Impact of Limiting Vancomycin Loading Doses in Patients With Methicillin-resistant Staphylococcus aureus Infections After Hospital Protocol Revision.

Background: Vancomycin loading doses are commonly used to quickly attain target serum concentrations; however, data supporting their effect on clinical patient outcomes is limited. In April 2020, our institution revised our pharmacist-driven vancomycin dosing protocol to reserve loading doses for hemodynamically unstable patients with suspected serious methicillin-resistant Staphylococcus aureus (MRSA) infections. Prior to the protocol update, all patients treated with vancomycin at our institution received a weight-based loading dose. The purpose of this study is to assess clinical efficacy and safety outcomes related to the use of vancomycin loading doses. Methods: A retrospective, quasi-experimental study was performed to compare clinical outcomes in adult patients treated with vancomycin for laboratory-confirmed MRSA infections. Patients who received vancomycin therapy prior to our institution's vancomycin dosing protocol revisions (pre-intervention) were compared to patients who received vancomycin after the revisions (post-intervention). The primary outcome was all-cause, inpatient mortality. Secondary outcomes included persistent signs and symptoms of infection ≥5 days after vancomycin initiation, switch to alternative anti-MRSA therapy, and nephrotoxicity. Results: A total of 122 patients (63 pre-intervention patients and 59 post-intervention patients) were included. Receipt of a vancomycin loading dose did not impact the rate of inpatient mortality (4.76%vs 6.78%; OR 1.46, 95% CI [0.31, 6.79]). All secondary outcomes were similar between the two groups, including persistent signs and symptoms of infection, switch to alternative anti-MRSA therapy, and nephrotoxicity. Conclusions: Routine use of vancomycin loading doses is not associated with improved outcomes in hemodynamically stable patients with MRSA infections.

Differences in kinetic variables between injured and uninjured rearfoot runners: A hierarchical cluster analysis.

Running is a popular form of physical activity with a high incidence of running-related injuries. However, the etiology of running-related injuries remains elusive, possibly due to the heterogeneity of movement patterns. The purpose of this study was to investigate whether different clusters existed within a large group of injured and uninjured runners based on their kinetic gait patterns. A sample of 134 injured and uninjured runners were acquired from an existing database and 12 discrete kinetic and spatiotemporal variables which are commonly associated with running injuries were extracted from the ground reaction force waveforms. A principal components analysis followed by an unsupervised hierarchical cluster analysis was performed. The results revealed two distinct clusters of runners which were not associated with injury status (OR = 1.14 [0.57, 2.30], χ2  = 0.143, p = 0.706) or sex (OR = 1.72 [0.85, 3.49], χ2  = 2.3258, p = 0.127). These results suggest that while there appeared to be evidence for two distinct clusters within a large sample of injured and uninjured runners, there is no association between the kinetic variables and running related injuries.

Amyloidosis in surgically resected atrial appendages: a study of 345 consecutive cases with clinical implications.

Histomorphologic parameters of atrial appendages removed during the Cox-Maze procedure have been shown to correlate with recurrence of atrial fibrillation. While amyloid deposition has been noted within atrial appendages, the incidence and significance remains incompletely understood. More accurate amyloid typing methodologies and targeted pharmacotherapeutics have recently been developed, prompting pathologists to provide more detailed information about the type of amyloid identified in such samples. This study sought to fully characterize the morphologic characteristics of atrial amyloid as well as its incidence and clinical significance. Tissue archives were queried for atrial appendages removed during the cardiac surgeries (2010-2014). Patient demographics, imaging features, and salient clinical findings were recorded. Pattern and extent of amyloid deposition were recorded. Typing of the amyloid protein, when present, was performed on a subset of cases by laser capture microdissection with mass spectrometry-based proteomic analysis. A total of 383 atrial appendages from 345 consecutive patients were included in the study (mean age, 69 years; range, 26-92 years). Amyloid was present in 46% of patients. A linear relationship was observed between age and presence of atrial amyloidosis. Women were more likely to have atrial amyloidosis. Two distinct morphologies of amyloid were observed: filamentous and nonfilamentous, and correlated perfectly with amyloid type (filamentous = AANF-type amyloid; nonfilamentous = ATTR-type amyloid). Filamentous deposits were observed in 91% of those with amyloid. Amyloid was more likely to be found in the left atrial appendage than the right. Patients with atrial amyloid, irrespective of type, were more likely to have experienced stroke or TIA and more likely to have atrial arrhythmia preoperatively. Postoperatively, those with atrial amyloid are more likely to experience recurrence of arrhythmia than those who did not have atrial amyloid. Understanding the morphologic characteristics of AANF-type amyloid will allow for identification by the light microscopy and obviates the need for expensive ancillary typing techniques. The finding of nonfilamentous amyloid, should still prompt confirmation of amyloid type so that targeted therapy may be employed.

