An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to ...identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing.
An institutional review board-approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act-compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results.
More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher's exact test P = .4241).
Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.
Abstract Background Previous studies have observed high rates of perioperative cardiovascular events in patients with coronary stents undergoing noncardiac surgery (NCS). It is uncertain whether this ...finding reflects an independent association. Objectives The goal of this study was to assess the independent relationship between prior coronary stent implantation and the occurrence of perioperative major adverse cardiac and cerebrovascular events (MACCE) and bleeding and its relation with time from stenting to NCS. Methods A total of 24,313 NCS cases at the Mayo Clinic (Rochester, Minnesota) from 2006 through 2011 were included in the study; 1,120 (4.6%) cases involved patients with coronary stents. MACCE was defined as death, myocardial infarction, cardiac arrest, or stroke. Age-adjusted odds ratios (aORs) were calculated after propensity adjustment for Revised Cardiac Risk Index factors and other conventional risk factors. Results The 30-day MACCE rates were 3.7% and 1.5% in stented and unstented patients, respectively (p < 0.001). The risk of MACCE was largely related to the time from stent implantation to NCS, indicating substantially elevated risk in the first year after stenting (aOR: 2.59; 95% confidence interval CI: 1.36 to 4.94) but not thereafter (aOR: 0.89; 95% CI: 0.59 to 1.36). Bleeding displayed a similar pattern, indicating elevated risk in the first year after stenting (aOR: 2.23; 95% CI: 1.55 to 3.21) but not thereafter (aOR: 1.07; 95% CI: 0.89 to 1.28). Subgroup analysis in patients with known stent type found that the increased risk of both MACCE and bleeding >1 month after stent implantation was not limited to only those with drug-eluting stents. Conclusions This study found that prior coronary stent implantation is an independent risk factor for MACCE and bleeding when time from stenting to NCS is <1 year, both in patients with bare-metal and drug-eluting stents.
By 13,000 BP human populations were present across North America, but the exact date of arrival to the continent, especially areas south of the continental ice sheets, remains unclear. Here we ...examine patterns in the stratigraphic integrity of early North American sites to gain insight into the timing of first colonization. We begin by modeling stratigraphic mixing of multicomponent archaeological sites to identify signatures of stratigraphic integrity in vertical artifact distributions. From those simulations, we develop a statistic we call the Apparent Stratigraphic Integrity Index (ASI), which we apply to pre- and post-13,000 BP archaeological sites north and south of the continental ice sheets. We find that multiple early Beringian sites dating between 13,000 and 14,200 BP show excellent stratigraphic integrity. Clear signs of discrete and minimally disturbed archaeological components do not appear south of the ice sheets until the Clovis period. These results provide support for a relatively late date of human arrival to the Americas.
The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in ...human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics
. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.
This study sought to validate a pharmacokinetically derived measure of the risk of an early increase in serum creatinine after percutaneous coronary intervention (PCI).
The ratio of the volume of ...contrast media to the creatinine clearance (V/CrCl) has been shown to correlate with the area under the curve of contrast media concentration over time.
We calculated V/CrCl in 3,179 consecutive patients undergoing PCI. An increase in serum creatinine of >0.5 mg/dl by 24 to 48 h was considered abnormal. Receiver-operator characteristic methods were used to identify the optimal sensitivity and specificity for the observed range of V/CrCl. The predictive value of V/CrCl for the risk of an early increase in creatinine was assessed using multivariable logistic regression.
The overall incidence of an abnormal, early increase in creatinine was 1.5%. The mean and median values of V/CrCl for patients with (mean 5.2 +/- 4.4, median 4.3, interquartile range 2.7 to 6.0) and without (mean 3.0 +/- 2.0, median 2.5, interquartile range 1.7 to 3.8) an early creatinine increase were each significantly (p < 0.001) different between groups. Furthermore, there was a significant association between V/CrCl and an early increase in creatinine (overall and trend, p < 0.001). The receiver-operator characteristic curve analysis indicated that a V/CrCl ratio of 3.7 was a fair discriminator for the early creatinine increase (C-statistic 0.69). After adjusting for other known predictors of post-PCI creatinine increase, V/CrCl > or =3.7 remained significantly associated with an early abnormal increase in serum creatinine (odds ratio 3.84; 95% confidence interval 2.0 to 7.3, p < 0.001).
A V/CrCl ratio >3.7 was a significant and independent predictor of an early abnormal increase in serum creatinine after PCI in this unselected patient population.
We previously reported that four cycles of docetaxel/cyclophosphamide (TC) produced superior disease-free survival (DFS) compared with four cycles of doxorubicin/cyclophosphamide (AC) in early breast ...cancer. Older women are under-represented in adjuvant chemotherapy trials. In our trial 16% of patients were > or = 65 years. We now report 7-year results for DFS and overall survival (OS) as well as the impact of age, hormone receptor status, and HER2 status on outcome and toxicity.
Patients were randomly assigned to receive either four cycles of standard-dose AC (60/600 mg/m(2); n = 510), or TC (75/600 mg/m(2); n = 506), administered by intravenous infusion every 3 weeks.
The median age in women younger than 65, was 50 years (range, 27 to 64) and for women > or = 65 was 69 years (range, 65 to 77). Baseline characteristics in the two age subgroups were generally well matched, except that older women tended to have more lymph node involvement. At a median of 7 years follow-up, the difference in DFS between TC and AC was significant (81% TC v 75% AC; P = .033; hazard ratio HR, 0.74; 95% CI 0.56 to 0.98) as was OS (87% TC v 82% AC; P = .032; HR, 0.69; 95% CI, 0.50 to 0.97). TC was superior in older patients as well as younger patients. There was no interaction of hormone-receptor status or HER-2 status and treatment. Older women experienced more febrile neutropenia with TC and more anemia with AC.
