A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. METHODS: The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). RESULTS: Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). CONCLUSIONS: Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

The Potential Protective Role of RUNX1 in Nonalcoholic Fatty Liver Disease.

The pathogenic mechanisms underlying nonalcoholic fatty liver disease (NAFLD) are beginning to be understood. RUNX1 is involved in angiogenesis, which is crucial in inflammation, but its role in nonalcoholic steatohepatitis (NASH) remains unclear. The aim of this study was to analyze RUNX1 mRNA hepatic and jejunal abundance in women with morbid obesity (MO) and NAFLD. RUNX1, lipid metabolism-related genes, and TLRs in women with MO and normal liver (NL, n = 28), NAFLD (n = 41) (simple steatosis (SS, n = 24), or NASH (n = 17)) were analyzed by RT-qPCR. The RUNX1 hepatic expression was higher in SS than in NL or NASH, as likewise confirmed by immunohistochemistry. An increased expression of hepatic FAS was found in NAFLD. Hepatic RUNX1 correlated positively with FAS. There were no significant differences in the jejunum RUNX1 expressions in the different groups. Jejunal FXR expression was lower in NASH than in NL, while the TLR9 expression increased as NAFLD progressed. Jejunal RUNX1 correlated positively with jejunal PPARγ, TLR4, and TLR5. In summary, the hepatic expression of RUNX1 seems to be involved in the first steps of the NAFLD process; however, in NASH, it seems to be downregulated. Our findings provide important insights into the role of RUNX1 in the context of NAFLD/NASH, suggesting a protective role.

Hot money: Illuminating the financing of high-carbon infrastructure in the developing world.

Major infrastructure financiers will have to significantly decarbonize their investments to meet mounting promises to cut carbon emissions to "net-zero" by mid-century. We provide new details about those needed shifts. Using two World Bank databases of infrastructure projects throughout the developing world, and applying a methodology for imputing the projects' likely future carbon output, we assess the emissions profile of power-plant projects executed from 2018 through 2020 - the three years immediately preceding the spate of net-zero pledges. We find that approximately half the generation executed in those years is too carbon-intensive to align with keeping Earth's average temperature from exceeding 1.5°C above pre-industrial levels, largely because of the prevalence of new natural-gas-fired power plants. We also find new evidence of host countries' agency in shaping carbon trajectories: Much of the climate-misaligned financing is not foreign but domestic. And we find different institutions are financing infrastructure portfolios with significantly differing carbon intensities.

Effect of part-time cardiac catheterization facilities in patients with acute myocardial infarction.

BACKGROUND: Although the easy availability of invasive cardiac care facilities is associated with an increase in their use, their influence on outcomes is not clear. We sought to investigate whether a newly available cardiac catheterization laboratory (CCL) performing percutaneous coronary intervention (PCI) on a part-time (PT) basis might improve outcomes in patients with acute myocardial infarction (AMI). METHODS: This was an observational cohort study that included all consecutive patients with AMI admitted to a secondary-level hospital in Spain before and after the PT-CCL opened in January 2006: during 1998-2005 and 2006-2014, respectively. All-cause in-hospital and long-term mortality were the co-primary endpoints. In-hospital complications and length of stay were secondary endpoints. For the analyses, patients were stratified according to propensity-score (PS) quintiles. RESULTS: A total of 5339 patients were recruited, and 50.3% were managed after the opening of the PT-CCL. The PT-CCL was associated with greater use of PCI (81.2 vs. 32.5%, p<0.001) and guidelines-recommended medication (all p<0.001), lower risk of recurrent angina (PS-adjusted RR=0.160, 95% CI 0.115-0.222) and shorter length of hospital stay (PS-adjusted RR for length of stay <8days=0.357, 95% CI 0.301-0.422). In patients with NSTEMI, PT-CCL was associated with improved long-term survival (PS-adjusted HR=0.764, 95% CI 0.602-0.970). CONCLUSIONS: In patients with AMI, a new PT-CCL was associated with greater use of PCI and guideline-recommended medication, lower risk of recurrent angina and shorter length of hospital stay. In a subset of patients with NSTEMI, PT-CCL was associated with improved long-term survival.