Biomechanics of graded running: Part I - Stride parameters, external forces, muscle activations.

Biomechanical alterations with graded running have only been partially quantified, and the potential interactions with running speed remain unclear. We measured spatiotemporal parameters, ground reaction forces, and leg muscle activations (EMG) in nineteen adults (10F/9M) running on an instrumented treadmills at 2.50, 3.33, and 4.17 m·s-1 and 0, ±5°, and ±10°. Step frequency illustrated a significant speed × grade interaction (P < .001) and was highest (+3%) at the steepest grade (+10°) and fastest speed (4.17 m·s-1 ) when compared to level running (LR) at the same speed. Significant interaction was also observed for ground reaction forces (all P ≤ .047). Peak ground reaction forces in the normal direction increased with running speed during downhill running (DR) only (+9% at -10° and 4.17 m·s-1 ). Impulse in the normal direction decreased at fastest speed and steepest DR (-9%) and uphill running (UR) (-17%) grades. Average normal loading rate increased and decreased at fastest speed and steepest DR (+52%) and UR (-28%) grades, respectively. Negative parallel impulse increased and decreased at fastest speed and steepest DR (+166%) and UR (-90%), respectively. Positive parallel impulse decreased and increased at fastest speed and steepest DR (-75%) and UR (+111%), respectively. EMG showed comparable u-shaped curves across the grades investigated, although only a change in vastus lateralis and tibilias anterior activity was detectable at the steepest grades and fastest speed. Overall, running grade and speed significantly influences spatiotemporal parameters, ground reaction forces, and muscle activations.

Biomechanics of graded running: Part II-Joint kinematics and kinetics.

Compared to level running (LR), different strategies might be implemented by runners to cope with specific challenges of graded running at different speeds. The changes in joint kinetics and kinematics associated with graded running have been investigated, but their interactions with speed are unknown. Nineteen participants ran on an instrumented treadmill at five grades (0°, ±5° and ± 10°) and three speeds (2.50, 3.33 and 4.17 m/s), while 3D motion and forces were recorded. Three speed × five-grade repeated-measures ANOVA was used to analyze kinetic and kinematic variables. A speed × grade interaction was observed for hip range of motion (ROM). Downhill running (DR) at fastest speed did not reduce ROM at the hip, compared to LR. Compared to LR, it was observed that the hip joint was responsible for a greater contribution of energy generation while running at the fastest speed at +10°. Speed × grade interactions were also observed for the energy absorption, peak moment, and peak power at the knee. Contrary to LR, running faster during UR did not require higher peak power at the knee. Finally, DR at the fastest speed did not increase peak negative power at the knee compared to LR. This study demonstrates that ankle, knee, and hip joint kinetics depend on speed and grade of running, while the effect of grade on joint kinematics was not substantially modulated by speed.

Pathogen-mediated selection in free-ranging elk populations infected by chronic wasting disease.

