Risultati per: L'automisurazione della pressione arteriosa: I target pressori

Background
Tumourigenesis in right-sided and left-sided colons demonstrated distinct features.

Objective
We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis.

Design
Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results.

Results
Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11+ epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer.

Conclusion
Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer.

Introduction
Preclinical studies have shown that oxygen therapy can improve ischaemic brain tissue oxygen tension, reduce reperfusion injury after revascularisation, promote neuroregeneration and inhibit inflammatory responses potentially exerting a beneficial effect after endovascular treatment (EVT) in patients with acute ischaemic stroke (AIS). However, the optimal fraction of inspired oxygen (FiO2) during EVT under general anaesthesia is currently unknown. Therefore, we are conducting a randomised controlled trial (RCT) to evaluate the impact of high-concentration oxygen vs low-concentration normobaric oxygen on early neurological function after EVT.

Methods and analysis
The Oxy-TARGET trial is an ongoing prospective, open-label, parallel-design RCT being conducted at Beijing Tiantan Hospital, Capital Medical University. It aims to enrol 200 anterior circulation AIS patients undergoing EVT under general anaesthesia between February 2024 and December 2026. Eligible participants are randomly assigned at a 1:1 ratio to receive FiO2=80% or FiO2=30% through endotracheal intubation, with the gas flow rate set at 4 L/min. The inspiratory oxygen concentration at the tracheal intubation site (delivered FiO2) was recorded concurrently. The primary outcome is the incidence of early neurological improvement (a National Institutes of Health Stroke Scale (NIHSS) score

This cohort study evaluates the use of urate-lowering therapy to achieve target serum urate levels in patients with gout and stage 3 chronic kidney disease.

Objectives
The US Preventive Services Task Force recommends screening of adults aged 35–70 with a body mass index ≥25 kg/m2 for type 2 diabetes and referral of individuals who screen positive for pre-diabetes to evidence-based prevention strategies. The diabetes burden in the USA is predicted to triple by 2060 necessitating strategic diabetes prevention efforts, particularly in areas of highest need. This study aimed to identify pre-diabetes hotspots using geospatial mapping to inform targeted diabetes prevention strategies. A ‘hotspot’ is defined as a cluster of 3 or more neighbouring census tracts with elevated pre-diabetes prevalence.

Design
A cross-sectional study using ArcGIS software to geospatially map pre-diabetes prevalence hotspots. We used health system and census data to identify pre-diabetes hotspots using a systematic five-step geoprocessing approach that made use of incremental spatial autocorrelation and Getis-Ord Gi*.

Setting
This study was set in Kaiser Permanente Northern California (KPNC), an integrated health delivery system with over four million members.

Participants
KPNC adults ages 35–70 who underwent a haemoglobin A1c (HbA1c) or fasting plasma glucose (FPG) screening test in 2019 were mapped to census tracts in Northern California. People were considered to have pre-diabetes with an HbA1c of 5.7%–6.4% (39–46 mmol/mol) or FPG 100–125 mg/dL.

Primary and secondary outcome measures
Individual and census-level characteristics were compared between hotspots and non-hotspots using 2 and Wilcoxon rank sum tests, as well as risk differences (RDs) and Hodges-Lehmann (HL) estimates of location shift. Individual-level characteristics were derived from electronic health records and administrative data, while census-level characteristics were derived from the 2019 American Community Survey.

Results
A total of 760 044 adults met the study inclusion criteria and 40% had pre-diabetes. Individuals in pre-diabetes hotspots were less likely to be non-Hispanic white (33.6% vs 50.6%, RD: –17.04%, 95% CI –17.26% to –16.81%, p

Mood disorders and DGBI are highly prevalent, commonly co-morbid and lack fully effective therapies. Although SSRIs are first line pharmacological treatments for these disorders, they may impart adverse effects including anxiety, anhedonia, dysmotility and, in children exposed in utero, an increased risk of cognitive, mood and gastrointestinal disorders. SSRIs act systemically to block SERT and enhance serotonergic signaling in the brain, intestinal epithelium and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development.

Background
Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified.

Objective
We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA.

Design
We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)—an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors—in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms.

Results
PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions.

Conclusion
PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.

