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1.  The Performance of Silk Scaffolds in a Rat Model of Augmentation Cystoplasty 
Biomaterials  2013;34(20):4758-4765.
The diverse processing plasticity of silk-based biomaterials offers a versatile platform for understanding the impact of structural and mechanical matrix properties on bladder regenerative processes. Three distinct groups of 3-D matrices were fabricated from aqueous solutions of Bombyx mori silk fibroin either by a gel spinning technique (GS1 and GS2 groups) or a solvent-casting/salt-leaching method in combination with silk film casting (FF group). SEM analyses revealed that GS1 matrices consisted of smooth, compact multi-laminates of parallel-oriented silk fibers while GS2 scaffolds were composed of porous (pore size range, 5–50µm) lamellar-like sheets buttressed by a dense outer layer. Bi-layer FF scaffolds were comprised of porous foams (pore size, ~400 µm) fused on their external face with a homogenous, nonporous silk film. Silk groups and small intestinal submucosa (SIS) matrices were evaluated in a rat model of augmentation cystoplasty for 10 weeks of implantation and compared to cystotomy controls. Gross tissue evaluations revealed the presence of intra-luminal stones in all experimental groups. The incidence and size of urinary calculi was the highest in animals implanted with gel spun silk matrices and SIS with frequencies ≥57% and stone diameters of 3–4mm. In contrast, rats augmented with FF scaffolds displayed substantially lower rates (20%) and stone size (2mm), similar to the levels observed in controls (13%, 2mm). Histological (hematoxylin and eosin, Masson's trichrome) and immunohistochemical (IHC) analyses showed comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites supported by all matrix groups similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent uroplakin and p63 protein expression in all experimental groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by Fox3-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. In comparison to other biomaterial groups, cystometric analyses at 10 weeks post-op revealed that animals implanted with the FF matrix configuration displayed superior urodynamic characteristics including compliance, functional capacity, as well as spontaneous non voiding contractions consistent with control levels. Our data demonstrate that variations in scaffold processing techniques can influence the in vivo functional performance of silk matrices in bladder reconstructive procedures.
PMCID: PMC3676949  PMID: 23545287
silk; bladder tissue engineering; bladder; wound healing
3.  Hydroxyethyl starch in severe sepsis: end of starch era? 
Critical Care  2013;17(2):310.
Expanded abstract
Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Åneman A, Madsen KR, Møller MH, Elkjær JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Søe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjældgaard AL, Fabritius ML, Mondrup F, Pott FC, Møller TP, Winkel P, Wetterslev J; 6S Trial Group; Scandinavian Critical Care Trials Group: Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012, 367:124-34.
Hydroxyethyl starch (HES) is widely used for fluid resuscitation in ICUs, but its safety and efficacy have not been established in patients with severe sepsis.
To assess the effects of HES 130/0.4 compared with a balanced crystalloid solution on mortality and end-stage kidney failure in patients with severe sepsis.
Multicenter, parallel-group, blinded, randomized clinical trial, in patients with severe sepsis.
Patients with severe sepsis admitted to the ICU received fluid resuscitation with either 6% HES 130/0.42 (Tetraspan) or Ringer's acetate at a dose of up to 33 ml per kilogram of ideal body weight per day.
Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer's acetate (relative risk, 1.17; 95% confidence interval (CI), 1.01 to 1.36; P = 0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal replacement therapy versus 65 patients (16%) assigned to Ringer's acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P = 0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P = 0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.
Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal replacement therapy compared with those receiving Ringer's acetate.
PMCID: PMC3672539  PMID: 23509901
4.  The Department of Veterans Affairs National Quality Scholars Fellowship Program 
The Department of Veterans Affairs National Quality Scholars Fellowship Program (VAQS) was established in 1998 as a post-graduate medical education fellowship to train physicians in new methods of improving the quality and safety of health care for Veterans and the nation. The VAQS curriculum is based on adult learning theory, with a national core curriculum of face-to-face components, technologically mediated distance learning components, and a unique local curriculum that draws from the strengths of regional resources.
VAQS has established strong ties with other VA programs. Fellows’ research and projects are integrated with local and regional VA leaders’ priorities, enhancing the relevance and visibility of the fellows’ efforts and promoting recruitment of fellows to VA positions.
VAQS has enrolled 96 fellows from 1999 to 2008; 75 have completed the program and 11 are currently enrolled. Fellowship graduates have pursued a variety of career paths: 20% are continuing training (most in VA); 32% hold a VA faculty/staff position; 63% are academic faculty; and 80% conduct clinical or research work related to health care improvement. Graduates have held leadership positions in VA, Department of Defense, and public health.
