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1.  Decontamination Efficacy of Three Commercial-Off-The-Shelf (COTS) Sporicidal Disinfectants on Medium-Sized Panels Contaminated with Surrogate Spores of Bacillus anthracis 
PLoS ONE  2014;9(6):e99827.
In the event of a wide area release and contamination of a biological agent in an outdoor environment and to building exteriors, decontamination is likely to consume the Nation’s remediation capacity, requiring years to cleanup, and leading to incalculable economic losses. This is in part due to scant body of efficacy data on surface areas larger than those studied in a typical laboratory (5×10-cm), resulting in low confidence for operational considerations in sampling and quantitative measurements of prospective technologies recruited in effective cleanup and restoration response. In addition to well-documented fumigation-based cleanup efforts, agencies responsible for mitigation of contaminated sites are exploring alternative methods for decontamination including combinations of disposal of contaminated items, source reduction by vacuuming, mechanical scrubbing, and low-technology alternatives such as pH-adjusted bleach pressure wash. If proven effective, a pressure wash-based removal of Bacillus anthracis spores from building surfaces with readily available equipment will significantly increase the readiness of Federal agencies to meet the daunting challenge of restoration and cleanup effort following a wide-area biological release. In this inter-agency study, the efficacy of commercial-of-the-shelf sporicidal disinfectants applied using backpack sprayers was evaluated in decontamination of spores on the surfaces of medium-sized (∼1.2 m2) panels of steel, pressure-treated (PT) lumber, and brick veneer. Of the three disinfectants, pH-amended bleach, Peridox, and CASCAD evaluated; CASCAD was found to be the most effective in decontamination of spores from all three panel surface types.
PMCID: PMC4062434  PMID: 24940605
2.  CDR-restricted engineering of native human scFvs creates highly stable and soluble bifunctional antibodies for subcutaneous delivery 
mAbs  2013;5(6):882-895.
While myriad molecular formats for bispecific antibodies have been examined to date, the simplest structures are often based on the scFv. Issues with stability and manufacturability in scFv-based bispecific molecules, however, have been a significant hindrance to their development, particularly for high-concentration, stable formulations that allow subcutaneous delivery. Our aim was to generate a tetravalent bispecific molecule targeting two inflammatory mediators for synergistic immune modulation. We focused on an scFv-Fc-scFv format, with a flexible (A4T)3 linker coupling an additional scFv to the C-terminus of an scFv-Fc. While one of the lead scFvs isolated directly from a naïve library was well-behaved and sufficiently potent, the parental anti-CXCL13 scFv 3B4 required optimization for affinity, stability, and cynomolgus ortholog cross-reactivity. To achieve this, we eschewed framework-based stabilizing mutations in favor of complementarity-determining region (CDR) mutagenesis and re-selection for simultaneous improvements in both affinity and thermal stability. Phage-displayed 3B4 CDR-mutant libraries were used in an aggressive “hammer-hug” selection strategy that incorporated thermal challenge, functional, and biophysical screening. This approach identified leads with improved stability and >18-fold, and 4,100-fold higher affinity for both human and cynomolgus CXCL13, respectively. Improvements were exclusively mediated through only 4 mutations in VL-CDR3. Lead scFvs were reformatted into scFv-Fc-scFvs and their biophysical properties ranked. Our final candidate could be formulated in a standard biopharmaceutical platform buffer at 100 mg/ml with <2% high molecular weight species present after 7 weeks at 4 °C and viscosity <15 cP. This workflow has facilitated the identification of a truly manufacturable scFv-based bispecific therapeutic suitable for subcutaneous administration.
PMCID: PMC3896602  PMID: 23995618
affinity optimization; phage display; thermal stability; high concentration formulation; bispecific scFv-Fc-scFv
3.  Detection and Tracking of a Novel Genetically Tagged Biological Simulant in the Environment 
Applied and Environmental Microbiology  2012;78(23):8281-8288.
