Despite the outstanding measles vaccine coverage (MVC) in Eritrea, sporadic outbreaks are not uncommon. Therefore, understanding the incidence of laboratory-confirmed measles virus cases, related factors, and spatial inequalities in testing and surveillance remains crucial. In this analysis, we evaluated the incidence and spatiotemporal distribution of measles in Eritrea. An evaluation of the factors associated with measles vaccination and IgM positive (+) febrile rash was also undertaken.A retrospective (period: 2002–2020) study was carried out by abstracting data from the integrated disease surveillance and response database (IDSR). Data was analyzed using descriptive statistics and binary logistic regression. Spatial variability and distribution of confirmed cases was evaluated using ArcGIS Pro version 3.0.1.p = 0.005); 15–29 years: OR = 7.0 ; and > =30 years: OR = 16.7  p < 0.001]. Other associations included: Address – higher in Anseba ; Debub ; Gash-Barka ; Northern Red Sea ; and Southern Red Sea . Further, test positivity was higher in health centers  and hospitals . Additional factors included vaccination status - higher in the unvaccinated ; and year of onset of rash – . Uptake of measles vaccine associated with a similar complement of factors.In total, 9,111 suspected cases, 2,767  were serologically tested. The median (IQR) age, minimum-maximum age were 7 years (IQR: 4–14 years) and 1 month-97 years, respectively. Among the 608(21.9%) laboratory-confirmed cases, 534 (87.8%) were unvaccinated and 53 (9.92%) were < 1 year old. The crude incidence rate for MV was 14/100,000 persons. The age-specific positivity rate per 100,000 suspected cases tested was 21.5 with individuals >30 years presenting with the highest rates . Higher odds (OR) of MV test positivity was associated with age at onset – higher in the following age-bands [10–14 years: OR = 1.6 (95%CI, 1.1–2.2, value of In large part, efforts to eliminate measles in Eritrea are hindered by disparities in vaccine coverage, under-surveillance, and low vaccination rates in neighboring countries. Enhanced surveillance and regional micro planning targeting hard-to-reach areas can be an effective strategy to improve measles elimination efforts in Eritrea. Morbilivirus, family Paramyxoviridae, is an antigenically monotypic, enveloped, single-stranded (SS) virus with a non-segmented negative (−) sense RNA genome  and can cause multiple complications  (Measles virus (MV), a member of the genus A genome . Like otber R0 = 0–18 and  adults) . The 1 tBefore the introduction of the measles vaccine in the 1960s, MV epidemics occurred periodically every 2–3 years), with approximately 2.6 million mortalities annually  years, w. GloballBy most accounts, the remarkable decline in the burden of measles in Sub-Saharan Africa (SSA) is closely intertwined with multiple policy prescriptions of the World Health Organisation (WHO) policy prescription on immunization. In 2008, following the earlier standards set by the 2006–2015 Global Immunisation Vision and Strategy; the WHO adopted its four-point pre-elimination plan for the African Region (AFR) . These iIn Eritrea, the Expanded Programme on Immunisation (EPI) began in 1980 (pre-independence era). The original EPI included the provision of the first dose of measles-containing vaccine (MCV1) at 9 months of age. However, the coverage of MCV1 in this period was very low, 34% : Maekel , Gash Barka, Anseba, Debub, Debubawi Keih Bahri (DKB) (Southern Red Sea) and Semanawi Keih Bahri (SKB) (Northern Red Sea). The regions are further subdivided into 58 sub-zones, 699 administrative areas, and 2,564 villages. Healthcare is provided, almost exclusively, by the Eritrea Ministry of Health through a three-tier system, namely primary care level (serves ~500–2000 people), secondary care level  and tertiary care level . Using the reaching every district approach, the country’s EPI program, which is housed as a unit within the Department of Public Health; delivers immunization services, 6 days per week, through 302 (85%) health facilities and 450 outreach sites  was abstracted IDSR using a form designed for this purpose. The variables captured included age at the beginning of the rash, years, address (region / zone), facility level, vaccination status, and last vaccination. To ensure compliance with specific ethical requirements, all participant data were de-identified. At this stage, the data were managed using CSPro software (version 7.0).■ A suspected measles case was defined according to the WHO-AFR Measles and Rubella Surveillance Guideline [WHO-AFR] – persons with a generalized maculopapular rash, fever, plus one or more of the following: coryza, cough, conjunctivitis, OR any person in whom a clinician suspects measles .+) of a titer that exceeded the thresholds indicative of infection in people without evidence of vaccination in the last 30 days  to a laboratory confirmed case .■ A non-measles case was defined as any notified case/suspected case that was measles-specific IgM (−) after testing as per established protocols.■ The status of measles vaccination was categorized into vaccination (at least MCV1), non-vaccination, and unknown status.The outcome variables included the crude incidence rate (CIR), age adjusted incidence rates, and age-specific measles IgM positivity. Additional outcomes included factors associated with measles-specific IgM positive febrile rash and vaccination. The spatial distribution of measles tests and positive cases from 2002 to 2020 across Eritrean sub-zones was also evaluated.U, or Chi-squire statistics . Crude incidence rates (CIR), age standardized rates (ASR), and specific measures of central tendency, medians [±Interquartile ranges (IQR)] and means [±standard deviations (SD) were computed where applicable]. The CIR was calculated by dividing the total number of confirmed cases (by laboratory serology) per year or age category as the number of the total population. The numbers used in these denominators were obtained from the Eritrea National Statistics Office . To testThe study was carried out according to the Declaration of Helsinki and was approved by Ethical Committee of the Eritrean Ministry of Health (EMH). Written consent was not obtained from the patients. Instead, the data were identified and all ethical and professional considerations undergirding confidentiality/or others protections of patient information were rigorously implemented.From 2002 to 2020, ~ 9,111 cases of febrile rash notifications were reported in Eritrea. However, of 2,767 (30.4%) cases were tested; MV IgM was 607 (21.9%) and 82 (3% of the tested) were epidemiologically linked. Mean (±SD), 10.5 months (±10.4 months) with a minimum age – maximum age of the cases was 1 and 97 months, respectively. The overall CIR of MV was 14 per 100,000. Overall, 17  cases died due to measles and/or its complications. This translates into a reported MV-related death rate of 24.6 per 1,000. See In this analysis, a higher CIR and age-specific incidence of measles was observed in adults: = < 4 years, 11.7 per 100 samples tested; 5–9 years, 8.6 per 100 samples tested; 9–14 years, 17.4 per 100 samples tested; 15–29 years, 49.8 per 100 tested; > = 30 years, 69.9 per 100 tested. The CIR (ASR) during the study period: = < 4 years, 3 per 100,000 ; 5–9 years, 2.5 per 100,000 ; 9–14 years, 2 per 100,000 ; 15–29 years, 6.4 per 100,000; > = 30 years, 4.2 per 100,000 . Furthermore, there was a pan age group increase in measles incidents from 2015 to 2018. See n = 334). The median age of positive individuals is higher than that of negative individuals . The highest proportion of positives lie in the age group 15–29 years: 212 (35.1%) followed by more than 30 years 146 (24.2%), less than 4 years 102 (16.9%), 5–9 years 79 (13.1%), and 10–14 years 65 (10.8%), chi-square test p < 0.001. Among the countries zones, a higher positivity was observed in the regions of NRS 145 (23.8%) and Anseba 142 (23.4%), chi-square p < 0.001. No apparent differences in the number of incidence cases by sex were observed , p < 0.001], Northern Red Sea , Debub  and Anseba  when compared to Maekel region. Hospitals’ samples showed higher of odds of MCV positivity  when compared to health centers or stations . Higher odds of test positivity were also observed in unvaccinated individuals . See Among the measles positive individuals’ females account for 55% , 235 (19.26%), 150 (12.3%), 365 (29.8%) and 198(97.1%) of patients = <4 years, 5–9 years, 10–14 years, 15–29 years and > =30 years were not vaccinated. In the respective administrative zones, namely: Maekel, Anseba, Debub, Gash-Barka, NRS, and SRS; 270 (25.62%), 332 (41.4%), 153 (48.57%), 189 (84.00%), 232 (84.06%), 55 (94.83%) of patients presenting morbiliform rash were unvaccinated. Additionally, 228 (30.9%), 304 (44.7%) and 315 (66.63%) of patients with rashes in health stations, health centers and hospitals were not vaccinated. Last but not least, = < 2014 vs. > =2015 analysis of = 2014 vs. > = 2015 of the vaccination status of individuals who presented a rash indicated that 720 (49.38%) and 510 (40.13%) were not vaccinated.In the bivariate analysis, we demonstrated that unvaccinated individuals were older with a median age (IQR) of 9 (IQR: 1–25) years vs. the vaccinated 3 (IQR: 3–8) years, Mann–Whitney p-value<0.001]; administrative zone ; [NRS: aOR = 7.6 (95% CI: 4.6–12.7)]; [Anseba: aOR = 2.4 (95% CI: 1.8–3.2)] [Debub: aOR = 1.8 ]; and health facility [Health centre: 0.95 ]; . Lastly, there was a notable association between year of rash onset and vaccination status . In other words, for each increase in year, there was a 6% increase in vaccination status of individuals with febrile rash (p = 0.02) ,  = 0.02) .In an era where measles elimination is increasingly becoming a reality even in countries in some of the most disadvantaged parts of the world; sound evidence on incidence, trends, and associated factors at the national and rural level is essential. The current exploratory study aims to investigate these themes in Eritrea. In each and every one of these domains, we discovered multiple standout features. Foremost is the fact that the incidence of measles in Eritrea undulated between moderate to low rate periods over the course of 18 