1,243 results on '"Thomas J Walsh"'
Search Results
2. A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia.
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Antonio C Arrieta, Lillian Sung, John S Bradley, C Michel Zwaan, Davis Gates, Hetty Waskin, Patricia Carmelitano, Andreas H Groll, Thomas Lehrnbecher, Eric Mangin, Amita Joshi, Nicholas A Kartsonis, Thomas J Walsh, and Amanda Paschke
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Medicine ,Science - Abstract
BACKGROUND:Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS:This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to
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- 2019
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3. Predictors of sperm recovery after cryopreservation in testicular cancer
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James M Hotaling, Darshan P Patel, Christopher Vendryes, Natalya A Lopushnyan, Angela P Presson, Chong Zhang, Charles H Muller, and Thomas J Walsh
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cryopreservation ,fertility preservation ,seminoma ,testicular neoplasms ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Our objective was to identify predictors of improved postthaw semen quality in men with testicular cancer banking sperm for fertility preservation. We reviewed 173 individual semen samples provided by 67 men with testicular germ cell tumor (TGCT) who cryopreserved sperm before gonadotoxic treatment between 1994 and 2010 at our tertiary university medical center. Our main outcomes measures were independent predictors for the greater postthaw total motile count (TMC) in men with TGCT. Men with NSGCT were more likely to be younger (P < 0.01) and had high cancer stage (II or III, P < 0.01) compared with men with seminoma. In our multiple regression model, NSGCT histology, use of density gradient purification, and fresh TMC > median fresh TMC each had increased odds of a postthaw TMC greater than median postthaw TMC. Interestingly, age, advanced cancer stage (II or III), rapid freezing protocol, and motility enhancer did not show increased odds of improved postthaw TMC in our models. In conclusion, men with TGCT or poor fresh TMC should consider preserving additional vials (at least 15 vials) before oncologic treatment. Density gradient purification should be routinely used to optimize postthaw TMC in men with TGCT. Larger, randomized studies evaluating cancer stage and various cryopreservation techniques are needed to assist in counseling men with TGCT regarding fertility preservation and optimizing cryosurvival.
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- 2016
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4. Testicular fine-needle aspiration for the assessment of intratesticular hormone concentrations
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Ada P Lee, Mara Y Roth, Jean-Jacques Nya-Ngatchou, Kat Lin, Thomas J Walsh, Stephanie T Page, Alvin M Matsumoto, William J Bremner, John K Amory, and Bradley D Anawalt
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male contraception ,physiology ,reproductive and urinary ,testis ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Measurement of intratesticular sex steroid concentrations in men informs both the development of male hormonal contraceptives and the understanding of male infertility. Given the challenges of using invasive techniques to measure testicular hormone physiology, our group has used a minimally-invasive fine-needle aspiration technique to measure intratesticular hormones in normal healthy men. Herein, we present a post-hoc analysis of the safety and efficacy of testicular fine-needle aspiration (FNA) completed as part of six clinical trials. From 2001 through 2011, a total of 404 procedures were conducted among 163 research volunteers, 85.9% of which were successful in obtaining sufficient fluid for the measurement of intratesticular steroid concentrations. Pain was the most common side effect, with 36.8% of procedures associated with moderate procedural pain and 4.7% with severe procedural pain. Postprocedural pain was uncommon and abated within a few days. Mild local bruising occurred with 14.9% of procedures. Two serious adverse events (0.5%) required surgical intervention. The risk of an adverse event was not associated with age, body mass index, testicular size, or the volume of fluid aspirated. Testicular FNA to obtain fluid for measurement of intratesticular steroid concentrations frequently causes mild to moderate procedural pain, but serious adverse events occur rarely. Testicular FNA has been instrumental for defining human intratesticular hormone physiology and is a minimally-invasive, safe, effective method for obtaining fluid for research on testicular physiology and pathology.
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- 2016
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5. Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels.
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Thomas J Walsh, Molly M Shores, Chloe A Krakauer, Christopher W Forsberg, Alexandra E Fox, Kathryn P Moore, Anna Korpak, Susan R Heckbert, Steven B Zeliadt, Chloe E Kinsey, Mary Lou Thompson, Nicholas L Smith, and Alvin M Matsumoto
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Medicine ,Science - Abstract
PURPOSE:Testosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP. MATERIALS AND METHODS:Retrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively. RESULTS:Of the 147,593 men included, 58,617 were treated with testosterone. 313 aggressive CaPs were diagnosed, 190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49-0.65) and 123 among treated men (IR 0.58 per 1000 person years; 95% CI 0.48-0.69). After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, testosterone treatment was not associated with incident aggressive CaP (HR 0.89; 95% CI 0.70-1.13) or any CaP (HR 0.90; 95% CI 0.81-1.01). No association between cumulative testosterone dose or formulation and CaP was observed. CONCLUSIONS:Among men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials.