Combining knowledge about the improvement of health care with adult learning strategies, distance learning technologies, face-to-face meetings, local mentorship, and experiential projects has been successful in improving care in VA and preparing physicians to participate in, study, and lead the improvement of health care quality and safety.
PMCID: PMC3800745  PMID: 19940583
5.  Quality of Diabetes Mellitus Care by Rural Primary Care Physicians 
To explore the relationship between degree of rurality and glucose (hemoglobin A1c), blood pressure (BP), and lipid (LDL) control among patients with diabetes.
Descriptive study; 1,649 patients in 205 rural practices in the United States. Patients’ residence ZIP codes defined degree of rurality (Rural-Urban Commuting Areas codes). Outcomes were measures of acceptable control (A1c <= 9%, BP < 140/90 mmHg, LDL < 130 mg/dL) and optimal control (A1c < 7%, BP < 130/80 mmHg, LDL < 100 mg/dL). Statistical significance was set at P < .008 (Bonferroni’s correction).
Although the proportion of patients with reasonable A1c control worsened by increasing degree of rurality, the differences were not statistically significant (urban 90%, large rural 88%, small rural 85%, isolated rural 83%; P = .10); mean A1c values also increased by degree of rurality, although not statistically significant (urban 7.2 [SD 1.6], large rural 7.3 [SD 1.7], small rural 7.5 [SD1.8], isolated rural 7.5 [SD1.9]; P = .16). We observed no differences between degree of rural and reasonable BP or LDL control (P = .42, P = .23, respectively) or optimal A1c or BP control (P = .52, P = .65, respectively). Optimal and mean LDL values worsened as rurality increased (P = .08, P = .029, respectively).
In patients with diabetes who seek care in the rural Southern US, we observed no relationship between degree of rurality of patients’ residence and traditional measures of quality of care. Further examination of the trends and explanatory factors for relative worsening of metabolic control by increasing degree of rurality is warranted.
PMCID: PMC3481192  PMID: 23083082
family medicine; health disparities; internal medicine; medical care; quality
6.  Buyers Beware: Lead Poisoning due to Ayurvedic Medicine 
Journal of General Internal Medicine  2012;27(10):1384-1386.
A 29-year-old man, who recently emigrated from India, presented with a 2-week history of abdominal pain, as well as nausea, constipation, and fatigue. He underwent removal of a parathyroid adenoma 6 weeks prior to admission and received a locally made Indian traditional medicine (Ayurveda) for pain control; however, this information was not initially available. He was instructed to take approximately 15 g/day. Initial evaluation revealed a normocytic anemia, but other workup including imaging and endoscopy was unrevealing. Given his recent use of Ayurvedic medicines, we tested for lead poisoning and found a blood lead level of 72 mcg/dl. We sent his medicine for analysis and found it had a high lead concentration of 36,000 mcg/g, which is over 25,000 times the maximum daily dose. He improved with cessation of the medicine and treatment with succimer. Lead poisoning can present with a variety of nonspecific signs and symptoms, including abdominal pain and anemia. Ayurvedic medicines, as well as traditional medicines from other cultures, may be a source of lead or other heavy metals. It is essential for physicians to be aware of adverse effects of Ayurvedic medicines as they are easily available and increasing in popularity.
PMCID: PMC3445671  PMID: 22476953
dietary supplements; lead; India; medicine; Ayurvedic; Phytotherapy; plant extracts/chemistry
7.  Use of Ecological Momentary Assessment to Determine Which Structural Factors Impact Perceived Teaching Quality of Attending Rounds 
Providing high-quality teaching to residents during attending rounds is challenging. Reasons include structural factors that affect rounds, which are beyond the attending's teaching style and control.
To develop a new evaluation tool to identify the structural components of ward rounds that most affect teaching quality in an internal medicine (IM) residency program.
The authors developed a 10-item Ecological Momentary Assessment (EMA) tool and collected daily evaluations for 18 months from IM residents rotating on inpatient services. Residents ranked the quality of teaching on rounds that day, and questions related to their service (general medicine, medical intensive care unit, and subspecialty services), patient census, absenteeism of team members, call status, and number of teaching methods used by the attending.
Residents completed 488 evaluation cards over 18 months. This found no association between perceived teaching quality and training level, team absenteeism, and call status. We observed differences by service (P < .001) and patient census (P  =  .009). After adjusting for type of service, census was no longer significant. Use of a larger variety of teaching methods was associated with higher perceived teaching quality, regardless of service or census (P for trend < .001).
The EMA tool successfully identified that higher patient census was associated with lower perceived teaching quality, but the results were also influenced by the type of teaching service. We found that, regardless of census or teaching service, attendings can improve their teaching by diversifying the number of methods used in daily rounds.
