bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography
Authors: Tascilar Koray , Fagni Filippo , Kleyer Arnd , Bayat Sara , Heidemann Robert , Steiger Florian , Krönke Gerhard , Bohr Daniela , Ramming Andreas , Hartmann Fabian , Klett Daniel , Federle Anna , Regensburger Adrian P , Wagner Alexandra L , Knieling Ferdinand , Neurath Markus F , Schett Georg , Waldner Maximilian , Simon David 
Published: June 2022

Abstract

Objective
To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths.

Methods
We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models.

Results
We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints.

Conclusion
MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.
Single‐cell sequencing reveals microglia induced angiogenesis by specific subsets of endothelial cells following spinal cord injury
Authors: Yao Chun , Cao Yuqi , Wang Dong , Lv Yehua , Liu Yan , Gu Xiaosong , Wang Yongjun , Wang Xuhua , Yu Bin 
Published: June 2022

AbstractSpinal cord injury (SCI) results in dynamic alterations of the microenvironment at the lesion site, which inevitably leads to neuronal degeneration and functional impairment. The destruction of the spinal vascular system leads to a significant deterioration of the milieu, which exacerbates inflammatory response and deprives cells of nutrient support in the lesion. Limited endogenous angiogenesis occurs after SCI, but the cellular events at the lesion site during this process are unclear so far. Here, we performed single‐cell RNA sequencing (scRNA‐seq) on spinal cord tissues of rats at different time points after SCI. After clustering and cell‐type identification, we focused on vascular endothelial cells (ECs), which play a pivotal role in angiogenesis, and drew the cellular and molecular atlas for angiogenesis after SCI. We found that microglia and macrophages promote endogenous angiogenesis by regulating EC subsets through SPP1 and IGF signaling pathways. Our results indicate that immune cells promote angiogenesis by regulating specific subsets of vascular ECs, which provides new clues for exploring SCI intervention.
THE DANTON STUDY - DISCONTINUATION OF ANTIHYPERTENSIVE TREATMENT IN OLDER PEOPLE WITH DEMENTIA LIVING IN A NURSING HOME: RESULTS OF A RANDOMIZED CONTROLLED TRIAL
Authors: Bogaerts Jonathan , Gussekloo Jacobijn , De Jong-Schmit Bianca , Achterberg Wilco , Poortvliet Rosalinde 
Published: June 2022

Objective:
Neuropsychiatric symptoms (NPS), such as apathy and agitation, are highly prevalent in nursing home (NH) residents with dementia. Literature suggests an association of both cerebral hypoperfusion and antihypertensive treatment (AHT) with NPS in patients with dementia. Therefore, we investigated whether discontinuation of AHT in NH residents with dementia reduces NPS and improves quality of life (QoL).

Design and method:
Randomized, single-blinded trial conducted in 26 Dutch NH organisations. Residents with moderate-severe dementia and a systolic blood pressure < 160 mmHg during AHT were randomized in an intervention (semi-protocolized discontinuation) and control (continuation) group during a period of 8 months. Exclusion criteria were heart failure NYHA-class-III/IV, angina pectoris, a recent cardiovascular event/reperfusion procedure, or a life-expectancy < 4 months. Co-primary endpoints were NPS (Neuropsychiatric Inventory-Nursing Home version) and QoL (Qualidem) at 4 months. Secondary endpoints include cognitive function, care dependency, general daily functioning and falls.

Results:
Between December 2018 and May 2021, 205 NH residents with dementia (median age 86 years-79.5% women) were randomized, of which 177 (86.3%) reached the primary endpoint at 4 months. During trial, 63 severe adverse events occurred in 61 residents. On advice of the Data Safety Monitoring Board, the study was preliminary finished in December 2021 due to futility based on the co-primary endpoints. Definitive results for all endpoints measured at 4 and 8 months follow-up will be available in April 2022.

