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2.  Disparities in Quality of Care among Publicly Insured Adults with Schizophrenia in Four Large US States, 2002–2008 
Health services research  2014;49(4):1121-1144.
Objective
To examine racial/ethnic disparities in quality of schizophrenia care and assess the size of observed disparities across states and over time.
Data Sources
Medicaid claims data from CA, FL, NY, and NC.
Study Design
Observational repeated cross-sectional panel cohort study of white, black, and Latino fee-for-service adult beneficiaries with schizophrenia. Main outcome was the relationship of race/ethnicity and year with a composite measure of quality of schizophrenia care derived from 14 evidence-based quality indicators.
Principal Findings
Quality was assessed for 325,373 12-month person-episodes between 2002 and 2008, corresponding to 123,496 Medicaid beneficiaries. In 2002, quality was lowest for blacks in all states. With the exception of FL, quality was lower for Latinos than whites. In CA, blacks had about 43% of the individual indicators met compared to 58% for whites. Quality improved annually for all groups in CA, NY, and NC. While in CA the improvement was slightly larger for Latinos, in FL quality improved for blacks but declined for Latinos and whites.
Conclusions
Quality of schizophrenia care is poor and racial/ethnic disparities exist among Medicaid beneficiaries from 4 states. The size of the disparities varied across the states, and most of the initial disparities were unchanged by 2008.
doi:10.1111/1475-6773.12162
PMCID: PMC4111783  PMID: 24628414
racial/ethnic disparities; schizophrenia; quality of care; trends; Medicaid
3.  Disparities in Quality of Care among Publicly Insured Adults with Schizophrenia in Four Large U.S. States, 2002–2008 
Health Services Research  2014;49(4):1121-1144.
Objective
To examine racial/ethnic disparities in quality of schizophrenia care and assess the size of observed disparities across states and over time.
Data Sources
Medicaid claims data from CA, FL, NY, and NC.
Study Design
Observational repeated cross-sectional panel cohort study of white, black, and Latino fee-for-service adult beneficiaries with schizophrenia. Main outcome was the relationship of race/ethnicity and year with a composite measure of quality of schizophrenia care derived from 14 evidence-based quality indicators.
Principal Findings
Quality was assessed for 325,373 twelve-month person-episodes between 2002 and 2008, corresponding to 123,496 Medicaid beneficiaries. In 2002, quality was lowest for blacks in all states. With the exception of FL, quality was lower for Latinos than whites. In CA, blacks had about 43 percent of the individual indicators met compared to 58 percent for whites. Quality improved annually for all groups in CA, NY, and NC. While in CA the improvement was slightly larger for Latinos, in FL quality improved for blacks but declined for Latinos and whites.
Conclusions
Quality of schizophrenia care is poor and racial/ethnic disparities exist among Medicaid beneficiaries from four states. The size of the disparities varied across the states, and most of the initial disparities were unchanged by 2008.
doi:10.1111/1475-6773.12162
PMCID: PMC4111783  PMID: 24628414
Racial/ethnic disparities; schizophrenia; quality of care; trends; Medicaid
4.  Evaluation of [111In]-Labeled Zinc-Dipicolylamine Tracers for SPECT Imaging of Bacterial Infection 
Purpose
This study prepared three structurally related zinc-dipicolylamine (ZnDPA) tracers with [111In] labels and conducted biodistribution and SPECT/CT imaging studies of a mouse leg infection model.
Methods
Two monovalent tracers, ZnDPA-[111In]DTPA and ZnDPA-[111In]DOTA, each with a single zinc-dipicolylamine targeting unit, and a divalent tracer, Bis(ZnDPA)-[111In]DTPA,with two zinc-dipicolylamine units were prepared. Organ biodistribution and SPECT/CT imaging studies were performed on living mice with a leg infection created by injection of clinically relevant Gram positive Streptococcus pyogenes. Fluorescent and luminescent Eu3+-labeled versions of these tracers were also prepared and used to measure relative affinity for the exterior membrane surface of bacterial cells and mimics of healthy mammalian cells.
Results
All three 111In-labeled radiotracers were prepared with radiopurity > 90%. The biodistribution studies showed that the two monovalent tracers were cleared from the body through the liver and kidney, with retained % injected dose for all organs of < 8 % at 20 hours and infected leg T/NT ratio of ≤ 3.0. Clearance of the divalent tracer from the bloodstream was slower and primarily through the liver, with a retained % injected dose for all organs < 37% at 20 hours and T/NT ratio rising to 6.2 after 20 hours. The SPECT/CT imaging indicated the same large difference in tracer pharmacokinetics and higher accumulation of the divalent tracer at the site of infection.