PMCID: PMC3444185  PMID: 23997876
8.  Evaluation of Gel Spun Silk-Based Biomaterials in a Murine Model of Bladder Augmentation 
Biomaterials  2010;32(3):808-818.
Currently, gastrointestinal segments are considered the gold standard for bladder reconstructive procedures. However, significant complications including chronic urinary tract infection, metabolic abnormalities, urinary stone formation, bowel dysfunction, and secondary malignancies are associated with this approach. Biomaterials derived from silk fibroin may represent a superior alternative due their robust mechanical properties, biodegradable features, and processing plasticity. In the present study, we evaluated the efficacy of a gel spun silk-based matrix for bladder augmentation in a murine model. Over the course of 70 d implantation period, H&E and Masson’s trichrome (MTS) analysis revealed that silk matrices were capable of supporting both urothelial and smooth muscle regeneration at the defect site. Prominent uroplakin and contractile protein expression (α-actin, calponin, and SM22α) was evident by immunohistochemical analysis demonstrating maturation of the reconstituted bladder wall compartments. Gel spun silk matrices also elicited a minimal acute inflammatory reaction following 70 d of bladder integration, in contrast to parallel assessments of small intestinal submucosa (SIS) and polyglycolic acid (PGA) matrices which routinely promoted evidence of fibrosis and chronic inflammatory responses. Voided stain on paper analysis revealed that silk augmented animals displayed similar voiding patterns in comparison to non surgical controls by 42 d of implantation. In addition, cystometric evaluations of augmented bladders at 70 d post-op demonstrated that silk scaffolds supported significant increases in bladder capacity, voided volume, and flow rate while maintaining similar degrees of compliance relative to the control group. These results provide evidence for the utility of gel spun silk-based matrices for functional bladder tissue engineering applications.
PMCID: PMC3742077  PMID: 20951426
silk; bladder tissue engineering; smooth muscle cell; SIS; Polyglycolic acid
9.  A 60-Year-Old Woman with Chorea and Weight Loss 
PMCID: PMC3358395  PMID: 22143453
diagnostic reasoning; clinical problem solving; dual process theory; illness scripts; chorea; paraneoplastic syndrome
10.  Evaluation of Silk Biomaterials in Combination with Extracellular Matrix Coatings for Bladder Tissue Engineering with Primary and Pluripotent Cells 
PLoS ONE  2013;8(2):e56237.
Silk-based biomaterials in combination with extracellular matrix (ECM) coatings were assessed as templates for cell-seeded bladder tissue engineering approaches. Two structurally diverse groups of silk scaffolds were produced by a gel spinning process and consisted of either smooth, compact multi-laminates (Group 1) or rough, porous lamellar-like sheets (Group 2). Scaffolds alone or coated with collagen types I or IV or fibronectin were assessed independently for their ability to support attachment, proliferation, and differentiation of primary cell lines including human bladder smooth muscle cells (SMC) and urothelial cells as well as pluripotent cell populations, such as murine embryonic stem cells (ESC) and induced pluripotent stem (iPS) cells. AlamarBlue evaluations revealed that fibronectin-coated Group 2 scaffolds promoted the highest degree of primary SMC and urothelial cell attachment in comparison to uncoated Group 2 controls and all Group 1 scaffold variants. Real time RT-PCR and immunohistochemical (IHC) analyses demonstrated that both fibronectin-coated silk groups were permissive for SMC contractile differentiation as determined by significant upregulation of α-actin and SM22α mRNA and protein expression levels following TGFβ1 stimulation. Prominent expression of epithelial differentiation markers, cytokeratins, was observed in urothelial cells cultured on both control and fibronectin-coated groups following IHC analysis. Evaluation of silk matrices for ESC and iPS cell attachment by alamarBlue showed that fibronectin-coated Group 2 scaffolds promoted the highest levels in comparison to all other scaffold formulations. In addition, real time RT-PCR and IHC analyses showed that fibronectin-coated Group 2 scaffolds facilitated ESC and iPS cell differentiation toward both urothelial and smooth muscle lineages in response to all trans retinoic acid as assessed by induction of uroplakin and contractile gene and protein expression. These results demonstrate that silk scaffolds support primary and pluripotent cell responses pertinent to bladder tissue engineering and that scaffold morphology and fibronectin coatings influence these processes.
PMCID: PMC3567020  PMID: 23409160
11.  Selecting the Best Clinical Vignettes for Academic Meetings: Should the Scoring Tool Criteria be Modified? 
The performance of scoring tools to select clinical vignettes for presentation at academic meetings has never been assessed.
To measure the psychometric properties of two scoring tools used to select clinical vignettes and to determine which elements are most helpful.
Prospective observational study.