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- 2018
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6. Multiple roles for hypoxia inducible factor 1-alpha in airway epithelial cells during mucormycosis
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Povilas Kavaliauskas, Yiyou Gu, Naushaba Hasin, Karen T. Graf, Abdullah Alqarihi, Amol C. Shetty, Carrie McCracken, Thomas J. Walsh, Ashraf S. Ibrahim, and Vincent M. Bruno
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Science - Abstract
Abstract During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response.
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- 2024
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7. Role of NADPH oxidase versus neutrophil proteases in antimicrobial host defense.
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R Robert Vethanayagam, Nikolaos G Almyroudis, Melissa J Grimm, David C Lewandowski, Christine T N Pham, Timothy S Blackwell, Ruta Petraitiene, Vidmantas Petraitis, Thomas J Walsh, Constantin F Urban, and Brahm H Segal
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Medicine ,Science - Abstract
NADPH oxidase is a crucial enzyme in mediating antimicrobial host defense and in regulating inflammation. Patients with chronic granulomatous disease, an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates (ROIs), suffer from life-threatening bacterial and fungal infections. The mechanisms by which NADPH oxidase mediate host defense are unclear. In addition to ROI generation, neutrophil NADPH oxidase activation is linked to the release of sequestered proteases that are posited to be critical effectors of host defense. To definitively determine the contribution of NADPH oxidase versus neutrophil serine proteases, we evaluated susceptibility to fungal and bacterial infection in mice with engineered disruptions of these pathways. NADPH oxidase-deficient mice (p47(phox-/-)) were highly susceptible to pulmonary infection with Aspergillus fumigatus. In contrast, double knockout neutrophil elastase (NE)(-/-)×cathepsin G (CG)(-/-) mice and lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI)-deficient mice that are defective in neutrophil serine protease activation demonstrated no impairment in antifungal host defense. In separate studies of systemic Burkholderia cepacia infection, uniform fatality occurred in p47(phox-/-) mice, whereas NE(-/-)×CG(-/-) mice cleared infection. Together, these results show a critical role for NADPH oxidase in antimicrobial host defense against A. fumigatus and B. cepacia, whereas the proteases we evaluated were dispensable. Our results indicate that NADPH oxidase dependent pathways separate from neutrophil serine protease activation are required for host defense against specific pathogens.
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- 2011
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8. Development of a Combat-Relevant Murine Model of Wound Mucormycosis: A Platform for the Pre-Clinical Investigation of Novel Therapeutics for Wound-Invasive Fungal Diseases
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Rex J. R. Samdavid Thanapaul, Yonas A. Alamneh, Daniel K. Finnegan, Vlado Antonic, Rania Abu-Taleb, Christine Czintos, Dylan Boone, Wanwen Su, Venkatasivasai S. Sajja, Derese Getnet, Ashleigh Roberds, Thomas J. Walsh, and Alexander G. Bobrov
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combat wound-invasive fungal disease ,mucormycosis ,Rhizopus arrhizus ,Lichtheimia corymbifera ,liposomal amphotericin B ,mice ,Biology (General) ,QH301-705.5 - Abstract
Wound-invasive fungal diseases (WIFDs), especially mucormycosis, have emerged as life-threatening infections during recent military combat operations. Many combat-relevant fungal pathogens are refractory to current antifungal therapy. Therefore, animal models of WIFDs are urgently needed to investigate new therapeutic solutions. Our study establishes combat-relevant murine models of wound mucormycosis using Rhizopus arrhizus and Lichtheimia corymbifera, two Mucorales species that cause wound mucormycosis worldwide. These models recapitulate the characteristics of combat-related wounds from explosions, including blast overpressure exposure, full-thickness skin injury, fascial damage, and muscle crush. The independent inoculation of both pathogens caused sustained infections and enlarged wounds. Histopathological analysis confirmed the presence of necrosis and fungal hyphae in the wound bed and adjacent muscle tissue. Semi-quantification of fungal burden by colony-forming units corroborated the infection. Treatment with liposomal amphotericin B, 30 mg/kg, effectively controlled R. arrhizus growth and significantly reduced residual fungal burden in infected wounds (p < 0.001). This study establishes the first combat-relevant murine model of wound mucormycosis, paving the way for developing and evaluating novel antifungal therapies against combat-associated WIFDs.
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- 2024
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9. Composing Efficient, Robust Tests for Policy Selection.