Conclusions
All three [111In]-ZnDPA tracers selectively targeted the site of a clinically relevant mouse infection model that could not be discerned by visual external inspection of the living animal. The highest target selectivity, observed with a divalent tracer equipped with two zinc-dipicolylamine targeting units, compares quite favorably with the imaging selectivities previously reported for other nuclear tracers that target bacterial cell surfaces. The tracer pharmacokinetics depended heavily on tracer molecular structure suggesting that it may be possible to rapidly fine-tune the structural properties for optimized in vivo imaging performance and clinical translation.
doi:10.1007/s11307-014-0758-8
PMCID: PMC4515950  PMID: 25115869
Zinc-dipicolylamine; infection imaging; SPECT/CT; 111-indium; molecular tracer
5.  Metabolic Engineering of Salmonella Vaccine Bacteria to Boost Human Vγ2Vδ2 T Cell Immunity 
Human Vγ2Vδ2 T cells monitor isoprenoid metabolism by recognizing foreign (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), a metabolite in the 2-C-methyl-D-erythritol-4-phosphate pathway used by most eubacteria and apicomplexan parasites, and self isopentenyl pyrophosphate, a metabolite in the mevalonate pathway used by humans. Whereas microbial infections elicit prolonged expansion of memory Vγ2Vδ2 T cells, immunization with prenyl pyrophosphates or aminobisphosphonates elicit short-term Vγ2Vδ2 expansion with rapid anergy and deletion upon subsequent immunizations. We hypothesized that a live, attenuated bacterial vaccine that overproduces HMBPP would elicit long lasting Vγ2Vδ2 T cell immunity by mimicking a natural infection. Therefore, we metabolically engineered the avirulent aroA− Salmonella enterica serovar Typhimurium SL7207 strain by deleting the gene for LytB (the downstream enzyme from HMBPP) and functionally complementing for this loss with genes encoding mevalonate pathway enzymes. LytB− Salmonella SL7207 had high HMBPP levels, infected human cells as efficiently as the wild-type bacteria, and stimulated large ex vivo expansions of Vγ2Vδ2 T cells from human donors. Importantly, vaccination of a rhesus monkey with live lytB− Salmonella SL7207 stimulated a prolonged expansion of Vγ2Vδ2 T cells without significant side effects or anergy induction. These studies provide proof-of-principle that metabolic engineering can be used to derive live bacterial vaccines that boost Vγ2Vδ2 T cell immunity. Similar engineering of metabolic pathways to produce lipid Ags or B vitamin metabolite Ags could be used to derive live bacterial vaccine for other unconventional T cells that recognize nonpeptide Ags.
doi:10.4049/jimmunol.1302746
PMCID: PMC4241231  PMID: 24943221
human; gamma delta T cell; Vγ2Vδ2 T cells; prenyl pyrophosphates; isopentenyl pyrophosphate; attenuated live bacterial vaccines; S. enterica serovar Typhimurium
6.  Bacterial Imaging and Photodynamic Inactivation Using Zinc(II)-Dipicolylamine BODIPY Conjugates† 
Targeted imaging and antimicrobial photodynamic inactivation (PDI) are emerging methods for detecting and eradicating pathogenic microorganisms. This study describes two structurally related optical probes that are conjugates of a zinc(II)-dipicolylamine targeting unit and a BODIPY chromophore. One probe is a microbial targeted fluorescent imaging agent, mSeek, and the other is an oxygen photosensitizing analogue, mDestroy. The conjugates exhibited high fluorescence quantum yield and singlet oxygen production, respectively. Fluorescence imaging and detection studies examined four bacterial strains: E. coli, S. aureus, K. pneumonia, and B. thuringiensis vegetative cells and purified spores. The fluorescent probe, mSeek, is not phototoxic and enabled detection of all tested bacteria at concentrations of ~100 CFU/mL for B. thuringiensis spores, ~1000 CFU/mL for S. aureus and ~10,000 CFU/mL for E. coli. The photosensitizer analogue, mDestroy, inactivated 99–99.99% of bacterial samples and selectively killed bacterial cells in the presence of mammalian cells. However, mDestroy was ineffective against B. thuringiensis spores. Together, the results demonstrate a new two-probe strategy to optimize PDI of bacterial infection/contamination.
doi:10.1039/c5pp00100e
PMCID: PMC4490101  PMID: 26063101
photodynamic inactivation; bacteria; spores; BODIPY; singlet oxygen; fluorescence microscopy
7.  Pancreatectomy Predicts Improved Survival for Pancreatic Adenocarcinoma: Results of an Instrumental Variable Analysis 
Annals of surgery  2015;261(4):740-745.