years. Highest CIR > 1 per 100,000 were reported in 2003 ; 2012 ; 2013 ; 2015 ; 2016 ; 2016 ; 2017 ; and 2018 . These results are in line with data from a recent study on progress towards measles elimination in Eritrea: 2003–2018 ; our study relied entirely on laboratory confirmed cases. Adoption of this approach was based on the fact that clinical case definition has a limited role in measles case classification in some pre-elimination settings. In other words, the likelihood that measles-like rash symptoms are due to other diseases like Scarlet fever, Rubella, Epstein–Barr virus, Parvovirus B19 Infection (Fifth disease), Chikungunya, and Dengue virus (which are increasingly affecting these populations) is high in some settings. Although outbreaks of Dengue virus, Rubella, and Chikungunya have been reported in Neighboring countries, data from Eritrea is limited. Therefore, the contribution to notified cases is hard to discern.Additionally, we are aware that the exclusive use of laboratory confirmed cases in estimating the incidence of measles incidence in recent years is severely undermined by suboptimal tests of suspected cases. With the exception of 2003, the frequency of serological tests was higher  prior to 2012; a sharp decline was observed in the subsequent years. In 2017 for instance, the testing frequency of suspected cases reached a nadir of 6.22%. Taking all this into account , the possibility that our study has underestimated the true incidence of measles is substantial. The underreporting of measles can also be attributed to existing surveillance methods. In general, measles surveillance in WHO-AFR is largely based on passive surveillance . In areas where access to hospital or other care facilities is compromised by sub-optimal awareness, poor health seeking behavior, long distances to facilities, vaccine hesitancy, self-medication, and use of alternative medicine; under-reporting of measles cases is inevitable. As such, reported cases reflect a small proportion of the actual case burden in most countries in WHO-AFR . In this study, the researchers demonstrated that only 76.4% of the study participants had the required concentration of protective antibody titers for measles . A diffeFurther stand-out features of our results include the low mortality rates, potential improvements in case notification efficiency, and as previously noted ; gaps inAccording to the WHO, suspected measles cases should be confirmed in the laboratory using serological tests or Nucleic Acid based tests (RT-PCR). This requirement is based on the assumption that the positive predictive value (PPV) of clinical case definition is low in settings with a low incidence of measles. The problem of low PPV can be compounded by the high prevalence of viruses that can cause morbiliform rashes . As noteIn a separate analysis, we investigated the epidemiology of laboratory confirmed measles cases. According to our analysis, the diagnosis of measles was associated with age, address, facility type, vaccination status, and year of the onset of rash. In the logistic regression analysis, we showed that children <5–9 years had a lower likelihood of measles-like rash compared to children <4 years. This finding is supported by previous research  and has Similar to other studies in the region , we obseAlthough our analysis has shown a higher measles positivity rate in patients with measles-like rash in NRS, Gash Barka, SRS, and the presence of a host of factors that can undermine measles vaccine coverage, testing or reporting; we are not suggesting that measles may be endemic in these regions. Previous mathematical calculations addressing the epidemiology of measles have shown that a population of 250,000–500,000 people is required to establish measles as an endemic disease . In contLast but not least, we showed that patients in hospitals had a higher probability of test positivity compared to patients from health centers/stations. A plausible explanation for this finding relates to the possibility that patients with measles-related complications are usually referred by primary health clinics (PHC) to hospitals where trained physicians are stationed. Unlike caregivers in PHCs; physicians in hospitals may be better at diagnosis and profiling. Separately, we found a connection between measles test positivity and vaccination. This outcome is supported by previous studies done in Ethiopia , 34, SouUnlike previous work which utilized data from WHO/UNICEF Joint Reporting Form (JRF) and administrative data, we sourced our data from the national and sub-national representative DHS database. This notwithstanding, our study suffers from a number of limitations including inconsistencies in measles testing between sub regions and over time. Additionally, information on vaccination status was based, to a large extent, on self-reported responses. Therefore, social desirability bias cannot be discounted. Last but not least, retrospective studies typically suffer from missing data problems, and we believe that this study was not an exception.Our report suggests that Eritrea has a relatively low incidence of measles but a high variability year-to-year. However, the potential for under-estimation of cases exists due to under-reporting of suspected cases and incomplete testing, particularly in recent years. Furthermore, age-based analysis of CIR and ASR revealed that the median age for measles cases was 7 years (IQR: 4–14 years). This means that SIV campaigns targeting individuals <14 years will miss a large proportion of individuals with residual susceptibility. Laboratory positivity for measles was associated with increasing age, residence in border regions , level of care facility, vaccination status, and year of onset of measles-like rash. Interestingly, uptake of MCV was associated with a similar complement of factors. In a separate analysis, we demonstrated that despite the high coverage of MCV in Eritrea, spatial inequalities in vaccine coverage or surveillance and extremely low vaccination rates in specific sub-regions in neighboring countries continue to undermine elimination efforts. To address these issues, there should be more focus on regional micro planning to create efficient systems for monitoring, reporting, and management of outbreaks. Additional strategies can include decentralization of testing; targeted serological surveys; ring vaccination in border areas; more frequent catch-up SIAs targeting unvaccinated adults and adolescents; building capacity for genetic testing of isolates, and enhancing regional coordination of elimination efforts.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The requirement of ethical approval was waived by the study was carried out according to the Declaration of Helsinki and was approved by the Ethical Committee of the Eritrean Ministry of Health (EMH). Written consent was not obtained from the patients. Instead, the data were identified and all ethical and professional considerations undergirding confidentiality/or other protections of patient information were rigorously implemented. For the studies on humans because written consent was not obtained from the patients. Instead, the data were identified and all ethical and professional considerations undergirding confidentiality/or other protections of patient information were rigorously implemented. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements. The human samples used in this study were acquired from a by- product of routine care or industry.SM conceived and designed the study. SM, AT, FT, IM, MS, DF, HA, RM, TT, and LW participated in the performed data collection. SM and OA did the statistical analysis and spatial mapping. SM, OA, MH, and WW did the data presentation and reviewed and edited the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


LDL cholesterol  better classified subjects as being insulin-resistant compared to other lipid markers. The odds of insulin resistance in dyslipidaemia were not statistically significant after adjusting for obesity. The link between insulin resistance and dyslipidaemia and hypertension in male diabetics may thus be mediated by obesity.Pathophysiologically, type 2 diabetes can result from insulin resistance or insulin insufficiency alone. It is unclear whether relative insulin shortage or pronounced insulin resistance is linked to poor cardiometabolic problems like obesity. Therefore, the objective of this study was to evaluate the relationship between insulin resistance (IR), hypertension, and dyslipidaemia, in men with type 2 diabetes mellitus. One hundred and twenty-one (121) type 2 diabetic men participated in this cross-sectional study, which was conducted between September 2018 and September 2019. Sociodemographic information was collected using a self-designed questionnaire. Anthropometric data were also taken and blood samples collected for estimation of insulin, glucose, and lipid concentrations. HOMA-IR was calculated from the fasting insulin and glucose values, and a HOMA − IR ≥ 2 was considered to indicate insulin resistance. Of the 121 participants, 39.7% were classified as insulin-resistant. Levels of total cholesterol (4.82 ± 1.2 mmol/L;  T2DM accounts for more than 90% of diabetes cases. T2DM is characterized by the existence of tissue insulin resistance (IR), a deficit in insulin secretion, and a lack of compensatory responses to insulin secretion , 2. TypeIn the vascular system, insulin typically promotes vasodilation through the production of NO. However, in the case of insulin resistance, the impaired synthesis of NO and impaired vasodilation may contribute to increased blood pressure (BP) . InsulinDiabetic dyslipidaemia, characterized by high levels of triglycerides and low levels of high-density lipoprotein cholesterol (HDL-C), is thought to contribute to the development of atherosclerosis in individuals with diabetes mellitus , 13. A nType 2 diabetes mellitus is typically diagnosed based on the presence of elevated blood glucose levels that can be managed without the use of exogenous insulin . Many inIt is not yet clear whether individuals with type 2 diabetes who are more insulin-resistant or who have a relative deficiency in insulin production are more closely associated with hypertension and dyslipidaemia. The relationship between insulin resistance, hypertension, and dyslipidaemia in type 2 diabetes in men is complex and requires further investigation. Improved understanding of the association and effective interventions targeting this relationship could potentially improve the health and well-being of this population and reduce the burden of type 2 diabetes. Additionally, studies which include both men and women may lack statistical power to detect meaningful results for men. This study therefore sought to assess the relationship between insulin resistance, hypertension, and dyslipidaemia among men clinically diagnosed with type 2 diabetes.This cross-sectional study was conducted among male diabetic subjects from September 2018 to September 2019. Adult male type 2 diabetics, visiting a selected tertiary health facility in Ghana, were selected using a convenience sampling technique. Type 1 diabetics and morbid type 2 diabetic were excluded from the study.