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1.  Forceps Delivery Volumes in Teaching and Nonteaching Hospitals: Are Volumes Sufficient for Physicians to Acquire and Maintain Competence? 
The decline in the use of forceps in operative deliveries over the last two decades raises questions about teaching hospitals' ability to provide trainees with adequate experience in the use of forceps. The authors examined: (1) the number of operative deliveries performed in teaching and nonteaching hospitals, and (2) whether teaching hospitals performed a sufficient number of forceps deliveries for physicians to acquire and maintain competence.
The authors used State Inpatient Data from nine states to identify all women hospitalized for childbirth in 2008. They divided hospitals into three categories: major teaching, minor teaching, and nonteaching. They calculated delivery volumes (total operative, cesarean, vacuum, forceps, two or more methods) for each hospital and compared data across hospital categories.
The sample included 1,344,305 childbirths in 835 hospitals. The mean cesarean volumes for major teaching, minor teaching, and nonteaching hospitals were 969.8, 757.8, and 406.9. The mean vacuum volumes were 301.0, 304.2, and 190.4, and the mean forceps volumes were 25.2, 15.3, and 8.9. In 2008, 31 hospitals (3.7% of all hospitals) performed no vacuum extractions, and 320 (38.3%) performed no forceps deliveries. In 2008, 13 (23%) major teaching and 44 (44%) minor teaching hospitals performed five or fewer forceps deliveries.
Low forceps delivery volumes may preclude many trainees from acquiring adequate experience and proficiency. These findings highlighted broader challenges, faced by many specialties, in ensuring that trainees and practicing physicians acquire and maintain competence in infrequently performed, highly technical procedures.
PMCID: PMC4317267  PMID: 24280847
2.  The Direct Assignment Option as a Modular Design Component: An Example for the Setting of Two Predefined Subgroups 
Background. A phase II design with an option for direct assignment (stop randomization and assign all patients to experimental treatment based on interim analysis, IA) for a predefined subgroup was previously proposed. Here, we illustrate the modularity of the direct assignment option by applying it to the setting of two predefined subgroups and testing for separate subgroup main effects. Methods. We power the 2-subgroup direct assignment option design with 1 IA (DAD-1) to test for separate subgroup main effects, with assessment of power to detect an interaction in a post-hoc test. Simulations assessed the statistical properties of this design compared to the 2-subgroup balanced randomized design with 1 IA, BRD-1. Different response rates for treatment/control in subgroup 1 (0.4/0.2) and in subgroup 2 (0.1/0.2, 0.4/0.2) were considered. Results. The 2-subgroup DAD-1 preserves power and type I error rate compared to the 2-subgroup BRD-1, while exhibiting reasonable power in a post-hoc test for interaction. Conclusion. The direct assignment option is a flexible design component that can be incorporated into broader design frameworks, while maintaining desirable statistical properties, clinical appeal, and logistical simplicity.
PMCID: PMC4310446  PMID: 25649690
3.  Evaluation of Aminohydantoins as a Novel Class of Antimalarial Agents 
Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure–activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.
PMCID: PMC4027786  PMID: 24900778
Malaria; antimalarial; aminohydantoin; medicinal chemistry; aspartic protease inhibitors
4.  Racial Disparities in Knee and Hip Total Joint Arthroplasty: An 18-year Analysis of National Medicare Data 
Annals of the rheumatic diseases  2013;73(12):2107-2115.
Examine whether racial disparities in utilization and outcomes of total knee and total hip arthroplasty (TKA and THA) have declined over time.
We used 1991-2008 Medicare Part A (MedPAR) data to identify four separate cohorts of patients (primary TKA, revision TKA, primary THA, revision THA). For each cohort, we calculated standardized arthroplasty utilization rates for White and Black Medicare beneficiaries for each calendar year and examined changes in disparities over time. We examined unadjusted and adjusted arthroplasty outcomes (30-day readmission rate, discharge disposition etc.) for Whites and Blacks and whether disparities decreased over time.
