bluuebunny/crossref_metadata_2025 huggingface dataset:
Performance of a points-based scoring system for assessing species limits in birds
Authors: Tobias Joseph A , Donald Paul F , Martin Rob W , Butchart Stuart H M , Collar Nigel J
Published: April 2021

Species are fundamental to biology, conservation, and environmental legislation; yet, there is often disagreement on how and where species limits should be drawn. Even sophisticated molecular methods have limitations, particularly in the context of geographically isolated lineages or inadequate sampling of loci. With extinction rates rising, methods are needed to assess species limits rapidly but robustly. Tobias et al. devised a points-based system to compare phenotypic divergence between taxa against the level of divergence in sympatric species, establishing a threshold to guide taxonomic assessments at a global scale. The method has received a mixed reception. To evaluate its performance, we identified 397 novel taxonomic splits from 328 parent taxa made by application of the criteria (in 2014‒2016) and searched for subsequent publications investigating the same taxa with molecular and/or phenotypic data. Only 71 (18%) novel splits from 60 parent taxa have since been investigated by independent studies, suggesting that publication of splits underpinned by the criteria in 2014–2016 accelerated taxonomic decisions by at least 33 years. In the evaluated cases, independent analyses explicitly or implicitly supported species status in 62 (87.3%) of 71 splits, with the level of support increasing to 97.2% when excluding subsequent studies limited only to molecular data, and reaching 100% when the points-based criteria were applied using recommended sample sizes. Despite the fact that the training set used to calibrate the criteria was heavily weighted toward passerines, splits of passerines and non-passerines received equally strong support from independent research. We conclude that the method provides a useful tool for quantifying phenotypic divergence and fast-tracking robust taxonomic decisions at a global scale.
The inflammatory role of silent urate crystal deposition in intercritical gout
Authors: Diaz-Torne Cesar , Ortiz M Angels , Garcia-Guillen Andrea , Jeria-Navarro Sicylle , Sainz Lluís , Fernandez-Sanchez Susana , Corominas Hector , Vidal Silvia
Published: April 2021

Objective

To study subclinical inflammation in intercritical gout patients and its relation to the estimated size of monosodium urate crystal deposition and cardiovascular risk factors.

Methods

We performed a secretome analysis and the quantification of cytokine and adipokine plasma levels [IL-1β, IL-18, IL-6, soluble IL-6 receptor (sIL-6R), TNF-α, C-X-C motif chemokine 5, RANTES (Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted), leptin, resistin and adiponectin] to analyse subclinical inflammation in intercritical gout patients. Since it is currently not feasible to determinate the whole body deposit of monosodium urate crystals, we created an indirect clinical classification to estimate it. Then we compared cytokine levels in controls and gout patients and in patients with different crystal deposition sizes. We also studied the association between cytokine-levels and the number of cardiovascular risk factors.

Results

Ninety consecutive patients attending a crystal arthritis unit were studied. IL-18, sIL-6R, RANTES, leptin and adiponectin were higher in intercritical gout patients than in controls. An association was observed between IL-18, sIL6-R and RANTES levels and the size of crystal deposition. IL-18, sIL6-R, RANTES and leptin were higher in patients with no cardiovascular risk factors compared with controls with no risk factors.

Conclusion

Our results showed that the levels of some pro-inflammatory cytokines and metabolic proteins are elevated in intercritical gout patients. The levels of certain cytokines were related to the estimated size of the monosodium urate crystal deposition and to the number of cardiovascular risk factors. These cytokine changes may help to explain the increase in cardiovascular events in gout patients.
Trait self-control mediates the association between resting-state neural correlates and emotional well-being in late adolescence
Authors: Li Qingqing , Xiang Guangcan , Song Shiqing , Xiao Mingyue , Chen Hong
Published: April 2021

Trait self-control (TSC), defined as the capacity to alter predominant response to promote desirable long-term goals, has been found to facilitate emotional well-being (EWB). However, the neural correlates underlying this association remain unclear. The present study estimated resting-state brain activity and connectivity with amplitude of low-frequency fluctuations (ALFFs) and resting-state functional connectivity (rsFC) among late adolescents. Whole-brain correlation analysis showed that higher TSC was associated with increased ALFFs in regions within the executive control network (inferior frontal gyrus, IFG) and the salience network (anterior insula, AI) and decreased ALFF in regions (e.g. medial frontal gyrus, MFG; posterior cingulate, PC) within the default-mode network (DMN). TSC was also linked with the integration (e.g. increased IFG-PC connectivity) and segregation (e.g. decreased AI-MFG connectivity) among brain networks. Mediation analysis indicated that TSC totally mediated the links from the IFG and the precuneus, FC of the AI and regions of the DMN (e.g. bilateral PC and MFG), to EWB. Additionally, ALFF in the IFG and the MFG could predict negative affect in the pandemic through TSC. These findings suggest that TSC is involved in several regions and functional organizations within and between brain networks and mediated the association between neural correlates and emotional wellness in adolescence.
Clinico-epidemiology of Hypnale zara (hump-nosed pit viper) envenoming in Sri Lanka
Authors: Rathnayaka R M M K Namal , Ranathunga P E A Nishanthi , Kularatne S A M
Published: April 2021

Background

Hump-nosed vipers of the genus Hypnale are the most common cause of venomous snakebites in Sri Lanka. The genus includes three species: Hypnale hypnale, Hypnale zara and Hypnale nepa. Of them, H. hypnale bites are the most common and are the subject of many publications. The epidemiology and clinical features of bites by the other two species have been less investigated.

Methods

We conducted a prospective observational study of H. zara bites from January 2015 to June 2020 at the Teaching Hospital, Ratnapura, Sri Lanka. Data were collected for 5.5 years in the wet zone of the island, where the principal investigator did assessment of all patients and the data collection.

