There is a low rate of major adverse cardiovascular events in chest pain patients with a moderate risk heart score referred from urgent care for expedited outpatient cardiology evaluation: a multi-center study

Background The HEART score is an effective method of risk stratifying emergency department (ED) patients with chest pain. The rate of major adverse cardiovascular events (MACE) in patients with moderate HEART score referred from an urgent care (UC) for an expedited outpatient cardiology evaluation for 11 months was described in 133 patients in a previous study. This is a follow-up study with 18 months of data and 206 patients.Aim. The primary outcome was to examine the rate of MACE when patients with moderate HEART score were referred for an expedited outpatient cardiology follow-up after evaluation in urgent care. The secondary outcome was to determine if there is a decrease in rate of ED transfer after this protocol was introduced.Methods. A cross-sectional study was conducted by a multispecialty group in Las Vegas, Nevada, which included 206 patients with a HEART score of 4 to 6 (i.e.: moderate risk) who presented to one of five UC centers with chest pain or an anginal equivalent. A streamlined evaluation protocol to assess each HEART score component was adopted by all UC providers to facilitate an expedited outpatient cardiology follow-up, as an alternative to referral to the emergency department. Data was collected from February 14, 2019 through August 13, 2020. The population was followed for 6 weeks with a primary endpoint of MACE determined by electronic medical record review and direct phone contact with patients. Outcomes were confirmed in 98% of patients. Chest pain transfer data was compared between 12 months prior to implementing HEART protocol and 18 months of data analysis while using the new protocol.Results. Over the course of 18 months, 206 patients with a moderate risk HEART score were referred to outpatient cardiology in an expedited manner. The average age was 65 with 53% female and 47% male patients. 150 patients (73% of the 206) were seen within 3 days, 114 (55%) underwent stress testing, 6 (3%) had coronary computed tomography angiogram, and 6 (3%) received an invasive coronary angiogram. Five patients were found to have MACE: one patient who had a non-ST-elevation myocardial infarction and subsequent coronary stent, two patients were found to have obstructive disease after coronary angiography with subsequent coronary artery bypass graft, one patient had an abnormal stress test and subsequent coronary stent, and one patient had critical mitral stenosis, multi-vessel coronary artery disease and underwent coronary artery bypass graft with mitral valve replacement with complications of renal failure and COVID-19 and expired. The emergency department referral rate declined by 21%.Conclusion. Patients with a moderate risk HEART score referred from UC for an expedited outpatient cardiology evaluation had a low rate of MACE and no deaths due to delay of care. There was also a significant decrease in the rate of ED referrals.Background. The HEART score is an effective method of risk stratifying emergency department (ED) patients with chest pain. The rate of major adverse cardiovascular events (MACE) in patients with moderate HEART score referred from an urgent care (UC) for an expedited outpatient cardiology evaluation for 11 months was described in 133 patients in a previous study. This is a follow-up study with 18 months of data and 206 patients.Aim. The primary outcome was to examine the rate of MACE when patients with moderate HEART score were referred for an expedited outpatient cardiology follow-up after evaluation in urgent care. The secondary outcome was to determine if there is a decrease in rate of ED transfer after this protocol was introduced.Methods. A cross-sectional study was conducted by a multispecialty group in Las Vegas, Nevada, which included 206 patients with a HEART score of 4 to 6 (i.e.: moderate risk) who presented to one of five UC centers with chest pain or an anginal equivalent. A streamlined evaluation protocol to assess each HEART score component was adopted by all UC providers to facilitate an expedited outpatient cardiology follow-up, as an alternative to referral to the emergency department. Data was collected from February 14, 2019 through August 13, 2020. The population was followed for 6 weeks with a primary endpoint of MACE determined by electronic medical record review and direct phone contact with patients. Outcomes were confirmed in 98% of patients. Chest pain transfer data was compared between 12 months prior to implementing HEART protocol and 18 months of data analysis while using the new protocol.Results. Over the course of 18 months, 206 patients with a moderate risk HEART score were referred to outpatient cardiology in an expedited manner. The average age was 65 with 53% female and 47% male patients. 150 patients (73% of the 206) were seen within 3 days, 114 (55%) underwent stress testing, 6 (3%) had coronary computed tomography angiogram, and 6 (3%) received an invasive coronary angiogram. Five patients were found to have MACE: one patient who had a non-ST-elevation myocardial infarction and subsequent coronary stent, two patients were found to have obstructive disease after coronary angiography with subsequent coronary artery bypass graft, one patient had an abnormal stress test and subsequent coronary stent, and one patient had critical mitral stenosis, multi-vessel coronary artery disease and underwent coronary artery bypass graft with mitral valve replacement with complications of renal failure and COVID-19 and expired. The emergency department referral rate declined by 21%.Conclusion. Patients with a moderate risk HEART score referred from UC for an expedited outpatient cardiology evaluation had a low rate of MACE and no deaths due to delay of care. There was also a significant decrease in the rate of ED referrals

