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1.  High-dimensional immune profiling of total and rotavirus VP6-specific intestinal and circulating B cells by mass cytometry 
Mucosal immunology  2015;9(1):68-82.
In-depth phenotyping of human intestinal antibody secreting cells (ASCs) and their precursors is important for developing improved mucosal vaccines. We used single-cell mass cytometry to simultaneously analyze 34 differentiation and trafficking markers on intestinal and circulating B cells. In addition, we labeled rotavirus double-layered particles with a metal isotope and characterized B cells specific to the rotavirus VP6 major structural protein. We describe the heterogeneity of the intestinal B cell compartment, dominated by ASCs with some phenotypic and transcriptional characteristics of long-lived plasma cells. Using principal component analysis, we visualized the phenotypic relationships between major B cell subsets in the intestine and blood, and revealed that IgM+ memory B cells (MBCs) and naïve B cells were phenotypically related as were CD27− MBCs and switched MBCs. ASCs in the intestine and blood were highly clonally related, but associated with distinct trajectories of phenotypic development. VP6-specific B cells were present among diverse B cell subsets in immune donors, including naïve B cells, with phenotypes representative of the overall B cell pool. These data provide a high dimensional view of intestinal B cells and the determinants regulating humoral memory to a ubiquitous, mucosal pathogen at steady-state.
PMCID: PMC4618273  PMID: 25899688
Human intestinal B cells; mass cytometry; rotavirus
2.  Effect of Vagal Nerve Blockade on Moderate Obesity with an Obesity-Related Comorbid Condition: the ReCharge Study 
Obesity Surgery  2016;26:983-989.
Vagal nerve blockade (vBloc) therapy was shown to be a safe and effective treatment for moderate to severe obesity. This report summarizes the safety and efficacy of vBloc therapy in the prespecified subgroup of patients with moderate obesity.
The ReCharge Trial is a double-blind, randomized controlled clinical trial of participants with body mass index (BMI) of 40–45 or 35–40 kg/m2 with at least one obesity-related comorbid condition. Participants were randomized 2:1 to implantation with either a vBloc or sham device with weight management counseling. Eighty-four subjects had moderate obesity (BMI 35–40 kg/m2) at randomization.
Fifty-three participants were randomized to vBloc and 31 to sham. Qualifying obesity-related comorbidities included dyslipidemia (73 %), hypertension (58 %), sleep apnea (33 %), and type 2 diabetes (8 %). The vBloc group achieved a percentage excess weight loss (%EWL) of 33 % (11 % total weight loss (%TWL)) compared to 19 % EWL (6 % TWL) with sham at 12 months (treatment difference 14 percentage points, 95 % CI, 7–22; p < 0.0001). Common adverse events of vBloc through 12 months were heartburn/dyspepsia and implant site pain; the majority of events were reported as mild or moderate.
vBloc therapy resulted in significantly greater weight loss than the sham control among participants with moderate obesity and comorbidities with a well-tolerated safety profile.
PMCID: PMC4831996  PMID: 27048437
Vagal nerve blocking; Obesity; Moderate obesity; Active implantable medical device; Bariatric surgery; Laparoscopic surgery; Randomized controlled trial
3.  The Human Gut Microbiome 
JAMA surgery  2013;148(6):563-569.
Recent advances in parallel genomic processing and computational mapping have been applied to the native human microbial environment to provide a new understanding of the role of the microbiome in health and disease. In particular, studies of the distal gut microbiome have proposed that changes in gut microbiota are related to obesity, the metabolic syndrome, and Western diet. We examined the changes in the distal gut microbiome composition as it relates to the lean and obese phenotypes, particularly after surgical weight loss. A PubMed search of publications from January 1, 2005, through December 31, 2012, used the search terms weight, obesity, microbiome, and bariatric surgery. We included studies that provided information on subjects' weight and/or body mass index and a formal assessment of the microbiome. Certain bacteria, specifically the archaeon Methanobrevibacter smithii, have enhanced ability to metabolize dietary substrate, thereby increasing host energy intake and weight gain. With weight loss, there is a decrease in the ratio of Firmicutes to Bacteroidetes phyla. One major finding from microbial sequencing analyses after Roux-en-Y gastric bypass is the comparative overabundance of Proteobacteria in the distal gut microbiome, which is distinct from the changes seen in weight loss without Roux-en-Y gastric bypass. This review provides the practicing surgeon with (1) an update on the state of a rapidly innovating branch of clinical bioinformatics, specifically, the microbiome; (2) a new understanding of the microbiome changes after Roux-en-Y gastric bypass and weight loss; and (3) a basis for understanding further clinical applications of studies of the distal gut microbiome, such as in Crohn disease, ulcerative colitis, and infectious colitis.