Background and Objective
Pancreatic resection is the standard therapy for patients with stage I/II pancreatic ductal adenocarcinoma (PDA), yet many studies demonstrate low rates of resection. The objective of this study is to evaluate whether increasing resection rates would result in an increase in average survival in patients with stage I/II PDA.
Methods
SEER data were analyzed for patients with stage I/II pancreatic head cancers treated from 2004–2009. Pancreatectomy rates were examined within Health Service Areas (HSA) across 18 SEER regions. An instrumental variables (IV) analysis was performed, using HSA rates as an instrument, to determine the impact of increasing resection rates on survival.
Results
Pancreatectomy was performed in 4,322 of the 8,323 patients evaluated with stage I/II PDA (overall resection rate=51.9%). The resection rate across HSAs ranged from an average of 38.6% in the lowest quintile to 67.3% in the highest quintile. Median survival was improved in HSAs with higher resection rates. IV analysis revealed that, for patients whose treatment choices were influenced by the rates of resection in their geographic region, pancreatectomy was associated with a statistically significant increase in overall survival.
Conclusions
When controlling for confounders using IV analysis, pancreatectomy is associated with a statistically significant increase in survival for patients with resectable PDA. Based on these results, if resection rates were to increase in select patients, then average survival would also be expected to increase. It is important that this information be provided to physicians and patients so they can properly weigh the risks and advantages of pancreatectomy as treatment for PDA.
doi:10.1097/SLA.0000000000000796
PMCID: PMC4277740  PMID: 24979599
pancreatic cancer; pancreatectomy; SEER; instrumental variable analysis; epidemiology; Health Services Area
8.  Effect of Steady-State Faldaprevir on the Pharmacokinetics of Steady-State Methadone and Buprenorphine-Naloxone in Subjects Receiving Stable Addiction Management Therapy 
The effects of steady-state faldaprevir on the safety, pharmacokinetics, and pharmacodynamics of steady-state methadone and buprenorphine-naloxone were assessed in 34 healthy male and female subjects receiving stable addiction management therapy. Subjects continued receiving a stable oral dose of either methadone (up to a maximum dose of 180 mg per day) or buprenorphine-naloxone (up to a maximum dose of 24 mg-6 mg per day) and also received oral faldaprevir (240 mg) once daily (QD) for 8 days following a 480-mg loading dose. Serial blood samples were taken for pharmacokinetic analysis. The pharmacodynamics of the opioid maintenance regimens were evaluated by the objective and subjective opioid withdrawal scales. Coadministration of faldaprevir with methadone or buprenorphine-naloxone resulted in geometric mean ratios for the steady-state area under the concentration-time curve from 0 to 24 h (AUC0–24,ss), the steady-state maximum concentration of the drug in plasma (Cmax,ss), and the steady-state concentration of the drug in plasma at 24 h (C24,ss) of 0.92 to 1.18 for (R)-methadone, (S)-methadone, buprenorphine, norbuprenorphine, and naloxone, with 90% confidence intervals including, or very close to including, 1.00 (no effect), suggesting a limited overall effect of faldaprevir. Although individual data showed moderate variability in the exposures between subjects and treatments, there was no evidence of symptoms of opiate overdose or withdrawal either during the coadministration of faldaprevir with methadone or buprenorphine-naloxone or after faldaprevir dosing was stopped. Similar faldaprevir exposures were observed in the methadone- and buprenorphine-naloxone-treated subjects. In conclusion, faldaprevir at 240 mg QD can be coadministered with methadone or buprenorphine-naloxone without dose adjustment, although given the relatively narrow therapeutic windows of these agents, monitoring for opiate overdose and withdrawal may still be appropriate. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637922.)