α) of 0.05 and an anticipated difference between the sample and the overall population of 5% were considered. n is the minimal sample size, d is the absolute standard error = 0.05, p is the prevalence = 6.5%, and z is the standard normal variance, 1.96, a power of 95% CI (β = 5%) and 5% type 1 error probability.On the assumption that 6.5% of the general population is diabetic, the minimum sample size for this study was estimated to be 93 adult male diabetics . A type The sample size was recalculated in this study, restricted to only adult male diabetics who responded to not less than 80% of the questionnaire items, to account for any potential loss of respondents. The sample size was computed with a response rate of 80% as follows: 93/0.80. The estimated sample size was roughly 116 using the formula above. One hundred and twenty-one (121) individuals were therefore selected for this study.Participants in the study who provided their assent were given a self-designed semistructured questionnaire to fill out regarding sociodemographic data like age, marital status, highest educational level, smoking, occupation, alcohol consumption, level of exercise, income, and duration of diabetes. Any action lasting more than 30 minutes that caused light sweating, a slight to moderate increase in respiration, or an increase in heart rate was considered exercise. Whether a person had the habit of smoking at least one cigarette each day determined whether they were considered a smoker. Education was divided into three levels: basic, secondary, and tertiary.A Gulick II spring-loaded measuring tape was used to measure the waist circumference (to the closest centimeter) halfway between the suprailiac crest and the inferior angle of the ribs . Hip circumference was estimated using the largest circumference over the buttocks. Waist to hip ratio was estimated as waist circumference (cm) divided by hip circumference (cm). A WHR of ≥0.90 was considered obese.Using a sphygmomanometer cuff and a stethoscope, blood pressure was taken while the subject was seated at the level of the heart. According to the American Heart Association's recommendation, measurements were collected from the left brachial artery after patients had been seated for at least five (5) minutes . The diaFollowing an overnight fast, each subject had ten milliliters of venous blood taken from them into a fluoride oxalate tube and serum separator tube (SST) under strict aseptic conditions . When it came the time for the biochemical investigations, samples in SSTs were centrifuged at 3000 g for 5 minutes, and the serum was aliquoted and kept in cryovials at a temperature of -70°C. On the other hand, samples in fluoride oxalate tubes were used for fasting blood glucose measurement. The Mindray BS-240 Chemistry Analyzer  was used to measure lipids and fasting blood glucose levels. MedSource Diagnostics reagents were utilized in each of these assays. The AxSYM analyzer was used to conduct the hormonal assays. Microparticle enzyme immunoassay is used by the AxSYM to measure the levels of adiponectin, leptin, and insulin. All hormonal assays were performed using the Elabscience® reagent kit. The automated equipment used procedures that followed the reagent makers' directions to determine biochemical and hormonal parameters.HOMR-IR was estimated based on the following mathematical formula: (fasting insulin (mlU/L) × fasting glucose (mmol/L))/22.5 .QUICKI was calculated using the following mathematical formula: 1/(log (fasting insulin (mU/L)) + log (fasting blood sugar (mg/dL))). Lower values indicate greater insulin resistance, and values below 0.34 were considered to indicate insulin resistance .HOMA-B was calculated based on the following formula: 20 × fasting insulin (mU/L)/fasting glucose (mmol/mL) − 3.5 .http://www.medcalc.be), GraphPad® version 9.0 , and the Statistical Package for Social Sciences (SPSS) version 26 . Indicators of data included mean, standard deviation, and percentages. When comparing continuous variables, the unpaired T-test and Mann-Whitney tests were used, and when comparing categorical variables, the chi-square test was used. The correlation between the variables was assessed using Pearson's correlation. Receiver operating characteristics (ROC) were used to evaluate the relative propensities of various characteristics to predict the dependent variable. All statistical analyses were considered significant at a value of <0.05.Analyses were conducted using MedCalc® version 10.2.0.0 (One hundred and thirty (130) questionnaires were administered in total, of which 125 (96%) followed through to the end of the data collection. 121 completed and evaluable questions, representing a response rate of 93%, were left after the set of questionnaires from 4 people was rejected because they were insufficiently completed. Following stratification based on a HOMA − IR ≥ 2, forty-eight (48) participants representing 39.7% had insulin resistance.When the population was stratified based on HOMA-IR, the proportion of subjects with at least secondary education (60%) was significantly higher in the HOMA − IR < 2 group than in their counterparts with a HOMA − IR ≥ 2 .p < 0.0001; 4.82 ± 1.2 mmol/L, p = 0.007; 3.17 ± 0.9 mmol/L, p = 0.001; and 3.93 ± 0.9, p = 0.042, respectively) group compared to their counterparts with HOMA − IR < 2  as shown in When the population was stratified based on their HOMA-IR, FBG, insulin levels, HOMA-IR, and HOMA-B were significantly higher among subjects with HOMA − IR ≥ 2 compared to their counterparts. However, QUICKI was significantly lower in the HOMA − IR ≥ 2 subjects compared to the HOMA − IR < 2 group. Also, WHR, total cholesterol, LDL cholesterol, and TC/HDL ratio were higher among the HOMA − IR ≥ 2  group compared to their counterparts with HOMA − IR < 2 , as shown in When the population was stratified based on HOMA-IR, the proportions of subjects with elevated blood pressure and high LDL cholesterol were significantly higher in the HOMA − IR ≥ 2  was found to significantly affect the occurrence of insulin resistance (HOMA − IR ≥ 2). After adjusting for obesity (WHR), none of the variables could independently predict the occurrence of insulin resistance as shown in The impact of haemodynamic and lipid parameters on the occurrence of insulin resistance is shown in r = 0.18, p < 0.05). QUICKI showed significant inverse relations with systolic blood pressure , total cholesterol , and LDL cholesterol  as shown in Pearson's correlation was done to assess the association between insulin, insulin resistance indices (HOMA-IR and QUICKI), index of pancreatic beta function (HOMA-B), and haemodynamic and lipid parameters as shown in p = 0.013), LDL cholesterol , and TC/HDL  significantly classified subjects as insulin-resistant, with LDL cholesterol showing the highest AUC for the classification of insulin resistance.The ROC curves and the area under curve (AUC) showing the comparable abilities of haemodynamic and lipid parameters to classify insulin resistance are shown in A higher Youden index indicates higher diagnostic value as evaluated by a balance between the sensitivity and specificity of a marker. From The study assessed the link between insulin resistance, hypertension, and dyslipidaemia and observed a 73.6% prevalence of elevated blood pressure among the study population. This figure is slightly lower than the self-reported figure of 78.5% by the study participants. The prevalence of hypertension in this study is similar to the 73.7% among type 2 diabetic men reported by Hu et al. . It is hThe prevalence of hypertension was higher among the insulin-resistant group, and systolic blood pressure showed significant inverse correlation with insulin sensitivity. The association between hypertension and insulin resistance has seen conflicting findings from different studies. In this study, even though the frequency of elevated blood pressure was significantly higher among the insulin-resistant group, it was not independently associated with insulin resistance after adjusting for obesity and other confounding variables. Ferrannini et al.  demonstrLipid profile analysis of the male diabetic subjects showed 62.8% subjects with at least one lipid abnormality. Diabetes has been shown to be an independent risk factor for the development of dyslipidaemia, and the phenomenon is well recognised , 34. TheRelations between different lipid parameters and insulin resistance have been studied in the past –41, and The comparative ability of various lipid markers as screening tools for insulin resistance was also explored in this study. LDL cholesterol concentration showed superiority in the classification of insulin resistance and at a cut-off of >2.3 mmol/L. LDL-C may prove useful in the classification of insulin resistance among diabetic men. Insulin resistance is characterized by increased LDL-C concentration, but the role and importance of LDL-C in the classification of IR is not fully investigated and is unclear from this current study.Insulin resistance is associated with hypertension and dyslipidaemia among type 2 diabetic men. This may however be mediated by obesity associated with insulin resistance. An LDL-C cut-off of >2.3 mmol/L better classifies insulin resistance in type 2 diabetic men.


