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1.  Prenatal care and childbirth assistance in Amazonian women before and after the Pacific Highway Construction (2003–2011): a cross-sectional study 
BMC Women's Health  2016;16:37.
Attention to prenatal care and child delivery is important for the health of women and children, but in the Amazon these indicators tend to be historically unfavorable, in part by geographical and political isolation. In 2003 both Brazilian and Peru governments have finished paving an international road connecting remotes areas in the Brazilian Amazon to the Pacific coast in Peru.
The situation of prenatal care and child delivery with mothers of children under 5 years old living in the urban area of Assis Brasil, Acre was assessed in two cross-sectional studies performed in 2003 and 2011, corresponding to the period before and after the Pacific highway construction.
In 2003, most mothers were of black/Afro-American ethnicity, or “pardos” (the offspring of a Caucasian with a African descendant) (77.69 %), had more than 4 years of schooling (73.40 %) and had a mean age of 22.18 years. In 2011, the number of as a migration of indigenous women increased from 0 to 14.40 % of the respondents, because of migration from communities along the rivers to urban areas, with no other significant changes in maternal characteristics. No significant improvement in childbirth assistance was noticed between 1997 and 2011; only the percentage of in-hospital vaginal deliveries performed by doctors increased from 17.89 to 66.26 % (p <0.001) during this period. Access to prenatal care was associated with white ethnicity in 2003, and higher socioeconomic level and white ethnicity in 2011, while the higher number of prenatal visits was associated with higher maternal education and higher socioeconomic levels in 2011. Vaginal child delivery at a hospital facility was associated with maternal age in 2003, and year of birth, being of white ethnicity and higher level of education in 2011.
The indicators of prenatal care and child delivery were below the national average, showing that geographical isolation still affects women’s health care in the Amazon, despite the construction of the highway and governmental health protocols adopted during this period.
PMCID: PMC4944242  PMID: 27412559
Amazon; Prenatal care; Childbirth
2.  Acellular Bi-Layer Silk Fibroin Scaffolds Support Functional Tissue Regeneration in a Rat Model of Onlay Esophagoplasty 
Biomaterials  2015;53:149-159.
Surgical management of long-gap esophageal defects with autologous gastrointestinal tissues is frequently associated with adverse complications including organ dysmotility, dysphagia, and donor site morbidity. In order to develop alternative graft options, bi-layer silk fibroin (SF) scaffolds were investigated for their potential to support functional tissue regeneration in a rodent model of esophageal repair. Onlay esophagoplasty was performed with SF matrices (N=40) in adult rats for up to 2 m of implantation. Parallel groups consisted of animals implanted with small intestinal submucosa (SIS) scaffolds (N=22) or sham controls receiving esophagotomy alone (N=20). Sham controls exhibited a 100% survival rate while rats implanted with SF and SIS scaffolds displayed respective survival rates of 93% and 91% prior to scheduled euthanasia. Animals in each experimental group were capable of solid food consumption following a 3 d post-op liquid diet and demonstrated similar degrees of weight gain throughout the study period. End-point μ-computed tomography at 2 m post-op revealed no evidence of contrast extravasation, fistulas, strictures, or diverticula in any of the implant groups. Ex vivo tissue bath studies demonstrated that reconstructed esophageal conduits supported by both SF and SIS scaffolds displayed contractile responses to carbachol, KCl and electrical field stimulation while isoproterenol produced tissue relaxation. Histological (Masson’s trichrome and hematoxylin and eosin) and immunohistochemical (IHC) evaluations demonstrated both implant groups produced de novo formation of skeletal and smooth muscle bundles positive for contractile protein expression [fast myosin heavy chain (MY32) and α-smooth muscle actin (α-SMA)] within the graft site. However, SF matrices promoted a significant 4-fold increase in MY32+ skeletal muscle and a 2-fold gain in α-SMA+ smooth muscle in comparison to the SIS cohort as determined by histomorphometric analyses. A stratified squamous, keratinized epithelium expressing cytokeratin 5 and involucrin proteins was also present at 2 m post-op in all experimental groups. De novo innervation and vascularization were evident in all regenerated tissues indicated by the presence of synaptophysin (SYP38)+ boutons and vessels lined with CD31 expressing endothelial cells. In respect to SIS, the SF group supported a significant 4-fold increase in the density of SYP38+ boutons within the implant region. Evaluation of host tissue responses revealed that SIS matrices elicited chronic inflammatory reactions and severe fibrosis throughout the neotissues, in contrast to SF scaffolds. The results of this study demonstrate that bi-layer SF scaffolds represent promising biomaterials for onlay esophagoplasty, capable of producing superior regenerative outcomes in comparison to conventional SIS scaffolds.