Conclusions:
This is, to our knowledge, the largest AHT deprescription trial in NH residents with dementia. Based on preliminary results of this study, the benefits of deprescribing AHT in NH residents with dementia for reduction of NPS and improvement of QoL, are unclear and may not be without any potential risk.
ASSOCIATIONS BETWEEN PLASMA METABOLOMICS AND BLOOD PRESSURE ACROSS ETHNICITIES: THE HELIUS STUDY
Authors: Verhaar Barbara , Mosterd Charlotte M. , Collard Didier , Galenkamp Henrike , Van den Born Bert-Jan H. , Muller Majon , Rampanelli Elena , Nieuwdorp Max , Van Raalte Daniël H. 
Published: June 2022

Objective:
Blood pressure (BP) is regulated by plasma metabolites from different neurohumoral and cardiometabolic systems. Since there are well-established differences in hypertension pathogenesis and treatment response between ethnicities, we hypothesized that plasma metabolites may be differently associated with BP across ethnic groups.

Design and method:
From the HELIUS study, 369 subjects (mean age 52 ± 11 years, 51%F) of African and non-African descent were included. Office systolic and diastolic BP levels were recorded. Plasma metabolites were measured with untargeted LC-MS from fasting plasma samples. Associations between metabolite profiles and BP were assessed with machine learning prediction models. Associations between the resulting best predictors and BP were assessed with linear regression models while adjusting for age, sex, renal function and diabetes, and interactions with ethnicity were tested.

Results:
Plasma metabolite profiles explained 14.1% of systolic BP variance and 10.6% of diastolic BP variance. Top predictors for both systolic and diastolic BP included N-formylmethionine, several acylcarnitines and polyunsaturated fatty acids such as hexadecadienoate. These metabolites were significantly associated with higher systolic BP with estimates ranging from 3.0–4.5 mmHg per 1 SD increase in the adjusted models. Associations with hexadecadienoate, dihomolinoleate and catecholamine metabolites, including vanillactate had significant interactions with ethnicity and were only significant in subjects of non-African descent. The top predictor N-formylmethionine was the most consistent predictor across ethnicities and sex. This metabolite was associated with higher levels of nitric oxide (NO)-related metabolites, including dimethylarginine (r = 0.42, p < 0.001) and citrulline (r = 0.24, p < 0.0001).

Conclusions:
Plasma metabolome composition explained a large proportion of BP variance, but best predicting metabolites were differently associated with BP across ethnicities. N-formylmethionine was the most consistent predictor for BP across ethnicities and sex. This metabolite was associated with metabolites in the NO-pathway. We hypothesize that formylmethionine affects BP through the inhibition of endothelial NO formation.
ESTIMATES OF CARDIOVASCULAR DISEASES BURDEN ATTRIBUTABLE TO HIGH SODIUM INTAKE FROM 1990 TO 2019: A SYSTEMATIC ANALYSIS OF DATA FROM THE GLOBAL BURDEN OF DISEASE STUDY
Authors: Wang Keke , Liu Jing , Bu Xiang , Mu Jianjun 
Published: June 2022

Background:
Sodium intake shows a positive correlation with blood pressure, resulting in an increased risk for cardiovascular diseases (CVDs). This study is aimed at evaluating global CVDs burden due to high sodium intake (HSI) from 1990 to 2019.

Methods:
Data on high dietary sodium attributable CVDs burden were extracted from the Global Burden of Disease (GBD) study 2019. The numbers and age-standardized rates (ASRs) of mortality and years of living with disability (YLDs), stratified by location, sex, and socio-demographic Index (SDI), were used to assess the high sodium intake attributable CVDs burden from 1990 to 2019.

Results:
Globally in 2019, the deaths and YLDs numbers caused by high sodium related CVDs were 1.72 million and 3.57 million, respectively, increasing by 41.1% and 93.4% from 1990. Meanwhile, the corresponding mortality and YLDs rates dropped by 35.2% and 5.0%. The relationship between CVDs burden and SDI exhibited an inverted V-shaped curve. Middle SDI countries bore the greatest burden and experienced the greatest increase, while high SDI countries had the lowest mortality rate and low SDI countries had the lowest YLDs rate. Men had a higher risk suffering CVDs from high dietary sodium. And the leading cause of high sodium attributable deaths and YLDs burdens was ischemic heart disease.