To investigate whether IV lidocaine improves emergence, early recovery, and late recovery after general anesthesia in women who undergo breast surgery.Sixty-seven women with American Society of Anesthesiologists physical status I-II, scheduled for breast surgery were randomized to receive an IV lidocaine 1.5 mg/kg bolus (n = 34) or saline placebo (n = 33) before tracheal extubation. Anesthesia was induced with thiopental, vecuronium, and fentanyl, and maintained with sevoflurane ~ 1 MAC and 50% nitrous-oxide in oxygen. No postoperative nausea and vomiting (PONV) prophylaxis was given. Time to extubation, bucking before extubation, and quality of emergence, as well as early and late recovery  within 24 hours postoperatively were evaluated. Diclofenac and meperidine were used for the treatment of pain and metoclopramide for PONV.P < 0.001), less bucking before extubation , less coughing after extubation , and less sore throat . Late PONV decreased . There were no differences in pain scores and treatment.The groups did not significantly differ in demographics, intraoperative data, or PONV risk scores. Extubation was ~ 8 minutes in both groups. Patients who received IV lidocaine had significantly smoother recovery, both statistically and clinically; they had better extubation quality scores (1.5 [1-3] vs 3 [1-5], In women who underwent breast surgery, IV lidocaine bolus administered just before extubation attenuated bucking, cough and sore throat, and PONV for 24 hours after general anesthesia, without prolonging the emergence.ISRCTN: 71855856. Smooth emergence and recovery from anesthesia are an important part of anesthesia practice. Avoiding bucking and coughing on emergence reduces multiple postoperative complications ranging from wound dehiscence and hematomas, especially in plastic and hernia repair surgeries, to an increase in hemodynamic response, which could lead to acute cardiovascular events and increased intraocular and intracranial pressure. One way of reducing bucking and coughing on emergence is IV lidocaine given before endotracheal extubation. A recent meta-analysis of 16 studies (n = 1516) showed that early recovery was improved by administration of 1-1.5 mg/kg of IV lidocaine . The secondary outcomes were PONV and postoperative pain.All procedures were performed at Zadar General Hospital, a single-center regional medical hospital, between July 2007 and December 2013. This study was retroactively registered in ISRCTN because at the time when it was approved by an institutional review board and recruitment started, registration was not required. Written informed consent was obtained from all patients before any study procedures were performed. This prospective, double-blinded, randomized controlled trial was approved by the Institutional Ethics Committee, General Hospital Zadar (01-1280/07). The study was conducted in accordance with the principles of the Declaration of Helsinki.2). Predictors for PONV were also assessed. Patients were not included if the protocol was broken or conditions arose that influenced outcomes during the surgery, such as unexpected intraoperative drug allergy, severe intraoperative hypotension lasting more than three minutes, perioperative hypoxia lasting more than one minute, excessive blood loss, difficult intubation, or serious postoperative surgical complications.We enrolled 67 adult women with American Society of Anesthesiologists physical status I to II undergoing breast tumor surgery . Exclusion criteria were expected difficult intubation, multiple intubation attempts, the history of sore throat, cough and respiratory infections, or having been intubated within the last two months, chronic obstructive lung disease, asthma, treatment with β-blocking agents, known hypersensitivity to drugs used in the study protocol, and obesity (body mass index >30 kg/mper os (PO) 1 hour before the surgery with no prophylactic antiemetics, which was the standard of care at the hospital at the time of the study. We used standard monitoring, including electrocardiography, noninvasive blood pressure, pulse oximetry, and capnography. Anesthesia was induced with thiopental 5 mg/kg, fentanyl 1 μg/kg, and vecuronium 0.1 mg/kg. Patients were manually ventilated via face mask with oxygen 6 L/min for three minutes before intubation. An endotracheal tube (ETT) 7.5 mm was used. ETT cuff pressure was measured with an analog manometer to avoid increases higher than 20 cmH2O owing to diffusion of nitrous oxide (N2O). Anesthesia was maintained with sevoflurane 0.8%-1.5% concentration ~ 1 minimum alveolar concentration (MAC) and 50% N2O in oxygen with fresh gas flow 2 L/min. Supplemental bolus doses of fentanyl (1 μg/kg) were added to keep heart rate (HR) and blood pressure within 20% of baseline values but not within the last 30 minutes before extubation. Additional vecuronium was added to maintain one to two twitches on the train-of-four (TOF) monitor. Patients’ lungs were mechanically ventilated to maintain normocapnia . All patients received about 10 mL/kg/h of crystalloids during surgery.All patients received 7.5 mg of midazolam 2O were switched off, neostigmine 2.5 mg and atropine 1 mg for neuromuscular blockade reversal were given, and the fresh gas inflow rate was increased to 7 L/min of 100% oxygen. At that time, patients received 2% lidocaine (1.5 mg/kg) or the same amount of saline. No physical stimulations were applied during emergence. Patients were extubated when they achieved a spontaneous respiratory rate greater than 10 per minute with end-tidal CO2≤45 mm Hg and minimum tidal volume of 300 mL, reversal of neuromuscular blockade TOF 4 with sustained tetany, eye opening, strong hand grip, or when demonstrating intentional movement of the extremities, raising the head, or attempting to self-extubate.Patients were randomized by computer-generated random numbers to receive either lidocaine (GLido) or the same volume of saline  on the emergence from anesthesia. At the end of skin closure, volatile anesthetic and NEarly recovery times  were recorded by a blinded anesthesiologist who did not perform anesthesia. A simple verbal order to “open your eyes,” “squeeze my hand,” “open your mouth,” or “stick out your tongue” was given every 15 seconds during emergence. The number of bucking episodes before extubation and the number of cough and sore throat episodes at one, three, and five minutes after extubation, as well as at two and 24 hours postoperatively were recorded. The quality of tracheal extubation was evaluated on a five-rating scale  , vomiting and/or retching, hypertension >35% of preoperative values, tachycardia >35% of preoperative values, bradycardia, or hypotension. The same blinded anesthesiologist estimated the quality of emergence .An anesthesiologist who was blinded to the study protocol noted complications during emergence in operating room (OR): laryngospasm, bronchospasm, cessation of breathing (number of episodes and duration in seconds), cyanosis, SpOA modified Aldrete score (0-10 points) was used to determine OR and post-anesthesia care unit discharge readiness (≥9 points). Postoperatively, patients were allowed to drink after three hours, if tolerated. All patients stayed in hospital for at least 24 hours. The incidence of postoperative nausea (PON), vomiting (POV), and the use of rescue antiemetic were assessed at two and 24 hours after surgery. Patients were considered to have had PONV if they experienced at least one episode of nausea, vomiting, or retching, or any combination of these during the initial 24 postoperative hours. POV was defined as at least one episode of vomiting or retching that occurred within 24 postoperative hours. PONV was defined as early (within the first two hours) or late (2-24 postoperative hours). Severity of pain was evaluated with a 100-mm visual analog scale (VAS) at the same time points (0 = no pain to 100 = maximum pain). The same blinded anesthesiologist collected postoperative data. Rescue antiemetic (metoclopramide 0.4 mg/kg IV) was given to patients who experienced two or more episodes of vomiting and/or retching within 30 min, any nausea lasting more than 15 min, or nausea VAS score 50 mm or greater, or when they requested treatment. The pain VAS score and the total amount of postoperative opioids were recorded at two and 24 h after surgery. Diclofenac 75 mg intramuscular injection (IM) was given immediately at the arrival to the recovery room. For severe pain (VAS>40 mm), meperidine up to 100 mg IV was used and repeated four hours later if needed.t test. P < 0.05 was considered significant. Data analysis was performed with IBM SPSS Statistics, v. 22.0 .The sample size was calculated on the assumption that the incidence of coughing at the end of the anesthesia would be in two-thirds of patients (66%) and that lidocaine would decrease by 50% , thus 33 patients in each group for the primary outcome were needed for a power of 0.8 and alpha level of <0.05. We estimated a 10% drop-out rate. Data are presented as mean (SD) or median (range). The normality of distribution was tested with a D'Agostino-Pearson test. The significance of differences between the categorical variables was assessed with a Fisher exact test or chi square test, and that between continuous variables with a Mann-Whitney test a or Of 73 women who were initially screened for eligibility, six were excluded. P < 0.001) (P < 0.001). The Extubation Quality Score was on average clinically and statistically significantly higher in GLido , as well as the Quality of Emergence Score   or objective criteria (bucking and hemodynamics), were significantly improved (< 0.001) . The gre< 0.001) .P = 0.026). Moreover, only one patient in GLido had more than one coughing episode (three episodes) compared with 10 patients in GSaline (two had 11 and 12 episodes). The average number of coughing episodes was significantly lower in GLido . Beyond the first minute, there was no difference in early coughing between groups, but there was a difference between two and 24 hours (P = 0.002) (P = 0.039) but not clinically significant. The hemodynamic response on emergence and extubation was significantly attenuated in the GLido group  . All patdo group . An incrP = 0.13) and late PON   . All pat = 0.27) . No signThe results of our Lidocaine at the End (LATE) study showed profound effects of IV lidocaine on early and late recovery without delaying extubation when given at the end of the surgery after the skin closure was completed, neuromuscular blockade reversal was given, and anesthetic gases were turned off.The most striking improvement was the decreased number of patients who bucked before extubation by more than half , number needed to treat (NNT) of two, as well as the number of bucking episodes . Early coughing was also improved , with a NNT of four. This agrees with the findings of a recent meta-analysis, which showed a NNT of five for postoperative cough (2O), and reversal was administered, which made extubation time ( ~ 8 minutes) highly predictable. This timing might correlate with IV lidocaine peak plasma concentration after a single IV bolus dose with a rapid decline after five minutes , as discussed above. The strength of our study is that anesthesia emergence was standardized and extubation timing was highly predictable. We believe that it is important to separate extubation bucking from postoperative coughing. These conditions may have different etiologies: pre-extubation bucking is mostly, if not exclusively, caused by direct ETT stimulation of the trachea but post-extubation coughing is mostly caused by secretions and injury of the tracheal mucosa. We think that in future studies pre-extubation bucking should be separately reported from post-extubation/post-operative coughing. An additional strength is that our study showed “raw” (without any PONV prophylaxis) effect of IV lidocaine on PONV.In summary, our LATE study showed an overwhelming beneficial effect of an IV lidocaine 1.5 mg/kg bolus given eight minutes before extubation on bucking, coughing, sore throat, increase in HR and BP, as well as PONV without any delay in extubation time.