Participants submitting clinical vignette abstracts, Society of General Internal Medicine annual meetings (2006–2007).
The 2006 scoring tool had three criteria (clarity, significance, and relevance) with brief general descriptors. The 2007 modified tool had five criteria (clarity, significance, relevance, teaching value, and overall assessment) with more detailed descriptors.
A total of 938 clinical vignette abstracts were submitted (484 in 2006; 454 in 2007); 59.5% (n = 288) were accepted for presentation. Cronbach’s alpha was 0.81 for the 2006 three-item tool and 0.95 for the 2007 modified five-item tool. Simplifying the five-item 2007 tool to three items (relevance, teaching value, overall assessment) yielded a Cronbach’s alpha of 0.95. The agreement between the number of clinical vignettes accepted for presentation (2007) using the average score of the five items with the number that would have been accepted using the simplified three items (relevance, teaching value, overall assessment) was almost perfect, with kappa 0.89 (95% confidence interval, 0.85 to 0.93).
Both scoring tools performed well, but a simplified tool with three items (relevance, teaching value, and overall assessment) and detailed descriptors was optimal; the simplified tool could improve the reviewer efficiency and quality of clinical vignettes presented at national meetings.
PMCID: PMC3270243  PMID: 21927965
professional competence; internship and residency; education medical/methods; educational measurement/methods/standards; congresses as topic; reproducibility of results
12.  Draft Genome of Streptomyces tsukubaensis NRRL 18488, the Producer of the Clinically Important Immunosuppressant Tacrolimus (FK506) 
Journal of Bacteriology  2012;194(14):3756-3757.
The macrocyclic polyketide tacrolimus (FK506) is a potent immunosuppressant that prevents T-cell proliferation produced solely by Streptomyces species. We report here the first draft genome sequence of a true FK506 producer, Streptomyces tsukubaensis NRRL 18488, the first tacrolimus-producing strain that was isolated and that contains the full tacrolimus biosynthesis gene cluster.
PMCID: PMC3393489  PMID: 22740677
13.  A multimethod approach for cross-cultural training in an internal medicine residency program 
Medical Education Online  2013;18:10.3402/meo.v18i0.20352.
Cultural competence training in residency is important to improve learners’ confidence in cross-cultural encounters. Recognition of cultural diversity and avoidance of cultural stereotypes are essential for health care providers.
We developed a multimethod approach for cross-cultural training of Internal Medicine residents and evaluated participants’ preparedness for cultural encounters. The multimethod approach included (1) a conference series, (2) a webinar with a national expert, (3) small group sessions, (4) a multicultural social gathering, (5) a Grand Rounds presentation on cross-cultural training, and (6) an interactive, online case-based program.
The program had 35 participants, 28 of whom responded to the survey. Of those, 16 were white (62%), and residents comprised 71% of respondents (n=25). Following training, 89% of participants were more comfortable obtaining a social history. However, prior to the course only 27% were comfortable caring for patients who distrust the US system and 35% could identify religious beliefs and customs which impact care. Most (71%) believed that the training would help them give better care for patients from different cultures, and 63% felt more comfortable negotiating a treatment plan following the course.
Multimethod training may improve learners’ confidence and comfort with cross-cultural encounters, as well as lay the foundation for ongoing learning. Follow-up is needed to assess whether residents’ perceived comfort will translate into improved patient outcomes.
PMCID: PMC3657071  PMID: 23683845
cultural competence; residency education; community resources; web-based curriculum; racial disparities; internal medicine
14.  Preparing for Oral Scientific and Clinical Vignette Presentations 
Little is known about how faculty, residents, and fellows practice for oral presentations at academic meetings. We sought to categorize presenters' practice styles and the impact of feedback.
We surveyed oral presenters at 5 annual academic general internal medicine meetings between 2008 and 2010, using a cross-sectional design. Main measures were frequency and settings of practice, most helpful practice setting, changes made in response to feedback, impact of feedback, and perceived quality of presentation.
The response rate was 63% (333/525 responders). Respondents represented 59 academic medical centers. Presenters reported practicing in a mean ± SD of 2.3 (±1.3) of 5 different settings. Of the 46% of presenters (152/333) who practiced in front of a group of more experienced colleagues, 80% of presenters (122/152) reported it was the most helpful setting. Eighty-one percent of presenters (268/333) practiced alone, and 25% of presenters (82/333) reported practicing alone was the most helpful setting. The mean numbers of change types reported by faculty were fewer than those reported by residents and fellows (mean 2.3 ± 1.8, and 3.1 ± 2.0, respectively; P < .001). Practicing alone was not associated with changes in content (P  =  .30), visual aids (P  =  .12), or delivery style (P  =  .53).