doi:10.1128/AAC.04046-14
PMCID: PMC4291392  PMID: 25385094
9.  Thiosquaramides: pH switchable anion transporters† 
The transport of anions across cellular membranes is an important biological function governed by specialised proteins. In recent years, many small molecules have emerged that mimick the anion transport behaviour of these proteins, but only a few of these synthetic molecules also display the gating/switching behaviour seen in biological systems. A small series of thiosquaramides was synthesised and their pH-dependent chloride binding and anion transport behaviour was investigated using 1H NMR titrations, single crystal X-ray diffraction and a variety of vesicle-based techniques. Spectrophotometric titrations and DFT calculations revealed that the thiosquaramides are significantly more acidic than their oxosquaramide analogues, with pKa values between 4.0 and 9.0. This led to the observation that at pH 7.2 the anion transport ability of the thiosquaramides is fully switched OFF due to deprotonation of the receptor, but is completely switched ON at lower pH.
doi:10.1039/C4SC01629G
PMCID: PMC4486358  PMID: 26146535
10.  Practice Guidance for Buprenorphine for the Treatment of Opioid Use Disorders: Results of an Expert Panel Process 
Substance abuse  2015;36(2):209-216.
Background
Although numbers of physicians credentialed to prescribe buprenorphine has increased over time, many credentialed physicians may be reluctant to treat individuals with opioid use disorders due to discomfort with prescribing buprenorphine. Though prescribing physicians are required to complete a training course, many have questions about buprenorphine and treatment guidelines have not been updated to reflect clinical experience in recent years. We report on an expert panel process to update and expand buprenorphine guidelines.
Methods
We identified candidate guidelines through expert opinion and a review of the literature and used a modified RAND/UCLA Appropriateness Method to assess the validity of the candidate guidelines. An expert panel completed two rounds of rating, with a meeting to discuss the guidelines between the first and second rating.
Results
Through the rating process, expert panel members rated 90 candidate guideline statements across eight domains, including candidacy for buprenorphine treatment, dosing of buprenorphine, psychosocial counseling, and treatment of co-occurring depression and anxiety. A total of 65 guideline statements (72%) were rated as valid. Expert panel members had agreement in some areas, such as the treatment of co-occurring mental health problems, but disagreement in others, including the appropriate dosing of buprenorphine given patient complexities.
Conclusions
Through an expert panel process, we developed an updated and expanded set of buprenorphine treatment guidelines; this additional guidance may increase credentialed physicians’ comfort with prescribing buprenorphine to patients with opioid use disorders. Future efforts should focus on appropriate dosing guidance and ensuring that guidelines can be adapted to a variety of practice settings.
doi:10.1080/08897077.2015.1012613
PMCID: PMC4470850  PMID: 25844527
opioid use disorders; buprenorphine; clinical practice guidelines
11.  Assessment of Radiation and Heavy Metals Risk due to the Dietary Intake of Marine Fishes (Rastrelliger kanagurta) from the Straits of Malacca 
PLoS ONE  2015;10(6):e0128790.
The environment of the Straits of Malacca receives pollution as a result of various industrial and anthropogenic sources, making systematic studies crucial in determining the prevailing water quality. Present study concerns concentrations of natural radionuclides and heavy metals in marine fish (Rastrelliger kanagurta) collected from the Straits of Malacca, since aquatic stock form an important source of the daily diet of the surrouding populace. Assessment was made of the concentrations of key indicator radionuclides (226Ra, 232Th, 40K) and heavy metals (As, Mn, Fe, Cr, Ni, Zn, Cu, Co, Sr, Al, Hg and Pb) together with various radiation indices linked to the consumption of seafish. The annual effective dose for all detected radionuclides for all study locations has been found to be within UNSCEAR acceptable limits as has the associated life-time cancer risk. The overall contamination of the sampled fish from heavy metals was also found to be within limits of tolerance.
doi:10.1371/journal.pone.0128790
PMCID: PMC4467845  PMID: 26075909
13.  Interactions of Francisella tularensis with Alveolar Type II Epithelial Cells and the Murine Respiratory Epithelium 
PLoS ONE  2015;10(5):e0127458.