Results

H. zara envenoming was confirmed through identification of dead or live snake specimens brought with the patients. Of the 480 patients with proven hump-nosed viper bites, H. zara bites accounted for 105 (22%), including dry bites (n=5 [5%]) and envenoming (n=100 [95%]), with gender distribution of 65 (62%) males and a mean age of 43.1 y. Most bites occurred on the lower limbs (n=71 [68%]) in the daytime (n=69 [66%]) in home gardens (n=45 [43%]). A total of 100 (95%) patients had local manifestations, including pain (n=100 [95%]), swelling (n=100 [95%]), bleeding (n=20 [19%]), bruising (n=11 [10%]), lymphadenopathy (n=10 [9%]), necrosis at the bite site (n=9 [9%]) and blistering (n=8 [8%]). Seven (6.7%) patients showed systemic effects, including acute kidney injury (n=2 [2%]), microangiopathic haemolysis (n=2 [2%]), sinus bradycardia (2 [2%]) and one (1%) each had coagulopathy, thrombotic microangiopathy, Kounis syndrome and ischaemic changes on electrocardiography. Eosinophilia was a significant haematological finding (n=26 [25%]) and 16 (15%) had leucocytosis and 15 (14%) had neutrophilia. Ninety six percent of patients (n=101) recovered. Antivenom is not available for hump-nosed viper bites in Sri Lanka and therefore patients were managed conservatively.

Conclusions

This study shows that H. zara bites mainly cause local envenoming and rarely systemic effects.
EFFECTS OF BLOOD PRESSURE AND SALT ON ARTERIAL LIPID DEPOSITION IN THE APOE-DEPLETED SHR
Authors: Matsuo Hiroyuki , Kawakami Kohei , Fujikawa Koichi , Ohara Hiroki , Yamada Takaya , Nabika Toru
Published: April 2021

Objective:

Hypertension and oxidative stress are both risk factors for atherosclerosis. Although apoprotein E (ApoE)-knockout mice have been widely used as a model for atherosclerosis, chronic effects of high blood pressure (BP) were not fully elucidated because of lack of hypertensive models in mice. In this study, we therefore constructed ApoE-knockout SHR (ApoE-KO SHR) to address this issue. As SHR is a genetic model for hypertension, ApoE-KO SHR would be a good model to evaluate effects of hypertension on atherosclerosis. Here, we examined effects of blood pressure and salt-loading on the ApoE-KO SHR.

Design and method:

ApoE-KO SHR was made using the genome editing technology with CRISPR/CAS9. We successfully obtained ApoE-KO SHR with 13 bps deletion causing a frame-shift. ApoE-KO SHR was then backcrossed with WKY for 3 generations to make an ApoE-KO model with lower BP (ApoE-KO WKY). Rats were fed high-fat diet for 8 weeks from 8 weeks of age with or without 1% salt water. Rats were then sacrificed and lipid deposition in mesenteric arteries were evaluated on microscope.

Results:

In ApoE-KO rats, serum total cholesterol and triglyceride were dramatically increased. Under salt-loading condition, oxidative stress estimated with urinary isoprostane was significantly increased. BP in ApoE-KO SHR and ApoE-KO WKY were comparable with that in SHR and WKY, respectively. Under the salt-loading condition, lipid deposition in mesenteric arteries was significantly greater in ApoE-KO SHR than in ApoE-KO WKY.

Conclusions:

These results suggested that high blood pressure and/or salt aggravated arterial lipid deposition in mesenteric arteries probably through endothelial dysfunction in the salt-loaded ApoE-KO SHR.
NEUTROPHIL TO LYMPHOCYTE RATIO AND PLATELET TO LYMPHOCYTE RATIO AS ASSESSMENT TOOLS FOR LIPID CONTROL AND CARDIOVASCULAR RISK
Authors: Vintila Ana Maria , Horumba Mihaela , Cimpu Cristiana , Dumitrescu Diana , Miron Paul , Alucai Andreea , Cristea George Gabriel , Vintila Vlad Damian
Published: April 2021

Objective:

NLR (neutrophil to lymphocyte ratio) and PLR (platelet to lymphocyte ratio) are parameters associated with a higher mortality in patients with atherosclerotic cardiovascular disease (ASCVD). The purpose of our study was to determine if there were any differences in NLR or PLR in very-high risk patients who achieve LDL-cholesterol < 55 mg/dl and those who do not.

Design and method:

We performed a unicentric, retrospective study on hypertensive, diabetic patients admitted to the Internal Medicine and Cardiology Department from 2014 to 2018. Demographics, comorbidities and laboratory test results were recorded including complete blood count, erythrocyte sedimentation rate (ESR) and lipid profile. Data analysis was performed using SPSS version 20.

Results:

A total of 1239 patients were enrolled with a mean age of 71.3 ± 10.1 years and a slight female predominance (59.4% female). Little over half of patients (56.3%) had very-high cardiovascular risk: 54.3% had ASCVD and 4.2% had severe CKD, while all other had high CV risk. There were no significant differences in terms of NLR and PLR between patients at high or very-high CV risk as long as the LDL-cholesterol target was met (3.589 vs. 4.745, p = 0.163; 153.9 vs. 196.5, p = 0.055). However, if LDL-cholesterol targets were not achieved, there were NLR and PLR were higher in patients with very-high CV risk (2.857 vs. 3.940, p < 0.001; 143.5 vs. 174.0, p = 0.001). Both NLR and PLR had a positive correlation with ESR irrespective of high or very-high CV risk (NLR: r = 0.153 p = 0.022 vs. r = 0.264, p < 0.001; PLR: r = 0.214, p = 0.001 vs. r = 0.278, p < 0.001).