PMCID: PMC4405663  PMID: 25890715
silk; scaffold; wound healing; muscle; epithelium
4.  A Web-based Cultural Competency Training for Medical Students: A Randomized Trial 
The objectives of this research were to compare a web-based curriculum to a traditional lecture format on medical students’ cultural competency attitudes using a standardized instrument and to examine the internal consistency of the standardized instrument.
In 2010, we randomized all 180 first-year medical students into a web-based (intervention group) or a lecture-based (control group) cultural competency training. The main outcome was the overall score on the Health Belief Attitudes Survey (HBAS)(1=lowest, 6=highest). We examined internal consistency with factor analysis.
No differences were observed in the overall median scores between the intervention (median 5.2; 25th percentile [Q1] 4.9, 75th percentile [Q3] 5.5) and the control groups (5.3, Q1 4.9, Q3 5.6)(p=0.77). The internal consistency of the two main sub-components was good (Cronbach’s alpha 0.83) to acceptable (Cronbach’s alpha 0.69).
A web-based and a lecture-based cultural competency training strategies were associated with equally high positive attitudes among first-year medical students. Our findings warrant further evaluation of web-based cultural competency educational interventions.
PMCID: PMC4400184  PMID: 25325193
Clinical Clerkship/methods; cultural competence; medical education; educational intervention
5.  Child Health in the Peruvian Amazon: Prevalence and Factors Associated with Referred Morbidity and Health Care Access in the City of Iñapari 
Journal of Tropical Medicine  2015;2015:157430.
Introduction. Children under 5 years of age are more susceptible to developing morbidities such as diarrhea, respiratory infections, anemia, and malnutrition. The objective of the study is to evaluate the prevalence of reported morbidities in this age group in the city of Iñapari (Peru) and the access to health services in this municipality. Methods. Data collection using interviews that assessed socioeconomic and demographic conditions, child morbidity, and access to health services was performed in 2011. Statistical analysis was performed using SPSS 13.0. Results. Regarding morbidities that occurred during lifetime, 39.8% reported previous anemia and intestinal parasite infection. About 53.7% of the children reported any type of morbidities in the last 15 days before interview, being most frequent respiratory symptoms (38.9%), diarrhea (23,4%), and fever (23,1%). Only 63.1% of those reporting recent morbidities sought health care. These morbidities were associated with precarious sanitation and lack of infrastructure, the presence of other comorbidities, and poor access to health services. Conclusion. The main referred morbidities in Amazonian Peruvian children were diarrhea, respiratory symptoms, anemia, and vomiting. Incentives and improvements in the health and sanitation conditions would be important measures to improve the quality of life of the Amazonian child population.
PMCID: PMC4657107  PMID: 26640493
6.  Inosine Improves Neurogenic Detrusor Overactivity following Spinal Cord Injury 
PLoS ONE  2015;10(11):e0141492.
Neurogenic detrusor overactivity and the associated loss of bladder control are among the most challenging complications of spinal cord injury (SCI). Anticholinergic agents are the mainstay for medical treatment of detrusor overactivity. However, their use is limited by significant side effects such that a search for new treatments is warranted. Inosine is a naturally occurring purine nucleoside with neuroprotective, neurotrophic and antioxidant effects that is known to improve motor function in preclinical models of SCI. However, its effect on lower urinary tract function has not been determined. The objectives of this study were to determine the effect of systemic administration of inosine on voiding function following SCI and to delineate potential mechanisms of action. Sprague−Dawley rats underwent complete spinal cord transection, or cord compression by application of an aneurysm clip at T8 for 30 sec. Inosine (225 mg/kg) or vehicle was administered daily via intraperitoneal injection either immediately after injury or after a delay of 8 wk. At the end of treatment, voiding behavior was assessed by cystometry. Levels of synaptophysin (SYP), neurofilament 200 (NF200) and TRPV1 in bladder tissues were measured by immunofluorescence imaging. Inosine administration decreased overactivity in both SCI models, with a significant decrease in the frequency of spontaneous non−voiding contractions during filling, compared to vehicle−treated SCI rats (p<0.05), including under conditions of delayed treatment. Immunofluorescence staining demonstrated increased levels of the pan-neuronal marker SYP and the Adelta fiber marker NF200, but decreased staining for the C-fiber marker, TRPV1 in bladder tissues from inosine-treated rats compared to those from vehicle-treated animals, including after delayed treatment. These findings demonstrate that inosine prevents the development of detrusor overactivity and attenuates existing overactivity following SCI, and may achieve its effects through modulation of sensory neurotransmission.