Practicing in front of a group of experienced colleagues was the most helpful setting in which to prepare for an oral academic meeting presentation, but it was not universally utilized. Feedback given at these sessions was more likely to result in changes made to the presentation; however, broader implementation of such sessions 5 require institutional support.
PMCID: PMC3244325  PMID: 23205208
15.  A web-based diabetes intervention for physician: a cluster-randomized effectiveness trial 
To determine the effectiveness of a provider-based education and implementation intervention for improving diabetes control.
Cluster-randomized trial with baseline and follow-up cross sections of diabetes patients in each participating physician's practice.
Eleven US Southeastern states, 2006–08.
Two hundred and five rural primary care physicians.
Multi-component interactive intervention including Web-based continuing medical education, performance feedback and quality improvement tools.
Primary Outcome Measures
‘Acceptable control’ [hemoglobin A1c ≤9%, blood pressure (BP) <140/90 mmHg, low-density lipoprotein cholesterol (LDL) <130 mg/dl] and ‘optimal control’ (A1c <7%, BP <130/80 mmHg, LDL <100 mg/dl).
Of 364 physicians attempting to register, 205 were randomized to the intervention (n= 102) or control arms (n= 103). Baseline and follow-up data were provided by 95 physicians (2127 patients). The proportion of patients with A1c ≤9% was similar at baseline and follow-up in both the control [adjusted odds ratio (AOR): 0.94; 95% confidence interval (CI): 0.61, 1.47] and intervention arms [AOR: 1.16 (95% CI: 0.80, 1.69)]; BP <140/90 mmHg and LDL <130 mg/dl were also similar at both measurement points (P= 0.66, P= 0.46; respectively). We observed no significant effect on diabetes control attributable to the intervention for any of the primary outcome measures. Intervention physicians engaged with the Website over a median of 64.7 weeks [interquartile range (IQR): 45.4–81.8) for a median total of 37 min (IQR: 16–66).
A wide-reach, low-intensity, Web-based interactive multi-component intervention did not improve control of glucose, BP or lipids for patients with diabetes of physicians practicing in the rural Southeastern US.
PMCID: PMC3247785  PMID: 21831967
internet; translational research; diabetes mellitus; rural health services; education; medical; continuing process assessment (Health Care)
CME providers may be interested in identifying effective marketing strategies to direct users to specific content. The use of online advertisements to recruit participants for clinical trials, public health programs, and Continuing Medical Education (CME) has been shown to be effective in some but not all studies. The purpose of this study was to compare the impact of two marketing strategies in the context of an online CME cultural competence curriculum (
In an interrupted time-series quasi-experimental design, two marketing strategies were tested: a) wide dissemination to relevant organizations over a period of approximately four months, and b) Internet paid search using Google Ads (five consecutive eight-week periods--control 1, cultural/ CME advertisement, control 2, hypertension/ content advertisement, control 3). Outcome measures were CME credit requests, Web traffic (visits per day, page views, pages viewed per visit), and cost.
Overall, the site was visited 19,156 times and 78,160 pages were viewed. During the wide dissemination phase, the proportion of visits requesting CME credit decreased between the first (5.3%) and second halves (3.3%) of this phase (p= .04). During the Internet paid search phase, the proportion of visits requesting CME credit was highest during the cultural/ CME advertisement period (control 1, 1.4%; cultural/CME ad, 4.3%; control 2, 1.5%; hypertension/content ad, 0.6%; control 3, 0.8%; p<.001). All measures of Web traffic changed during the Internet paid search phase (p<.01); however, changes were independent of the advertisement periods. The incremental cost for the cultural advertisement per CME credit requested was $0.64US.
Internet advertisement focusing on cultural competence and CME was associated with about a three-fold increase in requests for CME credit at an incremental cost of under $1; however, Web traffic changes were independent of the advertisement strategy.
PMCID: PMC3500657  PMID: 21425356
Marketing; Continuing Medical Education; Internet; Web; Online; Cultural Competence
17.  Important role of CCR2 in a murine model of coronary vasculitis 
BMC Immunology  2012;13:56.
Chemokines and their receptors play a role in the innate immune response as well as in the disruption of the balance between pro-inflammatory Th17 cells and regulatory T cells (Treg), underlying the pathogenesis of coronary vasculitis in Kawasaki disease (KD).
Here we show that genetic inactivation of chemokine receptor (CCR)-2 is protective against the induction of aortic and coronary vasculitis following injection of Candida albicans water-soluble cell wall extracts (CAWS). Mechanistically, both T and B cells were required for the induction of vasculitis, a role that was directly modulated by CCR2. CAWS administration promoted mobilization of CCR2-dependent inflammatory monocytes (iMo) from the bone marrow (BM) to the periphery as well as production of IL-6. IL-6 was likely to contribute to the depletion of Treg and expansion of Th17 cells in CAWS-injected Ccr2+/+ mice, processes that were ameliorated following the genetic inactivation of CCR2.