Francisella tularensis is classified as a Tier 1 select agent by the CDC due to its low infectious dose and the possibility that the organism can be used as a bioweapon. The low dose of infection suggests that Francisella is unusually efficient at evading host defenses. Although ~50 cfu are necessary to cause human respiratory infection, the early interactions of virulent Francisella with the lung environment are not well understood. To provide additional insights into these interactions during early Francisella infection of mice, we performed TEM analysis on mouse lungs infected with F. tularensis strains Schu S4, LVS and the O-antigen mutant Schu S4 waaY::TrgTn. For all three strains, the majority of the bacteria that we could detect were observed within alveolar type II epithelial cells at 16 hours post infection. Although there were no detectable differences in the amount of bacteria within an infected cell between the three strains, there was a significant increase in the amount of cellular debris observed in the air spaces of the lungs in the Schu S4 waaY::TrgTn mutant compared to either the Schu S4 or LVS strain. We also studied the interactions of Francisella strains with human AT-II cells in vitro by characterizing the ability of these three strains to invade and replicate within these cells. Gentamicin assay and confocal microscopy both confirmed that F. tularensis Schu S4 replicated robustly within these cells while F. tularensis LVS displayed significantly lower levels of growth over 24 hours, although the strain was able to enter these cells at about the same level as Schu S4 (1 organism per cell), as determined by confocal imaging. The Schu S4 waaY::TrgTn mutant that we have previously described as attenuated for growth in macrophages and mouse virulence displayed interesting properties as well. This mutant induced significant airway inflammation (cell debris) and had an attenuated growth phenotype in the human AT-II cells. These data extend our understanding of early Francisella infection by demonstrating that Francisella enter significant numbers of AT-II cells within the lung and that the capsule and LPS of wild type Schu S4 helps prevent murine lung damage during infection. Furthermore, our data identified that human AT-II cells allow growth of Schu S4, but these same cells supported poor growth of the attenuated LVS strain in vitro. Collectively, these data further our understanding of the role of AT-II cells in Francisella infections.
doi:10.1371/journal.pone.0127458
PMCID: PMC4444194  PMID: 26010977
14.  Enhanced Activity and Stability of Organophosphorus Hydrolase via Interaction with an Amphiphilic Polymer 
A simple approach to enhancing the activity and stability of organophosphorous hydrolase (OPH) is developed based on interactions between the hydrophobic poly(propylene oxide) (PPO) block of amphiphillic Pluronics and the enzyme. This strategy provides an efficient route to new formulations for decontaminating organophosphate neurotoxins.
doi:10.1039/c3cc47675h
PMCID: PMC4059822  PMID: 24558645
15.  Fluorescence Imaging of Interscapular Brown Adipose Tissue in Living Mice† 
Brown adipose tissue (BAT) plays a key role in energy expenditure and heat generation and is a promising target for diagnosing and treating obesity, diabetes and related metabolism disorders. While several nuclear and magnetic resonance imaging methods are established for detecting human BAT, there are no convenient protocols for high throughput imaging of BAT in small animal models. Here we disclose a simple but effective method for non-invasive optical imaging of interscapular BAT in mice using a micellar formulation of the commercially available deep-red fluorescent probe, SRFluor680. Whole-body fluorescence imaging of living mice shows extensive accumulation of the fluorescent probe in the interscapular BAT and ex vivo analysis shows 3.5-fold selectivity for interscapular BAT over interscapular WAT. Additional imaging studies indicate that SRFluor680 uptake is independent of mouse species and BAT metabolic state. The results are consistent with an unusual pharmacokinetic process that involves irreversible translocation of the lipophilic SRFluor680 from the micelle nanocarrier into the adipocytes within the BAT. Multimodal PET/CT and planar fluorescence/X-ray imaging of the same living animal shows co-localization of BAT mass signal reported by the fluorescent probe and BAT metabolism signal reported by the PET agent, 18F-FDG. The results indicate a path towards a new, dual probe molecular imaging paradigm that allows separate and independent non-invasive visualization of BAT mass and BAT metabolism in a living subject.
doi:10.1039/C4TB01914H
PMCID: PMC4442081  PMID: 26015867
brown adipose tissue; molecular imaging; in vivo fluorescence imaging; PET imaging; dual modality imaging
16.  Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity 
Science (New York, N.Y.)  2014;346(6212):1000-1003.
Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium (RPE) in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease (GVHD), and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.
doi:10.1126/science.1261754
PMCID: PMC4274127  PMID: 25414314
17.  Gellan gum microgel-reinforced cell-laden gelatin hydrogels 
The relatively weak mechanical properties of hydrogels remain a major drawback for their application as load-bearing tissue scaffolds. Previously, we developed cell-laden double-network (DN) hydrogels that were composed of photocrosslinkable gellan gum (GG) and gelatin. Further research into the materials as tissue scaffolds determined that the strength of the DN hydrogels decreased when they were prepared at cell-compatible conditions, and the encapsulated cells in the DN hydrogels did not function as well as they did in gelatin hydrogels. In this work, we developed microgel-reinforced (MR) hydrogels from the same two polymers, which have better mechanical strength and biological properties in comparison to the DN hydrogels. The MR hydrogels were prepared by incorporating stiff GG microgels into soft and ductile gelatin hydrogels. The MR hydrogels prepared at cell-compatible conditions exhibited higher strength than the DN hydrogels and the gelatin hydrogels, the highest strength being 2.8 times that of the gelatin hydrogels. MC3T3-E1 preosteoblasts encapsulated in MR hydrogels exhibited as high metabolic activity as in gelatin hydrogels, which is significantly higher than that in the DN hydrogels. The measurement of alkaline phosphatase (ALP) activity and the amount of mineralization showed that osteogenic behavior of MC3T3-E1 cells was as much facilitated in the MR hydrogels as in the gelatin hydrogels, while it was not as much facilitated in the DN hydrogels. These results suggest that the MR hydrogels could be a better alternative to the DN hydrogels and have great potential as load-bearing tissue scaffolds.
doi:10.1039/C3TB20984A
PMCID: PMC4191820  PMID: 25309744
18.  Characterization of Francisella tularensis Schu S4 mutants identified from a transposon library screened for O-antigen and capsule deficiencies 
The lipopolysaccharide (LPS) and O-antigen polysaccharide capsule structures of Francisella tularensis play significant roles in helping these highly virulent bacteria avoid detection within a host. We previously created pools of F. tularensis mutants that we screened to identify strains that were not reactive to a monoclonal antibody to the O-antigen capsule. To follow up previously published work, we characterize further seven of the F. tularensis Schu S4 mutant strains identified by our screen. These F. tularensis strains carry the following transposon mutations: FTT0846::Tn5, hemH::Tn5, wbtA::Tn5, wzy::Tn5, FTT0673p/prsA::Tn5, manB::Tn5, or dnaJ::Tn5. Each of these strains displayed sensitivity to human serum, to varying degrees, when compared to wild-type F. tularensis Schu S4. By Western blot, only FTT0846::Tn5, wbtA::Tn5, wzy::Tn5, and manB::Tn5 strains did not react to the capsule and LPS O-antigen antibody 11B7, although the wzy::Tn5 strain did have a single O-antigen reactive band that was detected by the FB11 monoclonal antibody. Of these strains, manB::Tn5 and FTT0846 appear to have LPS core truncations, whereas wbtA::Tn5 and wzy::Tn5 had LPS core structures that are similar to the parent F. tularensis Schu S4. These strains were also shown to have poor growth within human monocyte derived macrophages (MDMs) and bone marrow derived macrophages (BMDMs). We examined the virulence of these strains in mice, following intranasal challenge, and found that each was attenuated compared to wild type Schu S4. Our results provide additional strong evidence that LPS and/or capsule are F. tularensis virulence factors that most likely function by providing a stealth shield that prevents the host immune system from detecting this potent pathogen.
doi:10.3389/fmicb.2015.00338
PMCID: PMC4419852  PMID: 25999917
Francisella tularensis; O-antigen; capsule; transposon mutagenesis; innate immunity; intracellular growth; mouse virulence
19.  Retrospective analysis of safety and feasibility of a 3 days on/11 days off temozolomide dosing regimen in recurrent adult malignant gliomas 
CNS oncology  2014;3(4):257-265.
SUMMARY
Aims
We report the safety and feasibility of a 3 days on/11 days off temozolomide regimen for the treatment of recurrent malignant gliomas.
Patients & methods
Fifteen adult patients were treated; 14 were treated with 300 mg/m2 and one treated with 250 mg/m2.
Results
We reviewed the toxicity, progression-free survival (PFS), overall survival and objective response rate. Two patients (13%) experienced grade 3 nausea/vomiting and six patients (40%) experienced grade 3 lymphopenia. Dose reduction and treatment delay occurred in eight (53%) cases. One patient discontinued treatment due to uncontrolled nausea/vomiting. Median PFS for glioblastoma patients was 4.1 months and 6-month PFS was 25%. Twelve patients exhibited stable disease (86%), one patient (7%) had progressive disease and one patient (7%) showed a partial response.