Several studies have highlighted the significance of targeting fat mass and obesity-associated protein (FTO) in gastrointestinal cancers including hepatocellular carcinoma (HCC) .1 The recent study from the group of Irene Oi-Lin Ng presented in Gut by Chen et al2 introduces new insights into the molecular dynamics of HCC, focusing on the pivotal role of FTO in the disease’s pathophysiology. Functioning as an eraser of N6-methyladenosine (m6A), FTO modulates RNA stability and translation. In the context of HCC, FTO’s activity leads to the stabilisation of oncogenic transcripts, thereby promoting cancer cell proliferation and survival.3 The study identifies glycoprotein non-metastatic melanoma protein B (GPNMB) as a downstream effector of FTO (figure 1). By diminishing the m6A modification on GPNMB, FTO enhances its stability, thereby protecting it from YTHDF2-mediated degradation. This stabilisation facilitates the incorporation of GPNMB into small extracellular vesicles (sEVs), which are…

Suicide is a pressing public health concern in the US and the last decades have seen rising suicide rates, but also increased research focused on the development and evaluation of effective suicide prevention treatments. Prior to the development and validation of suicide-specific treatments, traditional models conceptualized suicidal thoughts and behaviors as symptoms of psychiatric disorders, such as depression. It thus followed that treating the primary psychiatric disorder was sufficient to reduce suicide risk. We have since learned that while psychiatric diagnoses are one of many potential risk factors for suicide, suicide risk is transdiagnostic. Indeed, some suicidal patients do not meet criteria for any psychiatric disorder. There are now several efficacious suicide-specific psychosocial interventions that conceptualize and treat suicidal ideation and behaviors as the primary treatment targets and are recommended components of comprehensive suicide prevention approaches such as Zero Suicide.

New England Journal of Medicine, Ahead of Print.

Objectives
Target trial emulation is an approach that is increasingly used to improve transparency in observational studies and help mitigate biases. For studies declaring that they emulated a target trial, we aimed to evaluate the specification of the target trial, examine its consistency with the observational emulation and assess the risk of bias in the observational analysis.

Design
Methodological systematic review reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Data sources
The database MEDLINE (Medical Literature Analysis and Retrieval System Online) was interrogated for all studies published from 1 January 2021 to 3 July 2022. We performed an additional manual search of 20 general medical and specialised journals that spanned the same period.

Eligibility criteria
All studies that declared emulating a hypothetical or real randomised trial were eligible.

Data extraction and synthesis
Two independent reviewers performed the whole systematic review process (screening and selection of studies, data extraction and risk of bias assessment). The main outcomes were the definition of the key protocol components of the target trial and its emulation, consistency between the target trial and its emulation and risk of bias according to the ROBINS-I (Risk Of Bias In Non-randomised Studies – of Interventions) tool.

Results
Among the selected sample of 100 studies, 24 (24%) did not specify the target trial. Only 40 studies (40%) provided detailed information on all components of the target trial protocol. Eligibility criteria, intervention strategies and outcomes were consistent between the target trial and its emulation in 35 studies (46% of those specifying the target trial). Overall, 28 studies (28%) exhibited serious risk of bias and 41 (41%) had misalignments in the timing of eligibility assessment, treatment assignment and the start of follow-up (time-zero). As compared with studies that did not specify the target trial, those that did specify the trial less frequently seemed to have both time-zero issues (39% vs 52%) and serious risk of bias (26% vs 33%).

Conclusions
One-quarter of studies declaring that they emulated a target trial did not specify the trial. Target trials and their emulations were particularly inconsistent for studies emulating a real randomised trial. Risk of methodological issues seemed lower in observational analyses that specified versus did not specify the target trial.

Circulation, Volume 150, Issue Suppl_1, Page A4126731-A4126731, November 12, 2024. Introduction:Cardiovascular health (CVH) in young adulthood (YA) is strongly associated with subclinical and clinical outcomes in later life. Longitudinal patterns of CVH exposure through YA (e.g., cumulative CVH exposure) may be particularly important. However, no studies have assessed cumulative CVH in YA and its association with target organ damage (TOD).Methods:CVH was defined using Life’s Essential 8 (LE8) score. CARDIA participants (ppts) with CVH assessed at ≥3 exams over 20 years of follow-up in YA (year [Y]0 to Y20 exams; mean ages 25 to 45 years) were included. Cumulative LE8 scores (cumLE8; higher = better CVH over time) were calculated as the sum of LE8 scores through YA carried forward between exams measured as point*years. Eight markers of TOD (listed in Results) were measured at subsequent exams (Y20 or Y25) including cardiac, renal, pulmonary, and neurologic markers. Associations of cumLE8 with markers of TOD were assessed using partial effects regression models adjusted for race, sex, and maximal education.Results:There were 3,485 ppts (43.4% men, 46.2% Black) with mean cumLE8 score of 1,448.6 (SD 211.4) point*years. Higher cumLE8 in YA was linearly associated with lower measures of cardiac (left ventricular mass index, carotid intima media thickness, prevalence of coronary artery calcium), renal (estimated glomerular filtration rate [eGFR] in men), and neurologic damage (proportion of white matter hyperintensity on brain MRI) (Figure). Higher cumLE8 was also linearly associated with better lung function (forced expiratory volume in 1 second, forced vital capacity). Urine albumin-creatinine ratio (in men and women) and eGFR (in women) were non-linearly associated with cumLE8.Conclusions:Our findings underscore the importance of high cumLE8 in YA and its association with reduced onset of TOD later in life. Primordial prevention strategies are needed to achieve and maintain high CVH through the critical period of YA.

