Fatal S. aureus Hemorrhagic Pneumonia: Genetic Analysis of a Unique Clinical Isolate Producing both PVL and TSST-1

In 2008, an unusual strain of methicillin-sensitive Staphylococcus aureus (MSSA68111), producing both Panton-Valentine leukocidin (PVL) and toxic shock syndrome toxin-1 (TSST-1), was isolated from a fatal case of necrotizing pneumonia. Because PVL/TSST-1 co-production in S. aureus is rare, we characterized the molecular organization of these toxin genes in strain 68111. MSSA68111 carries the PVL genes within a novel temperate prophage we call ФPVLv68111 that is most similar, though not identical, to phage ФPVL – a phage type that is relatively rare worldwide. The TSST-1 gene (tst) in MSSA68111 is carried on a unique staphylococcal pathogenicity island (SaPI) we call SaPI68111. Features of SaPI68111 suggest it likely arose through multiple major recombination events with other known SaPIs. Both ФPVLv68111 and SaPI68111 are fully mobilizable and therefore transmissible to other strains. Taken together, these findings suggest that hypervirulent S. aureus have the potential to emerge worldwide

Adverse Events Associated With Meropenem Versus Imipenem/Cilastatin Therapy in a Large Retrospective Cohort of Hospitalized Infants

Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin

Interior pathways of the North Atlantic meridional overturning circulation

To understand how our global climate will change in response to natural and anthropogenic forcing, it is essential to determine how quickly and by what pathways climate change signals are transported throughout the global ocean, a vast reservoir for heat and carbon dioxide. Labrador Sea Water (LSW), formed by open ocean convection in the subpolar North Atlantic, is a particularly sensitive indicator of climate change on interannual to decadal timescales. Hydrographic observations made anywhere along the western boundary of the North Atlantic reveal a core of LSW at intermediate depths advected southward within the Deep Western Boundary Current (DWBC). These observations have led to the widely held view that the DWBC is the dominant pathway for the export of LSW from its formation site in the northern North Atlantic towards the Equator. Here we show that most of the recently ventilated LSW entering the subtropics follows interior, not DWBC, pathways. The interior pathways are revealed by trajectories of subsurface RAFOS floats released during the period 2003-2005 that recorded once-daily temperature, pressure and acoustically determined position for two years, and by model-simulated 'e-floats' released in the subpolar DWBC. The evidence points to a few specific locations around the Grand Banks where LSW is most often injected into the interior. These results have implications for deep ocean ventilation and suggest that the interior subtropical gyre should not be ignored when considering the Atlantic meridional overturning circulation.Dissertatio

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases.

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood

The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = −0.62, P = 5.30 × 10−5) but not between CCT and primary open-angle glaucoma (r = −0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

The acute effects of exercise and inactivity on vascular function

Poor endothelial function can predict future cardiac events. Exercise is effective in modifying cardiovascular risk by enhancing endothelial function, although the amount necessary to see benefits is not clear. The first aim was to examine the effects of acute exercise to alter endothelial function and nitric oxide metabolites in overweight and sedentary individuals. Twenty-nine subjects were placed into 3 groups (Exercise, Inactive Control, Active Control). Sedentary and overweight subjects were assigned to the Exercise or Inactive Control Group, active normal weight individuals were assigned to the Active Control Group. The Exercise Group (N=15) came to the lab daily and had their resting blood flow, vascular resistance, conductance and peak reactive hyperemia measured in the calf. Measurements were made daily for 3 familiarization sessions and 24-hours following each of the 5 exercise sessions. The Exercise Group performed 60 minutes of cycling exercise for 5 days at 65% of their predicted maximal workload. Exercise was separated into 4 bouts of 15 minutes with 2 minutes of rest between each bout. Blood was drawn daily to determine if exercise altered plasma nitrate + nitrite concentration. These data were compared to the Inactive Control Group (N=5) who came to the lab for 6 consecutive days. The subjects in the Active Control Group (N=9) had 3 days of criterion measures to compare baseline differences with the Exercise Group. At baseline the Active Group had significantly lower mean arterial pressure and greater peak reactive hyperemia and nitric oxide metabolites than the Exercise and Inactive Control Groups. There were no significant main effects for time (5 days of exercise) or group (Exercise vs. Inactive Control) and no interaction of group vs. time. Thus, 5 days of exercise is not sufficient to alter calf vascular function or nitric oxide metabolites in sedentary overweight individuals. The second aim of this dissertation was to examine how 5 days of rest following the cessation of exercise would alter calf reactive hyperemia and nitric oxide metabolites. Following the exercise protocol, subjects were inactive for 5 consecutive days. There were no significant changes in criterion measures on any of the rest days