Introduction: Opioid deprescription is the process of supervised tapering and safe withdrawal when a potentially inappropriate use is detected. This represents a challenge in chronic non-cancer pain (CNCP) patients who may respond differently to the procedure. Our aim was to analyze the potential impact of CYP2D6 phenotypes and sex on the clinical and safety outcomes during an opioid use disorder (OUD) tapering process.Methods: A prospective observational study was conducted on CNCP ambulatory OUD patients  who underwent a 6-month opioid dose reduction and discontinuation. Pain intensity, relief and quality of life , global activity , morphine equivalent daily dose (MEDD), analgesic drugs adverse events (AEs) and opioid withdrawal syndrome  were recorded at basal and final visits. Sex differences and CYP2D6 phenotypes (poor (PM), extensive (EM) and ultrarapid (UM) metabolizers based on CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, *41, 2D6*5, 2D6 × N, 2D6*4 × 2 gene variants) were analyzed.Results: Although CYP2D6-UM consumed three-times less basal MEDD , they showed the highest number of AEs  and opioid withdrawal symptoms  after deprescription. This was inversely correlated with their quality of life . Sex-differences were evidenced with a tendency to a lower analgesic tolerability in females and lower quality of life in men.Discussion: These data support the potential benefits of CYP2D6-guided opioid deprescription, in patients with CNCP when OUD is detected. Further studies are required to understand a sex/gender interaction. The current international analgesic landscape is characterized by a significant global increase in the use of prescription opioid . In factCurrent evidence suggests potential genetic factors that could be used to predict one’s risk of opioid misuse or a problematic use , harmfulIn this sense, there is increasing evidence in humans and laboratory animals for sex differences in processes of reward and addictive behavior, withdrawal, craving, and relapse due to psychostimulants and opioids . In factThe primary goal of the present study was to evaluate the impact of CYP2D6 phenotypes and sex influence on OUD deprescription ambulatory CNCP patients. As a primary hypothesis, it was considered that CYP2D6-UM metabolizers would show a different clinical outcome pattern when compared to the other groups, as would be also observed between sexes.This manuscript adheres to the applicable STROBE guidelines. This prospective observational pharmacogenetic study followed the current Declaration of Helsinki and European Medicines Agency Guidelines for Good Clinical Practice and was approved by the Ethics Committee of The General University Hospital of Alicante. Written informed consent was obtained from all participants prior to their inclusion in the study.n = 138) by clinical practice at the Pain Unit  from May 2013 to May 2019 were included under the inclusion criteria prior to deprescription: 1) patients aged 18 years or older; 2) with CNCP and long-term opioid use (>6 months); 3) OUD diagnosis according to diagnostic DSM-5 criteria  and clinical variables were collected using validated questionnaires and scales completed at each of the patients’ visit. Pain intensity and relief were measured using the Visual Analogue Scale (VAS) . Both VAOpioid and co-adjuvant medications were strictly prescribed by clinical judgement by the physician without any experimental decision. Use of opioid and non-opioid analgesics, NSAIDs, antidepressants (duloxetine), anxiolytics (benzodiazepines) and neuromodulators  was obtained from EHRs. MEDD were estimated using the available opioids equivalent doses  and clasTo assess the tolerability, a questionnaire with the list of the most frequently occurring AEs   and a blApproximately 2 mL of saliva was collected in PBS containing tubes. Genomic DNA was extracted using an E.N.Z.A. Forensic DNA Kit (Omega bio-tek), according to the manufacturer’s instructions. Genetic analysis was based in usual PCR-methods following the instructions of the Consortium of Pharmacogenetics (CEIBA) and the pharmacogenomics iberoamerican network (RIBEF) for the analysis of samples. XL-polymerase chain (XL-PCR) analysis was used for identification of duplications and deletions . These XBased on the observational prospective nature of the study and to the inclusion limited by the low frequency of patients with an OUD, a convenience sample was proposed. As an estimated prevalence of 3.2% of OUD was detected in our setting . Out of t-test for parametric data, meanwhile for non-parametric, U Mann-Whitney test was used. When analyzing categorical data between two groups, Fischer’s exact test was performed. For the analyses of the three metabolic phenotypes, ANOVA test was performed for parametric continuous data and Kruskal-Wallis for non-parametric. In this case, Chi-square test was used for categorical analyses. t-test and/or U Mann-Whitney  were performed too. Gene by sex interaction was explored by invoking a regression model. All the obtained variables included a separate description and analysis by sex.Data distribution was analyzed using Kolmogorov-Smirnov normality test. Quantitative parametric data are presented as mean (SD) while median (IQR) was used for non-parametric data and discrete variables. Categorical data are expressed by percentages. Comparisons of continuous data between two groups were conducted using a p ≤ 0.05 was considered statistically significant. In all cases, multiple testing was adjusted using Bonferroni correction. All statistical analyses were carried out using R (3.2.0 version) software.The Pearson correlation coefficient (r) and its 95% confidence intervals (CI) were calculated to analyze the correlation between opioid withdrawal and quality of life. Two groups (subjects included between 2013–2015 and 2016–2019) were compared to determine if deprescription outcomes changed over time. The MEDD difference between groups was expressed using the Hodges-Lehmann estimator shift with the 95% CI. In the assumption of missing completely at random, complete case (or available case) analysis was performed. A n = 21) of the patients were lost to follow-up  with 117 , of them completing the program. Data from a total of 231 subjects  were included as a control group  with an OUD were recruited and enrolled in the ambulatory opioid deprescription. Fifteen percent  mm) and quality of life [45 (24) mm], with mild relief [37 (29) mm] and a mean of [32 (19) OWS scores]. No differences based on the inclusion period or between visits during deprescription were found in these outcomes. Here, patients evidenced “some mild symptoms or difficulties in social, interpersonal relationships or occupational functioning, but generally functioning pretty well” due GAF 71 (15) scores.p < 0.001], with a higher basal pain relief  probably due to a higher MEDD  at basal visit  vs. 63 (14) years, al visit .Clinical and pharmacological data of the total case population and classified by the CYP2D6 metabolic phenotypes is shown in p < 0.001, difference Hodges-Lehmann: −80 (−83 to −40)]. In consonance, the percentage of patients with a high MEDD level (>100 mg/day) decreased significantly from 55% to 27% (p < 0.001) without differences due to sex. Interestingly, cases included in later time period (2016–2019) showed a significant lower final MEDD [0 (0–80) mg/day] compared to those included in early time-period (2013–2015)   mg/day [ = 0.02] .CYP2D6 variants can be seen in Metabolic CYP2D6 phenotypes were classified as 6% PM, 85% EM and 9% UM according to their genotype without differences in frequency between sexes  or compared with the control group . Allelic frequencies of p = 0.04, difference Hodges-Lehmann: −63 (−140 to 0)]. However, when only CYP2D6 metabolism mediated opioids were selected, no differences between CYP2D6 phenotypes and consumed MEDD were observed. What’s more, CYP2D6-UMs presented a lower rate of neuromodulators use in comparison to the other phenotypes in both basal and final visits  with no differences between sex or time period.Here, UM phenotypes showed a significantly lower three-times MEDD compared to PM-EMs  while women remained stable .At final visit, even though a significant reduction in MEDD and opioid use was reached, most of the clinical outcomes remained stable without any significant changed after opioid deprescription or cessation. Only men showed a non-significant reduction of quality of life  with a significant inverse correlation with levels of quality of life, both in males  and females   (A median of 5 (2–8) AEs per patient were reported in cases, being the most prevalent dry mouth, sleep disturbance, constipation and nervousness (present in >40% of the patients), while controls showed a lower frequency of AEs  . Cases i13–2015) . Furtherp = 0.02], with higher frequencies of headache , edema , dry mouth  and nervousness  (p = 0.01) and general  systems’ disorders. No gene-sex interactions by regression model were found in those variables where CYP2D6 metabolic phenotypes showed differences (data not shown).Data related to AEs by CYP2D6 metabolic phenotype are shown in  = 0.04) . In accop = 0.05), dry mouth  and nervousness . Meanwhile, men retained sexual impotence issues at a significantly higher rate than females  mostly due to erectile dysfunction (p = 0.02).Related to sex, women reported a higher frequency of edema .This study aims to demonstrate the clinical interest of genotyping when deprescribing in order to identify patients at risk of insufficient analgesia or adverse events. In this way, there is also a need to carry out studies that analyze the cost-effectiveness of genetic testing when genotyping is included in these procedures. Along with this, it is important the need to develop clinical guidelines as a vehicle to assist the providers of opioids, in order to detect a potential issue not only with per se (Also, the need to implement pain research with a sex perspective is necessary to understand interindividual variability in terms of safety. Still, the remarkable female predominance in our study merits further attention. Nearly two thirds of our patients were adult women, given that female predominance in our CNCP population has been previously highlighted . Furtherper se .Some limitations should be taken under consideration. First, a convenience sample of patients attending a single pain clinic was established, along with this, a power analysis was not performed in order to know the best scenario to detect differences between groups. Furthermore, the total number of extreme phenotype subjects studied was relatively small. All this can compromise the power of statistical analyses, which may have made it difficult to detect significant differences between groups. Second, an 80% of UM were females, it would be difficult to assess the effect of CYP2D6 on the observed clinical outcome. Even more, drug inhibition or induction effects on CYP2D6 should be deeply analyzed , becauseIn conclusion, CYP2D6 metabolizer phenotypes may contribute to differential and improved opioid deprescription in CNCP. Sex may play a relevant role in the tolerability when deprescribing. Further studies considering these potential genetics, as well as sex/gender differences could help to understand the interindividual variability in real-world patients.


