Defining blood-induced microglia functions in neurodegeneration through multiomic profiling.

Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.

Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood-brain barrier disruption.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

Changes in cardiovascular health and white matter integrity with aerobic exercise, cognitive and combined training in physically inactive healthy late-middle-aged adults: the "Projecte Moviment" randomized controlled trial.

INTRODUCTION: This is a 12-weeks randomized controlled trial examining the effects of aerobic exercise (AE), computerized cognitive training (CCT) and their combination (COMB). We aim to investigate their impact on cardiovascular health and white matter (WM) integrity and how they contribute to the cognitive benefits. METHODS: 109 participants were recruited and 82 (62% female; age = 58.38 ± 5.47) finished the intervention with > 80% adherence. We report changes in cardiovascular risk factors and WM integrity (fractional anisotropy (FA); mean diffusivity (MD)), how they might be related to changes in physical activity, age and sex, and their potential role as mediators in cognitive improvements. RESULTS: A decrease in BMI (SMD = - 0.32, p = 0.039), waist circumference (SMD = - 0.42, p = 0.003) and diastolic blood pressure (DBP) (SMD = - 0.42, p = 0.006) in the AE group and a decrease in BMI (SMD = - 0.34, p = 0.031) and DBP (SMD = - 0.32, p = 0.034) in the COMB group compared to the waitlist control group was observed. We also found decreased global MD in the CCT group (SMD = - 0.34; p = 0.032) and significant intervention-related changes in FA and MD in the frontal and temporal lobes in the COMB group. CONCLUSIONS: We found changes in anthropometric measures that suggest initial benefits on cardiovascular health after only 12 weeks of AE and changes in WM microstructure in the CCT and COMB groups. These results add evidence of the clinical relevance of lifestyle interventions and the potential benefits when combining them. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT031123900.

[Evolution of the prevalence of peripheral artery disease in clinical practice: A descriptive population study with real databases (SIDIAP-CMBD)]. / Evolución de la prevalencia de arteriopatía periférica en la práctica clínica: Estudio descriptivo poblacional con bases de datos reales (SIDIAP-CMBD).

OBJECTIVE: To evaluate, with real world data (SIDIAP and CMBD), the evolution of the prevalence of peripheral arterial disease (PAD) in the Catalan population and the cardiovascular risk factors present in people with this pathology. DESIGN: Longitudinal descriptive population study. SITE: Primary health care. PARTICIPANTS: Patients listed in SIDIAP and CMBD with a diagnosis of peripheral artery disease between 2008 and 2018 ≥ 35 years, as well as those without a diagnosis, but with an ABI < 0.9 in SIDIAP. INTERVENTIONS AND MAIN MEASUREMENTS: Main variable AP (ICD-9, ICD-10). Sociodemographic data, risk factors and cardiovascular disease, drug use and prevalent cardiovascular events at the time of diagnosis. RESULTS: 141,520 patients were studied. 75% had hypertension, 58% were smokers or former smokers, and 23% had a myocardial infarction. The global prevalence increased from 1.15% in 2008 to 3.10% in 2018. The prevalence of PAD increased with age, with a moderate increase at younger ages, and more pronounced in > 55 years, exceeding 10% in > 85 years. CONCLUSION: This is a population study where it is observed that the evolution of the prevalence of peripheral artery disease has presented a constant increase during the years 2008-2018, being higher in men, especially from 55 years of age. Studies with large databases can facilitate the design and implementation of new policies in national health systems.

Severe COVID-19 during Pregnancy and Possible Vertical Transmission.

There are few cases of pregnant women with novel corona virus 2019 (COVID-19) in the literature, most of them with a mild illness course. There is limited evidence about in utero infection and early positive neonatal testing. A 41-year-old G3P2 with a history of previous cesarean deliveries and diabetes mellitus presented with a 4-day history of malaise, low-grade fever, and progressive shortness of breath. A nasopharyngeal swab was positive for COVID-19, COVID-19 serology was negative. The patient developed respiratory failure requiring mechanical ventilation on day 5 of disease onset. The patient underwent a cesarean delivery, and neonatal isolation was implemented immediately after birth, without delayed cord clamping or skin-to-skin contact. The neonatal nasopharyngeal swab, 16 hours after delivery, was positive for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) real-time polymerase chain reaction (RT-PCR), and immunoglobulin (Ig)-M and IgG for SARS-CoV-2 were negative. Maternal IgM and IgG were positive on postpartum day 4 (day 9 after symptom onset). We report a severe presentation of COVID-19 during pregnancy. To our knowledge, this is the earliest reported positive PCR in the neonate, raising the concern for vertical transmission. We suggest pregnant women should be considered as a high-risk group and minimize exposures for these reasons. KEY POINTS: · We report a severe presentation of COVID-19 in pregnancy requiring invasive ventilatory support.. · This is a case of positive RT-PCR in first day of life, suggesting possible vertical transmission.. · There were no detectable maternal antibodies for COVID-19 until after delivery..