Pathogens can exert a large influence on the evolution of hosts via selection for alleles or genotypes that moderate pathogen virulence. Inconsistent interactions between parasites and the host genome, such as those resulting from genetic linkages and environmental stochasticity, have largely prevented observation of this process in wildlife species. We examined the prion protein gene (PRNP) in North American elk (Cervus elaphus nelsoni) populations that have been infected with chronic wasting disease (CWD), a contagious, fatal prion disease, and compared allele frequency to populations with no history of exposure to CWD. The PRNP in elk is highly conserved and a single polymorphism at codon 132 can markedly extend CWD latency when the minor leucine allele (132L) is present. We determined population exposure to CWD, genotyped 1,018 elk from five populations, and developed a hierarchical Bayesian model to examine the relationship between CWD prevalence and PRNP 132L allele frequency. Populations infected with CWD for at least 30-50 y exhibited 132L allele frequencies that were on average twice as great (range = 0.23-0.29) as those from uninfected populations (range = 0.04-0.17). Despite numerous differences between the elk populations in this study, the consistency of increase in 132L allele frequency suggests pathogen-mediated selection has occurred due to CWD. Although prior modeling work predicted that selection will continue, the potential for fitness costs of the 132L allele or new prion protein strains to arise suggest that it is prudent to assume balancing selection may prevent fixation of the 132L allele in populations with CWD.

Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction.

BACKGROUND: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. METHODS: Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ≥40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. RESULTS: The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls (P<0.0001 for all) but lower than PVOD (P≤0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50-70]) than in PVOD (median, 91 [interquartile range, 82-103]). PASP correlated with arterial percent medial thickness (r=0.41) and arterial %IT (r=0.35) but more strongly with venous %IT (r=0.49) and IV %IT (r=0.55) (P<0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. CONCLUSIONS: In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Neoplastic embolization to systemic and pulmonary arteries.

OBJECTIVE: Arterial neoplastic emboli are uncommon, accounting for <1% of thromboemboli in the current literature. Nonetheless, this event may be associated with significant morbidity and mortality. Herein, we report a series of 11 cases of arterial neoplastic emboli from a single tertiary care center along with a comprehensive review of the literature to date. The aim of this study was to document the incidence, clinical presentations, and complications of arterial neoplastic emboli as well as to highlight the importance of routine histologic examination of thrombectomy specimens. METHODS: Pathology archives from a single tertiary care institution were queried to identify cases of surgically resected arterial emboli containing neoplasm (1998-2014). Histopathology was reviewed for confirmation of diagnosis. Patient demographics and oncologic history were abstracted from the medical record. Comprehensive literature review documented 332 patients in 275 reports (1930-2016). RESULTS: Eleven patients (six men) with a median age of 63 years (interquartile range, 42-71 years) were identified through institutional archives. Embolism was the primary form of diagnosis in seven (64%) cases. Cardiac involvement (primary or metastasis) was present in more than half of the cohort. Comprehensive literature review revealed that pulmonary primaries were the most common anatomic origin of arterial neoplastic emboli, followed by gastrointestinal neoplasia. Cardiac involvement was present in 18% of patients, and sentinel identification of neoplasia occurred in 30% of cases. Postmortem evaluation was the primary means of diagnosis in 27%. CONCLUSIONS: This study highlights the importance of routine histopathologic evaluation of embolectomy specimens in patients with and without documented neoplasia.

Distributions of PCB Congeners and Homologues in White Sucker and Coho Salmon from Lake Michigan.

We tested the hypothesis of the proportion of higher chlorinated biphenyl (PCB) congeners increasing with increasing trophic level by comparing the respective PCB homologue distributions in an omnivore, white sucker ( Catostomus commersoni), and a top predator, coho salmon ( Oncorhynchus kisutch), from Lake Michigan. Adult females had the same congener and homologue proportions of total PCB concentration (ΣPCB) as adult males in both species. Hexachlorinated congeners comprised the largest proportion (32%) found in white sucker, followed by heptachlorinated (21%) and octochlorinated (18%) congeners. In contrast, pentachlorinated congeners comprised the largest proportion (33%) of ΣPCB found in coho salmon, followed by hexachlorinated (26%) and tetrachlorinated (24%) congeners. Coho salmon contained significantly higher proportions of tri-, tetra-, and pentachlorinated congeners, whereas white sucker contained significantly higher proportions of hexa- through decachlorinated congeners. Our results were opposite of the hypothesis of greater degree of PCB chlorination with increasing trophic level, and supported the contention that the PCB congener proportions in fish depends mainly on diet, and does not necessarily reflect the trophic level of the fish. Our results also supported the contention that diets do not vary between the sexes in most fish populations.