High blood pressure (BP) is the primary risk factor for recurrent strokes. Despite established clinical guidelines, some stroke survivors exhibit uncontrolled BP over the first 12 months post-stroke. Furthermore, research on BP trajectories in stroke survivors admitted to inpatient rehabilitation hospitals is limited. Exercise is recommended to reduce BP after stroke. However, the effect of high repetition gait training at aerobic intensities  during inpatient rehabilitation on BP is unclear. We aimed to determine the effect of an aerobic gait training intervention on BP trajectory over the first 12 months post-stroke.n = 24), DOSE1 , or DOSE2  groups. Resting BP [systolic (SBP) and diastolic (DBP)] was measured at baseline (inpatient rehabilitation admission), post-intervention (near inpatient discharge), 6- and 12-month post-stroke. Linear mixed-effects models were used to examine the effects of group and time (weeks post-stroke) on SBP, DBP and hypertension , controlling for age, stroke type, and baseline history of hypertension.This is a secondary analysis of the Determining Optimal Post-Stroke Exercise (DOSE) trial. Participants with stroke admitted to inpatient rehabilitation hospitals were recruited and randomized to usual care (n = 15/72) to 32.8% (n = 19/58). These increases in BP were statistically significant: an effect  of time was observed on SBP , DBP , and hypertension . A baseline history of hypertension was associated with higher SBP by 13.45 (8.73–18.17) mmHg, higher DBP by 5.57 (2.02–9.12) mmHg, and 42.22 (6.60–270.08) times the odds of being hypertensive at each timepoint, compared to those without.No effect of intervention group on SBP, DBP, or hypertension was observed. BP increased from baseline to 12-month post-stroke for SBP (from [mean ± standard deviation] 121.8 ± 15.0 to 131.8 ± 17.8 mmHg) and for DBP (74.4 ± 9.8 to 78.5 ± 10.1 mmHg). The proportion of hypertensive participants increased from 20.8% (Blood pressure increased after inpatient rehabilitation over the first 12 months post-stroke, especially among those with a history of hypertension. The 4-week aerobic gait training intervention did not influence this trajectory. Stroke n = 1,031) and reported that aerobic exercise interventions can reduce BP in transient ischaemic attack (TIA) and stroke survivors , pre-stroke disability <2 on the Modified Rankin Scale, ability to ambulate ≥5 meters with up to one person maximum assist and assistive/orthotic device as required, over-ground walking speed of <1.0 m/s, able to follow directions, and successful completion of a graded exercise stress test using criteria set out by the American College of Sports Medicine . Exclude2.2.Participants were randomized to one of three groups  on a 1:1:1 ratio, stratified by age (<60 or ≥ 60), using a fully concealed internet-based dynamic allocation randomization that was generated in real-time. The Usual Care group received standard inpatient physical therapy which progressed upper and lower limb functional exercises as tolerated and typically provided over 5, 1-h sessions per week, until the participant was discharged . The DOSE1 group received an intervention that replaced standard inpatient physical therapy session for a total of 20 sessions . The therapist progressed the participants to complete a minimum of 30 min at an intensity ≥40% HRR, gradually progressing to >60% HRR, and achieve >2000 walking steps per session by the end of the 4-week intervention. The DOSE2 group received an intervention that consisted of DOSE1 activities  and received a similar second session later in the day .Detailed description of the intervention fidelity has been previously reported . In brie2.3.Study outcomes were assessed at four timepoints: baseline at rehabilitation admission (2–10 weeks post-stroke), post-intervention (after the 4-week intervention), and 6- and 12-month post-stroke. Participant characteristics were collected at the baseline evaluation, including age, sex, date and type of stroke, and self-reported history of hypertension or diabetes . Stroke severity [National Institutes of Health Stroke Scale ; NIH StrBlood pressure was assessed and recorded as a screening tool for the primary outcome measure of the 6 min walk test (6MWT) at each timepoint. Systolic BP (SBP) and diastolic BP (DBP) were assessed in concordance with the body positions recommended by the Hypertension Canada Guidelines . Partici≥80 mmHg .2.4.Statistical analyses were conducted using the R computing environment , with an alpha of 0.05. Three linear mixed-effects models were undertaken to first determine whether there was an effect of group  and the four timepoints on (1) SBP and (2) DBP and on (3) presence of hypertension. Subsequently, longitudinal modeling was undertaken for SBP using linear mixed-effects modeling, with a random effect for each participant. The null hypothesis tested that the SBP remained the same over time. Time was included as a continuous variable to allow for a non-linear slope of recovery. Time since stroke (weeks), age , stroke type (ischemic or hemorrhagic), and baseline history of hypertension (yes/no) were included in all models. A separate linear mixed-effects model was undertaken to estimate potential interaction effects between time since stroke and history of hypertension on SBP, including age (years) and stroke type (ischemic or hemorrhagic). These longitudinal models were repeated with DBP and the presence/absence of hypertension. The package lme4: Linear Mixed-Effects Models used “Eigen” and S4 (R software), which utilizes all available data and has been demonstrated to be valid in the presence of data missing at random .A sensitivity analysis to investigate the impact of influential observations was conducted. All observations with a Cook’s D value equal to or greater than four times the mean were excluded, and the models were rerun. To explore potential mechanisms of missing data at 6- and 12-month post-stroke, bivariable logistic regression was used to examine the associations between demographic  and baseline SBP to those who completed and did not complete follow-up assessment at 6- and 12-month post-stroke (yes/no).3.n = 9), study drop-out for medical reasons (n = 3), and loss to follow-up (n = 6), BP measurements were missed at the attended study visits on four occasions. Seventy-four participants were included in the current study, and their characteristics are summarized in n = 15/72) to 32.8% (n = 19/58).n = 49, 66.2%) were associated with higher SBP by 13.45 (8.73–18.17) mmHg, higher DBP by 5.57 (2.02–9.12) mmHg, and 42.22 (6.60–270.08) times the odds of being hypertensive at each timepoint, compared to those without. An interaction effect was observed between time after stroke and history of hypertension on DBP, where participants with history of hypertension were associated with an increase in 0.10 (0.00–0.19) mmHg per week post-stroke, and not for those without a history of hypertension  on reducing SBP , with poThe current study presents a unique dataset that describes BP trajectories in a clinically distinct group of stroke survivors discharged from acute hospitalization with moderate-to-severe physical deficits requiring rehabilitation  . All stun = 1,383,399) of non-stroke populations suggests that a 10 mmHg reduction in SBP or 5 mmHg reduction in DBP were associated with a 30–40% risk reduction of stroke  , 7. The f stroke . Given tf stroke .A key strength to the current study is that we included stroke survivors from six distinct rehabilitation hospitals and three provinces across Canada, with varying practices in rehabilitation and BP control by rehabilitation or community physicians in each setting. This improves the generalizability of our study findings. However, this study has some limitations. BP was only measured once as part of the safety screening for assessments at each timepoint. Multiple measures (at least 2) are recommended by most national hypertension guidelines for clinical research and diagnosis of hypertension , 46. Fur5.For DOSE participants, BP increased over the first 12 months post-stroke. This trajectory was not influenced by whether or not participants received the 4-week DOSE interventions. Participants with a baseline history of hypertension were more likely to have increased BP and be hypertensive over the first 12 months post-stroke. Further investigation on optimal BP control strategies for stroke survivors discharged from inpatient rehabilitation is needed, including the role of high repetition gait training at aerobic intensities.The original contributions presented in the study are included in the article/The studies involving humans were approved by the University of British Columbia Clinical Research Ethics Board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.SH led the data analysis and preparation of the manuscript. CT assisted with manuscript preparation, and reviewed and approved the manuscript. TK led and designed the study, collected the data, and reviewed and approved the manuscript. AS advised and contributed to data analysis. MB, SD, MH, AK, SP, MP, and JY contributed to study design, data collection, and reviewed and approved the manuscript. JE supervised the study conception and design, data collection, manuscript preparation, and reviewed and approved of the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Canadian Institutes of Health Research ; Canada Research Chair Program (JE); Heart and Stroke Foundation Canadian Partnership for Stroke Recovery Operating Grant (JE); and Michael Smith Health Research BC (Trainee award to SH). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Parenting involves major behavioral transitions that are supported by coordinated neuroendocrine and physiological changes to promote the onset of novel offspring-directed behaviors. In comparison to maternal care, however, the mechanisms underlying the transition to paternal care are less understood. Male laboratory mice are predominantly infanticidal as virgins but show paternal responses 2 weeks after mating. Interestingly, males show a mating-induced surge of prolactin, which we hypothesized may be involved in initiating this behavioral transition. During pregnancy, prolactin stimulates olfactory bulb neurogenesis, which is essential for maternal behavior. Mating induces olfactory bulb neurogenesis in males, but it is unknown whether this is driven by prolactin or is important for subsequent paternal care. New olfactory neurons are generated from cells in the subventricular zone (SVZ) and take about 2 weeks to migrate to the olfactory bulb, which may account for the delayed behavioral change in mated males. We investigated whether mating increases cell proliferation at the SVZ. Males were either mated, exposed to receptive female cues, or left alone (control) and injected with Bromodeoxyuridine . Contrary to our hypothesis, we found that mating decreased cell proliferation in the caudal lateral portion of the SVZ. Next, we tested whether prolactin itself mediates cell proliferation in the SVZ and/or new cell survival in the olfactory bulb by administering bromocriptine (prolactin inhibitor), vehicle, or bromocriptine + prolactin prior to mating. While suppressing prolactin had no effect on cell proliferation in the SVZ, administering exogenous prolactin resulted in significantly higher BrdU-labeled cells in mated but not