Conclusions:

Tighter cholesterol control has a significant role in lowering cardiovascular risk. Our study shows that based on NLR and PLR very-high risk patients who achieve the LDL-cholesterol target of 55 mg/dl have the same risk of CV events as patients who are at high CV risk.
VALIDITY OF FIVE FORMULAS TO ESTIMATE 24-HOUR URINARY SODIUM BY SPOT URINE SAMPLES IN ADULTS LIVING IN NORTHEAST CHINA
Authors: Song Wei , Qian Ni , Guo Ran , Zhang Ying , Jiang Yinong
Published: April 2021

Objective:

Although several formulas from spot urine have been used to assess 24-hour urinary sodium excretion in order to estimate salt intake, the validity in Chinese adult population is uncertain. The objective was to evaluate the accuracy of five formulas, including INTERSALT without urine potassium, Kawasaki, Tanaka, Uechi simple-mean, and a new formula, by spot urinary to predict 24-hour sodium excretion in adults living in northeast China.

Design and method:

This was a multi-center clinical study, conducted from April 2016 to October 2019. There were 1092 hospitalized patients aged from 18 to 85 years enrolled. Five different formulas were used to predict 24-hour urinary sodium (UNa) excretions by spot morning urinary samples. Actual urinary sodium excretion was measured from 24-hour urine samples. The estimated value is compared with the actual value by examining bias (observed minus predicted UNa), the intraclass correlation coefficients (ICC), and Bland–Altman plots. The differences between actual and estimated sodium excretion across subgroups divided by salt intake were analyzed.

Results:

The average excretion of sodium was 2958.15 mg/d, which is equivalent to 7.51 g/day of sodium chloride intake. Formulas produced biases for actual urinary sodium were 328.31 mg/d for INTERSALT, 517.56 mg/d for new formula, 897.59 mg/d for Tanaka, 1169.06 mg/d for Uechi, 1971.12 mg/d for Kawasaki. The correlation was positive for all equations, the highest and lowest ICC were 0.37 for new formula and 0.3 for Uechi respectively. There was no significant difference in number of patients which were beyond the mean ± 1.96 standard deviation. The least mean biases in lower salt intake subgroup (UNa no more than 2362.20 mg/d) and middle salt intake subgroup of five equations were 1283.00 mg/d and 74.46 mg/d respectively, which are calculated by INTERSALT. The least mean biases in higher salt intake subgroup (UNa more than 4724.41 mg/d) was 147.62 mg/d for Uechi.

Conclusions:

INTERSALT without urine potassium and new formula may offer a good performance of mean 24-h sodium estimation in lower and middle salt intake subgroups for adults living in Northeast China. The Uechi simple-mean formula performed best in higher salt intake subgroup.
SYSTOLIC INTER-ARM BLOOD PRESSURE DIFFERENCE AND COGNITIVE DECLINE: FINDINGS FROM THE INTERPRESS-IPD COLLABORATION
Authors: Clark Christopher , Boddy Kate , Warren Fiona , Mcdonagh Sinead , Moore Sarah , Aboyans Victor , Cloutier Lyne , McManus Richard , Shore Angela , Taylor Rod , Campbell John
Published: April 2021

Objective:

Hypertension and dementia are associated with older age and each other. As the populations age, prevalence of dementia will rise, representing substantial costs and care burdens for society. Currently, no interventions halt established cognitive decline, therefore approaches focus on prevention. Systolic inter-arm differences (IAD) in blood pressure (BP) and cognitive decline are associated with cardiovascular disease. We recently published initial evidence for associations of IAD with prospective cognitive decline and now present findings from the INTERPRESS-IPD Collaboration, examining associations of IAD with mild cognitive impairment (MCI) development and dementia.

Design and method:

Individual participant data meta-analyses. We examined time-to-event data for new diagnoses of MCI and dementia, according to IAD status in univariable and multivariable regression models, stratified by study. Multivariable analyses were adjusted for systolic BP, age, sex and highest educational attainment. We also examined changes in Mental State Examination (MSE) scores, with adjustments as above, plus follow-up duration.

Results:

Mean age was 66.2 years, 55% were female, 84% were of White ethnicity and mean systolic IAD was 7.0 mmHg. During 10-year follow-up, 5.9% of 4,635 individuals, from 3 cohorts, had new diagnoses of MCI. In univariable analyses, MCI was associated with systolic IAD >/=5mmHg [Hazard Ratio, 1.34 (95%CI 1.04 to 1.72); p=0.022] and >/= 0mmHg [1.33 (1.03 to 1.73); p = 0.032]. After adjustment, associations with systolic IADs >/ = 5mmHg [1.31 (1.02 to 1.67); p = 0.036] and >/=10mmHg [1.29 (0.99 to 1.68); p = 0.056] remained. There were 95 new diagnoses of dementia during follow-up; no associations were observed between dementia diagnosis and IAD.

MSE scores were recorded for 2,709 participants; 15.5% showed clinically meaningful reductions (>/=5 points) during follow-up. Decreases were associated with IADs >/=5mmHg (p=0.004) and >/=10mmHg (p = 0.006) on univariable analyses. After adjustment, associations with IADs >/=5mmHg remained (p = 0.033); age and educational attainment attenuated the association with IADs >/ = 10mmHg (p = 0.11).

Conclusions:

We present the first time-to-event analyses of MCI development with IAD and demonstrate that systolic IADs >/ = 5mmHg and >/ = 10mmHg are associated with MCI onset. If confirmed, these findings could inform individualised treatment decisions to minimise risk of future cognitive decline.
SYSTOLIC BLOOD PRESSURE IS A MAJOR COMPONENT OF THE RISK SCORE FOR NEW PROGRESSION OF CAROTID PLAQUE: THE SUITA STUDY
Authors: Kokubo Yoshihiro , Watanabe Makoto , Higashiyama Aya , Honda-Kohmo Kyoko , Miyamoto Yoshihiro
Published: April 2021

Objective:

We first showed that the new progression of carotid plaque (Prog-PQ) is a risk factor for cardiovascular disease (CVD), but the Prog-PQ risk score has not been established.