Circulation, Volume 150, Issue Suppl_1, Page A4139465-A4139465, November 12, 2024. Introduction:Pulmonary arterial hypertension (PAH) is characterized by progressive obstruction and decreased compliance of pulmonary arteries (PA), leading to right ventricular failure and premature death. Sustained proliferation and resistance to apoptosis of PAs smooth muscle and endothelial cells (PASMCs, PAECs) and accumulation of extracellular matrix (ECM) elements are key features contributing to vascular remodeling. Integrins, members of the cell adhesion receptor superfamily, are known to promote cell proliferation and survival through ECM binding. Despite the recognition of the role of ECM elements in vascular remodeling in PAH, the contribution of integrins remains poorly studied. We hypothesized that integrin signaling could promote PAH-PASMCs and PAH-PAECs proliferation and resistance to apoptosis contributing to vascular remodeling.Methods&Results:Using Western blot (WB) and Meso Scale Discovery, we found that α5β1 was upregulated in distal PAs, PA smooth muscle cells (PASMC) and PA endothelial cells (PAEC) from PAH patients compared to controls. Small molecule, antibody (M200), or siRNA-mediated inhibition of α5β1 decreased PAH-PASMC and PAH-PAEC proliferation (WB, MCM2 and Ki67 labeling), resistance to apoptosis (WB, Survivin and Annexin V labeling) and migration (scratch test assay). RNA sequencing analysis revealed that inhibition of α5β1 regulates a FOXM1-dependant gene network through the activation of focal adhesion kinase, resulting in mitotic defects (Immunofluorescence: α-tubulin and pericentrin labeling).In vivo, in both monocrotaline and Sugen/hypoxia rats with established PAH, inhibition of α5β1 using a small molecule inhibitor or a neutralizing antibody alone or in combination with macitentan and tadalafil improved hemodynamics (RHC and echocardiography: mean pulmonary arterial pressure, cardiac output, pulmonary artery acceleration time) and vascular remodeling (Elastica Van Gieson staining).Ex vivo, inhibition of α5β1 decreased vascular remodeling in human precision-cut lung slices (PCLS) from PAH patients and attenuated growth factors-induced vascular remodeling in control PCLS.Conclusion:Integrin α5β1 plays a key role in vascular remodeling in PAH and represents a novel therapeutic target.

Circulation, Volume 150, Issue Suppl_1, Page A4140333-A4140333, November 12, 2024. Background:Circulating proteins are attractive candidate drug targets for cardiometabolic diseases. Identifying promising circulating proteins that have a causal role in disease pathogenesis is challenging and expensive. Mendelian randomization (MR) has emerged as an important tool for testing potential causal effects while mitigating biases from confounding and reverse causation. MR findings require validation by colocalization analysis to guard against bias due to correlation between genetic variants (linkage disequilibrium, LD). However, existing colocalization methods often fail to validate MR findings because of highly complex LD structures in the genome, rendering a low yield of human genetics-based target discovery.Methods:In this study, we developed a new computational method, called SharePro, to effectively assess colocalization evidence for MR-identified circulating proteins as targets for cardiometabolic diseases. Based on large-scale genome-wide association studies, we performed MR analyses to assess the associations between 1,535 circulating proteins and key cardiometabolic traits, including diastolic blood pressure, systolic blood pressure, serum hemoglobin A1c, serum low-density lipoprotein cholesterol, and serum triglycerides. We then benchmarked SharePro against state-of-the-art colocalization methods, including coloc, coloc+SuSiE, and PWCoCo, and evaluated the power and robustness of these methods in supporting MR findings. We further examined whether colocalization evidence-supported associations implicated known drug targets for cardiometabolic diseases.Results:SharePro demonstrated the highest power and robustness in supporting 160 (79.6%) of the 201 Bonferroni-significant protein-trait associations identified by MR, while existing methods supported up to 46.8% of these associations. Protein-trait associations identified by MR and supported by SharePro were more likely to implicate known drug targets for cardiometabolic diseases (Figure 1). Furthermore, eight protein-trait associations were exclusively supported by SharePro, suggesting novel targets, such as HSF1 and HAVCR2.Conclusions:SharePro most effectively supports promising protein-trait associations identified through MR for cardiometabolic diseases. Combining multiple lines of evidence using different methods may substantially increase the yield of human genetics-based drug target discovery by nearly twofold.