Conclusions:
From 1990 to 2019, the global deaths and YLDs rates of high sodium intake attributable CVDs decreased with spatiotemporal and sexual heterogeneity. However, CVDs burden attributable to high sodium still remains a major public health challenge because of the increasing absolute numbers of deaths and YLDs. The regional socioeconomic status needs to be considered when establishing the targeted controls to reduce the high sodium related CVDs burden.
HIGH MOBILITY GROUP BOX-1 IS INCREASED IN NEWLY DIAGNOSED ESSENTIAL HYPERTENSIVES AND CORRELATES WITH HYPERTENSION-MEDIATED TARGET ORGAN DAMAGE
Authors: Lazaridis Antonios , Gavriilaki Eleni , Dolgyras Panagiotis , Koletsos Nikolaos , Triantafyllou Areti , Anyfanti Panagiota , Pavlidou Olga , Goulas Kyriakos , Douma Stella , Gkaliagkousi Eugenia 
Published: June 2022

Objective:
Chronic immune-mediated inflammation is increasingly recognized as an important contributor to target organ damage (TOD) in essential hypertension (EH). High mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule which stimulates innate immunity, hence exerting significant proinflammatory properties including vascular inflammation and thrombosis. So far, no clinical data exist regarding the role of HMGB1 in EH and its association with vascular damage. Our objective was to measure HMGB1 levels in newly diagnosed, untreated patients with EH (UHTs) compared to normotensive controls (NTs) and correlate them with indices of macro- and microvascular dysfunction, which play a core role in the pathogenesis of TOD in EH.

Design and method:
HMGB1 was measured in serum with ELISA. Ambulatory and central blood pressure (BP) parameters, and pulse wave velocity (PWV), were measured by using the Mobil-O-Graph device. Skin microcirculation was assessed with Laser Speckle Contrast Imaging (LSCI) coupled with post-occlusive reactive hyperemia (PORH). Results are expressed as a percentage increase between peak and baseline perfusion (%), and the amplitude of PORH response defined as peak Cutaneous Vascular Conductance (CVC) minus baseline CVC. The CVC was calculated as the flux in each period divided by mean arterial pressure [(PUs)/mmHg].

Results:
We consecutively enrolled 55 UHTs and 25 NTs matched for age and sex. HMGB1 levels were significantly higher in UHTs compared to NTs. HMGB1 showed a significant positive association with measures of macrocirculation including 24 h central systolic (0.325, p < 0.01) and diastolic BP (0.371, p < 0.01), day central systolic (0.353, p < 0.01) and diastolic BP (0.402, p < 0.01), and 24 h PWV (0.224, p < 0.05) and day PWV (0.230, p < 0.05) in the total study population. In addition, HMGB1 presented a significant negative association with skin microvascular parameters including base to peak flux (-0.247, p < 0.05) and PORH amplitude (-0.225, p < 0.01).

Conclusions:
HMGB1 is significantly increased in UHTs compared to NTs and correlates with indices of macro- and microvascular damage. These results reinforce the concept that immune system activation contributes to hypertension-mediated TOD from the very early stages and point towards intense research in order to investigate novel potential therapeutic targets related to EH.
PATIENTS WITH PSORIASIS PRESENT IMPAIRED MICROVASCULAR REACTIVITY INDEPENDENTLY OF TRADITIONAL CARDIOVASCULAR RISK FACTORS
Authors: Margouta Anastasia , Anyfanti Panagiota , Nikolaidou Barbara , Dolgyras Panagiotis , Lazaridis Antonios , Vakalopoulos Nikolaos , Lazaridou Elizabeth , Patsatsi Aikaterini , Douma Stella , Gkaliagkousi Eugenia 
Published: June 2022

Objective:
Psoriasis is associated with increased rates of cardiovascular complications. Altered microvascular responses in divergent vascular beds are considered as an early precursor of cardiovascular disease and have been well-described in patients with cardiovascular risk factors and chronic inflammatory diseases. Laser Speckle Contrast Imaging (LSCI) has emerged as a novel, non-invasive and highly reproducible technique for the in vivo, real-time evaluation of microvascular perfusion.

Design and method:
We aimed to assess real-time skin microvascular function in patients with psoriasis free from established cardiovascular disease, in comparison with controls matched for cardiovascular risk factors. Microvascular function was evaluated dynamically using LSCI coupled with a post-occlusive reactive hyperaemia (PORH) protocol. Well-established markers of arterial stiffness, i.e. pulse wave velocity (PWV) and augmentation index (AIx), were assessed as surrogate markers of cardiovascular disease through a whole 24 h period using the Mobil-O-Graph device.