virgin male mice. No effects of prolactin were observed on new olfactory cell survival. Taken together, prolactin may have context-dependent effects on new cell division in the SVZ, while other unknown mechanisms may be driving the effects on new olfactory cell survival following mating. Parental behavior is critical for offspring survival in mammalian species. While females generally provide the majority of offspring care, for some species, including humans, males also display paternal behaviors and contribute to the raising of the young. Although substantial work has been undertaken to investigate the neurobiological mechanisms that support the onset of maternal behavior, far less is known about the mechanisms which support the onset of paternal behavior in males.Parenting involves major behavioral transitions that are supported by a number of coordinated neuroendocrine and other physiological changes to promote the onset of novel offspring-directed behaviors  is required to make the transition from infanticidal to paternal behavior. New olfactory cells arise from neural stem cells located along the wall of the subventricular zone of the lateral ventricle (SVZ), which migrate along the rostral migration stream where they then disperse and differentiate into functional interneurons in the olfactory bulb . This prIn addition to mating-induced neurogenesis, mating is also associated with a large (up to fivefold increase), transient surge in the hormone prolactin in male mice . This suRRID:IMSR JAX:000664, the Jackson Laboratory, Bar Harbor, ME, USA). Mice were housed in individually ventilated cages with shredded paper nesting material and kept in temperature-controlled rooms (22 ± 1°C) on 12:12 h reverse light/dark cycles (lights on at 20:00 h) with ad libitum chow and water. All animal behaviors were tested during the dark phase of the light/dark cycle under sodium lighting . Adult C57BL/6J mice were sourced from the Taieri Resource Unit  from stock regularly refreshed from Jackson Laboratory , female only control (n = 6), or control (n = 6). In the mated condition, a female stimulus was placed in the male’s home cage for 2 h. Female stimuli were reproductively experienced, ovariectomized wildtype mice which were steroid-primed by using a standard protocol of injecting estradiol  48 h prior and progesterone  4 h before testing  and control males . Adult virgin C57BL/6J males were initially group housed and habituated to daily handling for at least 3 weeks prior to the study in order to reduce stress associated with handling and injections during the experiment. The day before testing, males were individually housed and randomly assigned to one of three groups: mated ( testing  to induc testing  at the en = 18) or vehicle injections  1.5 h prior to adding a steroid-primed female to their cage . We have previously demonstrated that bromocriptine completely suppresses prolactin secretion for at least 4 h post-mating using this protocol (n = 8) received an additional injection of ovine prolactin . Males then received an injection of BrdU 2 h after the prolactin/vehicle injection and a second BrdU injection 2 h later. Brains were collected 30 min following the second BrdU dose and were analyzed for BrdU immunoreactivity.To test whether prolactin had context-dependent effects on neurogenesis, we also aimed to test whether circulating prolactin affects cell proliferation rates at the SVZ in the absence of mating. Adult virgin C57BL/6J males were habituated to daily handling and individually housed the day before testing as described in sections “2.2.1. Characterizing the effects of mating on cell proliferation at the SVZ” and “2.2.2. Effects of mating-induced prolactin on cell proliferation at the SVZ” On the day of testing, males were randomly assigned to receive an injection of ovine prolactin (n = 6) or vehicle control-treated mice (n = 6). After the 2-h mating trial concluded, females were removed, and the males remained in their home cage alone for 2 weeks. Only males that were observed to ejaculate during the trial were used for brain collection. On day 15 post-mating, brains were collected and later analyzed for positive BrdU and NeuN immunoreactivity.Finally, we investigated whether the mating-induced prolactin surge affects new cell survival in the olfactory bulb (OB). Adult virgin C57BL/6J male mice were habituated and tested in the same way as described in section “2.2.2. Effects of mating-induced prolactin on cell proliferation at the SVZ,” except only using bromocriptine  , includi–1; ip injection) before transcardial perfusion with 4% paraformaldehyde in 0.1 mol L–1 phosphate buffer (pH 7.4). Brains were post-fixed in the same fixative overnight before being cryoprotected in 30% sucrose solution for 2 days and stored at −80°C. Brains were cut into 3 series of 30 μm-thick sections on a freezing microtome and kept in cryoprotectant at −20°C until processing.Mice were deeply anaesthetized with sodium pentobarbital (100 mg/kg2O2 in TBS), a second blocking step was conducted in 5% normal goat serum (NGS) for 20 min at room temperature. Tissue was incubated with mouse anti-BrdU  at 1:1,000 in 5% NGS for 48 h at 4°C. Sections were then treated with secondary antibody  and reacted with glucose oxidase and nickel 3,3′-Diaminobenzidine (DAB) for visualization.Free floating sections were subjected to an antigen retrieval step in 2 M HCl at 37°C for 30 min. After blocking endogenous peroxidases (40% methanol and 3% HRRID:SCR_018257) using the DAB staining algorithms tuned to custom parameters for our staining. Brains were analyzed in this way for section “2.2.1. Characterizing the effects of mating on cell proliferation at the SVZ,” “2.2.2. Effects of mating-induced prolactin on cell proliferation at the SVZ,” and “2.2.3. Effects of prolactin on cell proliferation at the SVZ in virgin males.”Images were taken on an Olympus AX70 brightfield microscope using 4 and 10X objectives. Rostral SVZ regions of interest were based on the Bregma levels most commonly analyzed in the literature  were cut through the entire brain, float-mounted onto superfrost plus slides and stored at −70°C until processing. For immunofluorescence, sections were thawed at room temperature (RT) and antigen retrieval performed using 2 M HCl at 37°C for 30 min. Endogenous peroxidases were quenched in 3% (v/v) hydrogen peroxide, 40% methanol in 0.01 M Tris Buffered Saline (TBS) and sections were then incubated in blocking solution  for 20 min at RT. Tissue was incubated with rat anti-BrdU  at 1:500 in blocking solution with 2% NGS for 16 h at 4°C, before being incubated in goat anti-rat IgG Alexa Fluor 488  at 1:1000 in blocking solution with no NGS for 2 h at RT. A mouse NeuN antibody , 1:500 in blocking solution with 2% NGS for 16 h at 4°C was subsequently applied to sections to identify post-mitotic neurons. Tissue was then treated with biotinylated goat anti-mouse IgG  at 1:250 in blocking solution with no NGS for 2 h at RT. Sections were immersed in avidin-biotin complex  for 90 min at RT prior to incubation with Streptavidin 647 fluorophore solution (1:400) for 2 h at 37°C. Slides were coverslipped with fluoromount aqueous medium with DAPI  to label cell nuclei.1 To quantify the density of BrdU-positive and BrdU/NeuN colocalized cells in the olfactory bulb, three circular areas of 400 μm diameter were randomly placed in both the glomerular (GR) and granular layers (GL) within the MOB, and six of those with 200 μm diameter in both layers within the AOB using the software NIS-element Advanced Research 4.5 in accordance with a previously described method  were photographed using a fluorescent microscope (Nikon Ti2E Inverted Widefield with Nikon DS-Qi2 camera) under 20× objective. Images were taken within lateral coordinates 0.60 to 1.32 mm  to includ method . The cirRRID:SCR_002798, San Diego, CA, USA). In all cases, data were checked for normality, all tests were two-tailed, and significance was accepted if p-values were less than 0.05.Data were analyzed using PRISM 9  were quantified and tested for correlations with BrdU-positive cell counts in the dorsal, lateral, or medial regions of the rostral or caudal SVZ using Pearson’s post-hoc tests.The average number of BrdU-positive cell counts in the rostral and caudal SVZ were compared between bromocriptine, vehicle control, and prolactin rescue control males for the dorsal, lateral, and medial regions separately using one-way ANOVAs and Tukey’s multiple comparison t-tests. Note that only these two groups were analyzed as the prolactin injection was given after mating was complete, and therefore we would not expect prolactin to affect any prior mating behavior. Latency to first mount and to ejaculate were compared between bromocriptine and control-treated animals using survival analysis and curve comparison with the Mantel-Cox Log-rank test  and the control group using unpaired ank test . Mating t-tests.The average number of BrdU-positive cell counts in the rostral and caudal SVZ were compared between prolactin and vehicle-treated males for the dorsal, lateral, and medial regions separately using unpaired t-tests.The average percentage of BrdU and NeuN positive double-labeled cells were compared between bromocriptine-treated and control males for each region of the olfactory bulb analyzed  separately using unpaired t-tests. Latency to first mount and to ejaculate were compared between treatment groups using survival analysis as described in section “2.2.2. Effects of mating-induced prolactin on cell proliferation at the SVZ.” Mating behavior parameters were tested for correlations with percent Brdu + /NeuN + colocalization in each of the OB regions analyzed using Pearson’s r-test.Mean mating behaviors were compared between bromocriptine and control groups using unpaired F = 2.09, p = 0.16], lateral , or medial  regions of the rostral SVZ , p = 0.29], but there was a significant effect in the lateral region   and female-only control groups (p = 0.03) had lower BrdU-positive cell counts relative to the control male group  on BrdU-positive cell counts in the dorsal [tral SVZ . In the  = 0.01] . Post hole group .Person’s r-test, all p > 0.05).In the mated male group, none of the mating behavior parameters  were significantly correlated with BrdU-positive cell counts in the dorsal, lateral, or medial regions of the rostral or caudal SVZ .There was no effect of treatment  on any of the mating behaviors measured , p = 0.004] and lateral  regions, but not the medial region   and lateral  regions of the rostral SVZ , p = 0.01] and lateral  regions in the caudal SVZ, with the prolactin-rescue group having significantly higher positive BrdU immunoreactivity relative to control males in the dorsal  and lateral  region of the caudal SVZ  in the dorsal [ = 0.92] . Post hotral SVZ . Similarudal SVZ .t = 0.22, df = 10, p = 0.83), lateral , or medial , or the caudal SVZ: dorsal , lateral  (These effects of prolactin appear to be context-specific as there was no effect of treatment (prolactin or vehicle) in virgin males on positive BrdU labeling for any of the regions analyzed in the rostral SVZ: dorsal ( = 0.51) .t = 0.27, df = 6, p = 0.80), pAOB GL , aAOB GR , pAOB GR , MOB GL , MOB GR   or any significant correlations between mating behavior and BrdU + NeuN + colocalization .There was no effect of treatment (bromocriptine or vehicle) on the