In 1991 utilization of primary TKA was 36% lower for Blacks compared to Whites (20.6 per 10,000 for Blacks; 32.1 per 10,000 for Whites; p<0.0001); in 2008 utilization of primary TKA for Blacks was 40% lower for Blacks (41.5 per 10,000 for Blacks; 68.8 per 10,000 for Whites; p<0.0001) with similar findings for the other cohorts. Black-White disparities in 30-day hospital readmission increased significantly from 1991-2008 among three patient cohorts. For example in 1991 30-day readmission rates for Blacks receiving primary TKA were 6% higher than for Whites; by 2008 readmission rates for Blacks were 24% higher (p<0.05 for change in disparity). Similarly, Black-White disparities in the proportion of patients discharged-to-home after surgery increased across the study period for all cohorts (p<0.05).
In an 18-year analysis of Medicare data we found little evidence of declines in racial disparities for joint arthroplasty utilization or outcomes.
PMCID: PMC4105323  PMID: 24047869
5.  Crystal structure of dimethyl 3,3′-[(3-fluoro­phenyl)methyl­ene]bis­(1H-indole-2-carboxyl­ate) 
In the title compound, the two indole ring systems are approximately perpendicular to one another, making a dihedral angle of 87.8 (5)°. In the crystal, pairs of N—H⋯O hydrogen bonds link the mol­ecules into the inversion dimers, which are further linked by N—H⋯O hydrogen bonds into supra­molecular chains propagating along the b-axis direction.
In the title compound, C27H21FN2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.0166 and 0.0086 Å) are approximately perpendic­ular to one another, making a dihedral angle of 87.8 (5)°; the fluorobenzene ring is twisted with respect to the mean planes of the two indole ring systems at 82.7 (5) and 85.5 (3)°. In the crystal, pairs of N—H⋯O hydrogen bonds link the mol­ecules into the inversion dimers, which are further linked by N—H⋯O hydrogen bonds into supra­molecular chains propagating along the b-axis direction. Weak C—H⋯π inter­actions are observed between neighbouring chains.
PMCID: PMC4257463  PMID: 25553001
crystal structure; indole; MRI contrast agent; N—H⋯O hydrogen bonds; C—H⋯π inter­actions
6.  Comparison of Contact Patterns Relevant for Transmission of Respiratory Pathogens in Thailand and the Netherlands Using Respondent-Driven Sampling 
PLoS ONE  2014;9(11):e113711.
Understanding infection dynamics of respiratory diseases requires the identification and quantification of behavioural, social and environmental factors that permit the transmission of these infections between humans. Little empirical information is available about contact patterns within real-world social networks, let alone on differences in these contact networks between populations that differ considerably on a socio-cultural level. Here we compared contact network data that were collected in the Netherlands and Thailand using a similar online respondent-driven method. By asking participants to recruit contact persons we studied network links relevant for the transmission of respiratory infections. We studied correlations between recruiter and recruited contacts to investigate mixing patterns in the observed social network components. In both countries, mixing patterns were assortative by demographic variables and random by total numbers of contacts. However, in Thailand participants reported overall more contacts which resulted in higher effective contact rates. Our findings provide new insights on numbers of contacts and mixing patterns in two different populations. These data could be used to improve parameterisation of mathematical models used to design control strategies. Although the spread of infections through populations depends on more factors, found similarities suggest that spread may be similar in the Netherlands and Thailand.
PMCID: PMC4244136  PMID: 25423343
7.  Improving bone mineral density reporting to patients with an illustration of personal fracture risk 
To determine patients’ preferences for, and understanding of, FRAX® fracture risk conveyed through illustrations.
Drawing on examples from published studies, four illustrations of fracture risk were designed and tested for patient preference, ease of understanding, and perceived risk. We enrolled a convenience sample of adults aged 50 and older at two medical clinics located in the Midwestern and Southern United States. In-person structured interviews were conducted to elicit patient ranking of preference, ease of understanding, and perceived risk for each illustration.
Most subjects (n = 142) were female (64%), Caucasian (76%) and college educated (78%). Of the four risk depictions, a plurality of participants (37%) listed a bar graph as most preferred. Subjects felt this illustration used the stoplight color system to display risk levels well and was the most “clear,” “clean,” and “easy to read”. The majority of subjects (52%) rated the pictogram as the most difficult to understand as this format does not allow people to quickly ascertain their individual risk category.