Collectively, our findings provide novel insights into the role of CCR2 in the pathogenesis of vasculitis as seen in KD and highlight novel therapeutic targets, specifically for individuals resistant to first-line treatments.
PMCID: PMC3519555  PMID: 23074996
CCR2; Coronary vasculitis; Treg; Treg/Th17 imbalance
18.  The effect of manipulation of silk scaffold fabrication parameters on matrix performance in a murine model of bladder augmentation 
Biomaterials  2011;32(30):7562-7570.
Autologous gastrointestinal segments are utilized as the primary option for bladder reconstructive procedures despite their inherent morbidity and significant complication rate. Multi-laminate biomaterials derived from Bombyx mori silk fibroin and prepared from a gel spinning process may serve as a superior alternative for bladder tissue engineering due to their robust mechanical properties, biocompatibility, and processing plasticity. In the present study, we sought to determine the impact of variations in winding (axial slew rate: 2 and 40 mm/sec) and post-winding (methanol and lyophilization) fabrication parameters on the in vivo performance of gel spun silk scaffolds in a murine model of bladder augmentation. Three silk matrix groups with distinct structural and mechanical properties were investigated following 10 weeks of implantation including our original prototype previously shown to support bladder regeneration, Group 1 (2mm/sec, methanol) as well as Group 2 (40mm/sec, methanol) and Group 3 (40mm/sec, lyophilization) configurations. Non surgical animals were assessed in parallel as controls. Quantification of residual scaffold area demonstrated that while Group 1 and 2 scaffolds were largely intact, processing parameters utilized for Group 3 led to significantly higher degrees of scaffold degradation in comparison to Group 1. Histological (hematoxylin and eosin, masson’s trichrome) and immunohistochemical (IHC) analyses showed comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within the original defect site throughout all matrix groups similar to controls. Parallel evaluations demonstrated transitional urothelial formation with prominent uroplakin and p63 protein expression supported by Group 1 and 3 scaffolds, while Group 2 variants supported a thin, immature epithelium composed primarily of uroplakin-negative, p63-positive basal cells. Voided stain on paper analysis revealed similar voiding patterns between all matrix groups; however Group 2 animals displayed substantially lower voided volumes with increased frequency in comparison to controls. In addition, cystometric assessments revealed all matrix groups supported comparable degrees of bladder compliance similar to control levels. The results of this study demonstrate that selective alterations in winding and post-winding fabrication parameters can enhance the degradation rate of gel spun silk scaffolds in vivo while preserving their ability to support bladder tissue regeneration and function.
PMCID: PMC3156349  PMID: 21764119
silk; bladder tissue engineering; smooth muscle cell; epithelium; urinary tract
19.  Medication intensification in diabetes in rural primary care: a cluster-randomised effectiveness trial 
BMJ Open  2012;2(5):e000959.
To determine the effectiveness of a provider-based intervention to improve medication intensification among patients with diabetes.
Effectiveness cluster-randomised trial. Baseline and follow-up cross-sections of diabetes physicians’ patients.
Eleven U.S. Southeastern states, 2006–2008.
205 Rural primary care physicians, 95 completed the study.
Multicomponent interactive intervention including web-based continuing medical education (CME), performance feedback and quality improvement tools.
Primary outcome measures
Medication intensification, a dose increase of an existing medication or the addition of a new class of medication for glucose, blood pressure and lipids control on any of the three most recent office visits.
Of 364 physicians attempting to register, 102 were randomised to the intervention and 103 to the control arms; 95 physicians (intervention, n=48; control, n=47) provided data on their 1182 of their patients at baseline (intervention, n=715; control, n=467) and 945 patients at follow-up (intervention, n=479; control, n=466). For A1c control, medication intensification increased in both groups (intervention, pre 26.4% vs post 32.6%, p=0.022; control, pre 24.8% vs post 31.1%, p=0.033) (intervention, adjusted OR (AOR) 1.37; 95% CI 1.06 to 1.76; control, AOR 1.41 (95% CI 1.06 to 1.89)); however, we observed no incremental benefit solely due to the intervention (group-by-time interaction, p=0.948). Among patients with the worst glucose control (A1c >9%), intensification increased in both groups (intervention, pre 34.8% vs post 62.5%, p=0.002; control, pre 35.7% vs post 61.4%, p=0.008).
A wide-reach, low-intensity, web-based interactive multicomponent intervention had no significant incremental effect on medication intensification for control of glucose, blood pressure or lipids for patients with diabetes of physicians practising in the rural Southeastern USA.