mean percentage of BrdU + /NeuN + colocalized cells for any of the olfactory bulb regions analyzed: aAOB GL ( = 0.76) . There wThis study aimed to test whether mating and/or the mating-induced prolactin surge plays a significant role in increasing neurogenesis, via increasing SVZ cell proliferation rates and/or by increasing new cell survival in the olfactory bulb, under the hypothesis that these processes may be important for the transition from infanticide to paternal behavior. Contrary to our predictions, mating did not cause a significant increase in cell proliferation in the SVZ. Blocking the endogenous mating-induced prolactin surge did not affect SVZ cell proliferation rates, but when this treatment was rescued by a replacement injection of exogenous prolactin together with mating, we did observe a significant increase in BrdU + labeled in the SVZ. This effect appears to be context specific as we saw no differences in SVZ cell proliferation rates when exogenous prolactin was injected in the absence of mating in virgin males. Finally, blocking mating-induced prolactin release did not affect the number of new neurons (BrdU + /NeuN + labeled cells) in the olfactory bulb 2 weeks after mating.decreased following either mating or female exposure, relative to control males. In all other regions examined, there was no difference between control, female-exposed, or mated males. These findings are in contrast to male prairie voles, in which both mating and social exposure  increased the percentage of BrdU + /doublecortin + (a marker for neuron precursor cells) labeled cells in the dorsal SVZ . Finally, it should also be noted that BrdU is being incorporated into the DNA during the S-phase of the cell cycle in all proliferating cells in the SVZ, so we cannot determine whether there are changes in proliferation rates of certain stem cell types  in SVZ, and potential differences may be there if one were to differentiate these cells with further work.The effect of prolactin on increased SVZ cell proliferation appear to be context specific to mating, however, as this effect was not replicated following prolactin administration to virgin males alone. This is in contrast to other studies which have found that prolactin was able to increase cell proliferation at the SVZ in virgin males . HoweverAs mating has been shown to increase olfactory bulb neurogenesis in male mice , we lastOur study has primarily focused on cell proliferation in the SVZ because olfactory bulb neurogenesis has been implicated in both maternal and paternal behavior  and it hOverall, while there was strong support from previous literature that mating behavior and mating-induced prolactin would increase SVZ cell proliferation and new olfactory cell survival in males, we found little evidence of this in our studies. While the endogenous rise in mating-induced prolactin had little effect on neurogenesis in the mated male, we showed that extra exogenous prolactin was able to stimulate increased cell proliferation at mating, but not in the absence of mating . Investigations into what other factors prolactin is interacting with at mating would be useful in order to gain a better understanding of the mechanisms driving cell proliferation in the SVZ. It is surprising that we still do not have an explanation for the role of mating-induced prolactin surge in males, and therefore additional research on this topic is warranted. Similarly, although mating-induced prolactin does not appear to affect olfactory neurogenesis outcomes, olfactory cell neurogenesis nonetheless still occurs after mating (as also previously described in The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the University of Otago Animal Ethics Committee.KS: conceptualization, formal analysis, investigation, writing—original draft, visualization, project administration, and funding acquisition. HP: methodology, writing—review editing, supervision, and project administration. CF: methodology, formal analysis, investigation, writing—review editing, and visualization. RB: conceptualization, writing—review editing, and supervision. DG: conceptualization, resources, writing—review editing, and supervision. All authors contributed to the article and approved the submitted version.


LASr progressively decreased from Group 1 to 3, both at rest  and at peak stress . Stress B-lines (≥2) were more frequent in AF . Inducible ischemia was less frequent in SR . Conclusions: In CCS, rest and stress LA dilation and reservoir dysfunction are often present in paroxysmal and, more so, in permanent AF and are associated with more frequent inducible ischemia and pulmonary congestion during stress.Background: Left atrial (LA) myopathy with paroxysmal and permanent atrial fibrillation (AF) is frequent in chronic coronary syndromes (CCS) but sometimes occult at rest and elicited by stress. Aim: This study sought to assess LA volume and function at rest and during stress across the spectrum of AF. Methods: In a prospective, multicenter, observational study design, we enrolled 3042 patients  with known or suspected CCS: 2749 were in sinus rhythm ; 191 in SR with a history of paroxysmal AF (Group 2); and 102 were in permanent AF (Group 3). All patients underwent stress echocardiography (SE). We measured left atrial volume index (LAVI) in all patients and LA Strain reservoir phase (LASr) in a subset of 486 patients. Results: LAVI increased from Group 1 to 3, both at rest (Group 1 = 27.6 ± 12.2, Group 2 = 31.6 ± 12.9, Group 3 = 43.3 ± 19.7 mL/m Atrial fibrillation (AF) is common in patients with chronic coronary syndromes (CCS) or heart failure (HF), and its development is associated with a worse prognosis . Left atPatients. The initial population comprised 3214 patients prospectively enrolled at 40 cardiology institutions from 14 countries, with recruitment from 16 March 2016, to 16 March 2023 [rch 2023 . Of 3214rch 2023 . TTE. TTE was performed using commercially available ultrasound machines. All patients underwent TTE at rest, including ejection fraction (EF), and, in a subset of 1148 patients, global longitudinal strain (GLS). All measurements were taken by certified cardiologists according to the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging [SE. SE was performed according to current guidelines as previously detailed [detailed ,13. Walldetailed . The ejedetailed . LAVI was measured from apical four- and two-chamber views with the modified method of disks and normalized by the body surface area. LASr was measured by STE using frame rates from 40 to 80/s. The left atrial strain was calculated from either an apical four-chamber view (average from six LA segments) or combined four- and two-chamber views  according to recommendations ,17. LASr2 and an abnormal LASr value < 24% [Based on previously reported lower limits of reference values, we considered an abnormal LAVI value ≥ 34 mL/mue < 24% . Previouue < 24% ,20,21. Statistical analysis. All data are presented as mean ± SD, number (percentage), or median (interquartile range) as appropriate. Group differences were evaluated using the Student’s t-test for normally distributed continuous variables, the Mann-Whitney U test for skewed continuous variables, and the chi-square or Fisher’s exact tests for categorical variables. One-way analysis of variance or Kruskal-Wallis tests were used to compare >2 groups. When a significant difference was found, post hoc testing with Bonferroni comparisons for identified specific group differences was used. Paired Student’s t-tests or Wilcoxon tests were used to compare differences within groups. Pearson’s correlation coefficient was used to examine relationships between continuous variables. All analyses were two-sided. Statistical significance was set at p < 0.05. All statistical calculations were performed using SPSS for Windows, release 20.0 .Accordingly, 3042  with interpretable LAVI formed the study group , with LAResting TTE findings. The resting echocardiographic LV EF in the entire study group was 59.9 ± 9.6%, with higher values in patients in SR than those with permanent AF , high-dose dobutamine (n = 417), or high-dose vasodilator , based on the patient’s characteristics and laboratory expertise. The main SE findings are reported in An abnormal stress response for B-lines and inducible RWMA were more frequent in patients of Group 3 than in those of Group 2 and Group 1 . p < 0.001, at peak stress: r = −412, p < 0.001) and pharmacological stress . Considering the subset of 486 patients with complete LAVI and LASr data, there was a linear inverse relationship between LAVI and LASr, both at rest and during stress, considering the different stressors . The corLAVI was normal at rest in 2290 patients and became abnormal during stress in 224 (9.8%). Of the 752 patients with abnormal LAVI at rest, 284 became normal during stress (37.8%), leading to a stress reclassification  in 508 patients (16.7%).LASr was normal at rest in 253 patients and became abnormal during stress in 55 (21.7%). Of the 233 patients with abnormal LASr at rest, 71 became normal during stress (30.5%), leading to a stress reclassification  in 126 patients (25.9%).In this study, we assessed LAVI and (in a subset) LASr at rest and during stress in patients with CCS. We demonstrated that patients with AF had more frequent LA dilation and dysfunction at rest and during stress than patients with SR. Among patients with AF, LA dilation and dysfunction were more frequent and more severe in patients with permanent than in those with a history of paroxysmal AF but in SR at the time of testing. LA dysfunction was accompanied by more severe pulmonary congestion and regional wall motion abnormalities. SE led to a reclassification of LA  in 16.7% of patients by LAVI criteria and in 25.9% by LASr criteria.Previous studies have shown that patients with AF exhibit LA dysfunction with increased LAVI and reduced LASr compared to controls without AF ,23. LA dLAVI is now an integral part of the TTE data set in several conditions, from valvular heart disease to dilated or hypertrophic cardiomyopathy. These parameters can be obtained with little extra imaging and analysis time, not only at rest but also during stress in patients with CCS. LASr could be a valuable parameter added to volume data. LAVI and LASr provide a combined assessment of LA size and function, which are often uncoupled. LASr may help to identify an occult LA dysfunction not apparent at rest or reclassify as normal patients with alterations at rest. LASr required more advanced technology than 2DE and was an optional variable, available only in 16% of patients. LA strain of the reservoir phase was available only in a minority of patients, limiting the robustness of this information. LAVI was assessed by 2DE but is more accurately measured with real-time three-dimensional echocardiography and artificial intelligence . LASr isLA dilation and/or dysfunction are frequent in patients with AF and can be detected with resting TTE and SE with 2DE and STE. Both rest and stress LA abnormalities are more prevalent in patients with permanent than those with paroxysmal AF. However, patients with paroxysmal AF have more pronounced LA abnormalities than patients with SR. LA dysfunction is often accompanied by signs of pulmonary congestion during stress. Subtle forms of LA myopathy may be unmasked by SE in patients with paroxysmal or permanent AF.