Quadricuspid Aortic Valve: Characteristics, Associated Structural Cardiovascular Abnormalities, and Clinical Outcomes.

BACKGROUND: Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect. This study sought to determine QAV frequency in a large echocardiography database, to characterize associated cardiovascular abnormalities, and to describe long-term outcomes. METHODS AND RESULTS: Fifty patients (mean ± SD age, 43.5 ± 21.8 years at the time of the index diagnosis; female sex, 52%) received a diagnosis of QAV between January 1, 1975, and March 14, 2014 (frequency, 0.006%). The QAV was type A in 32% and type B in 32% (Hurwitz and Roberts classification). Aortic dilatation was present in 29% of the patients, and 26% had moderate or severe aortic valve regurgitation at the index diagnosis. Stenosis affected only 8% of the valves and was mild. Other findings, including abnormalities of other cardiac valves, septal defects, persistent left superior vena cava, and patent ductus arteriosus, were present in 32% of patients. During a mean ± SD follow-up of 4.8 ± 5.6 years, 8 patients underwent aortic valve surgery, with severe aortic valve regurgitation being the surgical indication in 7 patients. One patient with mild to moderate aortic valve regurgitation underwent aortic valve repair for obstruction of the left coronary ostium by the accessory cusp of QAV. No infective endocarditis or aortic dissection was found. Overall survival was 91.5% and 87.7% at 5 and 10 years. CONCLUSIONS: Aortic dilatation and other structural cardiac abnormalities were relatively common among patients with QAV. Aortic valve regurgitation was the predominant hemodynamic abnormality and the indication for aortic valve surgery in most patients who received surgery. Long-term survival was excellent.

Clinical presentation and echocardiographic diagnosis of postinfarction papillary muscle rupture: A review of 22 cases.

BACKGROUND: Acute myocardial infarctions (AMI) continue to be common in the United States. Mechanical complications of AMI can lead to cardiogenic shock (CS) and death. The aim of this study was to review the cases of papillary muscle ruptures in the setting of myocardial infarctions at a tertiary care center, with a focus on the clinical presentation and echocardiographic diagnosis. METHODS: This was a retrospective study from January 1, 2000 through December 31, 2014. In all, 22 patients with AMI and papillary muscle rupture (AMI-PMR) who had surgical intervention were identified. RESULTS: The average age was 70 (±11) with 16 (73%) males. Six patients presented with ST-elevation myocardial infarctions (STEMI) and all underwent emergent revascularization with primary percutaneous coronary intervention (PCI) prior to the diagnosis of AMI-PMR. The other 16 patients presented with a non-STEMI. In total, 17 (77%) of the 22 patients were diagnosed with an AMI-PMR within 7 days from their onset of symptoms. In all, 12 patients (55%) had anterolateral papillary muscle ruptures (ALPMR), and the other 10 had posteromedial papillary muscle ruptures (PMPMR). Ruptures were complete in 10 patients (45%). Patients presented with pulmonary edema early (<7 days) more commonly than late (>14 days). Transthoracic echocardiography was able to demonstrate severe mitral regurgitation in 86% and a definitive or suggestive diagnosis in 93%. All 22 patients survived to operative management, and the overall in-hospital mortality rate was 9%. CONCLUSION: In conclusion, ischemic papillary muscle ruptures continue to occur, but with prompt diagnosis by echocardiography and rapid surgical management, the mortality rate continues to decline.