Conclusion
The ‘3 on/11 off’ temozolomide regimen for recurrent high-grade gliomas was tolerable and warrants further study in a larger, prospective study.
doi:10.2217/cns.14.29
PMCID: PMC4214215  PMID: 25286037
alternative regimens; chemotherapy; glioblastoma; glioma temodar; safety; temozolomide
20.  Protonation-Induced Microphase Separation in Thin Films of a Polyelectrolyte-Hydrophilic Diblock Copolymer 
ACS Macro Letters  2014;3(5):410-414.
Block copolymers composed of poly(oligo ethylene glycol methyl ether methacrylate) and poly(2-vinylpyridine) are disordered in the neat state but can be induced to order by protonation of the P2VP block, demonstrating a tunable and responsive method for triggering assembly in thin films. Comparison of protonation with the addition of salts shows that microphase separation is due to selective protonation of the P2VP block. Increasing acid incorporation and increasing 2-vinylpyridine content for P2VP minority copolymers both promote increasingly phase-separated morphologies, consistent with protonation increasing the effective strength of segregation between the two blocks. The self-assembled nanostructures formed after casting from acidic solutions may be tuned based on the amount and type of acid incorporation as well as the annealing treatment applied after casting, where both aqueous and polar organic solvents are shown to be effective. Therefore, POEGMA-b-P2VP is a novel ion-containing block copolymer whose morphologies can be facilely tuned during casting and processing by controlling its exposure to acid.
doi:10.1021/mz400650q
PMCID: PMC4045328  PMID: 24910809
21.  Patterns of cerebral and cerebellar white matter degeneration in ALS 
doi:10.1136/jnnp-2014-308172
PMCID: PMC4392231  PMID: 25053771
ALS; MRI; Cerebellar Disease; Neuroradiology; Motor Neuron Disease
22.  Evaluation of an Implementation Initiative for Embedding Dialectical Behavior Therapy in Community Settings 
We examined the effectiveness of Dialectical Behavior Therapy (DBT) training in community-based agencies. Data were gathered at four time points over a two-year period from front-line mental health therapists (N = 64) from 10 community-based agencies that participated in a DBT implementation initiative. We examined change on therapist attitudes towards consumers with Borderline Personality Disorder (BPD), confidence in the effectiveness of DBT, and use of DBT model components. All measures were self-report. Participating in DBT training resulted in positive changes over time, including improved therapist attitudes toward consumers with BPD, improved confidence in the effectiveness of DBT, and increased use of DBT components. Therapists who had the lowest baseline scores on the study outcomes had the greatest self-reported positive change in outcomes over time. Moreover, there were notable positive correlations in therapist characteristics; therapists who had the lowest baseline attitudes towards individuals with BPD, confidence in the effectiveness of DBT, or who were least likely to use DBT modes and components were the therapists who had the greatest reported increase over time in each respective area. DBT training with ongoing support resulted in changes not commonly observed in standard training approaches typically used in community settings. It is encouraging to observe positive outcomes in therapist self-reported skill, perceived self-efficacy and DBT component use, all of which are important to evidence-based treatment (EBT) implementation. Our results underscore the importance to recognize and target therapist diversity of learning levels, experience, and expertise in EBT implementation.
doi:10.1016/j.evalprogplan.2013.10.007
PMCID: PMC3946614  PMID: 24333657
Dialectical Behavior Therapy; DBT; implementation
23.  Accuracy Evaluation of Emergency Department Tracking System Timestamps 
Annals of emergency medicine  2008;52(5):504-511.
OBJECTIVES
Managers use timestamps from computerized tracking systems to evaluate emergency department (ED) processes. This study was designed to determine how accurately these timestamps reflect the actual ED events they purport to represent.
METHODS
An observer manually timestamped patient and provider movement events during all hours. The observed timestamps were then systematically matched to equivalent timestamps collected by an active tracking system (timestamps created by staff with keyboard/mouse) and a passive tracking system (timestamps created by sensor badge worn by staff members). The deviation time intervals between the matched timestamps were analyzed.
RESULTS
The observer noted a total of 901 events; 686 (76%) of these were successfully matched to active system timestamps and 60 (6.7%) were matched to passive system timestamps. For the active system, the median event was recorded 1.8 minutes before it was observed [IQR: 30.7 minutes before to 2.9 minutes after]. Protocol execution difficulties limited the study of the passive system (low number of successfully matched events). The median event was recorded by the passive system 1.1 minutes before it was observed [IQR: 1.3 minutes before to 0.9 minutes before] (n=60).