[Prognostic importance of cardiomegaly in patients with acute myocardial infarction]. / Importancia de la presencia de cardiomegalia en el pronóstico de los pacientes con infarto agudo de miocardio.

OBJECTIVES: To assess the in-hospital and long-term prognostic importance of cardiomegaly demonstrated by a simple admission radiograph in patients hospitalized for acute myocardial infarction. MATERIAL AND METHODS: Prospective study of 7644 patients admitted for acute myocardial infarction; 2 hospitals participated. We recorded detailed clinical data, especially noting the presence or absence of cardiomegaly in the chest radiograph. Adjusted predictive models for all-cause mortality in hospital or after discharge were constructed. The median followup was 6 years. RESULTS: Cardiomegaly was detected in 1351 (17.7%) of the patients. Hospital mortality was 11.2% overall; the incidence of long-term mortality was 5.7 per 100 patient-years. Patients with cardiomegaly were older and had more cardiovascular risk factors other than current smoking; they also had more concomitant conditions, had undergone fewer revascularization procedures, and received suboptimal care after discharge. Cardiomegaly was associated with higher in-hospital rates of adverse events, especially heart failure (70.8% in patients with cardiomegaly vs 21.4% in others, P<.001) and death (27.8% vs 7.7%, P<.001). Cardiomegaly was also an independent predictor of hospital mortality (odds ratio, 1.34; P=.02) as well as mortality after discharge (hazard ratio, 1.16; P<.01). CONCLUSION: Cardiomegaly was an independent predictor of both hospital mortality and long-term mortality after discharge in this series.

OBJETIVO: Conocer el significado pronóstico intrahospitalario y a largo plazo de la presencia de cardiomegalia en la radiología simple inicial de los pacientes ingresados por infarto agudo de miocardio. METODO: Estudio prospectivo de 7.644 pacientes ingresados por un infarto agudo de miocardio en dos hospitales. Se obtuvo información clínica detallada y se prestó especial atención a la presencia/ausencia de cardiomegalia en la radiografía de tórax. Realizamos modelos ajustados para predecir mortalidad (por cualquier causa) hospitalaria y tras el alta con una mediana de 6 años. RESULTADOS: 1.351 (17,7%) pacientes presentaron cardiomegalia. La mortalidad hospitalaria global fue 11,2% y la densidad de incidencia de mortalidad a largo plazo fue de 5,7 por cada 100 pacientes-año. Los pacientes con cardiomegalia presentaron mayor edad y más factores de riesgo cardiovascular excepto tabaquismo activo, mayor comorbilidad, fueron menos revascularizados y tratados al alta de forma subóptima. Durante la hospitalización, la cardiomegalia se asoció a mayores tasas de complicaciones, especialmente insuficiencia cardiaca (70,8 vs 21,4%, p < 0,001) y mortalidad (27,8 vs 7,7%, p < 0,001). La cardiomegalia resultó predictor independiente sobre la mortalidad hospitalaria (odds ratio = 1,34; p = 0,02) y tras el alta (hazard ratio = 1,16, p < 0,01). CONCLUSIONES: En pacientes con infarto agudo de miocardio la cardiomegalia resultó predictor independiente de mortalidad hospitalaria y a largo plazo tras el alta.

Short- and long-term prognosis of previous and new-onset atrial fibrillation in ST-segment elevation acute myocardial infarction.

