Potential of using an engineered indole lactic acid producing Escherichia coli Nissle 1917 in a murine model of colitis.

The gut microbiome is a significant factor in the pathophysiology of ulcerative colitis (UC), prompting investigations into the use of probiotic therapies to counter gastrointestinal inflammation. However, while much attention has been given to the therapeutic potential of microbes at the species and strain level, the discovery and application of their metabolic products may offer more precise and controlled solutions in battling disease. In this work, we examined the therapeutic potential of indole lactic acid (ILA) to alleviate inflammation in a murine model of colitis. A previously constructed ILA-producing Escherichia coli Nissle 1917 strain (EcN aldh) and its isogenic non-ILA producing counterpart (EcN) were studied in a murine model of Dextran Sodium Sulfate (DSS) induced colitis. The colitic animals suffered from severe colitic symptoms, with no differentiation between the groups in body weight loss and disease activity index. However, three days after cessation of DSS treatment the EcN aldh-treated mice showed signs of reduced intestinal inflammation, as manifested by lower concentrations of fecal lipocalin-2. Additionally, expression analysis of the inflamed tissue revealed distinct effects of the EcN aldh strain on proteins associated with intestinal health, such as TFF3, occludin and IL-1ß expression. These results show no impact of EcN or EcN aldh on acute DSS-induced colitis, but suggest that in particular EcN aldh may assist recovery from intestinal inflammation.

Completeness of revascularization by FFRCT in stable angina: Association to adverse cardiovascular outcomes.

BACKGROUND: The prognostic impact of complete coronary revascularization relative to non-invasive testing methods is unknown. OBJECTIVES: To assess the association between completeness of revascularization defined by CTA-derived fractional flow reserve (FFRCT) and cardiovascular outcomes in patients with stable angina. METHODS: Multicenter 3-year follow-up study of patients with new onset stable angina and ≥ 30% stenosis by CTA. The lesion-specific FFRCT value (two cm-distal-to-stenosis) was registered in all vessels with stenosis and considered abnormal when ≤ 0.80. Patients with FFRCT ≤ 0.80 were categorized as: Completely revascularized (CR-FFRCT), all vessels with FFRCT ≤ 0.80 revascularized; incompletely revascularized (IR-FFRCT), ≥ 1 vessels with FFRCT ≤ 0.80 non-revascularized. Early revascularization (< 90 days from index CTA) categorized vessels as revascularized. The primary endpoint comprised cardiovascular death and non-fatal myocardial infarction; the secondary endpoint vessel-specific late revascularization and non-fatal myocardial infarction. RESULTS: Amongst 900 patients and 1759 vessels, FFRCT was ≤ 0.80 in 377 (42%) patients, 536 (30%) vessels; revascularization was performed in 244 (27%) patients, 340 (19%) vessels. Risk of the primary endpoint was higher for IR-FFRCT (15/210 [7.1%]) compared to CR-FFRCT (4/167 [2.4%]), RR: 2.98; 95% CI: 1.01-8.8, p â€‹= â€‹0.036, and to normal FFRCT (3/523 [0.6%]), RR: 12.45; 95% CI: 3.6-42.6, p â€‹< â€‹0.001. Incidence of the secondary endpoint was higher in non-revascularized vessels with FFRCT ≤ 0.80 (29/250 [12%]) compared to revascularized vessels with FFRCT ≤ 0.80 (5/286 [1.7%]), p â€‹= â€‹0.001, and to vessels with FFRCT > 0.80 (10/1223 [0.8%]), p â€‹< â€‹0.001. CONCLUSION: Incomplete revascularization of patients with lesion-specific FFRCT ≤ 0.80 is associated to unfavorable cardiovascular outcomes compared to those with complete revascularization or FFRCT > 0.80.

Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant.