5G2 mutant mice model loss of a commonly deleted segment of chromosome 7q22 in myeloid malignancies.

Monosomy 7 and del(7q) are among the most common and poorly understood genetic alterations in myelodysplastic neoplasms and acute myeloid leukemia. Chromosome band 7q22 is a minimally deleted segment in myeloid malignancies with a del(7q). However, the rarity of "second hit" mutations supports the idea that del(7q22) represents a contiguous gene syndrome. We generated mice harboring a 1.5 Mb germline deletion of chromosome band 5G2 syntenic to human 7q22 that removes Cux1 and 27 additional genes. Hematopoiesis is perturbed in 5G2+/del mice but they do not spontaneously develop hematologic disease. Whereas alkylator exposure modestly accelerated tumor development, the 5G2 deletion did not cooperate with KrasG12D, NrasG12D, or the MOL4070LTR retrovirus in leukemogenesis. 5G2+/del mice are a novel platform for interrogating the role of hemopoietic stem cell attrition/stress, cooperating mutations, genotoxins, and inflammation in myeloid malignancies characterized by monosomy 7/del(7q).

Measurement of the ankle brachial index with a non-mercury sphygmomanometer in diabetic patients: a concordance study.

BACKGROUND: The removal of mercury sphygmomanometers from health centers requires the validation of other instruments to measure blood pressure in the limbs to calculate the ankle-brachial index (ABI). METHODS: Descriptive cross-sectional study of agreement between two measurement methods in type 2 diabetes patients from three urban primary healthcare centres in the Barcelonès Nord i Maresme area (Catalonia, Spain). RESULTS: 211 patients were included, from these, 421 limbs were available for study. The mean age of the participants was 67 years (SD = 10), 51.7% were women. CONCLUSION: The combination of a Doppler device with the hybrid sphygmomanometer is a simple and reliable method to measure ABI showing that hybrid sphygmomanometer is a good alternative to the use of mercury sphygmomanometers.

Ankle-brachial index and the incidence of cardiovascular events in the Mediterranean low cardiovascular risk population ARTPER cohort.

BACKGROUND: Peripheral arterial disease (PAD) of the lower limbs is a cardiovascular disease highly prevalent particularly in the asymptomatic form. Its prevalence starts to be a concern in low coronary risk countries like Spain. Few studies have analyzed the relationship between ankle-brachial index (ABI) and cardiovascular morbi-mortality in low cardiovascular risk countries like Spain where we observe significant low incidence of ischemic heart diseases together with high prevalence of cardiovascular risk factors. The objective of this study is to determine the relationship between pathological ABI and incidence of cardiovascular events (coronary disease, cerebrovascular disease, symptomatic aneurism of abdominal aorta, vascular surgery) and death in the >49 year population-based cohort in Spain (ARTPER). METHODS: Baseline ABI was measured in 3,786 randomly selected patients from 28 Primary Health Centers in Barcelona, distributed as: ABI<0.9 peripheral arterial disease (PAD), ABI ≥1.4 arterial calcification (AC), ABI 0.9-1.4 healthy; and followed during 4 years. RESULTS: 3,307 subjects were included after excluding those with previous vascular events. Subjects with abnormal ABI were older with higher proportion of men, smokers and diabetics. 260 people presented cardiovascular events (incidence 2,117/100,000 person-years) and 124 died from any cause (incidence 978/100,000 person-years). PAD had two-fold greater risk of coronary disease (adjusted hazard ratio (HR) = 2.0, 95% confidence interval (CI) 1.3-3.2) and increased risk of vascular surgery (HR = 5.6, 95%CI 2.8-11.5) and mortality (HR = 1.8, 95%CI 1.4-2.5). AC increased twice risk of cerebrovascular events (HR = 1.9, 95%CI 1.0-3.5) with no relationship with ischemic heart disease. CONCLUSIONS: PAD increases coronary disease risk and AC cerebrovascular disease risk in low cardiovascular risk Mediterranean population. ABI could be a useful tool to detect patients at risk in Primary Health Care.

