Inducing persistent flow disturbances accelerates atherogenesis and promotes thin cap fibroatheroma development in D374Y-PCSK9 hypercholesterolemic minipigs

BACKGROUND: -Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma (TCFA). METHODS AND RESULTS: -D374Y-PCSK9 hypercholesterolemic minipigs (N=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately post-stent, 19, and 34 weeks and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially-collected histological sections and co-registered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ~3-fold higher downstream of the SMS compared to both upstream of the SMS and in the control artery (p<0.001). Advanced plaques were also primarily observed downstream of the SMS, in locations initially exposed to both low (p<0.002) and multidirectional (p<0.002) shear stress. TCFA regions demonstrated significantly lower shear stress that persisted over the duration of the study compared to other plaque types (p<0.005). CONCLUSIONS: -These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of TCFA

Healthcare delivery for HIV-positive people with tuberculosis in Europe

Background In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) vs. western Europe (WE). Objectives To verify the differences in TB and HIV services in EE vs. WE. Methods Twenty-three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey. Results Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE vs. 89% in WE; P = 0.034), and continued TB follow-up in one location (42% vs. 100%; P = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi-drug-resistant TB (MDR-TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% vs. 92%; P = 0.073), as was access to moxifloxacin (46% vs. 91%; P = 0.033), linezolid (31% vs. 64%; P = 0.217), and bedaquiline (0% vs. 25%; P = 0.217). Integration of TB and HIV services (46% vs. 39%; P = 1.000) and provision of OST to patients with opioid dependency (54% vs. 46%; P = 0.695) remained unchanged. Conclusion Delivery of TB and HIV healthcare, including integration of TB and HIV care and access to MDR-TB drugs, still differs between WE and EE, as well as between individual EE sites

Coffee consumption modifies risk of estrogen-receptor negative breast cancer

10.1186/bcr2879Breast Cancer Research133R4

Delayed diagnosis of tuberculosis in persons living with HIV in Eastern Europe: associated factors and effect on mortality-a multicentre prospective cohort study

Background: Early diagnosis of tuberculosis (TB) is important to reduce transmission, morbidity and mortality in people living with HIV (PLWH). Methods: PLWH with a diagnosis of TB were enrolled from HIV and TB clinics in Eastern Europe and followed until 24 months. Delayed diagnosis was defined as duration of TB symptoms (cough, weight-loss or fever) for ≥ 1 month before TB diagnosis. Risk factors for delayed TB diagnosis were assessed using multivariable logistic regression. The effect of delayed diagnosis on mortality was assessed using Kaplan-Meier estimates and Cox models. Findings: 480/740 patients (64.9%; 95% CI 61.3-68.3%) experienced a delayed diagnosis. Age ≥ 50 years (vs. < 50 years, aOR = 2.51; 1.18-5.32; p = 0.016), injecting drug use (IDU) (vs. non-IDU aOR = 1.66; 1.21-2.29; p = 0.002), being ART naïve (aOR = 1.77; 1.24-2.54; p = 0.002), disseminated TB (vs. pulmonary TB, aOR = 1.56, 1.10-2.19, p = 0.012), and presenting with weight loss (vs. no weight loss, aOR = 1.63; 1.18-2.24; p = 0.003) were associated with delayed diagnosis. PLWH with a delayed diagnosis were at 36% increased risk of death (hazard ratio = 1.36; 1.04-1.77; p = 0.023, adjusted hazard ratio 1.27; 0.95-1.70; p = 0.103). Conclusion: Nearly two thirds of PLWH with TB in Eastern Europe had a delayed TB diagnosis, in particular those of older age, people who inject drugs, ART naïve, with disseminated disease, and presenting with weight loss. Patients with delayed TB diagnosis were subsequently at higher risk of death in unadjusted analysis. There is a need for optimisation of the current TB diagnostic cascade and HIV care in PLWH in Eastern Europe

Low-density lipoproteins cause atherosclerotic cardiovascular disease : pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel

Peer reviewe

Effects of childhood body size on breast cancer tumour characteristics

10.1186/bcr2564Breast Cancer Research122R2

Contribution of Recipient-Derived Cells in Allograft Neointima Formation and the Response to Stent Implantation

Allograft coronary disease is the dominant cause of increased risk of death after cardiac transplantation. While the percutaneous insertion of stents is the most efficacious revascularization strategy for allograft coronary disease there is a high incidence of stent renarrowing. We developed a novel rabbit model of sex-mismatched allograft vascular disease as well as the response to stent implantation. In situ hybridization for the Y-chromosome was employed to detect male cells in the neointima of stented allograft, and the population of recipient derived neointimal cells was measured by quantitative polymerase chain reaction and characterized by immunohistochemistry. To demonstrate the participation of circulatory derived cells in stent neointima formation we infused ex vivo labeled peripheral blood mononuclear cells into native rabbit carotid arteries immediately after stenting. Fourteen days after stenting the neointima area was 58% greater in the stented vs. non-stented allograft segments (p = 0.02). Male cells were detected in the neointima of stented female-to-male allografts. Recipient-derived cells constituted 72.1±5.7% and 81.5±4.2% of neointimal cell population in the non-stented and stented segments, respectively and the corresponding proliferation rates were only 2.7±0.5% and 2.3±0.2%. Some of the recipient-derived neointimal cells were of endothelial lineage. The ex vivo tagged cells constituted 9.0±0.4% of the cells per high power field in the stent neointima 14 days after stenting. These experiments provide important quantitative data regarding the degree to which host-derived blood-borne cells contribute to neointima formation in allograft vasculopathy and the early response to stent implantation