GABABRs are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits. Recently, three variants (G693W, S695I, I705N) have been identified in the gene (GABBR2) encoding for GABABR2. Individuals that harbour any of these variants exhibit severe developmental epileptic encephalopathy and intellectual disability, but the underlying pathogenesis that is triggered in neurons, remains unresolved. Using a range of confocal imaging, flow cytometry, structural modelling, biochemistry, live cell Ca2+ imaging of presynaptic terminals, whole-cell electrophysiology of HEK-293T cells and neurons, and two-electrode voltage clamping of Xenopus oocytes we have probed the biophysical and molecular trafficking and functional profiles of G693W, S695I and I705N variants. We report that all three point mutations impair neuronal cell surface expression of GABABRs, reducing signalling efficacy. However, a negative effect evident for one variant perturbed neurotransmission by elevating presynaptic Ca2+ signalling. This is reversed by enhancing GABABR signalling via positive allosteric modulation. Our results highlight the importance of studying neuronal receptors expressed in nervous system tissue and provide new mechanistic insights into how GABABR variants can initiate neurodevelopmental disease whilst highlighting the translational suitability and therapeutic potential of allosteric modulation for correcting these deficits.

Coronary Artery Disease Is A Stronger Predictor of All-Cause Mortality Than Left Ventricular Ejection Fraction Among Patients With Newly Diagnosed Heart Failure: Insights From the WDHR.

BACKGROUND: In patients with newly diagnosed heart failure (HF) and left ventricular ejection fraction (LVEF) <50%, little is known whether LVEF per se or presence of coronary artery disease (CAD) provides independent prognostic information on all-cause mortality. METHODS AND RESULTS: Using the WDHR (Western Denmark Heart Registry), we identified 3620 patients with newly diagnosed HF and LVEF 10% to 49% referred for first-time coronary angiography as part of general workup of HF. Patients were stratified by LVEF (10%-35% versus 36%-49%) and presence of CAD. We estimated 10-year all-cause mortality risk and calculated hazard ratios adjusted for relevant comorbidities and risk factors (aHRs). CAD was present in 1592 (44%) patients. Lower LVEF was associated with a relative 15% increased 10-year mortality: 37% for LVEF 36% to 49% versus 42% for LVEF 10% to 35% (aHR, 1.15 [95% CI, 0.99-1.34]). This result did not change when stratified into those with CAD (52% versus 56%; aHR, 1.11 [95% CI, 0.91-1.35]) and those without CAD (27% versus 33%; aHR, 1.24 [95% CI, 0.97-1.57]). In comparison, presence and extent of CAD were associated with a relative 43% increased 10-year mortality (CAD versus no CAD, 55.0% versus 31.5%; aHR, 1.43 [95% CI, 1.25-1.64]). Compared with a matched general population, excess mortality risk was higher for patients with HF and CAD (54.7% versus 26.3%; aHR, 2.10 [95% CI, 1.85-2.39]) versus those with HF and no CAD (31.4% versus 17.2%; aHR, 1.76 [95% CI, 1.52-2.02]). CONCLUSIONS: Among newly diagnosed patients with HF and LVEF <50%, presence and extent of CAD are associated with substantial higher all-cause mortality risk than lower LVEF.

Physio-chemical degradation of single-use plastics in natural weather and marine environments.

Plastic pollution has reached concerning levels globally, with single-use plastic products (SUPs) comprising at least 50% of plastic waste. This study investigates the physical and chemical degradation of frequently used SUPs, including petroleum-based and bio-based plastics, in natural Northern European coastal weather and marine environments over a three-year period from 2019 to 2022. Addressing a critical knowledge gap, this research was based on a hypothesis that real-world ageing studies on SUPs would produce more accurate time- and process-lines for their transformation from macro-to microplastics than are available today based on the modeling studies more frequently used. The study employs optical examination, mechanical testing, Fourier Transform Infrared (FTIR) spectroscopy, and Gas Chromatography-Mass Spectrometry (GC-MS) to determine and relate physical and chemical changes with time. The results indicate that SUPs undergo significantly faster degradation in natural weather than predicted to date. Photooxidation emerges as the primary degradation pathway for all SUPs, emphasizing the role of light in plastic breakdown. Importantly, physical degradation to microplastics in natural environments is not always associated with significant chemical changes such as breaking chemical bonds. Black SUPs exhibit greater resistance to visible light and ultraviolet radiation than equivalent white and transparent examples. In marine environments, SUPs degrade measurably slower than in air, their degradation slowing with increasing distance from the water surface. Our findings indicate the urgent need for strategies that mitigate the impacts of photo-oxidation of SUPs. Such strategies may include a focus on the removal of post-use SUPs from pavements, roads, beaches, and water surfaces where photo-oxidation is faster than underwater and underground. Preferential use of black SUPs over white or transparent should also be considered.