A variant of Bacillus thuringiensis subsp. kurstaki containing a single, stable copy of a uniquely amplifiable DNA oligomer integrated into the genome for tracking the fate of biological agents in the environment was developed. The use of genetically tagged spores overcomes the ambiguity of discerning the test material from pre-existing environmental microflora or from previously released background material. In this study, we demonstrate the utility of the genetically “barcoded” simulant in a controlled indoor setting and in an outdoor release. In an ambient breeze tunnel test, spores deposited on tiles were reaerosolized and detected by real-time PCR at distances of 30 m from the point of deposition. Real-time PCR signals were inversely correlated with distance from the seeded tiles. An outdoor release of powdered spore simulant at Aberdeen Proving Ground, Edgewood, MD, was monitored from a distance by a light detection and ranging (LIDAR) laser. Over a 2-week period, an array of air sampling units collected samples were analyzed for the presence of viable spores and using barcode-specific real-time PCR assays. Barcoded B. thuringiensis subsp. kurstaki spores were unambiguously identified on the day of the release, and viable material was recovered in a pattern consistent with the cloud track predicted by prevailing winds and by data tracks provided by the LIDAR system. Finally, the real-time PCR assays successfully differentiated barcoded B. thuringiensis subsp. kurstaki spores from wild-type spores under field conditions.
PMCID: PMC3497391  PMID: 23001670
4.  Corneal biomechanics in iatrogenic ectasia and keratoconus: A review of the literature 
Oman Journal of Ophthalmology  2013;6(1):12-17.
The Ocular Response Analyzer (ORA) (Reichert Ophthalmic Instruments, Buffalo, NY) allows direct measurement of corneal biomechanical properties. Since its introduction, many studies have sought to elucidate the clinical applications of corneal hysteresis (CH) and corneal resistance factor (CRF). More recently, detailed corneal deformation signal waveform analysis (WA) has potentially expanded the diagnostic capabilities of the ORA. In this review, the role of CH, CRF, and WA are examined in keratoconus (KC) and iatrogenic ectasia (IE). The PubMed database was searched electronically for peer-reviewed literature in July 2012 and August 2012 without date restrictions. The search strategy included medical subject heading (MeSH) and natural language terms to retrieve references on corneal biomechanics, CH, CRF, corneal deformation signal WA, IE, and KC. The evidence suggests that while CH and CRF are poor screening tools when used alone, increased sensitivity and specificity of KC and IE screening result when these parameters are combined with tomography and topography. Recent advances in WA are promising, but little is currently understood about its biomechanical and clinical relevance. Future studies should seek to refine the screening protocols for KC and IE as well as define the clinical applicability of WA parameters.
PMCID: PMC3678190  PMID: 23772119
Corneal hysteresis; corneal deformation signal waveform analysis; corneal resistance factor; keratoectasia; keratoconus; ocular response analyzer
5.  Astigmatism induced by conventional spherical ablation after PRK and LASIK in myopia with astigmatism < 1.00 D 
The purpose of this study was to evaluate surgically-induced astigmatism after spherical ablation in photorefractive keratectomy (PRK) and laser-assisted in situ keratomileusis (LASIK) for myopia with astigmatism < 1.00 D.
The charts of patients undergoing spherical PRK or LASIK for the correction of myopia with minimal astigmatism of <1.00 D from 2002 to 2012 at the John A Moran Eye Center in Salt Lake City, UT, were retrospectively reviewed. Astigmatism was measured by manifest refraction. The final astigmatic refractive outcome at 6 months postoperatively was compared with the initial refraction by Alpins vector analysis.
For PRK, average cylinder increased from 0.39 ± 0.25 (0.00–0.75) preoperatively to 0.55 ± 0.48 (0.00–1.75) postoperatively (P = 0.014), compared with an increase in LASIK eyes from 0.40 ± 0.27 (0.00–0.75) preoperatively to 0.52 ± 0.45 (0.00–2.00) postoperatively (P = 0.041). PRK eyes experienced an absolute value change in cylinder of 0.41 ± 0.32 (0.00–1.50) and LASIK eyes experienced a change of 0.41 ± 0.31 (0.00–1.50, P = 0.955). Mean surgically-induced astigmatism was 0.59 ± 0.35 (0.00–1.70) in PRK eyes, with an increase in surgically-induced astigmatism of 0.44 D for each additional 1.00 D of preoperative cylinder; in LASIK eyes, mean surgically-induced astigmatism was 0.55 ± 0.32 (0.00–1.80, P = 0.482), with an increase in surgically-induced astigmatism of 0.29 D for each 1.00 D of preoperative cylinder.
Spherical ablation can induce substantial astigmatism even in eyes with less than one diopter of preoperative astigmatism in both PRK and LASIK. No significant difference in the magnitude of surgically-induced astigmatism was found between eyes treated with PRK and LASIK, although surgically-induced astigmatism was found to increase with greater levels of preoperative astigmatism in both PRK and LASIK.