Communicating risk to patients with illustrations can be done effectively with clearly designed illustrations responsive to patient preference.
Trial Registration Identifier: NCT01507662
PMCID: PMC4260260
Osteoporosis; DXA Scan; Risk; Fracture; Bone; Patient education
8.  Abundance and Diversity of Bacterial Nitrifiers and Denitrifiers and Their Functional Genes in Tannery Wastewater Treatment Plants Revealed by High-Throughput Sequencing 
PLoS ONE  2014;9(11):e113603.
Biological nitrification/denitrification is frequently used to remove nitrogen from tannery wastewater containing high concentrations of ammonia. However, information is limited about the bacterial nitrifiers and denitrifiers and their functional genes in tannery wastewater treatment plants (WWTPs) due to the low-throughput of the previously used methods. In this study, 454 pyrosequencing and Illumina high-throughput sequencing, combined with molecular methods, were used to comprehensively characterize structures and functions of nitrification and denitrification bacterial communities in aerobic and anaerobic sludge of two full-scale tannery WWTPs. Pyrosequencing of 16S rRNA genes showed that Proteobacteria and Synergistetes dominated in the aerobic and anaerobic sludge, respectively. Ammonia-oxidizing bacteria (AOB) amoA gene cloning revealed that Nitrosomonas europaea dominated the ammonia-oxidizing community in the WWTPs. Metagenomic analysis showed that the denitrifiers mainly included the genera of Thauera, Paracoccus, Hyphomicrobium, Comamonas and Azoarcus, which may greatly contribute to the nitrogen removal in the two WWTPs. It is interesting that AOB and ammonia-oxidizing archaea had low abundance although both WWTPs demonstrated high ammonium removal efficiency. Good correlation between the qPCR and metagenomic analysis is observed for the quantification of functional genes amoA, nirK, nirS and nosZ, indicating that the metagenomic approach may be a promising method used to comprehensively investigate the abundance of functional genes of nitrifiers and denitrifiers in the environment.
PMCID: PMC4242629  PMID: 25420093
9.  Analysis of the bacterial community in chronic obstructive pulmonary disease sputum samples by denaturing gradient gel electrophoresis and real-time PCR 
BMC Pulmonary Medicine  2014;14(1):179.
The Global Initiative defines COPD for chronic obstructive lung disease as an entirely preventable and treatable disease characterized by sputum production, bacterial colonisation, neutrophilic bronchial airway inflammation and poor health status. The World Health Organization (WHO) estimates that COPD will become the fourth-most common cause of death worldwide, just behind ischemic heart disease, cerebrovascular disease and HIV/AIDS, by 2030. The aim of this study was to determine the main structure feature of sputum potentially pathogenic microorganisms in subjects with COPD during the clinical stable state.
We employed a molecular genetics-based investigation of the bacteria community, including DNA isolation, PCR amplification and DGGE profiling. PCR-denaturing gradient gel electrophoresis (DGGE) with universal primers targeting the V3 region of the 16S rRNA gene was employed to characterize the overall COPD patient sputum microbiota composition, and some excised gel bands were cloned for sequencing. Real-time PCR was further utilized to quantitatively analyze the subpopulation of microbiota using group-specific primers targeting Streptococcus pneumoniae, Klebsiella pneumoniae, Pseudomonas aeruginosa.
The DGGE profiles of two groups displayed significant differences between COPD and healthy groups (P < 0.05). Real-time PCR revealed significant increases of Streptococcus pneumoniae, Klebsiella pneumoniae and Pseudomonas aeruginosa (P < 0.05) in the COPD group compared with the healthy group.
This study revealed strong relationship between alterations of sputum microbiota and COPD. By determining the content of several types of bacteria, we can provide evidence to aid in the diagnosis and treatment of COPD.
PMCID: PMC4273488  PMID: 25403149
10.  ASPP2 Links the Apical Lateral Polarity Complex to the Regulation of YAP Activity in Epithelial Cells 
PLoS ONE  2014;9(10):e111384.