INTRODUCTION AND OBJECTIVES: The impact of atrial fibrillation on the prognosis of myocardial infarction is still the subject of debate. We analyzed the influence of previous and new-onset atrial fibrillation on in-hospital and long-term prognosis in patients with acute myocardial infarction. METHODS: Prospective study of 4284 patients with ST-segment elevation acute myocardial infarction. We studied all-cause in-hospital and long-term mortality (median, 7.2 years) using adjusted models. RESULTS: In total, 3.2% of patients had previous atrial fibrillation and 9.8% had new-onset atrial fibrillation. In general, both groups of patients had a high baseline risk profile and an increased likelihood of in-hospital complications. The crude in-hospital mortality rate was higher in patients with previous atrial fibrillation than in those with new-onset atrial fibrillation (22% vs 12%; P<.001; 30% vs 10%; P<.001). The long-term mortality rate was 11.11/100 patient-years in patients with previous atrial fibrillation and 5.35/100 patient years in those with new-onset atrial fibrillation (both groups, P<.001). New-onset fibrillation alone (odds ratio=1.55; 95% confidence interval, 1.08-2.22) was an independent predictor of in-hospital mortality. Previous atrial fibrillation (hazard ratio=1.24; 95% confidence interval, 0.94-1.64) and new-onset atrial fibrillation (hazard ratio=0.98; 95% confidence interval, 0.80-1.21) were not independent predictors of long-term mortality. CONCLUSIONS: New-onset atrial fibrillation during hospitalization is an independent risk factor for in-hospital mortality in acute myocardial infarction.

Educational Level and Long-term Mortality in Patients With Acute Myocardial Infarction.

INTRODUCTION AND OBJECTIVES: The value of socioeconomic status as a prognostic marker in acute myocardial infarction is controversial. The aim of this study was to evaluate the impact of educational level, as a marker of socioeconomic status, on the prognosis of long-term survival after acute myocardial infarction. METHODS: We conducted a prospective, observational study of 5797 patients admitted to hospital with acute myocardial infarction. We studied long-term all-cause mortality (median 8.5 years) using adjusted regression models. RESULTS: We found that 73.1% of patients had primary school education (n=4240), 14.5% had secondary school education (including high school) (n=843), 7.0% was illiterate (n=407), and 5.3% had higher education (n=307). Patients with secondary school or higher education were significantly younger, more were male, and they had fewer risk factors and comorbidity. These patients arrived sooner at hospital and had less severe heart failure. During admission they received more reperfusion therapy and their crude mortality was lower. Their drug treatment in hospital and at discharge followed guideline recommendations more closely. On multivariate analysis, secondary school or higher education was an independent predictor and protective factor for long-term mortality (hazard ratio=0.85; 95% confidence interval, 0.74-0.98). CONCLUSIONS: Our study shows an inverse and independent relationship between educational level and long-term mortality in patients with acute myocardial infarction.

Relation of New Permanent Right or Left Bundle Branch Block on Short- and Long-Term Mortality in Acute Myocardial Infarction Bundle Branch Block and Myocardial Infarction.

The aim of this study was to investigate the prognosis associated with bundle branch block (BBB) depending on location, time of appearance, and duration in patients with myocardial infarction (MI). From January 1998 to January 2008, we recruited 5,570 patients with acute MI. Thirty-day and 7-year all-cause mortality, according to BBB location, time of appearance, and duration were analyzed by multivariable analyses. BBB was present in 964 patients (17.3%); right BBB (RBBB) 10.6% and left BBB (LBBB) 6.7%. Overall mortality rate at 30 days was 13.2% (n = 738) and 7 years was 6.34 deaths per 100 patient-year. Both RBBB and LBBB were more frequently previous, 42.9% and 58.8%. Compared with non-BBB, all BBB groups showed higher prevalence of co-morbidities, especially rates of diabetes (49.0% vs 34.3%, p <0.001) and more often heart failure during hospitalization (54.5% vs 26.6%, p <0.001). Compared with RBBB, patients with LBBB had a higher prevalence of co-morbidities and a higher mortality, especially the new BBB, 30 days: 52.5% versus 31.6% and 7 years (incident rate): 27.2 versus 13.3 per 100 patient-year. New transient BBB had lower heart failure on admission (42.6% vs 58.3%, p = 0.008) and 30-day mortality (20.3% vs 69.6%, p <0.001) compared with permanent in both locations. New permanent RBBB was independently associated with 30-day (hazard ratio [HR] 2.01, 95% confidence interval [CI] 1.45 to 2.79) and 7-year mortality (HR 3.12, 95% CI 2.38 to 4.09). New-permanent LBBB was independently associated with 30-day (HR 2.15, 95% CI 1.47 to 3.15) and 7-year mortality (HR 2.91, 95% CI 2.08 to 4.08). In conclusion, in patients with acute MI, the appearance of a new BBB was independently associated with a higher 30-day and 7-year all-cause mortality.