Sex-related differences in calcific aortic stenosis: correlating clinical and echocardiographic characteristics and computed tomography aortic valve calcium score to excised aortic valve weight.

AIMS: Calcific aortic valve stenosis (AS) is purportedly associated with less calcium burden in women than in men. We sought to examine sex-related differences and correlates of surgically excised aortic valve weight (AVW) in pure AS. METHODS AND RESULTS: Clinical and echocardiographic characteristics of 888 consecutive patients who underwent aortic valve replacement for severe AS were correlated to AVW, and in 126 patients, AVW was also correlated to computed tomography aortic valve calcium (AVC) score. Women and men had similar indexed valve area (0.42 ± 0.09 vs. 0.42 ± 0.07 cm (2)/m(2), P = 0.95) and mean systolic gradient (53 ± 15 vs. 52 ± 13 mmHg, P = 0.11), but women had higher New York Heart Association class (2.63 ± 0.70 vs. 2.50 ± 0.70, P = 0.01) and less prevalent coronary artery disease (38 vs. 52%, P < 0.0001). Aortic valve weight was lower in women (1.94 ± 0.88 vs. 3.08 ± 1.32 g, P < 0.0001) even when indexed to body surface area (1.09 ± 0.48 vs. 1.48 ± 0.62 g/m(2), P < 0.0001) or left ventricular outflow tract (LVOT) area (0.54 ± 0.23 vs. 0.71 ± 0.29 g/cm(2), P < 0.0001). Using multivariate analysis, male sex (P < 0.0001), bicuspid valve (P < 0.0001), and larger LVOT area (P < 0.0001) were the major determinants of increased AVW, along with current cigarette smoking (P = 0.007). Diabetes (P = 0.004) and hypertension (P = 0.03) were independently associated with lower AVW. Aortic valve calcium correlated well with AVW (r = 0.81, P < 0.0001) and was lower in women than in men (2520 ± 1199 vs. 3606 ± 1632 arbitrary units, P < 0.0001). CONCLUSIONS: Despite the same degree of AS severity, women have less AVC and lower AVW compared with men, irrespective of valve morphology. Aortic valve calcium is correlated to excised AVW. Hypertension, diabetes, and current cigarette smoking were independently associated with AVW.

Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.

BACKGROUND: Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology. METHODS AND RESULTS: We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with ≥1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm(2)) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD. CONCLUSIONS: In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF.

Correlation of histomorphological pattern of cardiac amyloid deposition with amyloid type: a histological and proteomic analysis of 108 cases.

AIMS: Prognostication and treatment selection for cardiac amyloidosis requires accurate amyloid typing. The aim of this study was to investigate the utility of histomorphology for predicting type. METHODS AND RESULTS: Autopsy cases with cardiac amyloidosis (1998-2010) were typed by the use of mass spectrometry-based proteomics. Deposition patterns were correlated with amyloid type. Among 108 decedents (mean age 75 years; 69% men), 107 had a single type, including transthyretin (ATTR) (60 cases), amyloid light chain (AL) (32 λ; 12 κ), amyloid A (AA) (two), and apolipoprotein AIV (AApoAIV) (one). Interstitial deposition was more extensive in AL amyloidosis cases than in ATTR cases [odds ratio (OR) 6.8, P = 0.0004]. Histomorphological patterns of interstitial deposition were mixed in 61% of AL amyloidosis cases and in 61% of ATTR cases, but diffuse pericellular deposits favoured AL amyloidosis (OR 10.7, P = 0.0001), nodular deposits favoured ATTR (OR 3.1, P = 0.0229), and discrete pericellular deposits tended to partially favour ATTR (OR 1.7, P = 0.1970). Arterial and venous deposits each favoured AL amyloidosis (OR ranging from 9.3 to 192.0, P-value ranging from 0.0022 to <0.0001), and were severe in AL amyloidosis. Endocardial deposits favoured AL amyloidosis (OR 46.3, P < 0.0001) and were also more severe in AL amyloidosis. CONCLUSIONS: The extent and distribution of cardiac amyloidosis strongly correlate with amyloid type, suggesting fundamental differences in the pathobiology of deposition. The tendency for mixed patterns to occur limits the practicality and accuracy of using histopathology for amyloid typing.