PMCID: PMC3532022  PMID: 23277735
surgically-induced astigmatism; ablation; photorefractive keratectomy; laser-assisted in situ keratomileusis
6.  Laser in situ keratomileusis in patients with collagen vascular disease: a review of the literature 
To evaluate the current United States Food and Drug Administration (FDA) recommendations regarding laser in situ keratomileusis (LASIK) surgery in patients with collagen vascular diseases (CVD) and assess whether these patients make appropriate candidates for laser vision correction, and offer treatment recommendations based on identified clinical data.
A literature search was conducted using PubMed, Medline, and Ovid to identify all existing studies of LASIK in patients with collagen vascular diseases. The search was conducted without date limitations. Keywords used for the search included MeSH terms: laser in situ keratomileusis, LASIK, refractive surgery, ocular surgery, and cataract surgery connected by “and” with the following MeSH and natural-language terms: collagen vascular disease, rheumatic disease, systemic disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, seronegative spondyloarthropathy, HLA B27, ankylosing spondylitis, reactive arthritis, psoriatic arthritis. The abstracts for all studies meeting initial search criteria were reviewed; relevant studies were included. No prospective studies were found; however, four retrospective case studies were identified that examined LASIK surgery in patients with CVD. Several case reports were also identified in similar fashion.
The FDA considers CVD a relative contraindication to LASIK surgery, due largely to the ocular complications associated with disease in the CVD spectrum. However, recent studies of LASIK in patients with CVD indicate LASIK may be safe for patients with very well-controlled systemic disease, minimal ocular manifestations, and no clinical signs or history of dry-eye symptoms.
LASIK surgery may be safe in patients with rheumatoid arthritis or systemic lupus erythematosus and the seronegative spondyloarthropathies if stringent preoperative criteria are met. Evidence suggests patients with Sjögren’s syndrome are not suitable candidates for LASIK.
PMCID: PMC3497460  PMID: 23152662
refractive surgery; ocular surgery; rheumatoid arthritis; systemic lupus erythematosus; Sjögren’s syndrome; seronegative spondyloarthropathies
7.  Anesthetic keratopathy presenting as bilateral Mooren-like ulcers 
This observational case report describes the development of bilateral Mooren-like ulcers in a patient with anesthetic keratopathy. A 42-year-old man with a recent history of minor eye trauma and pain self-treated with tetracaine eye drops presented with complaints of acutely worsening vision and severe pain bilaterally. His visual acuity at presentation was limited to hand motion. Slit-lamp examination revealed bilateral epithelial defects at the center of the cornea, and an area of stromal infiltration and thinning with an undermining leading edge resembling a Mooren’s ulcer in both eyes. Corneal haze and hypopyon were visible. Anesthetic use was halted immediately and the patient was started on prednisolone and mycophenolate mofetil (Cellcept®), after which visual acuity gradually improved and pain decreased. Despite improvement of symptoms, residual epithelial defects remained, and the patient was ultimately treated with keratoplasty for recovery of vision. We suggest that anesthetic keratopathy should be included in the differential diagnosis for any patient presenting with ring-shaped stromal infiltrates or nonhealing epithelial defects.
PMCID: PMC3484722  PMID: 23118524
anesthetic abuse; corneal damage; corneal ulceration
8.  Laser in-situ keratomileusis in patients with diabetes mellitus: a review of the literature 
A growing number of diabetic patients request laser in situ keratomileusis (LASIK) for elective vision correction each year. While the United States Food and Drug Administration considers diabetes a relative contraindication to LASIK surgery, there are several reports in the literature of LASIK being performed safely in this patient population. The purpose of this review was to examine whether diabetes should still be considered a contraindication to LASIK surgery by reviewing the ocular and systemic complications of diabetes, and examining the existing data on the outcomes of LASIK in diabetic patients.
A literature review was conducted through PubMed, Medline, and Ovid to identify any study on LASIK surgery in patients with diabetes mellitus. This search was conducted without date restrictions. The search used the Medical Subject Headings (MeSH®) term LASIK linked by the word “and” to the following MeSH and natural language terms: diabetes, diabetes mellitus, systemic disease, and contraindications. Abstracts for all studies meeting initial search criteria were reviewed for relevance. There were no prospective clinical studies identified. Three retrospective studies were identified. Key sources from these papers were identified, reviewed, and included as appropriate. An additional literature search was conducted to identify any study of ocular surgery on patients with diabetes using the MeSH terms refractive surgery, photorefractive keratectomy, radial keratotomy, cataract surgery, vitrectomy, and iridectomy linked by the word “and” to the following MeSH terms: diabetes, diabetes mellitus, and systemic disease. This search was conducted without date restrictions. Abstracts of studies meeting the initial search criteria were reviewed and articles deemed relevant to the subject were included in this review.