Excess Apolipoprotein B and Cardiovascular Risk in Women and Men.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) are highly correlated measures of atherogenic lipoproteins. OBJECTIVES: The study investigators hypothesized that excess apoB is associated with an increased risk of myocardial infarction (MI), atherosclerotic cardiovascular disease (ASCVD), and all-cause mortality. METHODS: The study included 53,484 women and 41,624 men not taking statins from the Copenhagen General Population Study. Associations of excess apoB with the risk of MI, ASCVD, and all-cause mortality were estimated by Cox proportional hazards regressions with 95% CIs. Excess apoB was defined as measured levels of apoB minus expected levels of apoB from LDL-C alone; expected levels were defined by linear regressions of LDL-C levels vs apoB levels in individuals with triglycerides ≤1 mmol/L (89 mg/dL). RESULTS: During a median follow-up of 9.6 years, 2,048 MIs, 4,282 ASCVD events, and 8,873 deaths occurred. There was a dose-dependent association between excess apoB and the risk of MI and ASCVD in both women and men, as well as an association with the risk of all-cause mortality in women. For ASCVD in women compared with those with excess apoB <11 mg/dL, the multivariable adjusted HR was 1.08 (95% CI: 0.97-1.21) for excess apoB 11 to 25 mg/dL, 1.30 (95% CI: 1.14-1.48) for 26 to 45 mg/dL, 1.34 (95% CI: 1.14-1.58) for 46 to 100 mg/dL, and 1.75 (95% CI: 1.08-2.83) for excess apoB >100 mg/dL. Corresponding HRs in men were 1.14 (95% CI: 1.02-1.26), 1.41 (95% CI: 1.26-1.57), 1.41 (95% CI: 1.25-1.60), and 1.52 (95% CI: 1.13-2.05), respectively. Results were robust across the entire LDL-C spectrum. CONCLUSIONS: Excess apoB (ie, the value of apoB above that contributed by LDL-C levels alone) is associated dose-dependently with an increased risk of MI and ASCVD in women and men. This finding demonstrates that apoB provides important predictive value beyond LDL-C across the entire LDL-C spectrum.

10-Year Mortality After ST-Segment Elevation Myocardial Infarction Compared to the General Population.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is associated with high early mortality. However, it remains unclear if patients surviving the early phase have long-term excess mortality. OBJECTIVES: This study aims to assess excess mortality in STEMI patients treated with primary percutaneous coronary intervention (PCI) compared with an age- and- sex-matched general population at landmark periods 0 to 30 days, 31 to 90 days, and 91 days to 10 years. METHODS: Using the Western Denmark Heart Registry, we identified first-time PCI-treated patients who had primary PCI for STEMI from January 2003 to October 2018. Each patient was matched by age and sex to 5 individuals from the general population. RESULTS: We included 18,818 patients with first-time STEMI and 94,090 individuals from the general population. Baseline comorbidity burden was similar in STEMI patients and matched individuals. Compared with the matched individuals, STEMI was associated with a 5.9% excess mortality from 0 to 30 days (6.0% vs 0.2%; HR: 36.44; 95% CI: 30.86-43.04). An excess mortality remained present from 31 to 90 days (0.9% vs 0.4%; HR: 2.43; 95% CI: 2.02-2.93). However, in 90-day STEMI survivors, the absolute excess mortality was only 2.1 percentage points at 10-year follow-up (26.5% vs 24.5%; HR: 1.04; 95% CI: 1.01-1.08). Use of secondary preventive medications such as statins, antiplatelet therapy, and beta-blockers was very high in STEMI patients throughout 10-year follow-up. CONCLUSIONS: In primary PCI-treated STEMI patients with high use of guideline-recommended therapy, patients surviving the first 90 days had 10-year mortality that was only 2% higher than that of a matched general population.

Association of Autoimmune Diseases With Coronary Atherosclerosis Severity and Ischemic Events.