Apo A-I promoter polymorphism influences basal HDL-cholesterol and its response to pravastatin therapy.

Statins decrease cardiovascular morbidity and mortality, essentially, by reducing LDL-cholesterol levels and, additionally, by increasing HDL-cholesterol concentrations. Environmental and genetic factors are known to affect LDL-C response to statins but less is known regarding HDL-C. We have evaluated the lipid and lipoprotein response to 20 mg/day of pravastatin for 16 weeks in relation to the G/A polymorphism in the promoter region of the apo A-I gene in 397 hypercholesterolaemic subjects followed-up on an out-patient basis. In the study population, 61.7% were homozygous for the G allele and 36% were heterozygous. The A allele carriers had an HDL-C 6.5% higher than the G allele homozygotes (P=0.021 in univariate analysis; P=0.009 in multivariate analysis). However, on segregation by gender and smoking status the effect was significant only in non-smoking males. The A allele carriers did not increase their HDL-C concentrations after treatment (-0.3, 95%CI -3.3 to 2.7%) while G allele homozygotes had a 4.9% increase (95%CI 2.5-7.3%). Differences in the response between both groups were significant before (P=0.008) and after adjustment for confounding variables such as age and baseline HDL-C concentration (P=0.046). We conclude that the G/A polymorphism of the apo A-I promoter region affects not only baseline HDL-C concentrations but also its response to pravastatin treatment.

Impact of previous vascular burden on in-hospital and long-term mortality in patients with ST-segment elevation myocardial infarction.

INTRODUCTION AND OBJECTIVES: Patients with a current acute coronary syndrome and previous ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease are reported to have a poorer outcome than those without these previous conditions. It is uncertain whether this association with outcome is observed at long-term follow-up. METHODS: Prospective observational study, including 4247 patients with ST-segment elevation myocardial infarction. Detailed clinical data and information on previous ischemic heart disease, peripheral arterial disease, and cerebrovascular disease ("vascular burden") were recorded. Multivariate models were performed for in-hospital and long-term (median, 7.2 years) all-cause mortality. RESULTS: One vascular territory was affected in 1131 (26.6%) patients and ≥ 2 territories in 221 (5.2%). The total in-hospital mortality rate was 12.3% and the long-term incidence density was 3.5 deaths per 100 patient-years. A background of previous ischemic heart disease (odds ratio = 0.83; P = .35), peripheral arterial disease (odds ratio = 1.30; P = .34), or cerebrovascular disease (stroke) (odds ratio = 1.15; P = .59) was not independently predictive of in-hospital death. In an adjusted model, previous cerebrovascular disease and previous peripheral arterial disease were both predictors of mortality at long-term follow-up (hazard ratio = 1.57; P < .001; and hazard ratio = 1.34; P = .001; respectively). Patients with ≥ 2 diseased vascular territories showed higher long-term mortality (hazard ratio = 2.35; P < .001), but not higher in-hospital mortality (odds ratio = 1.07; P = .844). CONCLUSIONS: In patients with a diagnosis of ST-segment elevation acute myocardial infarction, the previous vascular burden determines greater long-term mortality. Considered individually, previous cerebrovascular disease and peripheral arterial disease were predictors of mortality at long-term after hospital discharge.