Restless legs syndrome shows increased silent postmortem cerebral microvascular disease with gliosis

Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T-cell marker); (3) CD19 (a B-cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease

Sixty years of genome biology

Sixty years after Watson and Crick published the double helix model of DNA's structure, thirteen members of Genome Biology's Editorial Board select key advances in the field of genome biology subsequent to that discovery

Extensive Gene Amplification as a Mechanism for Piperacillin-Tazobactam Resistance in Escherichia coli.

Although the TEM-1 β-lactamase (BlaTEM-1) hydrolyzes penicillins and narrow-spectrum cephalosporins, organisms expressing this enzyme are typically susceptible to β-lactam/β-lactamase inhibitor combinations such as piperacillin-tazobactam (TZP). However, our previous work led to the discovery of 28 clinical isolates of Escherichia coli resistant to TZP that contained only blaTEM-1 One of these isolates, E. coli 907355, was investigated further in this study. E. coli 907355 exhibited significantly higher β-lactamase activity and BlaTEM-1 protein levels when grown in the presence of subinhibitory concentrations of TZP. A corresponding TZP-dependent increase in blaTEM-1 copy number was also observed, with as many as 113 copies of the gene detected per cell. These results suggest that TZP treatment promotes an increase in blaTEM-1 gene dosage, allowing BlaTEM-1 to reach high enough levels to overcome inactivation by the available tazobactam in the culture. To better understand the nature of the blaTEM-1 copy number proliferation, whole-genome sequence (WGS) analysis was performed on E. coli 907355 in the absence and presence of TZP. The WGS data revealed that the blaTEM-1 gene is located in a 10-kb genomic resistance module (GRM) that contains multiple resistance genes and mobile genetic elements. The GRM was found to be tandemly repeated at least 5 times within a p1ESCUM/p1ECUMN-like plasmid when bacteria were grown in the presence of TZP.IMPORTANCE Understanding how bacteria acquire resistance to antibiotics is essential for treating infected patients effectively, as well as preventing the spread of resistant organisms. In this study, a clinical isolate of E. coli was identified that dedicated more than 15% of its genome toward tandem amplification of a ~10-kb resistance module, allowing it to escape antibiotic-mediated killing. Our research is significant in that it provides one possible explanation for clinical isolates that exhibit discordant behavior when tested for antibiotic resistance by different phenotypic methods. Our research also shows that GRM amplification is difficult to detect by short-read WGS technologies. Analysis of raw long-read sequence data was required to confirm GRM amplification as a mechanism of antibiotic resistance. MBio 2018 Apr 24; 9(2):e00583-18

The Genome of C57BL/6J Eve , the Mother of the Laboratory Mouse Genome Reference Strain.