BACKGROUND: Some autoimmune diseases carry elevated risk for atherosclerotic cardiovascular disease (ASCVD), yet the underlying mechanism and the influence of traditional risk factors remain unclear. OBJECTIVES: This study sought to determine whether autoimmune diseases independently correlate with coronary atherosclerosis and ASCVD risk and whether traditional cardiovascular risk factors modulate the risk. METHODS: The study included 85,512 patients from the Western Denmark Heart Registry undergoing coronary computed tomography angiography. A diagnosis of 1 of 18 autoimmune diseases was assessed. Adjusted OR (aOR) for any plaque, any coronary artery calcification (CAC), CAC of >90th percentile, and obstructive coronary artery disease as well as adjusted HR (aHR) for ASCVD were calculated. RESULTS: During 5.3 years (Q1-Q3: 2.8-8.2 years) of follow-up, 3,832 ASCVD events occurred. A total of 4,064 patients had a diagnosis of autoimmune disease, which was associated with both presence of any plaque (aOR: 1.29; 95% CI: 1.20-1.40), any CAC (aOR: 1.28; 95% CI: 1.19-1.37), and severe CAC of >90th percentile (aOR: 1.53; 95% CI: 1.39-1.68), but not with having obstructive coronary artery disease (aOR: 1.04; 95% CI: 0.91-1.17). Patients with autoimmune diseases had a 46% higher risk (aHR: 1.46; 95% CI: 1.29-1.65) for ASCVD. Traditional cardiovascular risk factors were strongly associated with future ASCVD events, and a favorable cardiovascular risk factor profile in autoimmune patients was associated with ∼54% lower risk compared to patients with presence of risk factors (aHR: 0.46; 95% CI: 0.27-0.81). CONCLUSIONS: Autoimmune diseases were independently associated with higher burden of coronary atherosclerosis and higher risk for future ASCVD events, with risk accentuated by traditional cardiovascular risk factors. These findings suggest that autoimmune diseases increase risk through accelerated atherogenesis and that cardiovascular risk factor control is key for improving prognosis in patients with autoimmune diseases.

Forty Years Searching for Neurosteroid Binding Sites on GABAA Receptors.

Brain inhibition is a vital process for controlling and sculpting the excitability of the central nervous system in healthy individuals. This level of control is provided over several timescales and involves the neurotransmitter GABA acting at inhibitory synapses to: rapidly inhibit neurons by activating the GABAA receptor; over a slower timescale, to tonically activate extrasynaptic GABAA receptors to provide a low level of background inhibition; and finally, to activate G-protein coupled GABAB receptors to control transmitter release by inhibiting presynaptic Ca2+ channels whilst providing postsynaptic inhibition via K+ channel activation. From this plethora of roles for GABA and its receptors, the GABAA receptor isoform is of major interest due to its dynamic functional plasticity, which in part, is due to being targeted by modulatory brain neurosteroids derived from sex and stress hormones. This family of neurosteroids can, depending on their structure, potentiate, activate and also inhibit the activity of GABAA receptors to affect brain inhibition. This review tracks the methods that have been deployed in probing GABAA receptors, and charts the sterling efforts made by several groups to locate the key neurosteroid binding sites that affect these important receptors. Increasing our knowledge of these binding sites will greatly facilitate our understanding of the physiological roles of neurosteroids and will help to advance their use as novel therapeutics to combat debilitating brain diseases.

Non-HDL cholesterol and residual cardiovascular risk in statin-treated patients with and without diabetes: The Western Denmark Heart Registry.

