coronary artery disease (cardiac ischemia), arrhythmias, and ischemic stroke. Continuous Positive Airway Pressure (CPAP) is one of the reliable and beneficial treatments for OSA patients. OSA is a treatable and modifiable risk factor for cardiac events and related deaths. The primary purpose of our review article was to address any existing gaps between OSA and its effect on the human body with particular emphasis on cardiovascular changes. Like William Shakespeare quotes, "Innocent sleep. Sleep that soothes away all our worries. Sleep that puts each day to rest. Sleep that relieves the weary laborer and heals hurt minds. Sleep, the main course in life's feast, and the most nourishing." . Sleep iQuite often, OSA remains unnoticed by the patient, and it is usually that their bed partner complains to them of loud snoring, snorting, choking, or cessation of respiration while they are asleep. A survey on OSA's current prevalence indicates that one-third of sleep studies showed some degree of OSA (AHI ≥5 events per hour of sleep). Nearly 13% of men and 6% of women between 30 and 70 have moderate to severe forms of OSA (AHI ≥15) ,5, whichOSA is the most common secondary cause and worsening of hypertension despite adequate anti-hypertensive medications . A compaMethodThe central electronic databases used were MEDLINE/PubMed and PubMed Central (PMC), including the terms of Medical Subject Heading (MeSH). 'Sleep apnea' and 'Hypertension' were the two MeSH words used together. Our investigation included studies on humans of 45-64 years, published in the last 10 years and in the English language. Gender differences were not taken into account. Studies in non-English language and performed on animals were excluded for this review. Our study was primarily targeted to find sleep apnea as an independent cardiovascular risk factor. We have worked as a team and divided members into two groups. Group one included three members, and group two included two members. Group two was assigned to read through all the titles and the abstract while group one read through all the free full-text articles' information. The information provided in those publications was recorded manually on Microsoft Excel sheets; this included the publication title, journal name, date of publication, Digital Object Identifier (DOI), abstract, and full-text information. Each detail on the datasheet was again read carefully by the team members to annotate points in a different datasheet that supported our research objective. As this was a traditional literature review, Quality Assessments of the studies and approval by the Research and Ethics Committee were not done.ResultA total of 31 articles were gathered for this literature review. Twenty-seven articles were free full-text publications, whereas the remaining four articles were only abstracts.'Sleep apnea' and 'Hypertension' in the MeSH search builder yielded 2094 articles. Five hundred thirty-nine publications remained with the inclusion criteria of human studies, age group 45-64 years, English language, and published within 10 years. Exclusion criteria included animal studies and non-English literature. The finding is summarized in the following table  diseases associated with OSA and the mechanism behind how OSA influences CV events. The detail of these findings is sub-headed as follows to understand them more vividly.Pathological Changes Seen in OSA2−) formation [In OSA, the mechanism of forced inspiration against the occluded upper airway produces negative intra-pleural pressure. As the apnea continues, there is a worsening of hypoxia and hypercapnia. Further, hypoxia causes vasoconstriction in the systemic and pulmonary circulation due to sympathetic nervous system activation. A vicious cycle of hypoxia-reoxygenation occurs during the apnea/hypopnea-recovery period that triggers the generation of homocysteine, cysteine, and free radicals, causing oxidative stress ,16. Recuormation .In a study by Drager et al. , we alsoOSA is commonly seen in men at a young age with significant changes in their diastolic blood pressure (DBP) and triglyceride (TG) levels. Such changes put men at higher cardiovascular risk than women. Abnormalities in inflammatory cells such as total white blood cells (WBC) or neutrophil counts were typical in age <65 years. However, dysfunction in monocyte or macrophage cells, a precursor for atherosclerotic plaques, were more strongly correlated in women and African Americans with OSA . OSA is a leading cause of secondary hypertension. It was observed that OSA patients (asymptomatic mild-to-moderate) who are middle-aged adults have concomitant metabolic syndrome , which i2) <92 independently correlated to E/A ratio, and they had an increased risk of experiencing left ventricular (LV) diastolic dysfunction by almost 2.76-fold. Pressure overload in LV occurs due to the increase in arterial blood pressure, sympathetic activity, and negative intrathoracic pressure. The pulmonary capillary wedge pressure (causing reduced LV compliance) and right ventricular (RV) overdistention (causing LV filling reduction) occurred in the initial stage of OSA [A marker for diastolic dysfunction indexed left atrial volume (LAV-i) was significantly altered in OSA patients; these patients were asymptomatic without any symptoms or signs of heart failure (HF). Other changes included the E'/A' ratio , E', and A wave  . Patiente of OSA . The newe of OSA .OSA increases both the systolic and diastolic BP , and theOne clinical trial  showed aCardiovascular Biomarkers in OSARepeated hypoxia observed in OSA causes the release of various proteins that leads to VEC injury, a precursor for cardiovascular diseases. These proteins can serve as biomarkers for diagnosing the severity of cardiovascular diseases, even in asymptomatic OSA patients. Detail of such proteins is given in Table Effect of OSA Treatment on Cardiovascular Diseases20) and placebo (4 mm H2O) CPAP. It was seen that patients on effective CPAP had decreased carotid-femoral pulse wave velocity (cfPWV) of 0.7 ± 0.6 m/sec , achieving their target cfPWV by a near increase of 1.5 times more. The above effect was comparable to the results seen in patients on lipid-lowering agents [A single-blinded clinical trial  for hypeg agents . A decreIn the clinical trial by Walia et al.  factors In one study , patientMiscellaneous Conditions Associated with OSAThe presence of OSA and chronic kidney disease (CKD) can mutually enhance the magnitude of each other's problems , especiaStrengths and limitationsThis literature review has mostly included observational studies and clinical trials. No meta-analysis was included. The majority of the selected studies have explained the independent effect of OSA on the cardiovascular system. However, a minority of them have also explained the co-existing effects of metabolic syndrome and obesity on OSA and CV health. Other drawbacks of this study are using a limited electronic database (PubMed and PMC) and excluding non-English literature. For this article, some of the points like definition have been quoted from other references in the original article, which dates more than 10 years back.In this review, we found distinct, independent effects of OSA on the cardiovascular system. The recurrent intermittent hypoxia occurring at the cellular level in OSA provokes neuro-humoral and biochemical changes. This includes sympathetic nervous system activation, systemic inflammation with oxidative stress, changes in lipid profile, VEC injury with dysfunction, and activation of the renin-angiotensin-system (RAS) and hypothalamic-pituitary-axis (HPA). These changes occur very early in an OSA patient, independent of the AHI events and OSA severity. Thus, OSA is linked with various cardiovascular changes/diseases as follows: an increase in arterial BP , atherosclerotic changes in the coronary and cerebral vasculature , left ventricular diastolic dysfunction (heart failure), alteration in the main pulmonary artery caliber, and the right ventricular system dysfunction. Successful reversal of such neuro-humoral and biochemical expressions is observed with CPAP treatment. OSA can be easily detected with polysomnography/sleep studies, which may not be cost-effective and convenient to perform in all patients. However, a high level of clinical suspicion should be present to detect OSA, especially in the setting where the cardiovascular disease is uncontrolled while on its usual treatment. OSA screening can be done simply by asking for symptoms such as snoring, choking, fatigue, or excessive daytime sleepiness. Annual polysomnography can be advised for screening OSA in suspected patients, as it may be better to over-diagnose than to underdiagnose an ominous disorder. Future research activities are required to determine when polysomnography as a screening tool for OSA can effectively improve cardiovascular outcomes.