The Hippo pathway, by tightly controlling the phosphorylation state and activity of the transcription cofactors YAP and TAZ is essential during development and tissue homeostasis whereas its deregulation may lead to cancer. Recent studies have linked the apicobasal polarity machinery in epithelial cells to components of the Hippo pathway and YAP and TAZ themselves. However the molecular mechanism by which the junctional pool of YAP proteins is released and activated in epithelial cells remains unknown. Here we report that the tumour suppressor ASPP2 forms an apical-lateral polarity complex at the level of tight junctions in polarised epithelial cells, acting as a scaffold for protein phosphatase 1 (PP1) and junctional YAP via dedicated binding domains. ASPP2 thereby directly induces the dephosphorylation and activation of junctional YAP. Collectively, this study unearths a novel mechanistic paradigm revealing the critical role of the apical-lateral polarity complex in activating this localised pool of YAP in vitro, in epithelial cells, and in vivo, in the murine colonic epithelium. We propose that this mechanism may commonly control YAP functions in epithelial tissues.
PMCID: PMC4216074  PMID: 25360797
11.  Network Structure and Community Evolution on Twitter: Human Behavior Change in Response to the 2011 Japanese Earthquake and Tsunami 
Scientific Reports  2014;4:6773.
To investigate the dynamics of social networks and the formation and evolution of online communities in response to extreme events, we collected three datasets from Twitter shortly before and after the 2011 earthquake and tsunami in Japan. We find that while almost all users increased their online activity after the earthquake, Japanese speakers, who are assumed to be more directly affected by the event, expanded the network of people they interact with to a much higher degree than English speakers or the global average. By investigating the evolution of communities, we find that the behavior of joining or quitting a community is far from random: users tend to stay in their current status and are less likely to join new communities from solitary or shift to other communities from their current community. While non-Japanese speakers did not change their conversation topics significantly after the earthquake, nearly all Japanese users changed their conversations to earthquake-related content. This study builds a systematic framework for investigating human behaviors under extreme events with online social network data and our findings on the dynamics of networks and communities may provide useful insight for understanding how patterns of social interaction are influenced by extreme events.
PMCID: PMC4209381  PMID: 25346468
12.  Trends in and disparities for acute myocardial infarction: an analysis of Medicare claims data from 1992 to 2010 
BMC Medicine  2014;12(1):190.
It is unknown whether previously reported disparities for acute myocardial infarction (AMI) by race and sex have declined over time.
We used Medicare Part A administrative data files for 1992 to 2010 to evaluate changes in per-capita hospitalization rates for AMI, rates of revascularization (percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)), and 30-day mortality for four distinct patient subcohorts: black women; black men; white women; and white men, adjusted for age, comorbidities and year using logistic regression.
The study sample consisted of 4,045,267 AMI admissions between the years 1992 and 2010 (166,660 black women; 116,201 black men; 1,870,816 white women; 1,891,590 white men). AMI hospitalization rates differed significantly in 1992 to 1993 among black women (61.6 hospitalizations per 10,000 Medicare enrollees), black men (73.2 hospitalizations), white women (72.0 hospitalizations) and white men (113.2 hospitalizations) (P <0.0001). By 2009 to 2010 AMI hospitalization rates had declined substantially in all cohorts but disparities remained with significantly lower hospitalization rates among women and blacks compared to men and whites, respectively (P <0.0001). In multivariable-adjusted analyses, despite narrowing of the differences between cohorts over time, disparities in AMI hospitalization rates by race and sex remained statistically significant in 2009 to 2010 (P <0.001). In 1992 to 1993 and 2009 to 2010, rates of PCI within 30-days of AMI differed significantly among black women (8.6% in 1992 to 1993; 24.2% in 2009 to 2010), black men (10.4% and 32.6%), white women (12.8% and 30.5%), and white men (16.1% and 40.7%) (P <0.0001). In multivariable-adjusted analyses, racial disparities in procedure utilization appeared somewhat larger and sex-based disparities remained significant. Unadjusted 30-day mortality after AMI in 1992 to 1993 for black women, black men, white women and white men was 20.4%, 17.9%, 23.1% and 19.5%, respectively (P <0.0001); in 2009 to 2010 mortality was 17.1%, 15.3%, 18.2% and 16.2%, respectively (P <0.0001). In adjusted analyses, racial differences in mortality declined over time but differences by sex (higher mortality for women) persisted.