Design and method:

We studied 4,724 Japanese (mean age 59.7 years) without CVD, whose intima-media thickness (IMT) was measured with carotid ultrasonography on both sides of the entire carotid artery areas (April 1994 to August 2001). Carotid plaque was defined as a maximum IMT of the common carotid artery > 1.1 mm. We excluded subjects with carotid plaque at baseline (n = 1,044), lost to follow-up (n = 167), and missing data (n = 2). For 3,511 subjects, the general examination and carotid ultrasonographic follow-ups were performed every two years until March 2016. Cox proportional hazard ratios were analyzed after adjusting for cardiovascular risk factors. We used the area under the receiver operating characteristic curve to evaluate the model's discrimination.

Results:

During 38,454 person-years of follow-up, 1,771 incidences of Prog-PQ were observed. Based on systolic blood pressure (SBP) of less than 120 mmHg, the adjusted hazard ratios of Prog-PQ were 1.18 (1.04–1.33), 1.35 (1.11–1.63), and 1.65 (1.23–2.23) in subjects with SBP = 120–139 mmHg, 140–159 mmHg, and 160 mmHg or more, respectively. We developed a scoring system for each risk factor as follows: 0, 2, 4, 6, 9, and 11 points for age 30's to 80's, respectively; -1 point for women; 0, 1, and 2 points for systolic blood pressure (<120, 120–159, and >  = 160mmHg); 0, 1, 2, and 3 points for total cholesterol (<160, 160–239, 240–279, and > = 280 mg/dL); 2, 0, and -1 points for HDL cholesterol (<35, 35–59, and > = 60 mg/dL); 1 point for overweight or current smoking; and 2 points for diabetes (C-statistic 0.647; 95%CI, 0.629–0.665). Individuals with 2 or 10 points had 27% or 62% observed probability of Prog-PQ in 10 years, respectively.

Conclusions:

We have developed a 10-year risk score for Prog-PQ, that can efficiently predict atherosclerosis in routine clinic/health examinations without carotid ultrasonography.
EFFECTS OF BLOOD PRESSURE-LOWERING ON CANCER RISK: AN INDIVIDUAL PARTICIPANT DATA META-ANALYSIS OF 300,000 PARTICIPANTS
Authors: Copland Emma , Canoy Dexter , Nazarzadeh Milad , Bidel Zeinab , Woodward Mark , Chalmers John , Teo Koon , Pepine Carl , Davis Barry , Kjeldsen Sverre , Sundstrom Johan , Rahimi Kazem
Published: April 2021

Objective:

Evidence for the effects of pharmaceutical blood pressure (BP)-lowering on cancer risk is inconsistent and based on observational data. We therefore investigated the effect of BP-lowering on the risk of cancer in a large collaborative study.

Design and method:

We included randomised trials participating in the Blood Pressure-Lowering Treatment Trialists’ Collaboration. Placebo-controlled trials, drug class comparison trials and trials comparing more-vs-less intensive BP-lowering that provided individual-level participant data (IPD) on cancer events were pooled. We investigated the effects of BP reduction on cancer risk by conducting one-stage IPD meta-analyses using Cox proportional hazard models, stratified by trial and accounting for competing risks. We also investigated effects stratified by age, gender, body mass index (BMI), smoking and previous antihypertensive use at baseline.

Results:

This analysis included 300,098 participants (42% women) from 39 trials. At baseline, the mean age of participants was 66 (standard deviation [SD] = 9), mean BMI was 28 (SD = 5), 18% were current smokers and 75% were previously on BP-lowering medication. Over a median duration of 4 years, 16,748 participants were diagnosed with cancer, and 4347 cancer deaths were reported. The hazard ratio (HR) per 5mmHg reduction in systolic BP was 1.03 (95% confidence interval [CI] 0.99–1.07) for any cancer and 1.05 (95% CI 0.98–1.12) for cancer death. We found heterogeneity in the effects of BP-lowering across age, gender, BMI and smoking groups for any cancer and cancer death, and across groups defined by previous antihypertensive use for any cancer. However, there was no evidence that BP-lowering significantly increased the risk of developing cancer in specific patient subgroups. We found no evidence for trends in increasing or decreasing risk over time for either outcome (P for trend: any cancer = 0.98, cancer death = 0.99).

Conclusions:

This large-scale IPD meta-analysis found no evidence that BP-lowering had an important effect on cancer risk. Although we found that BP-lowering effects differed across several patient characteristics, there was no evidence for trend in cancer risk over time. We plan to further investigate the effects of BP-lowering on site-specific cancers (breast, colorectal, kidney, lung, prostate and skin) and present these results at the meeting.
SOMATIC MUTATIONS IN ADRENALS FROM PATIENTS WITH PRIMARY ALDOSTERONISM NOT CURED AFTER ADRENALECTOMY SUGGEST COMMON PATHOGENIC MECHANISMS BETWEEN UNILATERAL AND BILATERAL DISEASE
Authors: Hacini Inès , De Sousa Kelly , Boulkroun Sheerazed , Meatchi Tchao , Amar Laurence , Zennaro Maria-Christina , Fernandes-Rosa Fabio Luiz
Published: April 2021

Objective:

Primary aldosteronism (PA) is the most common form of secondary and curable hypertension, with a prevalence of 5% in primary care and 10% in referred patients. Different germline and somatic mutations are found in aldosterone producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with aldosterone-producing adenoma (APA); however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy and the histological and genetic characteristics of their adrenal glands.

Design and method:

Clinical data from 16 PA patients undergoing adrenalectomy between 2008 and 2018 without biochemical success were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2 guided next generation sequencing on formalin-fixed paraffin-embedded APA tissues.

Results:

Patients with absent hormonal cure displayed longer duration of arterial hypertension before PA diagnosis and lower index of lateralization of aldosterone production on adrenal vein sampling. In 14 patients, APA expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with our without hormonal cure. Somatic mutations in APA driver genes were identified in 13 out of 14 CYP11B2 positive APA. Mutations in the CACNA1D gene were the most frequent genetic abnormality and associated with smaller nodules. The mutational status of APA in patients without hormonal cure was not associated with differences in CYP11B1 or CYP11B2 expression.