PMCID: PMC4631513  PMID: 26529505
7.  Socioeconomic inequities and hepatitis A virus infection in Western Brazilian Amazonian children: spatial distribution and associated factors 
BMC Infectious Diseases  2015;15:428.
Hepatitis A is still a neglected health problem in the world. The most affected areas are the ones with disadvantaged socioeconomic conditions. In Brazil, seroprevalence studies showed that 64.7 % of the general population has antibodies against HAV (hepatitis A virus), and the Amazon region has the highest seroprevalence in the country.
In the present study the seroprevalence of total HAV antibodies in children between 1 and 5 years old residing in the urban area of Assis Brasil, Acre was measured and spatial distribution of several socioeconomic inequities was evaluated.
In the year of 2011, seroprevalence rate was 16.66 %. Factors associated with having a positive serology identified by multivariate analysis were being of indigenous ethnicity [adjusted Odds Ratio (aOR) = 3.27, CI 1.45–7.28], usage of water from the public system (aOR = 8.18, CI 1.07–62.53), living in a house not located in a street (aOR = 3.48, CI 1.54–7.87), and child age over 4 years old (aOR = 2.43, CI 1.23–4.79). The distribution of seropositive children was clustered in the eastern part of the city, where several socioeconomic inequities (lack of flushed toilets, lack of piped water inside the household and susceptibility of the household to flooding during rain, low maternal education, having wood or ground floor at home, and not owning a house, lack of piped water at home, and type of drinking water) also clustered.
The findings highlight that sanitation and water treatment still need improvement in the Brazilian Amazon, and that socioeconomic development is warranted in order to decrease this and other infectious diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1164-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4608050  PMID: 26471064
Hepatitis A; Socioeconomic inequities; Serology; Spatial distribution; Amazon
8.  Evaluation of a Mobile Voiding Diary for Pediatric Patients with Voiding Dysfunction: A Prospective Comparative Study 
The Journal of urology  2014;192(3):908-913.
One potential strategy for improving voiding diary completion rates and data quality is use of a mobile electronic format. We evaluated the acceptability and feasibility of mobile voiding diaries for patients with nonneurogenic lower urinary tract dysfunction, and compared mobile and paper voiding diaries.
Materials and Methods
We prospectively enrolled children presenting with daytime symptoms of lower urinary tract dysfunction between July 2012 and April 2013. We enrolled an initial cohort of patients who were provided a paper voiding diary and a subsequent cohort who were provided a mobile voiding diary. We conducted in person interviews and assessed completion rates and quality, comparing paper and mobile voiding diary groups.
We enrolled 45 patients who received a paper voiding diary and 38 who received a mobile voiding diary. Completion rates were 78% for paper voiding diaries and 61% for mobile voiding diaries (p = 0.10). Data quality measures for patients completing paper vs mobile voiding diaries revealed a larger proportion (63% vs 52%) providing a full 5 days of data and a smaller proportion (20% vs 65%) with data gaps. However, the paper voiding diary also demonstrated a lower proportion (80% vs 100%) that was completely legible and a lower proportion (40% vs 65%) with completely prospective data entry.
The use of a mobile voiding diary was acceptable and feasible for our patients with lower urinary tract dysfunction, although completion rates were somewhat lower compared to paper voiding diaries. Data quality was not clearly better for either version. The mobile voiding diary format may offer data quality advantages for select groups but it did not display significant superiority when provided universally.
PMCID: PMC4143466  PMID: 24704008
defecation; lower urinary tract symptoms; mobile applications; urination
9.  The use of bi-layer silk fibroin scaffolds and small intestinal submucosa matrices to support bladder tissue regeneration in a rat model of spinal cord injury 
Biomaterials  2014;35(26):7452-7459.