Disparities in AMI have declined modestly, but remain a problem, particularly with respect to patient sex.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0190-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4212130  PMID: 25341547
Myocardial infarction; MI; Disparity; Outcomes; Race; Sex; Mortality; PCI; Hospitalization rates
13.  Commentary: Containing the Ebola Outbreak - the Potential and Challenge of Mobile Network Data 
PLoS Currents  2014;6:ecurrents.outbreaks.0177e7fcf52217b8b634376e2f3efc5e.
PMCID: PMC4205120  PMID: 25642369
cellphone; disease model; disease outbreak; ebola; mobility; travel
14.  A Natural Flavonoid Glucoside, Icariin, Regulates Th17 and Alleviates Rheumatoid Arthritis in a Murine Model 
Mediators of Inflammation  2014;2014:392062.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that causes deformity of the joints and physical disability. Icariin, a natural flavonoid glucoside isolated from plants in the Epimedium family, has been proven to have various pharmacological activities. A recent study showed that icariin suppressed cartilage and bone degradation in mice of collagen-induced arthritis. However, the mechanism needs to be further investigated. In our current study, we found that icariin reduced the arthritis score and the incidence of arthritis compared with that in mice treated with water. Icariin inhibits the expression of various osteoclastogenic markers, such as β3 integrin, cathepsin K, and MMP9 in vitro. Icariin treatment in mice with CIA also resulted in less number of Th17 cells and decreased ratio of CD4+IL-17+ cells. The alleviated arthritis score and incidence of arthritis and reduced serum levels of IgG2a induced by icariin were abolished with additional IL-17 administration. Furthermore, icariin inhibited STAT3 activation in T cells and STAT3 inhibitor resulted in decreased IL-17 production and alleviated RA. In conclusion, icariin decreases Th17 cells and suppresses the production of IL-17, which contributes to the alleviated rheumatoid arthritis, through the inhibition of STAT3 activation.
PMCID: PMC4211316  PMID: 25374443
15.  Siah2 regulates tight junction integrity and cell polarity through control of ASPP2 stability 
Oncogene  2013;33(15):2004-2010.
Changes in cell adhesion and polarity are closely associated with epithelial cell transformation and metastatic capacity. The tumor suppressor protein ASPP2 has been implicated in control of cell adhesion and polarity, through its effect on the PAR complex. Here we demonstrate that under hypoxic conditions the ubiquitin ligase Siah2 controls ASPP2 availability, with concomitant effect on epithelial cell polarity. LC-MS/MS analysis identified ASPP2 and ASPP1 as Siah2 interacting proteins. Biochemical analysis confirmed this interaction and mapped degron motifs within ASPP2, which are required for Siah2-mediated ubiquitination and proteasomal-dependent degradation. Inhibition of Siah2 expression increases ASPP2 levels and enhances ASPP2-dependent maintenance of TJ integrity and polarized architecture in 3D organotypic culture. Conversely, increase of Siah2 expression under hypoxia decreases ASPP2 levels and the formation of apical polarity in 3D culture. In all, our studies demonstrate the role of Siah2 in regulation of TJ integrity and cell polarity under hypoxia, through its regulation of ASPP2 stability.
PMCID: PMC3917971  PMID: 23644657
ASPP2; Siah2; epithelial polarity; tight junction; hypoxia
16.  Variation of Medicare payments for total knee arthroplasty 
The Journal of arthroplasty  2013;28(9):1513-1520.
We analyzed the 2009 Medicare inpatient claims data and other databases to estimate Medicare payments for primary or revision total knee arthroplasty (TKA). The average Medicare hospital payment per procedure was $13464 for primary TKA (n=227587) and $17331 for revision TKA (n=18677). For both primary and revision TKA Medicare payments varied substantially across patients, hospitals and healthcare markets. Less than one percent of primary TKA cases but seven percent of revision TKA cases triggered Medicare “outlier” payments, which were $10000 or higher per case beyond regular diagnosis-related-group payments. Urban and major teaching hospitals were more likely to treat these unusually expensive cases. Hospitals in the Northeast and West regions tended to receive higher Medicare payments than hospitals in the Midwest.