Prevalence of obesity and associated cardiovascular risk: the DARIOS study.

BACKGROUND: To estimate the prevalence of overweight and obesity in the Spanish population as measured with body mass index (BMI), waist circumference (WC) and waist to height ratio (WHtR) and to determine the associated cardiovascular risk factors. METHODS: Pooled analysis with individual data from 11 studies conducted in the first decade of the 21st century. Participants aged 35-74 years were asked about the history of cardiovascular diseases, hypertension, diabetes and hypercholesterolemia. Height, weight, WC, blood pressure, glycaemia, total cholesterol, low-density and high-density lipoprotein cholesterol and coronary risk were measured. The prevalence of overweight (BMI 25-29.9 kg/m(2)), general obesity (BMI ≥ 30 kg/m(2)), suboptimal WC (≥ 80 cm and < 88 in women, ≥ 94 and < 102 in men), abdominal obesity (WC ≥88 cm ≥102 cm in women and men, respectively) and WHtR ≥0.5 was estimated, standardized for the European population. RESULTS: We included 28,743 individuals. The prevalence of overweight and suboptimal WC was 51% and 30% in men and 36% and 22% in women, respectively; general obesity was 28% in both sexes and abdominal obesity 36% in men and 55% in women. The prevalence of WHtR ≥0.5 was 89% and 77% in men and women, respectively. All cardiovascular risk factors were significantly associated with abnormal increased values of BMI, WC and WHtR. Hypertension showed the strongest association with overweight [OR = 1.99 (95% confidence interval 1.81-2.21) and OR = 2.10 (1.91-2.31)]; suboptimal WC [OR = 1.78 (1.60-1.97) and OR = 1.45 (1.26-1.66)], with general obesity [OR = 4.50 (4.02-5.04), and OR = 5.20 (4.70-5.75)] and with WHtR ≥0.5 [OR = 2.94 (2.52-3.43), and OR = 3.02 (2.66-3.42)] in men and women respectively, besides abdominal obesity in men only [OR = 3.51 (3.18-3.88)]. Diabetes showed the strongest association with abdominal obesity in women [OR = 3,86 (3,09-4,89). CONCLUSIONS: The prevalence of obesity in Spain was high. Overweight, suboptimal WC, general, abdominal obesity and WHtR ≥0.5 was significantly associated with diabetes, hypertension, hypercholesterolemia and coronary risk. The use of lower cut-off points for both BMI and particularly WC and could help to better identify the population at risk and therefore achieve more effective preventive measures.

Cultural adaptations to a telephone genetic counseling protocol and booklet for Latina breast cancer survivors at risk for hereditary breast and ovarian cancer.

Telephone genetic counseling (TGC) is accepted as standard clinical care for people seeking hereditary cancer risk assessment. TGC has been shown to be non-inferior to in-person genetic counseling, but trials have been conducted with a predominantly highly educated, non-Hispanic White population. This article describes the process of culturally adapting a TGC protocol and visual aid booklet for Spanish-preferring Latina breast cancer survivors at risk for hereditary breast and ovarian cancers. The adaptation process included two phases. Phase 1 involved a review of the literature and recommendations from an expert team including community partners. Phase 2 included interviews and a pilot with the target population (n = 14) to collect feedback about the adapted protocol and booklet following steps from the Learner Verification and Revision Framework. We describe the adaptation process and report the main adaptations following the Framework for Reporting Adaptations and Modifications to Evidence-based Interventions (FRAME). Adaptations in Phase 1 were responsive to the target population needs and characteristics (e.g., delivered in Spanish at an appropriate health literacy level, addressing knowledge gaps, targeting cultural values). Phase 2 interviews were crucial to refine details (e.g., selecting words) and to add components to address GCT barriers (e.g., saliva sample video). Cultural adaptations to evidence-based TGC protocols can increase the fit and quality of care for historically underserved populations. As TGC visits become routine in clinical care, it is crucial to consider the needs of diverse communities to adequately promote equity and justice in cancer care.