AIMS: Assessment of residual cardiovascular risk in statin-treated patients with atherosclerotic cardiovascular disease (ASCVD) is pivotal for optimising secondary preventive therapies. This study investigates if non-high-density lipoprotein cholesterol (non-HDL-C) is associated with residual ASCVD risk in statin-treated ischemic heart disease (IHD) patients with and without diabetes. METHODS: Using the Western Denmark Heart Registry, we identified statin-treated patients with IHD examined by coronary angiography (CAG) from 2011-2020. Non-HDL-C was assessed within one year after CAG. Outcomes were ASCVD (myocardial infarction, ischemic stroke, and cardiovascular death) and all-cause death. Cox regression analyses obtained hazard ratios adjusted for age, sex, smoking, and hypertension. RESULTS: A total of 42,057 patients were included; 8,196 patients with diabetes and 33,861 without diabetes. During median 4.6 years of follow-up event rates per 1000 person-years of ASCVD were 28.8 (27.1-30.5) and 17.2 (16.5-17.8) among patients with and without diabetes. In patients with diabetes the adjusted hazard ratios (HR) of ASCVD as compared with non-HDL-C <25th percentile were 1.0 (0.9-1.2), 1.3 (1.1-1.6), and 1.6 (1.2-2.1) for patients in the 25th-74th, 75th-94th, and ≥95th percentile. In patients without diabetes corresponding adjusted HRs were 1.1 (0.9-1.1), 1.2 (1.1-1.4), and 1.7 (1.4-2.0). Results were consistent across sex, age, clinical presentation, and low-density lipoprotein cholesterol strata. CONCLUSIONS: In statin-treated IHD patients with and without diabetes non-HDL-C, especially above the 75th percentile, is associated with residual cardiovascular risk. These results have implications for secondary prevention targeting patients who may benefit most from intensified preventive therapy.

Relevant to individuals, both with and without diabetes, who receive cholesterol-lowering therapy due to ischemic heart disease, having a high level of non-HDL cholesterol is associated with risk of heart attack, stroke, and death. In individuals with diabetes, having a high compared to a low non-HDL cholesterol level was associated with a 30-60% increased risk of heart attack, stroke, and death. For individuals without diabetes, the high non-HDL cholesterol level was linked to an increased risk by up to 70%.In clinical practice calculation of non-HDL cholesterol, from the standard lipid profile with no inconvenience to the patient, offers a possibility to identify patients who face a high risk of heart attack, stroke, and death. Patients with high levels of non-HDL cholesterol may benefit from optimized preventive therapy.

Lactococcus cell envelope proteases enable lactococcal growth in minimal growth media supplemented with high molecular weight proteins of plant and animal origin.

Lactic acid bacteria (LAB) have evolved into fastidious microorganisms that require amino acids from environmental sources. Some LAB have cell envelope proteases (CEPs) that drive the proteolysis of high molecular weight proteins like casein in milk. CEP activity is typically studied using casein as the predominant substrate, even though CEPs can hydrolyze other protein sources. Plant protein hydrolysis by LAB has rarely been connected to the activity of specific CEPs. This study aims to show the activity of individual CEPs using LAB growth in a minimal growth medium supplemented with high molecular weight casein or potato proteins. Using Lactococcus cremoris MG1363 as isogenic background to express CEPs, we demonstrate that CEP activity is directly related to growth in the protein-supplemented minimal growth media. Proteolysis is analyzed based on the amino acid release, allowing a comparison of CEP activities and analysis of amino acid utilization by L. cremoris MG1363. This approach provides a basis to analyze CEP activity on plant-based protein substrates as casein alternatives and to compare activity of CEP homologs.

Left Main Coronary Artery Calcium and Diabetes Confer Very-High-Risk Equivalence in Coronary Artery Calcium >1,000.

BACKGROUND: Although a coronary artery calcium (CAC) of ≥1,000 is a subclinical atherosclerosis threshold to consider combination lipid-lowering therapy, differentiating very high from high atherosclerotic cardiovascular disease (ASCVD) risk in this patient population is not well-defined. OBJECTIVES: Among persons with a CAC of ≥1,000, the authors sought to identify risk factors equating with very high-risk ASCVD mortality rates. METHODS: The authors studied 2,246 asymptomatic patients with a CAC of ≥1,000 from the CAC Consortium without a prior ASCVD event. Cox proportional hazards regression modelling was performed for ASCVD mortality during a median follow-up of 11.3 years. Crude ASCVD mortality rates were compared with those reported for secondary prevention trial patients classified as very high risk, defined by ≥2 major ASCVD events or 1 major event and ≥2 high-risk conditions (1.4 per 100 person-years). RESULTS: The mean age was 66.6 years, 14% were female, and 10% were non-White. The median CAC score was 1,592 and 6% had severe left main (LM) CAC (vessel-specific CAC ≥300). Diabetes (HR: 2.04 [95% CI: 1.47-2.83]) and severe LM CAC (HR: 2.32 [95% CI: 1.51-3.55]) were associated with ASCVD mortality. The ASCVD mortality per 100 person-years for all patients was 0.8 (95% CI: 0.7-0.9), although higher rates were observed for diabetes (1.4 [95% CI: 0.8-1.9]), severe LM CAC (1.3 [95% CI: 0.6-2.0]), and both diabetes and severe LM CAC (7.1 [95% CI: 3.4-10.8]). CONCLUSIONS: Among asymptomatic patients with a CAC of ≥1,000 without a prior index event, diabetes, and severe LM CAC define very high risk ASCVD, identifying individuals who may benefit from more intensive prevention therapies across several domains, including low-density lipoprotein-cholesterol lowering.