Conclusions:

In conclusion, 93% of adrenals from patients with absent hormonal cure showed CYP11B2 expressing adenomas carrying somatic mutations, confirming the diagnosis of APA. However, these patients were diagnosed later and exhibited lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.
BLOOD PRESSURE EFFECTS OVER TIME OF BIPOLAR RADIOFREQUENCY RENAL DENERVATION IN UNTREATED HYPERTENSION
Authors: Weber Michael , Kirtane Ajay , Weir Matthew , Leon Martin
Published: April 2021

Objective:

It is believed that interruption of the renal nerves which lie in close proximity to the renal arteries, will effectively reduce blood pressure. As a first step, this study measured the blood pressure effects of ablating these nerves using radiofrequency energy produced by a bipolar catheter positioned into each renal artery in untreated hypertensive patients.

Design and method:

REINFORCE was a randomized, sham-controlled multicenter trial. Patients with office systolic blood pressure (SBP) of 150–180 mmHg and average 24-hour ambulatory SBP of 135–170 mmHg after medication washout underwent bipolar radiofrequency renal denervation or a sham procedure. The planned outcome was 8-week change in 24-hour ambulatory SBP. Enrollment was terminated for apparent futility before a sufficient sample for powered efficacy comparisons was enrolled, although patient observation continued. Safety assessments included all-cause death, renal failure, severe hypotension/syncope, hypertensive crisis, and renal artery stenosis.

Results:

Baseline 24-hour BP was 148.3 ± 10.9/85.7 ± 9.1 mmHg for the denervation group (N = 34, age 58.5 ± 10.1 years, 47% female) and 149.1 ± 7.2/86.4 ± 9.8 mmHg for the control group (N = 17, age 58.2 ± 9.8 years, 24% female). At 8 weeks, mean 24-hour SBP reductions for the renal denervation and control groups were 5.3 mmHg (95%CI -8.8, -1.8) and -8.5 mmHg (95%CI -13.3, -3.8), respectively (difference 3.3 [95%CI -2.8, 9.3]; p = .30). Antihypertensive medications could then be added. By 6 months, decreases in SBP were greater for the denervation group, yielding between-group differences of -7.2 (95%CI -15.2, 0.8; p = .08), -9.7 (95%CI -17.7, -1.7; p = .02), and -11.4 (95%CI -19.2, -3.7; p < .01) for 24-hour, daytime ambulatory, and office measurements, respectively. Control rates (office SBP < 140) were higher in the denervation group both at 6 months (52% vs. 12%, p < 0.01) and 12 months (42% vs. 13%, p = 0.048). Medication use was similar in both groups. By 12 months, one denervation patient had a hypertensive urgency and one experienced progression of renal artery stenosis.

Conclusions:

The antihypertensive effects of renal denervation can be delayed for weeks following the procedure, but then appear to be sustained for at least 12 months.
PATIROMER VS PLACEBO TO ENABLE SPIRONOLACTONE IN PATIENTS WITH RESISTANT HYPERTENSION AND CKD: ANALYSIS ACCORDING TO PATIENT SEX (AMBER TRIAL)
Authors: Williams Bryan , White William B. , Mayo Martha R. , Warren Suzette , Arthur Susan , Ackourey Gail , Rossignol Patrick , Agarwal Rajiv
Published: April 2021

Objective:

Spironolactone (SPIRO) effectively reduces BP in patients (pts) with resistant hypertension (RHTN), but hyperkalaemia (HK) may limit its use in pts with advanced CKD. In AMBER, patiromer (PAT) enabled more persistent SPIRO use in pts with RHTN and eGFR 25– < = 45 mL/min/1.73 m2. As biological differences between men and women may contribute to variations in drug response, we evaluated the AMBER results by sex in a prespecified analysis.

Design and method:

AMBER was a randomised, double-blind, placebo (PBO)-controlled RCT in adults with eGFR 25– < = 45 mL/min/1.73 m2 and uncontrolled RHTN (unattended systolic automated office blood pressure [AOBP]) 135–160 mm Hg, despite taking > = 3 antihypertensives. Pts were assigned (1:1) to receive PBO or PAT, and SPIRO 25 mg QD, to start along with their baseline (BL) BP medications. Dose titrations were permitted after 1 week for PAT/PBO and after 3 weeks for SPIRO. The primary endpoint (between-group difference at Wk 12 in % of pts on SPIRO) was assessed in prespecified subgroups by sex.

Results:

Of 295 pts randomised, there were 153 (51.9%) men and 142 (48.1%) women with BL mean (SD) systolic AOBP of 144.6 (6.7) mmHg and 143.5 (6.8) mmHg and serum K+ of 4.77 (0.37) mmol/L and 4.65 (0.35) mmol/L, respectively. More pts treated with PAT than PBO remained on SPIRO at Wk 12 in both subgroups (between treatment difference of 19.3% [P = 0.0035] for men and 19.7% [P = 0.0065] for women with P = 0.80 for interaction between subgroups) (Figure). LS Mean (SE) cumulative SPIRO dose was higher with PAT than PBO, by 449 (180) mg in men and 326 (178) mg in women. Similar reductions in AOBP were observed in both subgroups at 12 weeks (P < 0.0001). Adverse events occurred in 52% (PBO) and 53% (PAT) of men and 55% (PBO) and 59% (PAT) of women. One PBO (woman) and 3 PAT pts (2 men, 1 woman) had serum Mg 0.49 to < 0.58 mmol/L; none had serum Mg < 0.49 mmol/L.

Conclusions:

SPIRO reduced AOBP in pts with advanced CKD and RHTN and PAT enabled more of these pts to continue treatment with SPIRO, regardless of sex.
LACK OF FUNDING AND LONG-TERM JOB SECURITY THREATENS TO HAVE PROFOUND EFFECTS ON CARDIOVASCULAR RESEARCHER RETENTION IN AUSTRALIA
Authors: Marques Francine , Climie Rachel , Wu Jason , Calkin Anna , Chapman Niamh , Colafella Katrina , Picone Dean , Viola Helena , Murphy Andrew , Nelson Mark , Nichols Stephen , Hool Livia , Figtree Gemma
Published: April 2021

Objective:

Cardiovascular disease is the leading cause of death in Australia, yet funding has stagnated in recent years, resulting in economic challenges within the cardiovascular research sector. Here we investigated the challenges faced by cardiovascular researchers in Australia as an initiative of the Emerging Leaders Committee of the Australian Cardiovascular Alliance (ACvA).

