Faculty Bibliography

Early childhood is a critical stage for the foundation and development of both the microbiome and host. Early-life antibiotic exposures, cesarean section, and formula feeding could disrupt microbiome establishment and adversely affect health later in life. We profiled microbial development during the first 2 years of life in a cohort of 43 U.S. infants and identified multiple disturbances associated with antibiotic exposures, cesarean section, and formula feeding. These exposures contributed to altered establishment of maternal bacteria, delayed microbiome development, and altered alpha-diversity. These findings illustrate the complexity of early-life microbiome development and its sensitivity to perturbation.

BACKGROUND: Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are serious health concerns, especially in Western populations. Antibiotic exposure and high-fat diet (HFD) are important and modifiable factors that may contribute to these diseases. METHODS: To investigate the relationship of antibiotic exposure with microbiome perturbations in a murine model of growth promotion, C57BL/6 mice received lifelong sub-therapeutic antibiotic treatment (STAT), or not (control), and were fed HFD starting at 13 weeks. To characterize microbiota changes caused by STAT, the V4 region of the 16S rRNA gene was examined from collected fecal samples and analyzed. RESULTS: In this model, which included HFD, STAT mice developed increased weight and fat mass compared to controls. Although results in males and females were not identical, insulin resistance and NAFLD were more severe in the STAT mice. Fecal microbiota from STAT mice were distinct from controls. Compared with controls, STAT exposure led to early conserved diet-independent microbiota changes indicative of an immature microbial community. Key taxa were identified as STAT-specific and several were found to be predictive of disease. Inferred network models showed topological shifts concurrent with growth promotion and suggest the presence of keystone species. CONCLUSIONS: These studies form the basis for new models of type 2 diabetes and NAFLD that involve microbiome perturbation.

The etiology of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder characterized by progressive muscle weakness and spasticity, remains largely unknown. Approximately 5-10% of cases are familial, and of those, 15-20% are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Mutations of the SOD1 gene interrupt cellular homeostasis and contribute to cellular toxicity evoked by the presence of altered SOD1, along with other toxic species, such as advanced glycation end products (AGEs). AGEs trigger activation of their chief cell surface receptor, RAGE (receptor for advanced glycation end products), and induce RAGE-dependent cellular stress and inflammation in neurons, thereby affecting their function and leading to apoptosis. Here, we show for the first time that the expression of RAGE is higher in the SOD1 transgenic mouse model of ALS vs. wild-type mouse spinal cord. We tested whether pharmacological blockade of RAGE may delay the onset and progression of disease in this mouse model. Our findings reveal that treatment of SOD1 transgenic mice with soluble RAGE (sRAGE), a natural competitor of RAGE that sequesters RAGE ligands and blocks their interaction with cell surface RAGE, significantly delays the progression of ALS and prolongs life span compared to vehicle treatment. We demonstrate that in sRAGE-treated SOD1 transgenic animals at the final stage of the disease, a significantly higher number of neurons and lower number of astrocytes is detectable in the spinal cord. We conclude that RAGE antagonism may provide a novel therapeutic strategy for ALS intervention.

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

PURPOSE: Delivering the recommended care is an important quality measure that has been insufficiently studied in urology. Obstructive pyelonephritis is a suitable case study for this focus because many patients do not receive such care, although guidelines advocate decompression. We determined the influence of hospital factors, particularly familiarity with urolithiasis, on the likelihood of decompression in such patients. MATERIALS AND METHODS: We used the NIS from 2002 to 2011 to retrospectively identify patients admitted to community hospitals with severe infection and ureteral calculi. Hospital familiarity with nephrolithiasis was estimated by calculating hospital stone volume (divided into quartiles) and hospital treatment intensity (the decompression rate in patients with ureteral calculi and no infection). After calculating national estimates we performed logistic regression to determine the association between the receipt of decompression and hospital stone volume, controlling for treatment intensity and other covariates thought to be associated with receiving recommended care. RESULTS: Of an estimated 107,848 patients with obstructive pyelonephritis 27.4% failed to undergo decompression. Discrepancies were greatest between hospitals with the highest and lowest stone volumes (76% vs 25%, OR 2.77, 95% CI 1.94-3.96, p <0.01) as well as high and low treatment intensity (78% vs 37%, p <0.01). CONCLUSIONS: High hospital stone volume and treatment intensity were associated with an increased likelihood of receiving decompression. Such findings might be useful to identify hospitals and regions where access to quality urological care should be augmented.