Circulation, Volume 150, Issue Suppl_1, Page A4146556-A4146556, November 12, 2024. Introduction:Pulmonary hypertension (PH) is a fatal cardiovascular disease marked by extensive vascular remodeling. Pericytes, crucial for capillary function and typically associated with endothelial cells (ECs), are dysfunctional in PH and contribute significantly to vascular remodeling. Our research indicates that Aminopeptidase-N (APN) is overexpressed in the lungs of PH patients, contributing to pericyte proliferation, although the underlying mechanisms remain unclear. We recently discovered elevated stratifin (SFN) levels in the ECs of PH patients. SFN is known to interact with proteins like APN and activate downstream signaling pathways.Hypothesis:We hypothesize that elevated SFN binds to pericyte APN, triggering a pathological proliferative response.Methods:We utilized rats with the NFU1 (G208C) mutation, which develop spontaneous PH characterized by severe vascular remodeling and increased right ventricular systolic pressure (RVSP). To analyze cell phenotype shifts, we employed scRNA-seq and confocal imaging. Additionally, we used R18, a peptide that inhibits SFN activation of downstream targets, to explore if targeting SFN reverses PH.Results:We found elevated circulating SFN levels in PH patient plasma and observed high SFN expression and secretion in isolated ECs from PH patients. NFU1 rats mirrored these findings, showing significantly elevated SFN expression and secretion in ECs. Similarly, increased APN was found in both the lungs of PH patients and the isolated pericytes of NFU1 rats. scRNA-seq followed by Cell-Chat interaction analysis revealed that NFU1 pericytes had reduced interactions with ECs. Additionally, scRNA-seq indicated a shift to a “smooth muscle cell-like” phenotype in pericytes, characterized by increased calponin-3 and SMMHC expression. Confocal imaging confirmed significant disruption of pericyte-EC connections in NFU1 rats. Treatment with R18 in NFU1 rats significantly reversed vascular remodeling and RVSP. Echocardiography showed that R18 significantly improved the ratio of pulmonary acceleration to pulmonary ejection time. Furthermore, scRNA-seq demonstrated that R18 treatment improved pericyte-EC connections and regulated the pericyte phenotype shift in NFU1 rats.Conclusions:Endothelial stratifin induces a phenotype shift in pericytes, leading to vascular remodeling and PH. Targeting SFN signaling presents a novel strategy to combat PH.

Circulation, Volume 150, Issue Suppl_1, Page A4143207-A4143207, November 12, 2024. Background:The HeartMate 3 Device (HM3) is an afterload-sensitive left ventricular assist device (LVAD). International guidelines suggest a target Doppler blood pressure (BP) range between 70-90 mmHg, though this recommendation is supported mostly by expert consensus. Optimal real-world data remains lacking regarding the ideal BP for these patients. Remote patient monitoring (RPM) can be utilized for outpatient Doppler blood pressure monitoring. We aimed to evaluate the association between time spent in goal BP range and mortality in HM3 LVAD recipients.Methods:1,427 HM3 LVAD recipients from 74 centers using the ActiCare Health RPM system, which allows patients to measure Doppler BP and upload results to their care team, were included in this analysis. Inclusion criteria included patients with at least two BP measurements. Outpatient Doppler BP values were collected, and a standard therapeutic range (70–90 mmHg) was established. The percentage of time in the therapeutic range (TTR) was calculated, categorizing patients as ≥75%, 50-75%, and ≤50%. Survival at 600 days on LVAD support and reporting frequencies were compared between groups.Results:We studied 738 HM3 LVAD recipients, implanted from 2015 to 2024, with a mean duration of 715 ± 19 days on LVAD support. 140 (19%) patients died. A total of 144,562 Doppler BP readings were analyzed, with a mean value of 82.8 ± 0.02 mmHg. There were 481 patients with TTR ≥75% (65%), 138 patients with TTR 50-75% (19%), and 119 patients with TTR ≤50% (16%). There was a significantly greater probability of survival for those with TTR ≥75% compared to ≤50% (94% vs. 85% at 400 days and 88% vs. 84% at 600 days, p = 0.05, Figure). The mean number of BP submissions per 100 days for the ≥75% group was 37.8 ± 0.87, compared to 25.8 ± 0.87 in the 50-75% group and 21.7 ± 1.25 in the ≤50% group (p < 0.001).Discussion:The data suggest that HM3 patients who spend more than 75% of the time with a Doppler BP between 70-90 mmHg have greater survival compared to those who are within range less than 50% of the time. RPM can be used for closer monitoring of Doppler BP in HM3 LVAD recipients. Patients with Doppler BP 70-90 mmHg may have improved survival.