Design and method:

We developed a questionnaire, which was distributed via email and social media to ACvA members, Australian cardiovascular societies, councils, universities and research institutes for 6 months during April-November 2019.

Results:

There were 548 completed responses (out of 703, 80%). The respondents primary career stage was group leader or laboratory head (40%) followed by post-doctoral (33%), most were females (53%), and 31% reported career interruptions, especially parental leave. Only 23% had permanent (ongoing) employment. Eighty one percent of full-time workers said they regularly work more than 40 hours per week, and 85% were not compensated for overtime work. Sixty eight percent said they have considered leaving the cardiovascular research sector. If their position could not be funded in the next few years, 43% would consider leaving Australia to work in cardiovascular research overseas, and only 9% said they would not leave the sector. Greater job security (76%) and government investment in cardiovascular research (71%) were highlighted as the main strategies for retaining cardiovascular researchers in the sector in Australia. Compared to male cardiovascular researchers, women were less likely to be a laboratory head, hold secure funding or have confidence in a long-term career path as cardiovascular researcher, and were more likely to consider leaving the sector (all P < 0.05).

Conclusions:

Our survey suggests that the current lack of funding in cardiovascular research, combined with a lack of long-term job security, threatens to have profound effects on cardiovascular researcher retention in Australia, especially for women. Strategies to increase retention and address the issues highlighted by our survey are urgently needed.
SUSTAINABILITY OF BLOOD PRESSURE REDUCTIONS AT INTERVENTIONS LED AT BARBERSHOPS: SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED CONTROLLED TRIALS
Authors: Muruganathan A. , Rader Florian , Blyler Ciantel , Vijayaraghavan Krishnaswami , Maheshwari Anuj , Verma Narsingh , Mubarak Mr , Das Mk , Mohanan Pp , Mishra Sundeep , Mehta Ashwani
Published: April 2021

Objective:

Novel approaches are required in order to detect and manage hypertension in low and middle-income countries. One model is by using barbershops as a contact platform to engage with patients on a regular basis. We explored the evidence for the contemporary role of barbershop led interventions to manage hypertension in community setting, by only including randomized controlled clinical trials (RCCTs)

Design and method:

We searched Cochrane Library, pubmed- MEDLINE, IndMED online databases to conduct a systematic review of the published RCCTs. Studies with non-barbershop led, generalised community-based setting approaches were excluded by using the Boolean operators. Graphpad was utilised for statistical analysis

Results:

The results yielded four clinical trials of which three met inclusion criteria, published in last 10 years (2011 to 2019). The parameters were analysed for the study design, patient characteristics, impact factor of the journals, duration, and outcomes. Cumulatively, 1826 subjects (mean 609 subjects, SD ± 367, SEM ± 212, minimum 319, maximum 1022, range 703, 95% CI -304 to 1521, p = 0.103 NS) have been evaluated across three RCCTs. The cumulative duration of the trials was 32 months (mean 11 months, SD ± 1.2, SEM ± 0.67, minimum 10, maximum 12, range 2, 95% CI 7.8 to 13.5, p = 0.0039). The baseline systolic BP of upto 140 mm Hg has been the uniform enrolment criteria. Based on the impact factor of the journals (mean 31, SD ± 35, SEM ± 20, minimum 2.8, maximum 71, range 68, 95% CI -56 to 119; p = 0.26 NS), we formulated an indexed weightage score (mean 100, minimum 9, maximum 225, SD ± 112, SEM ± 65, range 216, 95% CI -178 to 378, p = 0.26 NS). The patients who were treated with specialists, received more BP medication and different classes of medication than those treated by primary care physicians and BP reduction was 21 mmHg (p < 0.0001)

Conclusions:

Barber based intervention model have demonstrated to be a feasible connect between the patients and healthcare providers resulting in sustained BP reductions in the community, especially when care linkage to hypertension specialists can be achieved
LONGITUDINAL CHANGE IN RENAL DYSFUNCTION BIOMARKERS PREDICT OUTCOME DIFFERENTLY IN HYPERTENSIVE AND NORMOTENSIVE PERSONS FROM THE GENERAL POPULATION. THE TROMSØ STUDY
Authors: Solbu Marit Dahl , Melsom Toralf , Norvik Jon Viljar , Eriksen Bjørn Odvar , Eggen Anne Elise , Løchen Maja -Lisa , Zykova Svetlana N. , Jenssen Trond Geir
Published: April 2021

Objective:

Serum uric acid (SUA), urinary albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) are associated with hypertension and adverse cardiovascular (CV) outcome. Little is known about outcome after longitudinal changes in these biomarkers. We aimed to assess the associations between seven years’ change in these renal biomarkers and the incidence of CV disease and mortality in hypertensive and normotensive individuals from the general population.

Design and method:

We included all participants with measurements of SUA, eGFR and ACR in survey 4 (1994/95) and 5 (2001/02) of the Tromsø Study. Hypertension at baseline (1994/95) was defined as systolic blood pressure (BP) >  = 140 mmHg, diastolic BP > = 90 mmHg and/or antihypertensive drug use. We used Cox regression to examine the associations between seven years’ > = 25% increase in SUA and/or ACR, and/or annual eGFR decline of > = 3 mL/min/1.73 m2, and myocardial infarction (MI), ischaemic stroke (IS) and all-cause mortality. Multivariable models adjusted for baseline CV risk factors, changes in systolic BP and body mass index were run separately in hypertensive and normotensive subjects

Results:

Of the 4663 participants included, 59% had hypertension. At baseline, mean age was 58.3 (9.8) years, eGFR 94 (13) mL/min/1.73 m2, SUA 310 (89) μmol/L and median ACR 0.53 (0.36, 0.87) mg/mmol. Between the 2001/02 visit and 31.12.2013, 479 persons suffered from MI, 394 IS and 1296 died. Increase in ACR > = 25% was associated with MI in normotensive (HR 2.09; 95% CI 1.47, 2.98), but not hypertensive subjects. Change in ACR, SUA or eGFR was not associated with IS. All three variables were associated with all-cause mortality in hypertensive, but not normotensive subjects. However, the association between SUA and death was no longer significant when adjusted for ACR and eGFR change.