With longer follow-up, four cycles of TC was superior to standard AC (DFS and OS) and was a tolerable regimen in both older and younger patients.
The aim of this study was to evaluate the safety and effectiveness of percutaneous mechanical thrombectomy using the FlowTriever System (Inari Medical, Irvine, California) in a prospective trial of ...patients with acute intermediate-risk pulmonary embolism (PE).
Catheter-directed thrombolysis has been shown to improve right ventricular (RV) function in patients with PE. However, catheter-directed thrombolysis increases bleeding risk and many patients with PE have relative and absolute contraindications to thrombolysis.
Patients with symptomatic, computed tomography-documented PE and RV/left ventricular (LV) ratios ≥0.9 were eligible for enrollment. The primary effectiveness endpoint was core laboratory-assessed change in RV/LV ratio. The primary safety endpoint comprised device-related death, major bleeding, treatment-related clinical deterioration, pulmonary vascular injury, or cardiac injury within 48 h of thrombectomy.
From April 2016 to October 2017, 106 patients were treated with the FlowTriever System at 18 U.S. sites. Two patients (1.9%) received adjunctive thrombolytics and were analyzed separately. Mean procedural time was 94 min; mean intensive care unit stay was 1.5 days. Forty-three patients (41.3%) did not require any intensive care unit stay. At 48 h post-procedure, average RV/LV ratio reduction was 0.38 (25.1%; p < 0.0001). Four patients (3.8%) experienced 6 major adverse events, with 1 patient (1.0%) experiencing major bleeding. One patient (1.0%) died, of undiagnosed breast cancer, through 30-day follow-up.
Percutaneous mechanical thrombectomy with the FlowTriever System appears safe and effective in patients with acute intermediate-risk PE, with significant improvement in RV/LV ratio and minimal major bleeding. Potential advantages include immediate thrombus removal, absence of thrombolytic complications, and reduced need for post-procedural critical care.
Movement behaviors (i.e. physical activity PA, sedentary behavior SB, and sleep) are intrinsically codependent, an issue resolved using compositional data analysis (CoDA). High-sensitivity C-reactive ...protein (hs-CRP) is a nonspecific inflammatory marker positively associated with cardiovascular diseases and affected by movement behaviors. Examine the relation between movement behaviors using CoDA and how time reallocation between two movement behaviors was associated with hs-CRP concentration.
The Jackson Heart Study was designed to investigate cardiovascular disease risk factors among African American participants in the Jackson, MS area. PA and sleep were self-reported with SB calculated as the remaining time in the day.
The median untransformed hs-CRP concentration was 0.28 mg·dL−1 (interquartile range; 0.11, 0.61). Reallocating 15 minutes of PA with SB, the hypothetical change in log hs-CRP concentration was 0.08 mg·dL−1 (95% CIs; 0.04, 0.11) greater than the average log hs-CRP concentration. Substituting 15 minutes of SB or sleep with PA was associated with a hypothetical change in log hs-CRP concentration difference of -0.05 mg·dL−1 (-0.08, -0.03) and -0.06 mg·dL−1 (-0.08, -0.03), respectively. Reallocations between SB and sleep were not associated with the hypothetical difference in log hs-CRP concentration.
Modeling estimates suggest replacing 15 minutes of SB with PA is associated with lower inflammation.
Summary Background Animals can act as a reservoir and source for the emergence of novel meticillin-resistant Staphylococcus aureus (MRSA) clones in human beings. Here, we report the discovery of a ...strain of S aureus (LGA251) isolated from bulk milk that was phenotypically resistant to meticillin but tested negative for the mecA gene and a preliminary investigation of the extent to which such strains are present in bovine and human populations. Methods Isolates of bovine MRSA were obtained from the Veterinary Laboratories Agency in the UK, and isolates of human MRSA were obtained from diagnostic or reference laboratories (two in the UK and one in Denmark). From these collections, we searched for mecA PCR-negative bovine and human S aureus isolates showing phenotypic meticillin resistance. We used whole-genome sequencing to establish the genetic basis for the observed antibiotic resistance. Findings A divergent mecA homologue ( mecALGA251 ) was discovered in the LGA251 genome located in a novel staphylococcal cassette chromosome mec element, designated type-XI SCC mec . The mecALGA251 was 70% identical to S aureus mecA homologues and was initially detected in 15 S aureus isolates from dairy cattle in England. These isolates were from three different multilocus sequence type lineages (CC130, CC705, and ST425); spa type t843 (associated with CC130) was identified in 60% of bovine isolates. When human mecA -negative MRSA isolates were tested, the mecALGA251 homologue was identified in 12 of 16 isolates from Scotland, 15 of 26 from England, and 24 of 32 from Denmark. As in cows, t843 was the most common spa type detected in human beings. Interpretation Although routine culture and antimicrobial susceptibility testing will identify S aureus isolates with this novel mecA homologue as meticillin resistant, present confirmatory methods will not identify them as MRSA. New diagnostic guidelines for the detection of MRSA should consider the inclusion of tests for mecALGA251. Funding Department for Environment, Food and Rural Affairs, Higher Education Funding Council for England, Isaac Newton Trust (University of Cambridge), and the Wellcome Trust.
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