PMCID: PMC3795823  PMID: 23845765
total knee arthroplasty; Medicare; payment; outlier payment; revision TKA
17.  Frequent mutations in chromatin-remodeling genes in pulmonary carcinoids 
Nature communications  2014;5:3518.
Pulmonary carcinoids are rare neuroendocrine tumors of the lung. The molecular alterations underlying the pathogenesis of these tumors have not been systematically studied so far. Here we perform gene copy number analysis (n=54), genome/exome (n=44) and transcriptome (n=69) sequencing of pulmonary carcinoids and observe frequent mutations in chromatin-remodeling genes. Covalent histone modifiers and subunits of the SWI/SNF complex are mutated in 40% and 22.2% of the cases respectively, with MEN1, PSIP1 and ARID1A being recurrently affected. In contrast to small-cell lung cancer and large-cell neuroendocrine tumors, TP53 and RB1 mutations are rare events, suggesting that pulmonary carcinoids are not early progenitor lesions of the highly aggressive lung neuroendocrine tumors but arise through independent cellular mechanisms. These data also suggest that inactivation of chromatin remodeling genes is sufficient to drive transformation in pulmonary carcinoids.
PMCID: PMC4132974  PMID: 24670920
18.  Total knee arthroplasty volume, utilization, and outcomes among Medicare beneficiaries, 1991–2010 
JAMA  2012;308(12):1227-1236.
Total Knee Arthroplasty (TKA) is one of the most common and costly surgical procedures performed in the United States (U.S.).
To examine longitudinal trends in volume, utilization and outcomes for primary and revision TKA between 1991 and 2010 in the U.S. Medicare population.
Design, Setting, and Participants
Observational cohort of 3,271,851 patients who underwent primary TKA and 318,563 who underwent revision TKA identified in Medicare Part A data files.
We examined changes in primary and revision TKA volume, per-capita utilization, hospital length of stay (LOS), readmission rates, and adverse outcomes.
Between 1991 and 2010 annual primary TKA volume increased 161.5% from 93,230 to 226,177 while per-capita utilization increased 99.2%. Revision TKA volume increased 105.9% from 9,650 to 19,871 while utilization increased 56.8%. For primary TKA, LOS decreased from 7.9 days (95% CI, 7.8–7.9) in 1991–1994 to 3.5 days (95% CI, 3.5-3.5) in 2007–2010 (P< 0.001). For primary TKA rates of adverse outcomes resulting in readmission remained stable between 1991–2010, but rates of all-cause 30-day readmission increased from 4.2% (95% CI, 4.1–4.2) to 5.0% (95% CI, 4.9–5.0) (P<0.001). For revision TKA, the decline in hospital LOS was accompanied by an increase in 30-day readmission from 6.1% (95% CI, 5.9–6.4) to 8.9% (95% CI, 8.7–9.2) (P<.001) and an increase in wound infection rates from 1.4% (95% CI, 1.3–1.5) to 3.0% (95% CI, 2.9–3.1) (P<.001).
Increases in TKA volume have largely been driven by increases in per-capita utilization. We also observed decreases in hospital LOS that were accompanied by increases in hospital readmission rates.
PMCID: PMC4169369  PMID: 23011713
19.  Nanotubular surface modification of metallic implants via electrochemical anodization technique 
Due to increased awareness and interest in the biomedical implant field as a result of an aging population, research in the field of implantable devices has grown rapidly in the last few decades. Among the biomedical implants, metallic implant materials have been widely used to replace disordered bony tissues in orthopedic and orthodontic surgeries. The clinical success of implants is closely related to their early osseointegration (ie, the direct structural and functional connection between living bone and the surface of a load-bearing artificial implant), which relies heavily on the surface condition of the implant. Electrochemical techniques for modifying biomedical implants are relatively simple, cost-effective, and appropriate for implants with complex shapes. Recently, metal oxide nanotubular arrays via electrochemical anodization have become an attractive technique to build up on metallic implants to enhance the biocompatibility and bioactivity. This article will thoroughly review the relevance of electrochemical anodization techniques for the modification of metallic implant surfaces in nanoscale, and cover the electrochemical anodization techniques used in the development of the types of nanotubular/nanoporous modification achievable via electrochemical approaches, which hold tremendous potential for bio-implant applications. In vitro and in vivo studies using metallic oxide nanotubes are also presented, revealing the potential of nanotubes in biomedical applications. Finally, an outlook of future growth of research in metallic oxide nanotubular arrays is provided. This article will therefore provide researchers with an in-depth understanding of electrochemical anodization modification and provide guidance regarding the design and tuning of new materials to achieve a desired performance and reliable biocompatibility.
