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Cysteamine as a Future Intervention in Cystic Fibrosis Against Current and Emerging Pathogens: A Patient-based ex vivo Study Confirming its Antimicrobial and Mucoactive Potential in Sputum. - EBioMedicine
Cysteamine has recently been shown to have in vitro properties potentially therapeutically beneficial in cystic fibrosis (CF). In this study we investigated the antimicrobial and mucolytic activity of cysteamine against the complex biologic matrix of CF sputum.Sputum samples were obtained from 23 CF adults. Sputum polymicrobial content after in vitro exposure to cysteamine and standard CF antibiotics was assessed after a single exposure and after 14Â days low-dose exposure. The effect of cysteamine on sputum spinnbarkeit was assessed.Cysteamine reduced sputum polymicrobial burden by 3Â Â·Â 18 (95% CI 2Â Â·Â 30-4Â Â·Â 07, pÂ <Â 0.001) log10 units after 24Â h incubation. Combined cysteamine and tobramycin reduced polymicrobial burden by a further 3Â Â·Â 75 (95% CI 2Â Â·Â 63-5Â Â·Â 07, pÂ <Â 0Â Â·Â 001) log10 units above that seen with tobramycin. Repeated low dosing with cysteamine reduced sputum polymicrobial load from day 10 onwards (pÂ =Â 0.032). Cysteamine reduced CF sputum viscoelasticity, sputum spinnbarkeit cysteamine 11.1Â mm/s (95% CI 3.95-18.2) vs DNAse 1.69Â mm/s (95% CI 0.73-2.65), pÂ =Â 0.016. Cysteamine was active against Mycobacterium abscessus as a monotherapy and also potentiated the effects of amikacin and azithromycin.Further investigation is required into the therapeutic potential of cysteamine in CF to treat emerging as well as established microbial pathogens and as a mucolytic agent.
Alert dwell time: introduction of a measure to evaluate interruptive clinical decision support alerts. - Journal of the American Medical Informatics Association : JAMIA
Metrics for evaluating interruptive prescribing alerts have many limitations. Additional methods are needed to identify opportunities to improve alerting systems and prevent alert fatigue. In this study, the authors determined whether alert dwell time-the time elapsed from when an interruptive alert is generated to when it is dismissed-could be calculated by using historical alert data from log files. Drug-drug interaction (DDI) alerts from 3 years of electronic health record data were queried. Alert dwell time was calculated for 25,965 alerts, including 777 unique DDIs. The median alert dwell time was 8â€‰s (range, 1-4913â€‰s). Resident physicians had longer median alert dwell times than other prescribers (Pâ€‰<â€‰.001). The 10 most frequent DDI alerts (nâ€‰=â€‰8759 alerts) had shorter median dwell times than alerts that only occurred once (Pâ€‰<â€‰.001). This metric can be used in future research to evaluate the effectiveness and efficiency of interruptive prescribing alerts.Â© The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
VRE and VSE Bacteremia Outcomes in the Era of Effective VRE Therapy: A Systematic Review and Meta-analysis. - Infection control and hospital epidemiology
BACKGROUND Prior data suggest that vancomycin-resistant Enterococcus (VRE) bacteremia is associated with worse outcomes than vancomycin-sensitive Enterococcus (VSE) bacteremia. However, many studies evaluating such outcomes were conducted prior to the availability of effective VRE therapies. OBJECTIVE To systematically review VRE and VSE bacteremia outcomes among hospital patients in the era of effective VRE therapy. METHODS Electronic databases and grey literature published between January 1997 and December 2014 were searched to identify all primary research studies comparing outcomes of VRE and VSE bacteremias among hospital patients, following the availability of effective VRE therapies. The primary outcome was all-cause, in-hospital mortality, while total hospital length of stay (LOS) was a secondary outcome. All meta-analyses were conducted in Review Manager 5.3 using random-effects, inverse variance modeling. RESULTS Among all the studies reviewed, 12 cohort studies and 1 case control study met inclusion criteria. Similar study designs were combined in meta-analyses for mortality and LOS. VRE bacteremia was associated with increased mortality compared with VSE bacteremia among cohort studies (odds ratio [OR], 1.80; 95% confidence interval [CI], 1.38-2.35; I2=0%; n=11); the case-control study estimate was similar, but not significant (OR, 1.93; 95% CI, 0.97-3.82). LOS was greater for VRE bacteremia patients than for VSE bacteremia patients (mean difference, 5.01 days; 95% CI, 0.58-9.44]; I2=0%; n=5). CONCLUSIONS Despite the availability of effective VRE therapy, VRE bacteremia remains associated with an increased risk of in-hospital mortality and LOS when compared to VSE bacteremia. Infect. Control Hosp. Epidemiol. 2015;37(1):26-35.