Trial registration
PMCID: PMC3467590  PMID: 22991217
Diabetes & Endocrinology; General Medicine (see Internal Medicine); Primary Care
20.  CD8α+ Dendritic Cells Improve Collagen-Induced Arthritis In CC Chemokine Receptor (CCR)-2 Deficient Mice 
Immunobiology  2011;216(9):971-978.
Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3+ regulatory T cells (Treg), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2−/−) mice had impaired DCs migration and reduced CD8α+ DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2−/− mice, we tested the hypothesis that CD8α+ DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8α+ DCs in Ccr2−/− and SKG mice.
To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant Flt3L-injections to expand endogenous DCs populations or adoptive transfers of CD8α+ DCs.
Flt3L-mediated expansion of endogenous CD8α+ DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8α+ DCs ameliorated arthritis in Ccr2−/− mice and enhanced TGFβ1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype.
CD8α+ DCs were tolerogenic to the development of arthritis. CD8α+ DCs deficiency heightened the sensitivity to arthritis in Ccr2−/− mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2−/− mice was T cell-independent.
PMCID: PMC3426926  PMID: 21531476
CCR2; dendritic cells; CD8α+ DC; arthritis; SKG
21.  Evaluation of Biomaterials for Bladder Augmentation using Cystometric Analyses in Various Rodent Models 
Renal function and continence of urine are critically dependent on the proper function of the urinary bladder, which stores urine at low pressure and expels it with a precisely orchestrated contraction. A number of congenital and acquired urological anomalies including posterior urethral valves, benign prostatic hyperplasia, and neurogenic bladder secondary to spina bifida/spinal cord injury can result in pathologic tissue remodeling leading to impaired compliance and reduced capacity1. Functional or anatomical obstruction of the urinary tract is frequently associated with these conditions, and can lead to urinary incontinence and kidney damage from increased storage and voiding pressures2. Surgical implantation of gastrointestinal segments to expand organ capacity and reduce intravesical pressures represents the primary surgical treatment option for these disorders when medical management fails3. However, this approach is hampered by the limitation of available donor tissue, and is associated with significant complications including chronic urinary tract infection, metabolic perturbation, urinary stone formation, and secondary malignancy4,5.
Current research in bladder tissue engineering is heavily focused on identifying biomaterial configurations which can support regeneration of tissues at defect sites. Conventional 3-D scaffolds derived from natural and synthetic polymers such as small intestinal submucosa and poly-glycolic acid have shown some short-term success in supporting urothelial and smooth muscle regeneration as well as facilitating increased organ storage capacity in both animal models and in the clinic6,7. However, deficiencies in scaffold mechanical integrity and biocompatibility often result in deleterious fibrosis8, graft contracture9, and calcification10, thus increasing the risk of implant failure and need for secondary surgical procedures. In addition, restoration of normal voiding characteristics utilizing standard biomaterial constructs for augmentation cystoplasty has yet to be achieved, and therefore research and development of novel matrices which can fulfill this role is needed.
In order to successfully develop and evaluate optimal biomaterials for clinical bladder augmentation, efficacy research must first be performed in standardized animal models using detailed surgical methods and functional outcome assessments. We have previously reported the use of a bladder augmentation model in mice to determine the potential of silk fibroin-based scaffolds to mediate tissue regeneration and functional voiding characteristics.11,12 Cystometric analyses of this model have shown that variations in structural and mechanical implant properties can influence the resulting urodynamic features of the tissue engineered bladders11,12. Positive correlations between the degree of matrix-mediated tissue regeneration determined histologically and functional compliance and capacity evaluated by cystometry were demonstrated in this model11,12. These results therefore suggest that functional evaluations of biomaterial configurations in rodent bladder augmentation systems may be a useful format for assessing scaffold properties and establishing in vivo feasibility prior to large animal studies and clinical deployment. In the current study, we will present various surgical stages of bladder augmentation in both mice and rats using silk scaffolds and demonstrate techniques for awake and anesthetized cystometry.
PMCID: PMC3486757  PMID: 22907252
Bioengineering; Issue 66; Medicine; Biomedical Engineering; Physiology; Silk; bladder tissue engineering; biomaterial; scaffold; matrix; augmentation; cystometry
22.  Contemporary Use of Nephron-Sparing Surgery for Children with Malignant Renal Tumors at Freestanding Children’s Hospitals 
Urology  2011;78(2):422-426.
It is widely accepted that, when feasible, nephron-sparing surgery (NSS) is preferable to radical nephrectomy (RN) for treatment of renal tumors in adults. However, RN is more frequently used in children. We sought to compare in-hospital outcomes after NSS and RN for malignant pediatric renal tumors.