This article describes the process of adapting a telephone genetic counseling protocol and visual aid booklet for Spanish-preferring Latina breast cancer survivors at increased risk for hereditary breast and ovarian cancer (HBOC). The cultural adaptation process followed two phases. In the first phase, the authors reviewed the literature and obtained insights from interdisciplinary experts. In the second phase, the authors received iterative feedback from fourteen Latina women who were breast cancer survivors, spoke Spanish as a first language, and met criteria to be considered at increased risk for HBOC. Revisions to the protocol and visual aid booklet were conducted iteratively following feedback from the expert team, after the first five women reviewed the booklet, after the second five women reviewed the booklet, and after the final four women completed the entire culturally adapted telephone genetic counseling protocol with the booklet. The final adaptations to the protocol and visual aid booklet were responsive to the target population's needs. Most adaptations made were regarding content. For example, simplifying the material presented, adding culturally relevant images, and developing a video explaining how to collect a saliva sample. Culturally adapting health interventions can improve health outcomes in historically marginalized populations and promote equity.

Biological signatures of asymptomatic extra- and intracranial atherosclerosis: the Barcelona-AsIA (Asymptomatic Intracranial Atherosclerosis) study.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic disease (ICAD) remains a challenge for stroke primary and secondary prevention. Molecular pathways involved in the development of ICAD from its asymptomatic stages are largely unknown. In our population-based study, we aimed to compare the risk factor and biomarker profiles associated with intracranial and extracranial asymptomatic cerebral atherosclerosis. METHODS: The Asymptomatic Intracranial Atherosclerosis (AsIA) study cohort includes a random sample population of 933 white subjects >50 years with a moderate to high vascular risk (based on REGICOR score) and without a history of stroke (64% males; mean age, 66 years). Carotid and intracranial atherosclerosis were screened by cervical and transcranial color-coded Duplex ultrasound, being moderate to severe stenoses confirmed by MR angiography. We registered clinical and anthropometric data and created a biobank with blood samples at baseline. A panel of biomarkers involved in atherothrombogenesis was determined: C-reactive protein, asymmetric-dimethylarginine, resistin, and plasminogen activator inhibitor-1. Insulin resistance was quantified by Homeostasis Model Assessment index. RESULTS: After multinomial regression analyses, male sex, hypertension, smoking, and alcoholic habits were independent risk factors of isolated extracranial atherosclerotic disease. Diabetes and metabolic syndrome conferred a higher risk for ICAD than for extracranial atherosclerotic disease. Moreover, metabolic syndrome and insulin resistance were independent risk factors of moderate to severe ICAD but were not risk factors of moderate to severe extracranial atherosclerotic disease. Regarding biomarkers, asymmetric-dimethylarginine was independently associated with isolated ICAD and resistin with combined ICAD-extracranial atherosclerotic disease. CONCLUSIONS: Our findings show distinct clinical and biological profiles in subclinical ICAD and extracranial atherosclerotic disease. Insulin resistance emerged as an important molecular pathway involved in the development of ICAD from its asymptomatic stage.

Laparoscopic Management of Cesarean Scar Pregnancy after Medical Treatment Failure Using Laparoscopic Bulldog Clamps.

Cesarean scar pregnancies are a rare complication of pregnancy, with an incidence rate of approximately 1 in 2000 pregnancies. Numerous treatment alternatives have been proposed and published for cesarean scar pregnancies (CSPs), including medical management with local or systemic methotrexate injection, resection through hysteroscopic, vaginal, abdominal or laparoscopic approach, and dilation and curettage. Concomitant strategies for achieving hemostasis/bleeding control have been attempted, including uterine artery embolization, the placement of a Foley balloon catheter, injection of vasopressin, and less commonly reported, the use of vascular clamps. We describe a case of failed medical management of a CSP, followed by laparoscopic resection with the use of vascular clamps to minimize bleeding. This approach can be considered for minimizing blood loss in the laparoscopic management of cesarean ectopic pregnancies.

Supervised physical activity in patients with symptomatic peripheral arterial disease: protocol for a randomized clinical trial (ARTPERfit Study).