Results:
We studied 90 patients with psoriasis and 45 control individuals. Traditional cardiovascular risk factors and surrogate markers of cardiovascular disease did not differ between groups. By contrast, several indices of microvascular responses assessed with LSCI were found impaired in patients with psoriasis compared to controls, specifically baseline flux [45.7 (11.7) vs 36.2 (7.5) LSPUs, p < 0.001], occlusion flux [11.6 (7.1) vs 7.4 (4.6) LSPUs, p < 0.001], peak-to-baseline magnitude [128.9 (46.4) vs 179.0 (62.0) %, p < 0.001], and baseline cutaneous vascular conductance (0.50 ± 0.13 vs 0.39 ± 0.10 LSPUs/mmHg, p < 0.001). 24 h PWV significantly correlated with nearly all LSCI parameters, including time-to-peak flux, baseline perfusion, occlusion flux, peak flux, peak-to-baseline magnitude, and baseline cutaneous vascular conductance (p < 0.05 for all). 24 h AIx significantly correlated only with occlusion flux (r = 0.223, p = 0.011). The latter was significantly associated with psoriasis duration (r = 0.300, p = 0.015).

Conclusions:
Our study shows for the first-time impaired microcirculation dynamics in patients with psoriasis using LSCI, in the absence of established cardiovascular disease and regardless of cardiovascular risk factors. A cross-talk between micro-macrovascular dysfunction apparently exists even at these early stages, before the establishment of clinically evident cardiovascular manifestations.
CATHETER-BASED RENAL DENERVATION – LONG TERM SAFETY AND BLOOD PRESSURE REDUCTION IN PATIENTS WITH RESISTANT HYPERTENSION
Authors: Schlaich Markus , Sesa-Ashton Jonathon , Lee Rebecca , Lambert Elisabeth , Lambert Gavin , Nolde Janis , Walton Antony , Esler Murray 
Published: June 2022

Objective:
Recent sham-controlled andomised clinical trials have confirmed the safety and efficacy of catheter-based renal denervation (RDN) with clinically meaningful blood pressure (BP) reductions in hypertensive patients on or off antihypertensive medication. Longer-term safety and efficacy data have so far only been documented out to 3 years. Here we provide a first report on safety and efficacy outcomes in a cohort of patients with resistant hypertension beyond 5 years of follow up.

Design and method:
We recruited patients with resistant hypertension who were previously enrolled in various RDN trials applying radiofrequency energy to ablate the renal nerves using the Symplicity Flex® system. All participants had baseline assessments prior to RDN and repeat assessment at current long term follow up including medical history, automated office and ambulatory BP measurement, and routine blood and urine tests.

Results:
A total of 60 participants (age: 70.0 ± 10.3 years (mean ± SD), 76.3% male) have completed long-term follow up investigations with an average of 6.8 (range 6–10) years post-procedure. Ambulatory systolic BP was reduced by 12.0 ± 21.6mmHg (from 145.7mmHg to 132.8mmHg; p < 0.001) and diastolic BP by 8.3 ± 12.8mmHg (from 81.6 mmHg to 72.0 mmHg; p < 0.001). This BP reduction occurred despite participants being on less antihypertensive medication with a reduction in the average defined daily dose, the assumed average maintenance dose per day for a drug used for its main indication in adults, from 4.91 ± 0.37 to 4.02 ± 0.27 (p < 0.01). eGFR remained stable at long-term follow up with no statistically significant difference in participants with pre-existing CKD from baseline.

Conclusions:
Our investigation indicates a significant and robust reduction in ambulatory systolic and diastolic blood pressure, despite reduction in antihypertensive medications, in the long-term following catheter-based renal denervation without evidence of adverse consequences on renal function.
GLOMERULAR PROSTAGLANDIN E2 IS UPREGULATED DURING ONSET OF ALBUMINURIA THAT IS SUPPRESSED AFTER DUAL BLOCKADE OF ITS EP2 AND EP4 RECEPTORS IN A RAT MODEL OF GLOMERULAR HYPERFILTRA
Authors: Schulz Angela , Mangelsen Eva , Kourpa Aikaterina , Kaiser Debora , Rothe Michael , Panakova Daniela , Bolbrinker Juliane , Kreutz Reinhold 
Published: June 2022

Objective:
Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. Recent in vitro data indicated an activation of an autocrine/paracrine cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) pathway resulting in podocyte injury in GH by using fluid flow shear stress exposure. This was mediated by concerted ignalling via both prostaglandin E2 receptors (EP), EP2 and EP4. Here, we explored the role to target this pathway in vivo by using a rat model with GH and albuminuria.