Adverse side-effects associated with enterocystoplasty for neurogenic bladder reconstruction have spawned the need for the development of alternative graft substitutes. Bi-layer silk fibroin (SF) scaffolds and small intestinal submucosa (SIS) matrices were investigated for their ability to support bladder tissue regeneration and function in a rat model of spinal cord injury (SCI). Bladder augmentation was performed with each scaffold configuration in SCI animals for 10 wk of implantation and compared to non-augmented control groups (normal and SCI alone). Animals subjected to SCI alone exhibited a 72% survival rate (13/18) while SCI rats receiving SIS and bi-layer SF scaffolds displayed respective survival rates of 83% (10/12) and 75% (9/12) over the course of the study period. Histological (Masson’s trichrome analysis) and immunohistochemical (IHC) evaluations demonstrated both implant groups supported de novo formation of smooth muscle layers with contractile protein expression [α-smooth muscle actin (α-SMA) and SM22α] as well as maturation of multi-layer urothelia expressing cytokeratin (CK) and uroplakin 3A proteins. Histomorphometric analysis revealed bi-layer SF and SIS scaffolds respectively reconstituted 64% and 56% of the level of α-SMA+ smooth muscle bundles present in SCI-alone controls, while similar degrees of CK+ urothelium across all experimental groups were detected. Parallel evaluations showed similar degrees of vascular area and synaptophysin+ boutons in all regenerated tissues compared to SCI-alone controls. In addition, improvements in certain urodynamic parameters in SCI animals, such as decreased peak intravesical pressure, following implantation with both matrix configurations were also observed. The data presented in this study detail the ability of acellular SIS and bi-layer SF scaffolds to support formation of innervated, vascularized smooth muscle and urothelial tissues in a neurogenic bladder model.
PMCID: PMC4111136  PMID: 24917031
Bladder tissue engineering; Small intestine submucosa; Silk; Urinary tract
10.  A 22-Year-Old Woman with Abdominal Pain 
Journal of General Internal Medicine  2014;29(7):1074-1078.
PMCID: PMC4061356  PMID: 24420866
clinical reasoning; illness script; expert clinician; acute intermittent porphyria; abdominal pain
11.  Impact of an educational intervention on provider knowledge, attitudes, and comfort level regarding counseling women ages 40–49 about breast cancer screening 
Mammography screening for women under the age of 50 is controversial. Groups such as the US Preventive Services Task Force recommend counseling women 40–49 years of age about mammography risks and benefits in order to incorporate the individual patient’s values in decisions regarding screening. We assessed the impact of a brief educational intervention on the knowledge and attitudes of clinicians regarding breast cancer screening.
The educational intervention included a review of the risks and benefits of screening, individual risk assessment, and counseling methods. Sessions were led by a physician expert in breast cancer screening. Participants were physicians and nurses in 13 US Department of Veterans Affairs primary care clinics in Alabama. Outcomes were as follows: 1) knowledge assessment of mammogram screening recommendations; 2) counseling practices on the risks and benefits of screening; and 3) comfort level with counseling about screening. Outcomes were assessed by survey before and after the intervention.
After the intervention, significant changes in attitudes about breast cancer screening were seen. There was a decrease in the percentage of participants who reported that they would screen all women ages 40–49 years (82% before the intervention, 9% afterward). There was an increase in the percentage of participants who reported that they would wait until the patient was 50 years old before beginning to screen (12% before the intervention, 38% afterward). More participants (5% before, 53% after; P<0.001) said that they would discuss the patient’s preferences. Attitudes favoring discussion of screening benefits increased, though not significantly, from 94% to 99% (P=0.076). Attitudes favoring discussion of screening risks increased from 34% to 90% (P<0.001). The comfort level with discussing benefits increased from a mean of 3.8 to a mean of 4.5 (P<0.001); the comfort level with discussing screening risks increased from 2.7 to 4.3 (P<0.001); and the comfort level with discussing cancer risks and screening preferences with patients increased from 3.2 to 4.3 (P<0.001). (The comfort levels measurements were assessed by using a Likert scale, for which 1= not comfortable and 5= very comfortable.)