PMCID: PMC4172084  PMID: 25258532
nanotubular arrays; anodization; implant; bioactivity; in vitro; in vivo
20.  Insurance status and the transfer of hospitalized patients: an observational study 
Annals of internal medicine  2014;160(2):81-90.
There is little objective evidence to support concerns that patients are transferred between hospitals based upon insurance status.
To examine the relationship between patients’ insurance coverage and inter-hospital transfer.
We analyzed data from the 2010 National Inpatient Sample.
All patients aged 18-64 years discharged alive from U.S. acute care hospitals with one of five common diagnoses (biliary tract disease, chest pain, pneumonia, septicemia, skin or subcutaneous infection).
For each diagnosis, we compared the proportion of hospitalized patients who were transferred to another acute-care hospital based upon insurance coverage (private, Medicare, Medicaid, and uninsured). We used logistic regression to estimate the odds of transfer for uninsured patients (reference category- privately insured) while adjusting for patient and hospital level factors. All analyses incorporated sampling and post-stratification weights.
Among 315,748 patients discharged from 1051 hospitals with our five diagnoses, the percentage of patients transferred to another acute-care hospital varied from 1.3% (skin infection) to 5.1% (septicemia). In unadjusted analyses uninsured patients were significantly less likely to be transferred for three diagnoses (p<.05). In adjusted analyses, uninsured patients were significantly less likely to be transferred than privately insured patients for the four diagnoses: biliary tract disease (Odds Ratio (OR) 0.73 (95% Confidence interval (CI) 0.55-0.96)); chest pain (OR 0.63 (CI 0.44-0.89)); septicemia (OR 0.76 (CI 0.64-0.91)); and skin infections (OR 0.64 (CI 0.46-0.89)). Women were significantly less likely to be transferred than men for all diagnoses.
This analysis relied on administrative data and lacked clinical detail.
Uninsured patients (and women) were significantly less likely to undergo inter-hospital transfer. Differences in transfer rates may contribute to healthcare disparities.
PMCID: PMC4157678  PMID: 24592493
21.  Identification of Genetic Bases of Vibrio fluvialis Species-Specific Biochemical Pathways and Potential Virulence Factors by Comparative Genomic Analysis 
Vibrio fluvialis is an important food-borne pathogen that causes diarrheal illness and sometimes extraintestinal infections in humans. In this study, we sequenced the genome of a clinical V. fluvialis strain and determined its phylogenetic relationships with other Vibrio species by comparative genomic analysis. We found that the closest relationship was between V. fluvialis and V. furnissii, followed by those with V. cholerae and V. mimicus. Moreover, based on genome comparisons and gene complementation experiments, we revealed genetic mechanisms of the biochemical tests that differentiate V. fluvialis from closely related species. Importantly, we identified a variety of genes encoding potential virulence factors, including multiple hemolysins, transcriptional regulators, and environmental survival and adaptation apparatuses, and the type VI secretion system, which is indicative of complex regulatory pathways modulating pathogenesis in this organism. The availability of V. fluvialis genome sequences may promote our understanding of pathogenic mechanisms for this emerging pathogen.