An Unusual Cause of Chest Pain in a Young Healthy Female. - The Journal of emergency medicine
Infection of the sternoclavicular joint is an uncommon disease that is usually seen in patients with underlying risk factors such as prior trauma, intravenous drug use, or diabetes mellitus. The true pathophysiology remains unknown, but underlying bacteremia has been found in a number of cases. Without proper diagnosis and treatment, severe complications such as mediastinitis, sepsis, or death can occur.This is a case of spontaneous stenoclavicular septic arthritis in an otherwise healthy female. The patient's lack of risk factors and minimal examination findings highlight the unusual nature of the case, as well as the challenges it presents in making an early diagnosis. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS CONDITION?: Emergency physicians should consider sternoclavicular joint infections in patients who present to the emergency department with chest pain, even in patients without risk factors. They should especially consider the diagnosis in patients with suspected musculoskeletal etiologies or in those with return visits for chest pain. Although most patients do well with treatment, the infection can be life threatening without appropriate interventions.Copyright Â© 2015 Elsevier Inc. All rights reserved.
CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRÎ² repertoire. - Blood
Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8(+) effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31(+)/CD4(+) putative thymic emigrants. T-cell receptor Î² (TCRÎ²) deep sequencing revealed a striking contraction of CD8(+) Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492.Â© 2015 by The American Society of Hematology.
Immune parameter analysis of children with sickle cell disease on hydroxycarbamide or chronic transfusion therapy. - British journal of haematology
Sickle cell disease (SCD) is increasingly appreciated as an inflammatory condition associated with alterations in immune phenotype and function. In this cross-sectional study we performed a multiparameter analysis of 18 immune markers in 114 paediatric SCD patients divided by treatment group [those receiving hydroxycrabamide (HC, previously termed hydroxyurea), chronic transfusion (CT), or no disease-modifying therapy] and 29 age-matched African American healthy controls. We found global elevation of most immune cell counts in SCD patients receiving no disease-modifying therapy at steady state. Despite the decrease in percentage of haemoglobin S associated with CT therapy, the abnormal cellular immune phenotype persisted in patients on CT. In contrast, in both univariate and multivariate analysis, treatment with HC was associated with normalization of the vast majority of leucocyte populations. This study provides additional support for HC treatment in SCD, as it appears that HC decreases the abnormally elevated immune cell counts in patients with SCD.Â© 2015 John Wiley & Sons Ltd.
Prehospital Breech Delivery with Fetal Head Entrapment -A Case Report and Review. - Prehospital emergency care : official journal of the National Association of EMS Physicians and the National Association of State EMS Directors
We present a case in which an emergency medical services (EMS) crew was called for a precipitous breech delivery with fetal head entrapment that was unrelieved following standard prehospital interventions and eventually resulted in neonatal cardiac arrest and death. Although this is a rare occurrence, EMS responders must have adequate training and guidelines on how to assist with vaginal delivery of breech presentation and how to appropriately manage fetal head entrapment in the field. There is little literature to provide guidance but it appears that standard EMS teaching does not represent current best obstetrical practice. We review the available literature, make expert recommendations, and provide a sample new treatment guideline for basic life support, advanced life support, and EMS physician response.