Most clinicians in the US Department of Veterans Affairs ambulatory practices in Alabama reported that they routinely discuss mammography benefits but not potential harms with patients. An educational intervention detailing recommendations and counseling methods affected the knowledge and attitudes about breast cancer screening. Participants expressed greater likelihood of discussing screening options in the future.
PMCID: PMC4427075  PMID: 25999731
breast cancer screening; education; primary care; mammography; counseling
12.  Splenic Infarcts Associated with Immune Reconstitution Inflammatory Syndrome 
PMCID: PMC3930794  PMID: 24002634
splenic infarction; immune reconstitution inflammatory syndrome; HIV infections/drug therapy; HIV infections/complications; inflammation; mycobacterium infections/etiology
13.  Learning by doing: observing an interprofessional process as an interprofessional team 
Journal of interprofessional care  2013;28(3):249-251.
New competencies exist for interprofessional education, which are centered on the goal of improving quality of care and patient safety through improved interprofessional collaboration. Interprofessional education and effective interprofessional collaboration are cornerstones of the Veterans Affairs Quality Scholars fellowship program. The purpose of this project was to evaluate an innovative interprofessional education strategy in which teams of physicians and nurses were “learning by doing” as they observed and analyzed the functioning of an interprofessional process, specifically, inpatient discharge. Fellows completed voluntary, anonymous surveys seeking their perspectives about the project. Fellows’ feedback revealed several themes, with both positive and negative characteristics related to team functioning, interprofessional understanding, microsystem knowledge, pooled knowledge and assignment challenges. The strength of this strategy is exemplified by the fact that fellows not only learned from each other’s separate professional observations, but also observed the emergence of a shared interprofessional perspective through working together.
PMCID: PMC4289149  PMID: 24070019
Interprofessional collaboration; interprofessional education; interprofessional evaluation; teams
14.  Documenting Quality Improvement and Patient Safety Efforts: The Quality Portfolio. A Statement from the Academic Hospitalist Taskforce 
Physicians increasingly investigate, work, and teach to improve the quality of care and safety of care delivery. The Society of General Internal Medicine Academic Hospitalist Task Force sought to develop a practical tool, the quality portfolio, to systematically document quality and safety achievements. The quality portfolio was vetted with internal and external stakeholders including national leaders in academic medicine. The portfolio was refined for implementation to include an outlined framework, detailed instructions for use and an example to guide users. The portfolio has eight categories including: (1) a faculty narrative, (2) leadership and administrative activities, (3) project activities, (4) education and curricula, (5) research and scholarship, (6) honors, awards, and recognition, (7) training and certification, and (8) an appendix. The authors offer this comprehensive, yet practical tool as a method to document quality and safety activities. It is relevant for physicians across disciplines and institutions and may be useful as a standalone document or as an adjunct to traditional promotion documents. As the Next Accreditation System is implemented, academic medical centers will require faculty who can teach and implement the systems-based practice requirements. The quality portfolio is a method to document quality improvement and safety activities.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2532-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3889978  PMID: 23807726
quality portfolio; quality improvement; patient safety; academic medicine; career development; quality of health care
15.  In vitro evaluation of bi-layer silk fibroin scaffolds for gastrointestinal tissue engineering 
Journal of Tissue Engineering  2014;5:2041731414556849.