Patients & Methods
The Pediatric Health Information System (PHIS) combines data from over 40 North American pediatric hospitals. We queried PHIS to identify children with malignant renal tumors who underwent surgery from 2003 to 2009. We examined whether outcomes (complication rates, cost and length of stay) differed by procedure type. Multivariate regression models were used to adjust for confounding and generalized estimating equations were used to adjust for hospital clustering.
We identified 1,235 children with renal tumors who underwent RN (91%) or NSS (9%). Patients undergoing RN and NSS had similar median co-morbidity scores (p=0.98), hospital length of stays (each 6.0 days, p=0.54), in-hospital charges, ($25,700 v. $37,000, p=0.11), and surgical complication rates (16.4 v. 20.5%, p=0.24). These outcomes remained similar after adjusting for other patient and hospital factors.
The majority of children with malignant renal tumors treated at children’s hospitals undergo RN. RN and NSS use were not significantly different in terms of their length of hospital stay, in-hospital charges, and complication rates. While oncologic outcomes are lacking, these data suggest that NSS may be performed in selected children with malignant renal tumors without significantly increasing their hospital charges, length of stay, or surgical complication rates.
PMCID: PMC3152612  PMID: 21689846
Kidney Neoplasms; Wilms Tumor; Renal Cell Carcinoma; Pediatrics
23.  Use of Ecological Momentary Assessment to Guide Curricular Change in Graduate Medical Education 
To assess whether a novel evaluation tool could guide curricular change in an internal medicine residency program.
The authors developed an 8-item Ecological Momentary Assessment tool and collected daily evaluations from residents of the relative educational value of 3 differing ambulatory morning report formats (scale: 8  =  best, 0  =  worst). From the evaluations, they made a targeted curricular change and used the tool to assess its impact.
Residents completed 1388 evaluation cards for 223 sessions over 32 months, with a response rate of 75.3%. At baseline, there was a decline in perceived educational value with advancing postgraduate (PGY) year for the overall mean score (PGY-1, 7.4; PGY-2, 7.2; PGY-3, 7.0; P < .01) and for percentage reporting greater than 2 new things learned (PGY-1, 77%; PGY-2, 66%; PGY-3, 50%; P < .001). The authors replaced the format of a lower scoring session with one of higher cognitive content to target upper-level residents. The new session's mean score improved (7.1 to 7.4; P  =  .03); the adjusted odds ratios before and after the change for percentage answering, “Yes, definitely” to “Area I need to improve” was 2.53 (95% confidence interval [CI], 1.45–4.42; P  =  .001) and to “Would recommend to others,” it was 2.08 (95% CI, 1.12–3.89; P  =  .05).
The Ecological Momentary Assessment tool successfully guided ambulatory morning report curricular changes and confirmed successful curricular impact. Ecological Momentary Assessment concepts of multiple, frequent, timely evaluations can be successfully applied in residency curriculum redesign.
PMCID: PMC3184922  PMID: 22655137
25.  What Should We Include in a Cultural Competence Curriculum? An Emerging Formative Evaluation Process to Foster Curriculum Development 
To identify, prioritize, and organize components of a cultural competence curriculum to address disparities in cardiovascular disease.
In 2006, four separate nominal group technique sessions were conducted with medical students, residents, community physicians, and academic physicians to generate and prioritize a list of concepts (i.e., ideas) to include in a curriculum. Afterward, 45 educators and researchers organized and prioritized the concepts using a card-sorting exercise. Multidimensional scaling (MDS) and hierarchical cluster analysis produced homogeneous groupings of related concepts and generated a cognitive map. The main outcome measures were the number of cultural competence concepts, their relative ranks, and the cognitive map.
Thirty participants generated 61 concepts, 29 were identified by at least 2 participants. The cognitive map organized concepts into four clusters, interpreted as: (1) patient’s cultural background (e.g.,, information on cultures, habits, values); (2) provider and health care (e.g., clinical skills, awareness of one’s bias, patient-centeredness, and professionalism), communication skills (e.g., history, stereotype avoidance, and health disparities epidemiology); (3) cross-culture (e.g., idiomatic expressions, examples of effective communication); and (4) resources to manage cultural diversity (e.g., translator guides, instructions and community resources). The MDS two-dimensional solution demonstrated a good fit (stress=0.07; R2=0.97).
A novel, combined approach allowed stakeholders’ inputs to identify and cognitively organize critical domains used to guide development of a cultural competence curriculum. Educators may use this approach to develop and organize educational content for their target audiences, especially in ill-defined areas like cultural competence.
PMCID: PMC3046368  PMID: 21248602

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