CONCLUSIONS
The timestamps recorded by both active and passive tracking systems contain systematic errors and non-normal distributions. The active system had much lower precision than the passive system, but similar accuracy when large numbers of active system observations are used. Medians should be used to represent timestamp and interval data for reporting purposes. Site specific data validation should be performed before using data in high-profile situations.Introduction
doi:10.1016/j.annemergmed.2007.11.036
PMCID: PMC4361868  PMID: 18313799
Emergency Service, Hospital: organization & administration; Medical Records Systems, Computerized: organization & administration; Hospital Information Systems: organization & administration; Automatic Data Processing/instrumentation/methods; Patient Identification Systems: organization & administration; Time Factors
24.  Dynamic, Nonsink Method for the Simultaneous Determination of Drug Permeability and Binding Coefficients in Liposomes 
Molecular Pharmaceutics  2014;11(4):1314-1325.
Drug release from liposomal formulations is governed by a complex interplay of kinetic (i.e., drug permeability) and thermodynamic factors (i.e., drug partitioning to the bilayer surface). Release studies under sink conditions that attempt to mimic physiological conditions are insufficient to decipher these separate contributions. The present study explores release studies performed under nonsink conditions coupled with appropriate mathematical models to describe both the release kinetics and the conditions in which equilibrium is established. Liposomal release profiles for a model anticancer agent, topotecan, under nonsink conditions provided values for both the first-order rate constant for drug release and the bilayer/water partition coefficient. These findings were validated by conducting release studies under sink conditions via dynamic dialysis at the same temperature and buffer pH. A nearly identical rate constant for drug release could be obtained from dynamic dialysis data when appropriate volume corrections were applied and a mechanism-based mathematical model was employed to account for lipid bilayer binding and dialysis membrane transport. The usefulness of the nonsink method combined with mathematical modeling was further explored by demonstrating the effects of topotecan dimerization and bilayer surface charge potential on the bilayer/water partition coefficient at varying suspension concentrations of lipid and drug.
doi:10.1021/mp400765n
PMCID: PMC3993891  PMID: 24628304
liposomes; nanoparticles; lipid bilayers; membrane partitioning; ultrafiltration; dynamic dialysis; drug release
25.  High Regional Variation in Urethroplasty in the United States 
The Journal of urology  2014;193(1):179-183.
Purpose
We identified clinical and regional factors associated with the use of urethroplasty vs repeat endoscopic management for urethral stricture disease.
Materials and Methods
We analyzed claims for patients 18 to 65 years old in the 2007 to 2011 MarketScan ® Commercial Claims and Encounters Database with a diagnosis of urethral stricture. The primary outcome was treatment with urethroplasty vs repeat endoscopic management, defined as more than 2 dilations or direct vision internal urethrotomies. The likelihood of urethroplasty vs repeat endoscopic management was determined for each major metropolitan area in the United States. Multivariate logistic regression was done to identify factors associated with urethroplasty.
Results
We identified 41,056 patients with urethral stricture, yielding a diagnosis rate of 296/100,000 men in MarketScan. Repeat endoscopic management and urethroplasty were performed in 2,700 and 1,444 patients, respectively. Compared to patients treated with repeat endoscopic management those with urethroplasty were younger (median age 44 vs 54 years) and more likely to have a Charlson comorbidity score of 0 (84% vs 77%), have traveled out of a metropolitan area for care (34% vs 17%) and have a reconstructive urologist in the treatment metropolitan area (76% and 62%, each p < 0.001). When controlling for age and Charlson comorbidity score, travel out of a metropolitan area (OR 2.7, 95% CI 2.2–3.3) and a reconstructive urologist in the treatment metropolitan area (OR 2.0, 95% CI 1.7–2.5) were associated with a greater likelihood of urethroplasty vs repeat endoscopic management.
Conclusions
Despite the well established benefits of urethroplasty compared to repeat endoscopic management a strong bias for repeat endoscopic management exists in many regions in the United States.
doi:10.1016/j.juro.2014.07.100
PMCID: PMC4359508  PMID: 25072180
urethra; urethral stricture; physician’s practice patterns; endoscopy; reconstructive surgical procedures

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