LASIK may be safe in diabetic patients with tight glycemic control and no ocular or systemic complications.
PMCID: PMC3474268  PMID: 23109803
diabetes mellitus; diabetic keratopathy; diabetic corneal neuropathy; refractive surgery; LASIK surgery
9.  Multigeneration Cross Contamination of Mail with Bacillus Species Spores by Tumbling ▿  
Applied and Environmental Microbiology  2010;76(14):4797-4804.
In 2001, envelopes loaded with Bacillus anthracis spores were mailed to Senators Daschle and Leahy as well as to the New York Post and NBC News buildings. Additional letters may have been mailed to other news agencies because there was confirmed anthrax infection of employees at these locations. These events heightened the awareness of the lack of understanding of the mechanism(s) by which objects contaminated with a biological agent might spread disease. This understanding is crucial for the estimation of the potential for exposure to ensure the appropriate response in the event of future attacks. In this study, equipment to simulate interactions between envelopes and procedures to analyze the spread of spores from a “payload” envelope (i.e., loaded internally with a powdered spore preparation) onto neighboring envelopes were developed. Another process to determine whether an aerosol could be generated by opening contaminated envelopes was developed. Subsequent generations of contaminated envelopes originating from a single payload envelope showed a consistent two-log decrease in the number of spores transferred from one generation to the next. Opening a tertiary contaminated envelope resulted in an aerosol containing 103 B. anthracis spores. We developed a procedure for sampling contaminated letters by a nondestructive method aimed at providing information useful for consequence management while preserving the integrity of objects contaminated during the incident and preserving evidence for law enforcement agencies.
PMCID: PMC2901736  PMID: 20511424
10.  Tetracyclines That Promote SMN2 Exon 7 Splicing as Therapeutics for Spinal Muscular Atrophy 
There is at present no cure or effective therapy for spinal muscular atrophy (SMA), a neurodegenerative disease that is the leading genetic cause of infant mortality. SMA usually results from loss of the SMN1 (survival of motor neuron 1) gene, which leads to selective motor neuron degeneration. SMN2 is nearly identical to SMN1 but has a nucleotide replacement that causes exon 7 skipping, resulting in a truncated, unstable version of the SMA protein. SMN2 is present in all SMA patients, and correcting SMN2 splicing is a promising approach for SMA therapy. We identified a tetracycline-like compound, PTK-SMA1, which stimulates exon 7 splicing and increases SMN protein levels in vitro and in vivo in mice. Unlike previously identified molecules that stimulate SMN production via SMN2 promoter activation or undefined mechanisms, PTK-SMA1 is a unique therapeutic candidate in that it acts by directly stimulating splicing of exon 7. Synthetic small-molecule compounds such as PTK-SMA1 offer an alternative to antisense oligonucleotide therapies that are being developed as therapeutics for a number of disease-associated splicing defects.
PMCID: PMC2818805  PMID: 20161659
11.  Surface Sampling of Spores in Dry-Deposition Aerosols▿  
The ability to reliably and reproducibly sample surfaces contaminated with a biological agent is a critical step in measuring the extent of contamination and determining if decontamination steps have been successful. The recovery operations following the 2001 attacks with Bacillus anthracis spores were complicated by the fact that no standard sample collection format or decontamination procedures were established. Recovery efficiencies traditionally have been calculated based upon biological agents which were applied to test surfaces in a liquid format and then allowed to dry prior to sampling tests, which may not be best suited for a real-world event with aerosolized biological agents. In order to ascertain if differences existed between air-dried liquid deposition and biological spores which were allowed to settle on a surface in a dried format, a study was undertaken to determine if differences existed in surface sampling recovery efficiencies for four representative surfaces. Studies were then undertaken to compare sampling efficiencies between liquid spore deposition and aerosolized spores which were allowed to gradually settle under gravity on four different test coupon types. Tests with both types of deposition compared efficiencies of four unique swabbing materials applied to four surfaces with various surface properties. Our studies demonstrate that recovery of liquid-deposited spores differs significantly from recovery of dry aerosol-deposited spores in most instances. Whether the recovery of liquid-deposited spores is overexaggerated or underrepresented with respect to that of aerosol-deposited spores depends upon the surface material being tested.
PMCID: PMC2612225  PMID: 18997021

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