Cysteamine (LynovexÂ®), a novel mucoactive antimicrobial & antibiofilm agent for the treatment of cystic fibrosis. - Orphanet journal of rare diseases
There remains a critical need for more effective, safe, long-term treatments for cystic fibrosis (CF). Any successful therapeutic strategy designed to combat the respiratory pathology of this condition must address the altered lung physiology and recurrent, complex, polymicrobial infections and biofilms that affect the CF pulmonary tract. Cysteamine is a potential solution to these unmet medical needs and is described here for the first time as (LynovexÂ®) a single therapy with the potential to deliver mucoactive, antibiofilm and antibacterial properties; both in oral and inhaled delivery modes. Cysteamine is already established in clinical practice for an unrelated orphan condition, cystinosis, and is therefore being repurposed (in oral form) for cystic fibrosis from a platform of over twenty years of safety data and clinical experience.The antibacterial and antibiofilm attributes of cysteamine were determined against type strain and clinical isolates of CF relevant pathogens using CLSI standard and adapted microbiological methods and a BioFlux microfluidic system. Assays were performed in standard nutrient media conditions, minimal media, to mimic the low metabolic activity of microbes/persister cells in the CF respiratory tract and in artificial sputum medium. In vivo antibacterial activity was determined in acute murine lung infection/cysteamine nebulisation models. The mucolytic potential of cysteamine was assessed against DNA and mucin in vitro by semi-quantitative macro-rheology. In all cases, the 'gold standard' therapeutic agents were employed as control/comparator compounds against which the efficacy of cysteamine was compared.Cysteamine demonstrated at least comparable mucolytic activity to currently available mucoactive agents. Cysteamine was rapidly bactericidal against both metabolically active and persister cells of Pseudomonas aeruginosa and also emerging CF pathogens; its activity was not sensitive to high ionic concentrations characteristic of the CF lung. Cysteamine prevented the formation of, and disrupted established P. aeruginosa biofilms. Cysteamine was synergistic with conventional CF antibiotics; reversing antibiotic resistance/insensitivity in CF bacterial pathogens.The novel mucolytic-antimicrobial activity of cysteamine (LynovexÂ®) provides potential for a much needed new therapeutic strategy in cystic fibrosis. The data we present here provides a platform for cysteamine's continued investigation as a novel treatment for this poorly served orphan disease.
Matrix metalloproteinase-19 promotes metastatic behavior in vitro and is associated with increased mortality in non-small cell lung cancer. - American journal of respiratory and critical care medicine
Lung cancer is the leading cause of cancer death in both men and women in the United States and worldwide. Matrix metalloproteinases (MMPs) have been implicated in the development and progression of lung cancer, but their role in the molecular pathogenesis of lung cancer remains unclear. We have found that MMP19, a relatively novel member of the MMP family, is overexpressed in lung tumors when compared with control subjects.To test the hypothesis that MMP19 plays a significant role in the development and progression of non-small cell lung cancer (NSCLC).We have analyzed lung cancer gene expression data, immunostained lung tumors for MMP19, and performed in vitro assays to test the effects of MMP19 in NSCLC cells.We found that MMP19 gene and protein expression is increased in lung cancer tumors compared with adjacent and histologically normal lung tissues. In three independent datasets, increased MMP19 gene expression conferred a poorer prognosis in NSCLC. In vitro, we found that overexpression of MMP19 promotes epithelial-mesenchymal transition, migration, and invasiveness in multiple NSCLC cell lines. Overexpression of MMP19 with a mutation at the catalytic site did not impair epithelial-mesenchymal transition or expression of prometastasis genes. We also found that miR-30 isoforms, a microRNA family predicted to target MMP19, is markedly down-regulated in human lung cancer and regulates MMP19 expression.Taken together, these findings suggest that MMP19 is associated with the development and progression of NSCLC and may be a potential biomarker of disease severity and outcome.
Novel fluorinated lipopeptides from Bacillus sp. CS93 via precursor-directed biosynthesis. - Amino acids
While attempting to improve production of fluoro-iturin A in Bacillus sp. CS93 new mono- and di-fluorinated fengycins were detected in culture supernatants by (19)F NMR and tandem mass spectrometry, after incubation of the bacterium with 3-fluoro-L-tyrosine. The fluorinated amino acid was presumably incorporated in place of one or both of the tyrosyl residues in fengycin. Investigations to generate additional new fluorinated derivatives were undertaken using commercially available fluorinated phenylalanines and 2-fluoro- and 2,3-difluoro-tyrosine that were synthesised by Negishi cross-coupling of iodoalanine and fluorinated bromo-phenols. The anti-fungal activity of the fluorinated lipopeptides was assayed against Trichophyton rubrum and found to be similar to that of the non-fluorinated metabolites.
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500 University Dr Hershey, PA 17033