Silk fibroin scaffolds were investigated for their ability to support attachment, proliferation, and differentiation of human gastrointestinal epithelial and smooth muscle cell lines in order to ascertain their potential for tissue engineering. A bi-layer silk fibroin matrix composed of a porous silk fibroin foam annealed to a homogeneous silk fibroin film was evaluated in parallel with small intestinal submucosa scaffolds. AlamarBlue analysis revealed that silk fibroin scaffolds supported significantly higher levels of small intestinal smooth muscle cell, colon smooth muscle cell, and esophageal smooth muscle cell attachment in comparison to small intestinal submucosa. Following 7 days of culture, relative numbers of each smooth muscle cell population maintained on both scaffold groups were significantly elevated over respective 1-day levels—indicative of cell proliferation. Real-time reverse transcription polymerase chain reaction and immunohistochemical analyses demonstrated that both silk fibroin and small intestinal submucosa scaffolds were permissive for contractile differentiation of small intestinal smooth muscle cell, colon smooth muscle cell, esophageal smooth muscle cell as determined by significant upregulation of α-smooth muscle actin and SM22α messenger RNA and protein expression levels following transforming growth factor-β1 stimulation. AlamarBlue analysis demonstrated that both matrix groups supported similar degrees of attachment and proliferation of gastrointestinal epithelial cell lines including colonic T84 cells and esophageal epithelial cells. Following 14 days of culture on both matrices, spontaneous differentiation of T84 cells toward an enterocyte lineage was confirmed by expression of brush border enzymes, lactase, and maltase, as determined by real-time reverse transcription polymerase chain reaction and immunohistochemical analyses. In contrast to small intestinal submucosa scaffolds, silk fibroin scaffolds supported spontaneous differentiation of esophageal epithelial cells toward a suprabasal cell lineage as indicated by significant upregulation of cytokeratin 4 and cytokeratin 13 messenger RNA transcript levels. In addition, esophageal epithelial cells maintained on silk fibroin scaffolds also produced significantly higher involucrin messenger RNA transcript levels in comparison to small intestinal submucosa counterparts, indicating an increased propensity for superficial, squamous cell specification. Collectively, these data provide evidence for the potential of silk fibroin scaffolds for gastrointestinal tissue engineering applications.
PMCID: PMC4228923  PMID: 25396043
Colon; esophagus; small intestine; silk fibroin; tissue engineering
16.  Rapid Antigen Group A Streptococcus Test to Diagnose Pharyngitis: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(11):e111727.
Pharyngitis management guidelines include estimates of the test characteristics of rapid antigen streptococcus tests (RAST) using a non-systematic approach.
To examine the sensitivity and specificity, and sources of variability, of RAST for diagnosing group A streptococcal (GAS) pharyngitis.
Data Sources
MEDLINE, Cochrane Reviews, Centre for Reviews and Dissemination, Scopus, SciELO, CINAHL, guidelines, 2000–2012.
Study Selection
Culture as reference standard, all languages.
Data Extraction and Synthesis
Study characteristics, quality.
Main Outcome(s) and Measure(s)
Sensitivity, specificity.
We included 59 studies encompassing 55,766 patients. Forty three studies (18,464 patients) fulfilled the higher quality definition (at least 50 patients, prospective data collection, and no significant biases) and 16 (35,634 patients) did not. For the higher quality immunochromatographic methods in children (10,325 patients), heterogeneity was high for sensitivity (inconsistency [I2] 88%) and specificity (I2 86%). For enzyme immunoassay in children (342 patients), the pooled sensitivity was 86% (95% CI, 79–92%) and the pooled specificity was 92% (95% CI, 88–95%). For the higher quality immunochromatographic methods in the adult population (1,216 patients), the pooled sensitivity was 91% (95% CI, 87 to 94%) and the pooled specificity was 93% (95% CI, 92 to 95%); however, heterogeneity was modest for sensitivity (I2 61%) and specificity (I2 72%). For enzyme immunoassay in the adult population (333 patients), the pooled sensitivity was 86% (95% CI, 81–91%) and the pooled specificity was 97% (95% CI, 96 to 99%); however, heterogeneity was high for sensitivity and specificity (both, I2 88%).
RAST immunochromatographic methods appear to be very sensitive and highly specific to diagnose group A streptococcal pharyngitis among adults but not in children. We could not identify sources of variability among higher quality studies. The present systematic review provides the best evidence for the wide range of sensitivity included in current guidelines.
PMCID: PMC4219770  PMID: 25369170
17.  Bladder Tissue Regeneration Using Acellular Bi-Layer Silk Scaffolds in a Large Animal Model of Augmentation Cystoplasty 
Biomaterials  2013;34(34):10.1016/j.biomaterials.2013.08.001.