Conclusions:

Increasing ACR was a risk factor for MI in normotensives, whereas increasing ACR and rapid eGFR decline predicted mortality in hypertensive individuals. Change in different biomarkers of kidney dysfunction may reflect different pathophysiological processes. Further research is needed to determine whether change in renal biomarkers may be useful in follow-up of hypertensive and normotensive persons.
REMAINING CARDIOVASCULAR RISK MARKERS IN PARTICIPANTS WITH WHITE-COAT HYPERTENSION DIAGNOSED BY HOME BLOOD PRESSURE RECORDINGS
Authors: Johansson Martina , Ström Edvin , Östgren Carl Johan , Engvall Jan , Wijkman Magnus , Nyström Fredrik
Published: April 2021

Objective:

White coat hypertension (WCH) is defined as having hypertensive blood pressure in the office but normal ambulatory or home blood pressure (HBP) levels. The cardiovascular prognosis in WCH is controversial. Some studies have demonstrated it to be a benign condition while others have linked it to possible health complications. The objective for this study is to evaluate remaining cardiovascular risk markers in WCH patients by analyzing interactions of WCH with metabolic factors, calcium score, pulse wave velocity (PWV) and carotid plaques in a large, randomly selected population-based cohort.

Design and method:

BP was measured in both clinic and at home in 5057 middle-aged participants. HBP was measured morning and evening for 7 days except for the first day in which the morning was spent in the clinic. WCH was defined as having a systolic OBP > = 140 mmHg and/or diastolic BP > = 90 mmHg while HBP systolic BP < 135 and diastolic BP < 85 mmHg. In some calculations WCH was lowered to HBP < 125/ < 75 mmHg. Normotensive BP was defined as OBP < 140/ < 90 and HBP < 135/ < 85. Blood tests, computer tomography (CT) scanning of the abdomen, coronary arterial angiography, arterial PWV, cardio-thoracic imaging and ultrasonography of the carotid arteries was performed. In addition, all participants filled out extensive electronic lifestyle questionnaires and this information was also accounted for. Independent t-tests were used for all calculations and to compare normotensives (NT) and WCH with the two different cut-offs, against known risk factors.

Results:

All tests showed significant signs of more metabolic and cardiovascular damage for WCH patients compared to normotensives, even with the stricter WCH definition (see table 1 and 2). Calculations from questionnaire data showed that normotensive women scored lower on a scale designed to measure nervousness than women with WCH (p = 0.022) and men with WCH reported a higher alcohol consumption than men with normal BP (0.012)

Conclusions:

Available data suggests that excessive BP reactivity limited to the doctor's office with stricter than usual definitions pose as a cardiovascular risk marker and that these patients probably could benefit from dedicated treatment.
SERUM CHLORIDE AND ADVERSE CARDIOVASCULAR RISK IN THE WEST OF SCOTLAND GENERAL POPULATION
Authors: McCallum Linsay , Lip Stefanie , Padmanabhan Sandosh
Published: April 2021

Objective:

To examine the association between serum Cl- and cardiovascular and non-cardiovascular morbidity and mortality outcomes in the West of Scotland general population.

Design and method:

Patients aged > 18 years resident in NHS Greater Glasgow and Clyde who had serum Cl- measured at baseline were included in the study. The study was approved by NHSGGC Local Privacy Advisory Committee (LPAC) (GSH/16/CA/012). Baseline defined as: first serum Cl- taken outwith one-month of an acute hospital admission or one-month post discharge and in the absence of prescription for diuretic therapy in the previous 3 months or serum sodium < =125 or > = 150 mmol/L; serum creatinine > 125 micromol/L. ICD-10 codes were used to characterise diagnosis and cause of death. Primary outcomes were a composite of fatal/non-fatal events for each specified outcome: all CV events, MI, IHD, heart failure, all stroke, stroke subtypes, PVD, cardiac dysrhythmia, COPD, asthma pneumonia/influenza, chronic liver disease, diabetes, kidney disease. The study population were divided into ten groups based on serum Cl- (< = 99,100–101.9,102–102.9,103–103.9,104–104.9,105–105.9,106–106.9,107–107.9,108–110.9 > = 111mmol/L). Outcomes assessed using Cox-PH models. Model 1 was adjusted for age and sex. Model 2–6 for age, sex, and variables including prevalent cardiovascular disease, prevalent diabetes, Scottish Indices of Multiple Deprivation (SIMD), serum Na+, serum bicarbonate, total cholesterol.

Results:

The study population contained 519,957 patients with serum Cl- measured at baseline. The population were 50.6 (17.7) years old; 43.5% were male; 9% had diabetes at baseline and 3.8% had a history of cardiovascular disease. One third (33.4%) of the population resided in an area within the SIMD quintile 1. There was a ’U’-shaped non-linear association between serum Cl- and risk of fatal/non-fatal events. The results from Model 1 are presented in Figure 1. The greatest risk was seen in groups 1–3 (Cl- < 103mmol/L) and groups 8–10 (Cl- > 106mmol/L) compared with group 6 (Cl- 104–105mmol/L) for all CV events, MI, heart failure, PVD, all stroke, ischaemic stroke, COPD, pneumonia/influenza, liver disease and kidney disease.