Coronary computed tomography angiography derived fractional flow reserve and risk of recurrent angina: A 3-year follow-up study.

BACKGROUND: The association between coronary computed tomography angiography (CTA) derived fractional flow reserve (FFRCT) and risk of recurrent angina in patients with new onset stable angina pectoris (SAP) and stenosis by CTA is uncertain. METHODS: Multicenter 3-year follow-up study of patients presenting with symptoms suggestive of new onset SAP who underwent first-line CTA evaluation and subsequent standard-of-care treatment. All patients had at least one ≥30 â€‹% coronary stenosis. A per-patient lowest FFRCT-value ≤0.80 represented an abnormal test result. Patients with FFRCT ≤0.80 who underwent revascularization were categorized according to completeness of revascularization: 1) Completely revascularized (CR-FFRCT), all vessels with FFRCT ≤0.80 revascularized; or 2) incompletely revascularized (IR-FFRCT) ≥1 vessels with FFRCT ≤0.80 non-revascularized. Recurrent angina was evaluated using the Seattle Angina Questionnaire. RESULTS: Amongst 769 patients (619 [80 â€‹%] stenosis ≥50 â€‹%, 510 [66 â€‹%] FFRCT ≤0.80), 174 (23 â€‹%) reported recurrent angina at follow-up. An FFRCT ≤0.80 vs â€‹> â€‹0.80 associated to increased risk of recurrent angina, relative risk (RR): 1.82; 95 â€‹% CI: 1.31-2.52, p â€‹< â€‹0.001. Risk of recurrent angina in CR-FFRCT (n â€‹= â€‹135) was similar to patients with FFRCT >0.80, 13 â€‹% vs 15 â€‹%, RR: 0.93; 95 â€‹% CI: 0.62-1.40, p â€‹= â€‹0.72, while IR-FFRCT (n â€‹= â€‹90) and non-revascularized patients with FFRCT ≤0.80 (n â€‹= â€‹285) had increased risk, 37 â€‹% vs 15 â€‹% RR: 2.50; 95 â€‹% CI: 1.68-3.73, p â€‹< â€‹0.001 and 30 â€‹% vs 15 â€‹%, RR: 2.03; 95 â€‹% CI: 1.44-2.87, p â€‹< â€‹0.001, respectively. Use of antianginal medication was similar across study groups. CONCLUSION: In patients with SAP and coronary stenosis by CTA undergoing standard-of-care guided treatment, FFRCT provides information regarding risk of recurrent angina.

Serial troponin-I and long-term outcomes in subjects with suspected acute coronary syndrome.

AIMS: It is unclear how serial high-sensitivity troponin-I (hsTnI) concentrations affect long-term prognosis in individuals with suspected acute coronary syndrome (ACS). METHODS AND RESULTS: Subjects who underwent two hsTnI measurements (Siemens TnI Flex® Reagent) separated by 1-7 h, during a first-time hospitalization for myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019, were identified through Danish national registries. Individuals were stratified per their hsTnI concentration pattern (normal, rising, persistently elevated, or falling) and the magnitude of hsTnI concentration change (<20%, >20-50%, or >50% in either direction). We calculated absolute and relative mortality risks standardized to the distributions of risk factors for the entire study population. A total of 20 609 individuals were included of whom 2.3% had died at 30 days, and an additional 4.7% had died at 365 days. The standardized risk of death was highest among persons with a persistently elevated hsTnI concentration (0-30 days: 8.0%, 31-365 days: 11.1%) and lowest among those with two normal hsTnI concentrations (0-30 days: 0.5%, 31-365 days: 2.6%). In neither case did relative hsTnI concentration changes between measurements clearly affect mortality risk. Among persons with a rising hsTnI concentration pattern, 30-day mortality was higher in subjects with a >50% rise compared with those with a less pronounced rise (2.2% vs. <0.1%). CONCLUSION: Among individuals with suspected ACS, those with a persistently elevated hsTnI concentration consistently had the highest risk of death. In subjects with two normal hsTnI concentrations, mortality was very low and not affected by the magnitude of change between measurements.