Echocardiographic Features of Cardiac Angiosarcomas: The Mayo Clinic Experience (1976-2013).

OBJECTIVE: Cardiac angiosarcoma is the most common primary malignant cardiac tumor. The dismal prognosis and nonspecific symptomatology underscore the need for an accurate and cost-effective approach to the identification and characterization of this rare tumor. METHODS: Mayo Clinic tissue registry archives were queried for all histologically confirmed cases of cardiac angiosarcoma (1976-2013) with available imaging data. Echocardiograms were retrospectively reviewed. RESULTS: Thirty-three cases of cardiac angiosarcoma were identified; of these, 17 had echocardiograms available (mean age, 46 years; six men). Transthoracic echocardiography (TTE) as the initial diagnostic test had 75% sensitivity for visualizing primary cardiac angiosarcoma (9/12 patients). Tumor extension into the pericardium was common and pericardial effusion was present in 15 patients (88%); however, pericardial fluid cytology was negative for malignancy in all tested patients (n = 15). Left ventricular ejection fraction (LVEF) was preserved in 16 patients (94%) (average LVEF, 62%). Right ventricular function was mildly reduced in two patients (12%) at initial presentation. Tricuspid valve obstruction was present in three patients (18%; mean diastolic gradient, 6.3 mmHg [range, 3-11 mmHg]). CONCLUSION: The sensitivity of TTE as the first diagnostic imaging modality compared favorably with computed tomography. Pericardial effusion was common, but pericardial fluid cytology was negative in all patients who underwent pericardiocentesis. The absence of a stalk was a universal finding that may help distinguish angiosarcoma from benign, primarily pedunculated tumors such as myxoma and papillary fibroelastoma.

Whole-genome resequencing uncovers molecular signatures of natural and sexual selection in wild bighorn sheep.

The identification of genes influencing fitness is central to our understanding of the genetic basis of adaptation and how it shapes phenotypic variation in wild populations. Here, we used whole-genome resequencing of wild Rocky Mountain bighorn sheep (Ovis canadensis) to >50-fold coverage to identify 2.8 million single nucleotide polymorphisms (SNPs) and genomic regions bearing signatures of directional selection (i.e. selective sweeps). A comparison of SNP diversity between the X chromosome and the autosomes indicated that bighorn males had a dramatically reduced long-term effective population size compared to females. This probably reflects a long history of intense sexual selection mediated by male-male competition for mates. Selective sweep scans based on heterozygosity and nucleotide diversity revealed evidence for a selective sweep shared across multiple populations at RXFP2, a gene that strongly affects horn size in domestic ungulates. The massive horns carried by bighorn rams appear to have evolved in part via strong positive selection at RXFP2. We identified evidence for selection within individual populations at genes affecting early body growth and cellular response to hypoxia; however, these must be interpreted more cautiously as genetic drift is strong within local populations and may have caused false positives. These results represent a rare example of strong genomic signatures of selection identified at genes with known function in wild populations of a nonmodel species. Our results also showcase the value of reference genome assemblies from agricultural or model species for studies of the genomic basis of adaptation in closely related wild taxa.

Females exceed males in mercury concentrations of burbot Lota lota.