PMCID: PMC4392891  PMID: 23571517
4.  Resolution of acute gastroenteritis symptoms in children and adults treated with a novel polyphenol-based prebiotic 
World Journal of Gastroenterology : WJG  2014;20(34):12301-12307.
AIM: To test efficacy and durability of a polyphenol-based prebiotic treatment for acute gastroenteritis in a 300 patient double-blinded clinical study.
METHODS: A two-arm randomized, double-blinded, placebo-controlled clinical study was conducted at two public health centers in Managua, Nicaragua. Potential subjects who qualified based on inclusion and exclusion criteria were randomly assigned to one of two treatment arms. Two thirds of the subjects (n = 200) received a single titrated 0.5-2 ounce liquid dose of a novel polyphenol-based prebiotic (AlivaTM) diluted with 2 to eight ounces of oral rehydration solution (ORS). One third of the subjects (n = 100) were randomized to receive two liquid ounces of a taste and color-matched placebo diluted in eight ounces of ORS. The outcome variables measured included stool consistency, stomach discomfort, gas and bloating, and heartburn/indigestion. The study subjects ranked their stool consistency and the severity of their subjective symptoms at specified intervals from immediately prior to treatment, to five days post treatment. All subjects recorded their symptoms in a study diary. The study subjects also recorded the time and consistencies of all stools in their study diary. Stool consistency was compared to the picture and descriptions on the Bristol Stool Chart, and any stool rated greater than Type 4 was considered unformed. The clinical study team reviewed the study diaries with subjects during daily follow-up calls and close-out visits, and recorded the data in case report forms.
RESULTS: After receiving a single dose, Aliva treated subjects reported shorter median time to their last unformed stool (1 h 50 min) than placebo treated subjects (67 h 50 min.), a statistically significant difference [95%CI: -3178-(-2018), P = 0.000]. Aliva treated subjects also reported shorter median their time to last unformed stool (TTLUS) (1hrs 50 min) than placebo treated subjects (67 h 50 min), which was also a statistically significant difference (P = 0.000).The percentage of subjects recording TTLUS was greater for those who received Aliva vs placebo at 30 min (P = 0.027), 2 h (P = 0.000), 24 h (P = 0.000), 48 h (P = 0.000), 72 h (P = 0.000), and 5 d (P = 0.000) post dose. There were 146 study subjects 14 years old or older, which was the criteria set for reliable self-reporting of subjective symptoms. Of those 146 subjects, 142 reported stomach pain and discomfort during screening. From 90 minutes [95%CI: -1.8-(-0.01), P = 0.048] through 5 d [95%CI: -3.4-(-1.9), P = 0.000), the subjects treated with Aliva experienced significantly less stomach pain and discomfort than those who received placebo. Of those same 146 participants, 114 subjects reported gas and bloating during screening. Similarly, subjects who received Aliva experienced significantly less gas and bloating from 2 h [95%CI: -1.7-(-0.39), P = 0.030] through 5 d (95%CI: -2.0-0.42, P = 0.005) compared with the placebo arm.
CONCLUSION: In this double-blind, randomized clinical study, subjects with acute gastroenteritis receiving Aliva prebiotic showed significant and sustained improvement of multiple symptoms vs those receiving placebo.
PMCID: PMC4161816  PMID: 25232265
Prebiotic; Gastroenteritis; Diarrhea; Rotavirus; Infant Mortality; Dehydration; Heartburn; Polyphenol; Aliva; Greenteaspoon
5.  Metabolic surgery: action via hormonal milieu changes, changes in bile acids or gut microbiota? A summary of the literature 
Obesity and type 2 diabetes remain epidemic problems. Different bariatric surgical techniques causes weight loss and diabetes remission to varying degrees. The underlying mechanisms of the beneficial effects of bariatric surgery are complex, and include changes in diet and behavior, as well as changes in hormones, bile acid flow, and gut bacteria. We summarized the effects of multiple different bariatric procedures, and their resulting effects on several hormones (leptin, ghrelin, adiponectin, glucagon-like peptide 1 (GLP-1), peptide YY, and glucagon), bile acid changes in the gut and the serum, and resulting changes to the gut microbiome. As much as possible, we have tried to incorporate multiple studies to try to explain underlying mechanistic changes. What emerges from the data is a picture of clear differences between restrictive and metabolic procedures. The latter, in particular the roux-en-Y gastric bypass, induces large and distinctive changes in most measured fat and gut hormones, including early and sustained increase in GLP-1, possible through intestinal bile acid signaling. The changes in bile flow and the gut microbiome are causally inseparable so far, but new studies show that each contributes to the effects of weight loss and diabetes resolution.