A cellular scaffolds derived from Bombyx mori silk fibroin were investigated for their ability to support functional tissue regeneration in a porcine model of augmentation cystoplasty. Two bi-layer matrix configurations were fabricated by solvent-casting/salt leaching either alone (Group 1) or in combination with silk film casting (Group 2) to yield porous foams buttressed by heterogeneous surface pore occlusions or homogenous silk films, respectively. Bladder augmentation was performed with each scaffold group (6×6cm2) in juvenile Yorkshire swine for 3 m of implantation. Augmented animals exhibited high rates of survival (Group 1: 5/6, 83%; Group 2: 4/4, 100%) and voluntary voiding over the course of the study period. Urodynamic evaluations demonstrated mean increases in bladder capacity over pre-operative levels (Group 1: 277%; Group 2: 153%) which exceeded non surgical control gains (144%) encountered due to animal growth. Similarly, elevations in bladder compliance were substantially higher in augmented animals from baseline (Group 1: 357%; Group 2: 147%) in comparison to controls (41%). Gross tissue evaluations revealed that both matrix configurations supported extensive de novo tissue formation throughout the entire original implantation site which exhibited ultimate tensile strength similar to nonsurgical counterparts. Histological and immunohistochemical analyses showed that both implant groups promoted comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent cytokeratin, uroplakin, and p63 protein expression in both matrix groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by synaptophysin-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. Ex vivo organ bath studies demonstrated that regenerated tissues supported by both silk matrices displayed contractile responses to carbachol, α,β-methylene-ATP, KCl, and electrical field stimulation similar to controls. Our data detail the ability of acellular silk scaffolds to support regeneration of innervated, vascularized smooth muscle and urothelial tissues within 3 m with structural, mechanical, and functional properties comparable to native tissue in a porcine model of bladder repair.
PMCID: PMC3810021  PMID: 23953839
silk; tissue engineering; bladder; wound healing
18.  A 76-Year-Old Woman with Diaphoresis and Anxiety 
Journal of General Internal Medicine  2013;28(10):1376-1380.
PMCID: PMC3785657  PMID: 23729373
19.  Bedside Hand Grip Assessment with the Sphygmomanometer 
PMCID: PMC3785662  PMID: 23568188
physical examination; hand Strength; muscle strength dynamometer
20.  Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery 
Graphical abstract
•There is an urgent need of new treatments against trypanosomatids-borne diseases.•DNA topoisomerases are pointed as potential drug targets against unicellular parasites.•Trypanosomatids have a full set of DNA topoisomerases in both nucleus and kinetoplast.•TopII and TopIII are located in the kinetoplast and fully involved in kDNA replication.•Tritryps TopIB differ in structure from mammalian’s pointing to an attractive target.
The Trypanosomatidae family, composed of unicellular parasites, causes severe vector-borne diseases that afflict human populations worldwide. Chagas disease, sleeping sickness, as well as different sorts of leishmaniases are amongst the most important infectious diseases produced by Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively. All these infections are closely related to weak health care services in low-income populations of less developed and least economically developed countries. Search for new therapeutic targets in order to hit these pathogens is of paramount priority, as no effective vaccine is currently in use against any of these parasites. Furthermore, present-day chemotherapy comprises old-fashioned drugs full of important side effects. Besides, they are prone to produce tolerance and resistance as a consequence of their continuous use for decades. DNA topoisomerases (Top) are ubiquitous enzymes responsible for solving the torsional tensions caused during replication and transcription processes, as well as in maintaining genomic stability during DNA recombination. As the inhibition of these enzymes produces cell arrest and triggers cell death, Top inhibitors are among the most effective and most widely used drugs in both cancer and antibacterial therapies. Top relaxation and decatenation activities, which are based on a common nicking–closing cycle involving one or both DNA strands, have been pointed as a promising drug target. Specific inhibitors that bind to the interface of DNA-Top complexes can stabilize Top-mediated transient DNA breaks. In addition, important structural differences have been found between Tops from the Trypanosomatidae family members and Tops from the host. Such dissimilarities make these proteins very interesting for drug design and molecular intervention. The present review is a critical update of the last findings regarding trypanosomatid’s Tops, their new structural features, their involvement both in the physiology and virulence of these parasites, as well as their use as promising targets for drug discovery.
PMCID: PMC4266802  PMID: 25516844
Top, DNA topoisomerase; CL, cutaneous leishmaniasis; VL, visceral leishmaniasis; DALYs, disability-adjusted life years; kDNA, kinetoplast DNA; NTD, neglected tropical diseases; NGO, non-governmental organization; lk, linking number; NLS, Nuclear Localization Signal; Kinetoplastids; Tritryps; Topoisomerases; DNA topology; Target-based drug discovery; Chemotherapy
21.  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
23.  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
24.  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
25.  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

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