Examination of differences in contaminant concentrations between the sexes of fish, across several fish species, may show clues for important behavioral and physiological differences between the sexes. We determined whole-fish total mercury (Hg) concentrations of 25 male and 25 female adult burbot Lota lota captured in Lake Erie during summer 2011 and of 14 male and 18 female adult burbot captured in Great Slave Lake (Northwest Territories, Canada) during winter 2013. On average, females had 22 % greater Hg concentrations than males. This difference was probably not due to a greater feeding rate by females because results from previous studies based on polychlorinated biphenyl determinations of these same burbot indicated that males fed at a substantially greater rate than females. Based on our determinations of Hg concentrations in the gonads and somatic tissue of 5 ripe females and 5 ripe males, this difference was not attributable to changes in Hg concentration immediately after spawning due to the release of gametes. Furthermore, bioenergetics modeling results from previous studies indicated that growth dilution would not explain any portion of this observed difference in Hg concentrations between the sexes. We therefore conclude that this difference was most likely due to a substantially faster rate of Hg elimination by males compared with females. Male burbot exhibit among the greatest gonadosomatic indices (GSIs) of all male fishes, with their testes accounting for between 10 and 15 % of their body weight when the fish are in ripe condition. Androgens have been linked to enhanced Hg-elimination rates in other vertebrates. If androgen production is positively related to GSI, then male burbot would be expected to have among the greatest androgen levels of all fishes. Thus, we hypothesize that male burbot eliminate Hg from their bodies faster than most other male fishes and that this explains the greater Hg concentration in females compared with males.

Atrial giant cell myocarditis: a distinctive clinicopathologic entity.

BACKGROUND: Giant cell myocarditis (GCM) typically causes fulminant heart failure, arrhythmias, or heart block, necessitating aggressive immunosuppression, ventricular assist device insertion, or cardiac transplantation. We describe a novel variant of GCM, primarily involving the atria, that displays distinctive clinical features and follows a more benign course than ventricular GCM. METHODS AND RESULTS: We identified 6 patients (median age 67.5 years, 4 male) with atrial GCM in our pathology consultation practices from 2010 to 2012. Clinical history, imaging, and pathology materials were reviewed. Clinically, 4 patients had atrial fibrillation, 1 had acute heart failure, and 1 had incidental disease at autopsy. Among the 5 living patients, echocardiography revealed severe atrial dilatation (5 cases), mitral/tricuspid regurgitation (5), atrial mural thrombus (3), atrial wall thickening (2), and atrial hypokinesis (2). Ventricular function was preserved in all 5. Histological review of surgically resected atria showed giant cell and lymphocytic infiltrates, lymphocytic myocarditis-like foci, cardiomyocyte necrosis, and cardiomyocyte hypertrophy in all cases. Other features included interstitial fibrosis (5), poorly-formed granulomas (4), eosinophils (4), neutrophils (1), and vasculitis (1). Treatment consisted of steroids and cyclosporine (1), pacemaker placement for sick sinus syndrome (1), and supportive care (3). All 5 living patients returned to baseline exercise tolerance after 6 to 16 weeks of follow-up. CONCLUSIONS: Atrial GCM represents a distinct clinicopathologic entity with a more favorable prognosis than classic ventricular GCM. This disorder should be included in the differential diagnosis of atrial dilatation, particularly when associated with atrial wall thickening. The utility of immunomodulatory therapy for this condition remains unknown.

Enantioselective component selection in multicomponent supramolecular gels.

We investigate a two-component acid-amine gelation system in which chirality plays a vital role. A carboxylic acid based on a second generation l-lysine dendron interacts with chiral amines and subsequently assembles into supramolecular gel fibers. The chirality of the amine controls the assembly of the resulting diastereomeric complexes, even if this chirality is relatively "poor quality". Importantly, the selective incorporation of one enantiomer of an amine over the other into the gel network has been demonstrated, with the R amine that forms complexes which assemble into the most stable gel being primarily selected for incorporation. Thermodynamic control has been proven by forming a gel exclusively with an S amine, allowing the R enantiomer to diffuse through the gel network, and displacing it from the "solidlike" fibers, demonstrating that these gels adapt and evolve in response to chemical stimuli to which they are exposed. Excess amine, which remains unincorporated within the solidlike gel fiber network, can diffuse out and be reacted with an isocyanate, allowing us to quantify the enantioselectivity of component selection but also demonstrating how gels can act as selective reservoirs of potential reagents, releasing them on demand to undergo further reactions; hence, component-selective gel assembly can be coupled with controlled reactivity.