In this Danish study of >20 000 individuals with suspected heart attack, we confirmed the clinical importance of drawing two consecutive blood samples for measurement of high-sensitivity troponin-I concentrations (a marker of damage to the heart): The risk of death was highest in persons with two elevated high-sensitivity troponin-I concentrations and lowest in those with two normal concentrations.Among persons who had a first normal and a subsequently elevated high-sensitivity troponin-I concentration, a >50% relative rise was associated with significantly higher risk of death at 30 days.

Thoracic Aortic Calcium Density and Area in Long-Term Atherosclerotic Cardiovascular Disease Risk Among Men Versus Women.

BACKGROUND: The development of thoracic aortic calcium (TAC) temporally precedes coronary artery calcium more often in women versus men. Whether TAC density and area confer sex-specific differences in atherosclerotic cardiovascular disease (ASCVD) risk is unknown. METHODS: We studied 5317 primary prevention patients who underwent coronary artery calcium scoring on noncontrast cardiac gated computed tomography with TAC >0. The Agatston TAC score (Agatston units), density (Hounsfield units), and area (mm2) were compared between men and women. Cox proportional hazards regression calculated adjusted hazard ratios for TAC density-area groups with ASCVD mortality, adjusting for traditional risk factors, coronary artery calcium, and TAC. Multinomial logistic regression calculated adjusted odds ratios for the association between traditional risk factors and TAC density-area groups. RESULTS: The mean age was 60.7 years, 38% were women, and 163 ASCVD deaths occurred over a median of 11.7-year follow-up. Women had higher median TAC scores (97 versus 84 Agatston units; P=0.004), density (223 versus 210 Hounsfield units; P<0.001), and area (37 versus 32 mm2; P=0.006) compared with men. There was a stepwise higher incidence of ASCVD deaths across increasing TAC density-area groups in men though women with low TAC density relative to TAC area (3.6 per 1000 person-years) had survival probability commensurate with the high-density-high-area group (4.8 per 1000 person-years). Compared with low TAC density-area, low TAC density/high TAC area conferred a 3.75-fold higher risk of ASCVD mortality in women (adjusted hazard ratio, 3.75 [95% CI, 1.13-12.44]) but not in men (adjusted hazard ratio, 1.16 [95% CI, 0.48-2.84]). Risk factors most strongly associated with low TAC density/high TAC area differed in women (diabetes: adjusted odds ratio, 2.61 [95% CI, 1.34-5.07]) versus men (hypertension: adjusted odds ratio, 1.45 [95% CI, 1.11-1.90]). CONCLUSIONS: TAC density-area phenotypes do not consistently associate with ASCVD mortality though low TAC density relative to area may be a marker of increased ASCVD risk in women.

10-Year Cardiovascular Risk in Patients With Newly Diagnosed Type 2 Diabetes Mellitus.