PMCID: PMC4399638  PMID: 25194186
Bariatric surgery; RYGB; hormone; bile acid; microbiome
6.  Relationship between Patient Safety and Hospital Surgical Volume 
Health Services Research  2011;47(2):756-769.
To examine the relationship between hospital volume and in-hospital adverse events.
Data Sources
Patient safety indicator (PSI) was used to identify hospital-acquired adverse events in the Nationwide Inpatient Sample database in abdominal aortic aneurysm, coronary artery bypass graft, and Roux-en-Y gastric bypass from 2005 to 2008.
Study Design
In this observational study, volume thresholds were defined by mean year-specific terciles. PSI risk-adjusted rates were analyzed by volume tercile for each procedure.
Principal Findings
Overall, hospital volume was inversely related to preventable adverse events. High-volume hospitals had significantly lower risk-adjusted PSI rates compared to lower volume hospitals (p < .05).
These data support the relationship between hospital volume and quality health care delivery in select surgical cases. This study highlights differences between hospital volume and risk-adjusted PSI rates for three common surgical procedures and highlights areas of focus for future studies to identify pathways to reduce hospital-acquired events.
PMCID: PMC3419887  PMID: 22091561
Patient safety indicators; adverse events; hospital surgical volume
7.  What Variables are Associated with Successful Weight Loss Outcomes for Bariatric Surgery After One Year? 
Prior evidence indicates that predictors of weight loss outcomes after gastric bypass surgery fall within 5 domains: 1) presurgical factors; 2) postsurgical psychosocial variables (e.g., support group attendance); 3) postsurgical eating patterns; 4) postsurgical physical activity; and 5) follow-up at postsurgical clinic. However, little data exist on which specific behavioral predictors are most associated with successful outcomes (e.g., ≥50% excess weight loss) when considering the 5 domains simultaneously.
Specify the behavioral variables, and their respective cutoff points, most associated with successful weight loss outcomes.
On-line survey.
Signal Detection Analysis evaluated associations between 84 pre-and postsurgical behavioral variables (within the 5 domains) and successful weight loss at ≥1 year in 274 post-gastric bypass surgery patients.
Successful weight loss was highest (92.6%) among those reporting dietary adherence of >3 on a 9 point scale (median=5) who grazed no more than once-per-day. Among participants reporting dietary adherence <3 and grazing daily or less, success rates more than doubled when highest lifetime Body Mass Index was <53.7 kg/m2. Success rates also doubled for participants with dietary adherence =3 if attending support groups. No variables from the physical activity or postsurgical follow-up domains were significant, nor were years since surgery. The overall model’s sensitivity =.62, specificity =.92.
To our knowledge, this is the first study to simultaneously consider the relative contribution of behavioral variables within 5 domains and offer clinicians an assessment algorithm identifying cut-off points for behaviors most associated with successful postsurgical weight loss. Such data may inform prospective study designs and postsurgical interventions.
PMCID: PMC4125556  PMID: 24913590
bariatric surgery; postoperative eating behaviors; weight loss outcome; signal detection analysis
8.  Is Patient Safety Improving? National Trends in Patient Safety Indicators: 1998–2007 
Health Services Research  2012;47(1 Pt 2):414-430.
Emphasis has been placed on quality and patient safety in medicine; however, little is known about whether quality over time has actually improved in areas such as patient safety indicators (PSIs).
To determine whether national trends for hospital PSIs have improved from 1998 to 2007.
Design, Setting, and Participants
Using PSI criteria from the Agency for Healthcare Research and Quality, PSIs were identified in the Nationwide Inpatient Sample (NIS) for all eligible inpatient admissions between 1998 and 2007. Joinpoint regression was used to estimate annual percentage changes (APCs) for PSIs.
Main Outcome Measure
Annual percent change for PSIs.
From 1998 to 2007, 7.6 million PSI events occurred for over 69 million hospitalizations. A total of 14 PSIs showed statistically significant trends. Seven PSIs had increasing APC: postoperative pulmonary embolism or deep vein thrombosis (8.94), postoperative physiological or metabolic derangement (7.67), postoperative sepsis (7.17), selected infections due to medical care (4.05), decubitus ulcer (3.05), accidental puncture or laceration (2.64), and postoperative respiratory failure (1.46). Seven PSIs showed decreasing APCs: birth trauma injury to neonate (−17.79), failure to rescue (−6.05), postoperative hip fracture (−5.86), obstetric trauma–vaginal without instrument (−5.69), obstetric trauma–vaginal with instrument (−4.11), iatrogenic pneumothorax (−2.5), and postoperative wound dehiscence (−1.8).