Isogenic laboratory mouse strains enhance reproducibility because individual animals are genetically identical. For the most widely used isogenic strain, C57BL/6, there exists a wealth of genetic, phenotypic, and genomic data, including a high-quality reference genome (GRCm38.p6). Now 20 years after the first release of the mouse reference genome, C57BL/6J mice are at least 26 inbreeding generations removed from GRCm38 and the strain is now maintained with periodic reintroduction of cryorecovered mice derived from a single breeder pair, aptly named Adam and Eve. To provide an update to the mouse reference genome that more accurately represents the genome of today\u27s C57BL/6J mice, we took advantage of long read, short read, and optical mapping technologies to generate a de novo assembly of the C57BL/6J Eve genome (B6Eve). Using these data, we have addressed recurring variants observed in previous mouse genomic studies. We have also identified structural variations, closed gaps in the mouse reference assembly, and revealed previously unannotated coding sequences. This B6Eve assembly explains discrepant observations that have been associated with GRCm38-based analyses, and will inform a reference genome that is more representative of the C57BL/6J mice that are in use today

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Risk Factors Associated With Severe Hypoglycemia in Older Adults With Type 1 Diabetes

OBJECTIVE Severe hypoglycemia is common in older adults with long-standing type 1 diabetes, but little is known about factors associated with its occurrence

Cognitive Profiles of Aging in Multiple Sclerosis

BackgroundIncreasingly favorable mortality prognosis in multiple sclerosis (MS) raises questions regarding MS-specific cognitive aging and the presence of comorbidities such as Alzheimer’s disease (AD).ObjectiveTo assess elderly with MS (EwMS) and age-matched healthy controls (HCs) using both MS- and AD-specific psychometrics.MethodsEwMS (n = 104) and 56 HCs were assessed on a broad spectrum of language, visual-spatial processing, memory, processing speed, and executive function tests. Using logistic regression analysis, we examined cognitive performance differences between the EwMS and HC groups. Cognitive impairment (CI) was defined using a -1.5 SD threshold relative to age and education years-matched HCs, in two cognitive domains.ResultsCI was observed in 47.1% of EwMS with differences most often seen on tests emphasizing cognitive processing speed as measured by Symbol Digit Modalities Test (SDMT) (d = 0.9, p < 0.001) and verbal fluency (both category-based d = 0.87, p < 0.001; letter-based d = 0.67, p < 0.001). After adjusting for age, sex and years of education, MS/HC diagnosis was best predicted (R2 = 0.27) by differences in category-based verbal fluency (Wald = 9.935, p = 0.002) and SDMT (Wald = 13.937, p < 0.001).ConclusionThis study confirms the common hallmark of slowed cognitive processing speed in MS among elderly patients. Defective verbal fluency, less often observed in younger cohorts, may represent emerging cognitive pathology due to other etiologies

Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry

Fixed, paraffin-embedded (FPE) tissues are a potentially rich resource for studying the role of NOTCH1 in cancer and other pathologies, but tests that reliably detect activated NOTCH1 (NICD1) in FPE samples have been lacking. Here, we bridge this gap by developing an immunohistochemical (IHC) stain that detects a neoepitope created by the proteolytic cleavage event that activates NOTCH1. Following validation using xenografted cancers and normal tissues with known patterns of NOTCH1 activation, we applied this test to tumors linked to dysregulated Notch signaling by mutational studies. As expected, frequent NICD1 staining was observed in T lymphoblastic leukemia/lymphoma, a tumor in which activating NOTCH1 mutations are common. However, when IHC was used to gauge NOTCH1 activation in other human cancers, several unexpected findings emerged. Among B cell tumors, NICD1 staining was much more frequent in chronic lymphocytic leukemia than would be predicted based on the frequency of NOTCH1 mutations, while mantle cell lymphoma and diffuse large B cell lymphoma showed no evidence of NOTCH1 activation. NICD1 was also detected in 38% of peripheral T cell lymphomas. Of interest, NICD1 staining in chronic lymphocytic leukemia cells and in angioimmunoblastic lymphoma was consistently more pronounced in lymph nodes than in surrounding soft tissues, implicating factors in the nodal microenvironment in NOTCH1 activation in these diseases. Among carcinomas, diffuse strong NICD1 staining was observed in 3.8% of cases of triple negative breast cancer (3 of 78 tumors), but was absent from 151 non-small cell lung carcinomas and 147 ovarian carcinomas. Frequent staining of normal endothelium was also observed; in line with this observation, strong NICD1 staining was also seen in 77% of angiosarcomas. These findings complement insights from genomic sequencing studies and suggest that IHC staining is a valuable experimental tool that may be useful in selection of patients for clinical trials