BACKGROUND: Contemporary data on cardiovascular disease (CVD) risk in patients with newly diagnosed type 2 diabetes mellitus (T2DM) is needed to guide appropriate preventive management. OBJECTIVES: The authors sought to investigate sex- and age-specific 10-year CVD risk in patients with newly diagnosed T2DM compared with the general population. METHODS: A cohort study was conducted of all Danish patients with T2DM diagnosed between 2006 and 2013 (n = 142,587) and sex- and age-matched individuals from the general population (n = 388,410), all without prior atherosclerotic CVD. Ten-year CVD risk (myocardial infarction, stroke, and fatal CVD) was estimated. RESULTS: A total of 52,471 CVD events were recorded. Compared with the general population, the 10-year CVD risks were higher in patients with T2DM in both sexes and across all age groups, especially among younger individuals. For example, patients aged 40 to 49 years had the largest 10-year CVD risk difference (T2DM 6.1% vs general population 3.3%; risk difference: 2.8%, subdistribution HR: 1.91; 95% CI: 1.76-2.07). The age when a given CVD risk was reached differed substantially between the cohorts. Thus, a 10-year CVD risk of 5% was reached at age 43 in men with T2DM compared with 12 years later, at age 55, in men without T2DM. A 10-year CVD risk of 5% was reached at age 51 in women with T2DM and 10 years later, at age 61, in women without T2DM. CONCLUSIONS: Newly diagnosed T2DM increased 10-year CVD risk across both sexes and all age groups, especially among younger patients, with CVD occurring ≤12 years earlier than in general population individuals.

Delivery of E. coli Nissle to the mouse gut by mucoadhesive microcontainers does not improve its competitive ability against strains linked to ulcerative colitis.

For patients with ulcerative colitis (UC), administration of the probiotic E. coli Nissle (EcN) holds promise for alleviation of disease symptoms. The mechanisms are unclear, but it has been hypothesised that a capacity of the probiotic to outcompete potentially detrimental UC-associated E. coli strains plays an important role. However, this could previously not be confirmed in a mouse model of competition between EcN and two UC-associated strains, as reported by Petersen et al. 2011. In the present study, we re-evaluated the idea, hypothesising that delivery of EcN by a micro device dosing system (microcontainers), designed for delivery into the intestinal mucus, could support colonisation and confer a competition advantage compared to classical oral dosing. Six groups of mice were pre-colonised with one of two UC-associated E. coli strains followed by oral delivery of EcN, either in capsules containing microcontainers with freeze-dried EcN powder, capsules containing freeze-dried EcN powder, or as a fresh sucrose suspension. Co-colonisation between the probiotic and the disease-associated strains was observed regardless of dosing method, and no competition advantages linked to microcontainer delivery were identified within this setup. Other approaches are thus needed if the competitive capacity of EcN in the gut should be improved.

Education level and the use of coronary computed tomography, functional testing, coronary angiography, revascularization, and outcomes-a 10-year Danish, nationwide, registry-based follow-up study.

BACKGROUND AND AIMS: Coronary computed tomography angiography (CCTA) can guide downstream preventive treatment and improve patient prognosis, but its use in relation to education level remains unexplored. METHODS: This nationwide register-based cohort study assessed all residents in Denmark between 2008-2018 without coronary artery disease (CAD) and 50-80 years of age (n = 1 469 724). Residents were divided according to four levels of education: low, lower-mid, higher-mid, and high. Outcomes were CCTA, functional testing, invasive coronary angiography (ICA), revascularization, and major adverse cardiovascular and cerebrovascular events (MACCE). RESULTS: Individuals with the lowest education level underwent CCTA (absolute risk [AR] 3.95% individuals aged ≥ 50-59, AR 3.62% individuals aged ≥ 60-69, AR 2.19% individuals aged ≥ 70-80) less often than individuals of lower-mid (AR 4.16%, AR 3.90%, AR 2.41%), higher-mid (AR 4.38%, AR 4.30%, AR 2.45%) and highest education level (AR 3.98%, AR 4.37%, AR 2.30%). Similar differences were observed for functional testing. Conversely, use of ICA, and risks of revascularization and MACCE were more common among individuals of lowest education level. Among patients examined with CCTA (n = 50 234), patients of lowest education level less often underwent functional testing and more likely initiated preventive medication, underwent ICA, revascularization, and experienced MACCE. CONCLUSION: Despite tax-financed healthcare in Denmark, individuals of lowest education level were less likely to undergo CCTA and functional testing than persons of higher education level. ICA utilization, revascularization and MACCE risks were higher for individuals of lowest education level. Among CCTA-examined patients, patients of lowest education level were more likely to initiate preventive medication and had the highest risks of revascularization and MACCE when compared to higher education level groups. These findings suggest that the preventive potential of CCTA is underutilized in individuals of lower education level, a proxy for socioeconomic status. Socioeconomic differences in CAD assessment, care, and outcomes are likely even larger without tax-financed healthcare.