This is the first study to establish national trends of PSIs during the past decade indicating areas for potential quality improvement prioritization. While many factors influence these trends, the results indicate opportunities for either emulation or elimination of current patient safety trends.
PMCID: PMC3393002  PMID: 22150789
Patient safety; quality; trends, outcomes, national
10.  Prevalence of congenital hereditary sensorineural deafness in Australian Cattle Dogs and associations with coat characteristics and sex 
Congenital hereditary sensorineural deafness (CHSD) occurs in many dog breeds, including Australian Cattle Dogs. In some breeds, CHSD is associated with a lack of cochlear melanocytes in the stria vascularis, certain coat characteristics, and potentially, abnormalities in neuroepithelial pigment production. This study investigates phenotypic markers for CHSD in 899 Australian Cattle Dogs.
Auditory function was tested in 899 Australian Cattle Dogs in family groups using brainstem auditory evoked response testing. Coat colour and patterns, facial and body markings, gender and parental hearing status were recorded.
Deafness prevalence among all 899 dogs was 10.8% with 7.5% unilaterally deaf, and 3.3% bilaterally deaf, and amongst pups from completely tested litters (n = 696) was 11.1%, with 7.5% unilaterally deaf, and 3.6% bilaterally deaf.
Univariable and multivariable analyses revealed a negative association between deafness and bilateral facial masks (odds ratio 0.2; P ≤ 0.001). Using multivariable logistic animal modelling, the risk of deafness was lower in dogs with pigmented body spots (odds ratio 0.4; P = 0.050).
No significant associations were found between deafness and coat colour.
Within unilaterally deaf dogs with unilateral facial masks, no association was observed between the side of deafness and side of mask. The side of unilateral deafness was not significantly clustered amongst unilaterally deaf dogs from the same litter. Females were at increased risk of deafness (odds ratio from a logistic animal model 1.9; P = 0.034) after adjusting for any confounding by mask type and pigmented body spots.
Australian Cattle Dogs suffer from CHSD, and this disease is more common in dogs with mask-free faces, and in those without pigmented body patches. In unilaterally deaf dogs with unilateral masks, the lack of observed association between side of deafness and side of mask suggests that if CHSD is due to defects in molecular pigment pathways, the molecular control of embryonic melanoblast migration from ectoderm to skin differs from control of migration from ectoderm to cochlea. In Australian Cattle Dogs, CHSD may be more common in females.
PMCID: PMC3489614  PMID: 23107143
11.  Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin ▿  
Journal of Virology  2010;84(9):4543-4555.
We have shown previously that rotavirus (RV) can infect murine intestinal B220+ cells in vivo (M. Fenaux, M. A. Cuadras, N. Feng, M. Jaimes, and H. B. Greenberg, J. Virol. 80:5219-5232, 2006) and human blood B cells in vitro (M. C. Mesa, L. S. Rodriguez, M. A. Franco, and J. Angel, Virology 366:174-184, 2007). However, the effect of RV on B cells, especially those present in the human intestine, the primary site of RV infection, is unknown. Here, we compared the effects of the in vitro RV infection of human circulating (CBC) and intestinal B cells (IBC). RV infected four times more IBC than CBC, and in both types of B cells the viral replication was highly restricted to the memory subset. RV induced cell death in 30 and 3% of infected CBC and IBC, respectively. Moreover, RV induced activation and differentiation into antibody-secreting cells (ASC) of CBC but not IBC when the B cells were present with other mononuclear cells. However, RV did not induce these effects in purified CBC or IBC, suggesting the participation of other cells in activating and differentiating CBC. RV infection was associated with enhanced interleukin-6 (IL-6) production by CBC independent of viral replication. The infection of the anti-B-cell receptor, lipopolysaccharide, or CpG-stimulated CBC reduced the secretion of IL-6 and IL-8 and decreased the number of ASC. These inhibitory effects were associated with an increase in viral replication and cell death and were observed in polyclonally stimulated CBC but not in IBC. Thus, RV differentially interacts with primary human B cells depending on their tissue of origin and differentiation stage, and it affects their capacity to modulate the local and systemic immune responses.
PMCID: PMC2863723  PMID: 20164228

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