BACKGROUND: Case managers are employed in medical homes to coordinate care for clinically complex patients. OBJECTIVE: To measure the association of patient perceptions of case manager performance with overall satisfaction and subsequent health care utilization. DESIGN: Retrospective cohort study. SETTING: Integrated health system in Pennsylvania. PATIENTS: Members of the health system-owned health plan who 1) received primary care in the health system's clinics, 2) were exposed to clinic-embedded case managers, and 3) completed a survey of satisfaction with care. MEASUREMENTS: Survey assessment of case manager performance and overall satisfaction with care and claims-based assessment of case manager performance and subsequent hospitalizations or emergency department visits. Survey measures were dichotomized into very good versus less than very good. RESULTS: A total of 1755 patients (44%) completed the survey and 1415 met study criteria. Survey respondents who reported very good ratings of case manager performance across all items had a higher probability of reporting very good overall satisfaction with care (92.2% vs. 62.5%; P < 0.001) and had a lower incidence of subsequent emergency department visits (incidence rate ratio, 0.79 [95% CI, 0.64 to 0.98]; P = 0.029) but not hospitalizations (incidence rate ratio, 0.92 [CI, 0.75 to 1.11]; P = 0.37) up to 2 years after the survey compared with survey respondents who reported less-than-very good case manager performance on 1 or more questions on the survey. LIMITATIONS: Satisfaction data demonstrated substantial ceiling effects. Survey nonresponse may have introduced bias in the results. CONCLUSION: Patients' favorable perceptions of case managers are associated with higher overall satisfaction with care and may lower risk for future acute care use. PRIMARY FUNDING SOURCE: Robert Wood Johnson Foundation and the U.S. Department of Veterans Affairs.

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:

BACKGROUND: The surgical robot has been widely adopted in the United States in spite of its high cost and controversy surrounding its benefit. Some have suggested that a "medical arms race" influences technology adoption. We wanted to determine whether a hospital would acquire a surgical robot if its nearest neighboring hospital already owned one. METHODS: We identified 554 hospitals performing radical prostatectomy from the Healthcare Cost and Utilization Project Statewide Inpatient Databases for seven states. We used publicly available data from the website of the surgical robot's sole manufacturer (Intuitive Surgical, Sunnyvale, CA) combined with data collected from the hospitals to ascertain the timing of robot acquisition during year 2001 to 2008. One hundred thirty four hospitals (24%) had acquired a surgical robot by the end of 2008. We geocoded the address of each hospital and determined a hospital's likelihood to acquire a surgical robot based on whether its nearest neighbor owned a surgical robot. We developed a Markov chain method to model the acquisition process spatially and temporally and quantified the "neighborhood effect" on the acquisition of the surgical robot while adjusting simultaneously for known confounders. RESULTS: After adjusting for hospital teaching status, surgical volume, urban status and number of hospital beds, the Markov chain analysis demonstrated that a hospital whose nearest neighbor had acquired a surgical robot had a higher likelihood itself acquiring a surgical robot. (OR=1.71, 95% CI: 1.07-2.72, p=0.02). CONCLUSION: There is a significant spatial and temporal association for hospitals acquiring surgical robots during the study period. Hospitals were more likely to acquire a surgical robot during the robot's early adoption phase if their nearest neighbor had already done so.

In mammals, changes in the metabolic state, including obesity, fasting, cold challenge and high fat diets activate complex immune responses. In many strains of rodents, high fat diets induce a rapid systemic inflammatory response and lead to obesity. Little is known about the molecular signals required for high fat diet (HFD)-induced phenotypes. Here we studied the function of the receptor for advanced glycation products (RAGE) in the development of phenotypes associated with high fat feeding in mice. RAGE is highly expressed on immune cells, including macrophages. High fat feeding induced expression of RAGE ligand HMGB1 and carboxy methyl lysine (CML)-advanced glycation endproducts (AGE) epitopes in liver and adipose tissue. Genetic deficiency of RAGE prevented the effects of HFD on energy expenditure, weight gain, adipose tissue inflammation, and insulin resistance. RAGE deficiency had no effect on genetic forms of obesity caused by impaired melanocortin signaling. Hematopoietic deficiency of RAGE or treatment with soluble RAGE partially protected against peripheral HFD-induced inflammation and weight gain. These data argue that high fat feeding induces peripheral inflammation and weight gain in a RAGE-dependent manner, providing a foothold in the pathways that regulate diet-induced obesity and offering the potential for therapeutic intervention.