INTRODUCTION: Peripheral arterial disease (PAD) is a marker of cardiovascular morbidity, causing disability, loss of mobility and poor quality of life, manifesting clinically in the form of intermittent claudication (IC). Physical exercise increases the distance walked and improves quality of life. The aim of our study will be increased walking distance prolonging the time of onset of pain in patients with symptomatic PAD (IC). METHODS AND ANALYSIS: This study will be performed in Mataró Hospital's vascular surgery service and School of Health Sciences, TecnoCampus. This population comes from 15 primary healthcare centres ofNorth Barcelona, Spain (450 000 inhabitants).This study will be a four-group parallel, longitudinal, randomised controlled trial, blind to analysis.The main primary outcome of this study will be the improvement in pain-free walking distance. Others primary objectives are and improvement in functional status, quality of life and Ankle-Brachial Index (ABI). Secondary outcomes will be the analysis of cardiorespiratory fitness, evaluation of muscle fitness, determine the maintenance of primary objectives at 6 and 12 months.We will be included 124 patients (31 per group). The changes of the outcome (Barthel, SF-12, VascQOL-6, ABI) of the three intervention groups vs the control group at 3, 6 and 12 months will be compared, both continuously (linear regression) and categorically (logistic regression). A person who has not performed at least 75% of the training will be considered to have not completed the intervention. ETHICS AND DISSEMINATION: The study will be conducted according to the Declaration of Helsinki . It was approved by the Ethics Committee of the Research Institute Primary Health IDIAP Jordi Gol (20/035 P),Barcelona 6 October 2020. Informed consent will be obtained from all patients before the start of the study. We will disseminate results through academic papers and conference presentations. TRIAL REGISTRATION NUMBER: NCT04578990.

The Non-pregnant and Pregnant Human Cervix: a Systematic Proteomic Analysis.

Appropriate timing of cervical remodeling (CR) is key to normal term parturition. To date, mechanisms behind normal and abnormal (premature or delayed) CR remain unclear. Recent studies show regional differences exist in human cervical tissue structure. While the entire cervix contains extracellular matrix (ECM), the internal os is highly cellular containing 50-60% cervical smooth muscle (CSM). The external os contains 10-20% CSM. Previously, we reported ECM rigidity and different ECM proteins influence CSM cell function, highlighting the importance of understanding not only how cervical cells orchestrate cervical ECM remodeling in pregnancy, but also how changes in specific ECM proteins can influence resident cellular function. To understand this dynamic process, we utilized a systematic proteomic approach to understand which soluble ECM and cellular proteins exist in the different regions of the human cervix and how the proteomic profiles change from the non-pregnant (NP) to the pregnant (PG) state. We found the human cervix proteome contains at least 4548 proteins and establish the types and relative abundance of cellular and soluble matrisome proteins found in the NP and PG human cervix. Further, we report the relative abundance of proteins involved with elastic fiber formation and ECM organization/degradation were significantly increased while proteins involved in RNA polymerase I/promoter opening, DNA methylation, senescence, immune system, and compliment activation were decreased in the PG compared to NP cervix. These findings establish an initial platform from which we can further comprehend how changes in the human cervix proteome results in normal and abnormal CR.

Automated Systems for Calculating Arteriovenous Ratio in Retinographies: A Scoping Review.

There is evidence of an association between hypertension and retinal arteriolar narrowing. Manual measurement of retinal vessels comes with additional variability, which can be eliminated using automated software. This scoping review aims to summarize research on automated retinal vessel analysis systems. Searches were performed on Medline, Scopus, and Cochrane to find studies examining automated systems for the diagnosis of retinal vascular alterations caused by hypertension using the following keywords: diagnosis; diagnostic screening programs; image processing, computer-assisted; artificial intelligence; electronic data processing; hypertensive retinopathy; hypertension; retinal vessels; arteriovenous ratio and retinal image analysis. The searches generated 433 articles. Of these, 25 articles published from 2010 to 2022 were included in the review. The retinographies analyzed were extracted from international databases and real scenarios. Automated systems to detect alterations in the retinal vasculature are being introduced into clinical practice for diagnosis in ophthalmology and other medical specialties due to the association of such changes with various diseases. These systems make the classification of hypertensive retinopathy and cardiovascular risk more reliable. They also make it possible for diagnosis to be performed in primary care, thus optimizing ophthalmological visits.

Lens-vault analysis and its correlation with other biometric parameters using swept-source OCT.