Conclusions:

In a large general population from the West of Scotland, there was a ’U’-shaped non-linear association between serum Cl- and risk of fatal/non-fatal CV and non-CV events.
NOX5 AND VASCULAR SIGNALLING IN HUMAN HYPERTENSION
Authors: Camargo Livia , Montezano Augusto , Hussain Misbah , Wang Yu , Zou Zhiguo , Rios Francisco , Awan Fazli , Touyz Rhian
Published: April 2021

Objective:

Nox5, a key ROS-generating oxidase in human vessels, regulates vascular contraction and is implicated in vascular damage. However molecular mechanisms regulating vascular Nox5 are elusive. We questioned the role of Nox5 in vascular smooth muscle cell signalling in hypertension.

Design and method:

Intact small arteries and vascular smooth muscle cells (VSMC) isolated from small arteries from normotensive (NT) and hypertensive (HT) subjects were studied. Nox5 expression and phosphorylation (western blot, immunoprecipitation); ROS generation (chemiluminescence); protein oxidation (oxidised peroxiredoxin/DJ-1), activation of signalling pathways (Src, PKC, MLC phosphorylation; immunoblotting), and actin cytoskeletal organization (phalloidin staining) were assessed in the absence and presence of Nox5 inhibition (mellitin, 100 nM). To exclude Nox1–4 effects, we used p22phox silenced VSMCs (siRNA).

Results:

Nox5 expression was increased in intact arteries from HT subjects (70 + 26.79% vs NT, p < 0.05). In VSMC, ROS levels (139 ± 27% vs NT, p < 0.05), and oxidation of peroxiredoxin (201.8 + 40.34% vs NT, p < 0.05) and DJ-1 (71.7 + 16.51% vs NT, p < 0.05) were increased in HT. Nox5 expression (103 ± 23% vs NT, p < 0.05) and phosphorylation (77 + 17.93% vs NT, p < 0.05) were increased in the HT group. Nox5 inhibition reduced Ang II-induced ROS generation in both groups (p < 0.05 vs Ctl). In contrast, p22phox silencing increased ROS in both groups, an effect blocked by mellitin (p < 0.05 vs Ctl). Nox5 associates with c-Src. Treatment with a Src inhibitor (PP2, 10 μM) did not reduce Nox5 phosphorylation. Furthermore, PP2 failed to reduce AngII-induced ROS generation in p22phox-silenced VSMCs. Nox5 inhibition reduced Ang II-induced c-Src activation (p < 0.05 vs Ctl), suggesting that Nox5 is upstream of c-Src. Next, we investigated the role of Nox5 in vascular signaling. In cells from hypertensive subjects, p22phox silencing was associated with sustained Ang II-induced PKC and MLC20 phosphorylation, an effect blocked by mellitin and PP2 (p < 0.05 vs Ctl). VSMC from hypertensive subjects had an increased number of stress fibres, which was attenuated by mellitin and PP2.

Conclusions:

Our findings demonstrate that in human hypertension Nox5 is upregulated. This is associated with activation of c-Src, increased redox-sensitive signalling and VSMC cytoskeletal reorganisation. We define a novel Nox5-ROS-c-Src signalling pathway that may play a role in vascular remodelling in hypertension.
ROLE OF INHIBITION OF CGMP-DEPENDENT PROTEIN KINASE (PKG) SIGNALLING ON ANTICONTRACTILE FUNCTION OF PERIVASCULAR ADIPOSE TISSUE
Authors: Rosei Claudia Agabiti , Rossini Claudia , De Ciuceis Carolina , Porteri Enzo , Brami Valeria , Nardin Matteo , Chiarini Giulia , Petelca Alina , Coschignano Maria Antonietta , Tiberio Guido Alberto , Muiesan Maria Lorenza , Rizzoni Damiano
Published: April 2021

Objective:

Perivascular adipose tissue (PVAT) has an anticontractile effect.This capacity is lost in obesity (Circulation 2009) through adipocyte hypertrophy, leading to hypoxia, inflammation and oxidative stress. It has been previously demonstrated that cGMP-dependent protein kinase (PKG) plays a key role in regulating normal PVAT function (Cardiovasc Res. 2014). Aim of the study was to investigate functional responses of small resistance arteries with and without PVAT in normotensive subjects and obese patients, testing the effects of DT-2,(a peptidic highly selective inhibitor of PKG) on contractile response

Design and method:

We have investigated 9 normotensive severely obese patients (Obese) and 6 hypertensive severely obese patients (Obese-Hyper) undergoing bariatric surgery, as well as 7 normotensive lean subjects (CTRL) undergoing an election surgical intervention.No sign of local or systemic inflammation was present in any subject or patient. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph. A concentration-response curve to noradrenaline (NA, from 10–9 to 10–5Mol/l) was evaluated in vessels with intact prerivascular fat tissue (WF)and in vessels in which perivascular fat tissue was removed (NoF). Concentration response to NA was repeated in small arteries WF and NoF in the presence of DT-2 (125 nM) in both normoxic and hypoxic (95% N2/5%CO2 for 30’)conditions

Results:

In normoxic conditions the presence of PVAT reduced contractile response to NA in small arteries from CTRL (ANOVA p = 0.04 vs. NoF). The anticontractile effect of PVAT completely disappeared in Obese and Obese-Hyper patients. In CTRL preincubation with DT-2 lead to increase contractile responses to NA in arteries WF (ANOVA p = 0,04 WF+DT-2 vs WF). This effect was more evident during hypoxic conditions after incubation with DT-2 in all groups. No significant effect was observed on contractile response to NA in arteries WF and NoF from Obese and Obese-Hyper patients after incubation of DT-2, in normoxic conditions

Conclusions:

The anticontractile effect of PVAT is present in normotensive subjects and it is lost after inhibition of PKG signalling. The absence of effect after preincubation of DT-2 on arteries WF from Obese and Obese-Hyper patients suggests a dysregulation of PKG signalling pathways in these groups, which seems essential for its downstream dilator function in small resistance arteries