Design and method:
We used the Munich Wistar Frömter (MWF) rat model with an inherited nephron deficit as a model of GH and albuminuria. Because analysis of PGE2 levels in vivo is limited by conventional methods, we developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify PGE2 levels in glomerular tissue. We then assessed glomerular PGE2 during the onset of albuminuria in young MWF at 4 to 8 weeks of age. Furthermore, the renoprotective effects of either separate or combined pharmacological blockade of EP2 (by PF-04418948) and EP4 (by ONO-AE3-208) in MWF was explored. Treatment started at the onset of albuminuria at 4 weeks and was continued for 8 weeks.

Results:
During the onset of albuminuria, PGE2 levels were significantly elevated in isolated glomeruli of MWF at both 4 and 8 weeks of age (p < 0.01, respectively) as compared to albuminuria resistant spontaneously hypertensive rats (SHR). At 12 weeks of age, untreated MWF developed pronounced albuminuria, which was significantly, although modestly, reduced by separate EP2 or EP4 blockade. Remarkably, combined EP2 and EP4 blockade resulted in a significant suppression (-71%) of albuminuria in MWF at 12 weeks. Importantly, this pharmacological treatment did not affect systolic blood pressure and creatinine clearance (Figure 1).

Conclusions:
We demonstrated the activation of glomerular PGE2 in vivo in the setting of hyperfiltration and albuminuria in the MWF rat model. Dual EP2 and EP4 receptor blockade exhibited a marked suppression of albuminuria without affecting systemic blood pressure and glomerular filtration rate. These data support further translational research to explore this therapeutic option for renoprotection.
THE VALUE OF MULTIPLE 24-HOUR URINE SAMPLES FOR ESTIMATING SODIUM INTAKE
Authors: Van Maaren Jolan , Esseghir Malik , van den Born Bert-Jan , Vogt Liffert , Engberink Rik Olde 
Published: June 2022

Objective:
A single 24-hour urine collection is frequently used to estimate daily sodium intake. Long-term balance studies, however, observed large discrepancies between 24-hour sodium intake and sodium excretion. In a controlled setting with stable sodium intake, the use of up to 7 consecutive 24-hour urine samples has been shown to increase the accuracy of sodium intake estimates. The value of multiple 24-hour urine collections for estimation of sodium intake has not been investigated in the clinical setting with uncontrolled intake, use of natriuretic medication and comorbidities that may affect sodium excretion.

Design and method:
In a retrospective cohort study, we included adult subjects who collected an outpatient 24-hour urine sample between 1998 and 2000, and had collected at least 6 additional 24-hour urine collections during follow-up. Mean sodium excretion was calculated for 2, 3, 4, 5, 6, and 7 consecutive 24-hour urine collections. We calculated the absolute change in 24-hour urine sodium excretion with each added urine sample. We considered a 0.4-gram change in sodium (1 gram salt) intake clinically relevant.

Results:
We included 316 subjects with an average age of 44 years, and 46% were male. 50% of the subjects had a history of hypertension, 30% had diabetes and 9% had a history with a cardiovascular event. Diuretics were used by 22% of the subjects and 44% used ennin-angiotensin-aldosterone system inhibitors. The median follow-up period was 16.4 years. The median time to collection of 7 urine samples was 2.5 years (IQR 1.3–4.8). Mean sodium excretion was 159 mmol/day (SD 62). With addition of a second 24-hour urine sample, individual estimated sodium intake changed with 0.43 gram sodium (IQR 0.17–0.90) and changed > 0.4 gram in 52% of the subjects. When a fifth or seventh collection was added, estimated sodium intake changed > 0.4 gram in 14% and 7% of our cohort (Figure).

Conclusions:
Collection of multiple 24-hour urine samples substantially changes estimated individual sodium intake in the clinical setting. The added value of collecting > 5 24-hour urine samples is limited and changes sodium intake estimations only in 14% of the subjects.