PURPOSE: To measure lens vault (LV) and to assess its correlation with various ocular parameters in healthy eyes, using for all measurements the same high-resolution swept-source optical coherence tomographer (SS-OCT). METHODS: We prospectively recruited 67 Caucasian healthy patients whose mean age was 41.9 ±â€¯12.4 years; only their right eye was included in the study. Data were all recorded with the ANTERION SS-OCT and comprised, for each patient, 5 consecutive measurements of LV, anterior chamber depth (ACD), lens thickness (LT), axial length (AL), white-to-white (WTW) distance, central corneal thickness (CCT), anterior chamber volume (ACV) and spur-to-spur (STS) distance. RESULTS: Mean LV was 0.26 ± 0.23 mm (ranging from -0.24 to 0.78 mm). Data analysis revealed a statistically significant negative correlation between LV and ACD (R=-0.80, p < 0.001), AL (R = -0.36, p = 0.002), and ACV (R = -0.68, p < 0.001), and a positive correlation between LV and LT (R = 0.67, p < 0.001), and age (R = 0.53, p < 0.001). In contrast, no statistically significant correlation was found between LV and WTW (R=-0.17, p = 0.15), CCT (R = 0.11, p = 0.36) or STS (R=-0.10, p = 0.41). CONCLUSIONS: Taking into account our findings about intra-parameter correlation levels, we believe that LV should be measured and analyzed together with other ocular parameters in clinical routine practice both for diagnosis and for some refractive surgeries.

Higher Arm Versus Lower Arm Systolic Blood Pressure and Cardiovascular Outcomes: a Meta-Analysis of Individual Participant Data From the INTERPRESS-IPD Collaboration.

BACKGROUND: Guidelines recommend measuring blood pressure (BP) in both arms, adopting the higher arm readings for diagnosis and management. Data to support this recommendation are lacking. We evaluated associations of higher and lower arm systolic BPs with diagnostic and treatment thresholds, and prognosis in hypertension, using data from the Inter-arm Blood Pressure Difference-Individual Participant Data Collaboration. METHODS: One-stage multivariable Cox regression models, stratified by study, were used to examine associations of higher or lower reading arm BPs with cardiovascular mortality, all-cause mortality, and cardiovascular events, in individual participant data meta-analyses pooled from 23 cohorts. Cardiovascular events were modelled for Framingham and atherosclerotic cardiovascular disease risk scores. Model fit was compared throughout using Akaike information criteria. Proportions reclassified across guideline recommended intervention thresholds were also compared. RESULTS: We analyzed 53 172 participants: mean age 60 years; 48% female. Higher arm BP, compared with lower arm, reclassified 12% of participants at either 130 or 140 mm Hg systolic BP thresholds (both P<0.001). Higher arm BP models fitted better for all-cause mortality, cardiovascular mortality, and cardiovascular events (all P<0.001). Higher arm BP models better predicted cardiovascular events with Framingham and atherosclerotic cardiovascular disease risk scores (both P<0.001) and reclassified 4.6% and 3.5% of participants respectively to higher risk categories compared with lower arm BPs). CONCLUSIONS: Using BP from higher instead of lower reading arms reclassified 12% of people over thresholds used to diagnose hypertension. All prediction models performed better when using the higher arm BP. Both arms should be measured for accurate diagnosis and management of hypertension. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: CRD42015031227.

Relationship between Retinal Microvasculature, Cardiovascular Risk and Silent Brain Infarction in Hypertensive Patients.

OBJECTIVE: The aims of this study are to analyze the role of artery-vein ratio AVR assessment using VesselMap 2 software (Imedos Systems) and cardiovascular risk evaluation by means of REGICOR in the prediction of silent brain infarction (SBI) in middle-age hypertensive patients from the ISSYS study. MATERIAL AND METHODS: A cross-sectional study with 695 patients with hypertension aged 50 to 70 years who participated in the project Investigating Silent Strokes in HYpertensives: a Magnetic Resonance Imaging Study (ISSYS), was conducted in two Primary Care Centres of Barcelona. Participants agreed to a retinography and an MRI to detect silent brain infarction (SBI). The IMEDOS software was used for the semiautomatic caliber measurement of retinal arteries and veins, and the AVR was considered abnormal when <0.66. The REGICOR score was calculated for all patients. RESULTS: Multivariate logistic regression analysis was used to evaluate the impact of AVR and REGICOR scores on SBI. The OR (odds ratio) for a high REGICOR score and an abnormal AVR were 3.16 and 4.45, respectively. When analysing the interaction of both factors, the OR of an abnormal AVR and moderate REGICOR score was 3.27, whereas with a high REGICOR score it reached 13.07. CONCLUSIONS: The measurement of AVR in patients with hypertension and with a high REGICOR score can contribute to the detection of silent brain infarction.