PMCID: PMC3957645  PMID: 24441165
22.  Geometric control of human stem cell morphology and differentiation† 
During tissue morphogenesis, stem cells and progenitor cells migrate, proliferate, and differentiate, with striking changes in cell shape, size, and acting mechanical stresses. The local cellular function depends on the spatial distribution of cytokines as well as local mechanical microenvironments in which the cells reside. In this study, we controlled the organization of human adipose derived stem cells using micro-patterning technologies, to investigate the influence of multi-cellular form on spatial distribution of cellular function at an early stage of cell differentiation. The underlying role of cytoskeletal tension was probed through drug treatment. Our results show that the cultivation of stem cells on geometric patterns resulted in pattern- and position-specific cell morphology, proliferation and differentiation. The highest cell proliferation occurred in the regions with large, spreading cells (such as the outer edge of a ring and the short edges of rectangles). In contrast, stem cell differentiation co-localized with the regions containing small, elongated cells (such as the inner edge of a ring and the regions next to the short edges of rectangles). The application of drugs that inhibit the formation of actomyosin resulted in the lack of geometrically specific differentiation patterns. This study confirms the role of substrate geometry on stem cell differentiation, through associated physical forces, and provides a simple and controllable system for studying biophysical regulation of cell function.
PMCID: PMC4124726  PMID: 20652175
23.  Initial Treatment of Men With Newly Diagnosed Lower Urinary Tract Dysfunction in the Veterans Health Administration 
Urology  2013;83(2):304-309.
To examine initial treatments given to men with newly diagnosed lower urinary tract dysfunction (LUTD) within a large integrated health care system in the United States.
We used data from 2003 to 2009 from the Veteran's Health Administration to identify newly diagnosed cases of LUTD using established ICD-9CM codes. Our primary outcome was initial LUTD treatment (3 months), categorized as watchful waiting (WW), medical therapy (MT), or surgical therapy (ST); our secondary outcome was pharmacotherapy class received. We used logistic regression models to examine patient, provider, and health system factors associated with receiving MT or ST when compared with WW.
There were 393,901 incident cases of LUTD, of which 58.0% initially received WW, 41.8% MT, and 0.2% ST. Of the MT men, 79.8% received an alpha-blocker, 7.7% a 5-alpha reductase inhibitor, 3.3% an anticholinergic, and 7.3% combined therapy (alpha-blocker and 5-alpha reductase inhibitor). In our regression models, we found that age (higher), race (white/black), income (low), region (northeast/south), comorbidities (greater), prostate-specific antigen (lower), and provider (nonurologist) were associated with an increased odds of receiving MT. We found that age (higher), race (white), income (low), region (northeast/south), initial provider (urologist), and prostate-specific antigen (higher) increased the odds of receiving ST.
Most men with newly diagnosed LUTD in the Veteran's Health Administration receive WW, and initial surgical treatment is rare. A large number of men receiving MT were treated with monotherapy, despite evidence that combination therapy is potentially more effective in the long-term, suggesting opportunities for improvement in initial LUTD management within this population.
PMCID: PMC4113078  PMID: 24286603
24.  Applications of RNA interference high-throughput screening technology in cancer biology and virology 
Protein & Cell  2014;5(11):805-815.
RNA interference (RNAi) is an ancient intra-cellular mechanism that regulates gene expression and cell function. Large-scale gene silencing using RNAi high-throughput screening (HTS) has opened an exciting frontier to systematically study gene function in mammalian cells. This approach enables researchers to identify gene function in a given biological context and will provide considerable novel insight. Here, we review RNAi HTS strategies and applications using case studies in cancer biology and virology.
PMCID: PMC4225462  PMID: 24952721
RNA interference (RNAi); short interfering RNA (siRNA); short hairpin RNA (shRNA); high-throughput screening; cancer; virology
25.  Applications of RNA interference high-throughput screening technology in cancer biology and virology 
Protein & Cell  2014;5(11):805-815.
RNA interference (RNAi) is an ancient intra-cellular mechanism that regulates gene expression and cell function. Large-scale gene silencing using RNAi high-throughput screening (HTS) has opened an exciting frontier to systematically study gene function in mammalian cells. This approach enables researchers to identify gene function in a given biological context and will provide considerable novel insight. Here, we review RNAi HTS strategies and applications using case studies in cancer biology and virology.
PMCID: PMC4225462  PMID: 24952721
RNA interference (RNAi); short interfering RNA (siRNA); short hairpin RNA (shRNA); high-throughput screening; cancer; virology

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