Sex-Specific Protective Effects of APOE ε2 on Cognitive Performance.

Apolipoprotein E (APOE) has an important role in the multiple trajectories of cognitive aging. However, environmental variables and other genes mediate the impact of APOE on cognition. Our main objective was to analyze the effect of APOE genotype on cognition and its interactions and relationships with sex, age, lipid profile, C-reactive protein, and Brain-derived neurotrophic factor (BDNF) genotype in a sample of 648 healthy participants over 50 years of age with a comprehensive neuropsychological assessment. Our results showed that APOE ε2 carriers performed better in the Verbal Memory (p = .002) and Fluency Domains (p = .001). When we studied the effect of sex, we observed that the beneficial effect of APOE ε2 on the normalized values of these cognitive domains occurred only in females (ß = 0.735; 95% confidence interval, 0.396-1.074; p = 3.167·10-5 and ß = 0.568; 95% confidence interval, 0.276-0.861; p = 1.853·10-4, respectively). Similarly, the sex-specific effects of APOE ε2 were further observed on lipidic and inflammation biomarkers. In the whole sample, APOE ε2 carriers showed significantly lower levels of total cholesterol, low-density lipoprotein cholesterol, and C-reactive protein. These differences were found only among females. Furthermore, total cholesterol and low-density lipoprotein cholesterol mediated the protective effect of APOE ε2 on cognition in the whole sample and total cholesterol in females, providing candidate physiological mechanisms for the observed genetic effects. Our results show that the neuroprotective role of APOE ε2 in cognition varies with sex and that the lipidic profile partially mediates this protection. Age-related cognitive and functional decline is a continuous biological process with different cognitive trajectories (1). Complex interactions between heritability, environmental influence, and cognitive functions in aging have been highlighted (2). In particular, genetic differences explain around 15%-25% of the variance in life expectancy (3). Therefore, the identification of susceptibility genes and their biological effects on cognitive aging is required to establish interindividual differences in this process and promote early personalized interventions to delay cognitive decline and minimize the financial burden of aging in the health care system.

Associations Between Systolic Interarm Differences in Blood Pressure and Cardiovascular Disease Outcomes and Mortality: Individual Participant Data Meta-Analysis, Development and Validation of a Prognostic Algorithm: The INTERPRESS-IPD Collaboration.

Systolic interarm differences in blood pressure have been associated with all-cause mortality and cardiovascular disease. We undertook individual participant data meta-analyses to (1) quantify independent associations of systolic interarm difference with mortality and cardiovascular events; (2) develop and validate prognostic models incorporating interarm difference, and (3) determine whether interarm difference remains associated with risk after adjustment for common cardiovascular risk scores. We searched for studies recording bilateral blood pressure and outcomes, established agreements with collaborating authors, and created a single international dataset: the Inter-arm Blood Pressure Difference - Individual Participant Data (INTERPRESS-IPD) Collaboration. Data were merged from 24 studies (53 827 participants). Systolic interarm difference was associated with all-cause and cardiovascular mortality: continuous hazard ratios 1.05 (95% CI, 1.02-1.08) and 1.06 (95% CI, 1.02-1.11), respectively, per 5 mm Hg systolic interarm difference. Hazard ratios for all-cause mortality increased with interarm difference magnitude from a ≥5 mm Hg threshold (hazard ratio, 1.07 [95% CI, 1.01-1.14]). Systolic interarm differences per 5 mm Hg were associated with cardiovascular events in people without preexisting disease, after adjustment for Atherosclerotic Cardiovascular Disease (hazard ratio, 1.04 [95% CI, 1.00-1.08]), Framingham (hazard ratio, 1.04 [95% CI, 1.01-1.08]), or QRISK cardiovascular disease risk algorithm version 2 (QRISK2) (hazard ratio, 1.12 [95% CI, 1.06-1.18]) cardiovascular risk scores. Our findings confirm that systolic interarm difference is associated with increased all-cause mortality, cardiovascular mortality, and cardiovascular events. Blood pressure should be measured in both arms during cardiovascular assessment. A systolic interarm difference of 10 mm Hg is proposed as the upper limit of normal. Registration: URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42015031227.