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Dustin Morrill, Thomas J. Walsh 0001, Daniel Hernandez, Peter R. Wurman, and Peter Stone
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- 2023
10. Combination of Systemic and Lock-Therapies with Micafungin Eradicate Catheter-Based Biofilms and Infections Caused by Candida albicans and Candida parapsilosis in Neutropenic Rabbit Models
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Ruta Petraitiene, Vidmantas Petraitis, Myo H. Zaw, Kaiser Hussain, Rodolfo J. Ricart Arbona, Emanuel Roilides, and Thomas J. Walsh
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micafungin ,Candida albicans ,Candida parapsilosis ,biofilm ,catheter ,lock therapy ,Biology (General) ,QH301-705.5 - Abstract
Vascular catheter-related infections, primarily caused by Candida albicans and Candida parapsilosis, pose significant challenges due to the formation of biofilms on catheters, leading to refractory disease and considerable morbidity. We studied the efficacy of micafungin in systemic and lock therapies to eliminate catheter-based biofilms and deep tissue infections in experimental central venous catheter (CVC)-related candidemia in neutropenic rabbits. Silastic CVCs in rabbits were inoculated with 1 × 103 CFU/mL of C. albicans or C. parapsilosis, establishing catheter-based biofilm, and subjected to various treatments. Neutropenic rabbits treated with a combination of lock therapy and systemic micafungin demonstrated the most significant reduction in fungal burden, from 5.0 × 104 to 1.8 × 102 CFU/mL of C. albicans and from 5.9 × 104 to 2.7 × 102 CFU/mL of C. parapsilosis (p ≤ 0.001), in the CVC after 24 h, with full clearance of blood cultures after 72 h from treatment initiation. The combination of lock and systemic micafungin therapy achieved eradication of C. albicans from all studied tissues (0.0 ± 0.0 log CFU/g) vs. untreated controls (liver 7.5 ± 0.22, spleen 8.3 ± 0.25, kidney 8.6 ± 0.07, cerebrum 6.3 ± 0.31, vena cava 6.6 ± 0.29, and CVC wash 2.3 ± 0.68 log CFU/g) (p ≤ 0.001). Rabbits treated with a combination of lock and systemic micafungin therapy demonstrated a ≥2 log reduction in C. parapsilosis in all treated tissues (p ≤ 0.05) except kidney. Serum (1→3)-β-D-glucan levels demonstrated significant decreases in response to treatment. The study demonstrates that combining systemic and lock therapies with micafungin effectively eradicates catheter-based biofilms and infections caused by C. albicans or C. parapsilosis, particularly in persistently neutropenic conditions, offering promising implications for managing vascular catheter-related candidemia and providing clinical benefits in cases where catheter removal is not feasible.
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- 2024
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11. Outracing champion Gran Turismo drivers with deep reinforcement learning.
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Peter R. Wurman, Samuel Barrett, Kenta Kawamoto, James MacGlashan, Kaushik Subramanian, Thomas J. Walsh 0001, Roberto Capobianco, Alisa Devlic, Franziska Eckert, Florian Fuchs 0004, Leilani Gilpin, Piyush Khandelwal, Varun Raj Kompella, HaoChih Lin, Patrick MacAlpine, Declan Oller, Takuma Seno, Craig Sherstan, Michael D. Thomure, Houmehr Aghabozorgi, Leon Barrett, Rory Douglas, Dion Whitehead, Peter Dürr, Peter Stone, Michael Spranger, and Hiroaki Kitano
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- 2022
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12. Does Type 1 Diabetes Affect Male Infertility: Type 1 Diabetes Exchange Registry-Based Analysis
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Omer A. Raheem, Marah C. Hehemann, Marc J. Rogers, Judy N. Fustok, Irl B. Hirsch, Thomas J. Walsh
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type 1 diabetes ,male infertility ,clinical predictors ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
IntroductionThe prevalence of type 1 diabetes (T1D) has been increasing over the last few decades and is commonly believed to negatively impact male fertility. We aimed to estimate the prevalence of infertility among men with T1D and to characterize potential clinical predictors for male infertility among men with T1D. MethodsWe used data collected from the T1D Exchange Registry from 2012 to 2017. Men with T1D completed an infertility questionnaire indicating whether they had ever had problems conceiving a child or had ever received abnormal results from infertility testing. Collected data included age at questionnaire, age at diagnosis of T1D, duration of T1D, race/ethnicity, insurance status, education level, annual household income, hemoglobin A1c (HbA1c), low density lipoprotein (LDL), diabetic retinopathy, micro/macroalbuminuria, and renal failure. ResultsThe survey was completed by 2171 registry members, 33 (1.5%) of whom reported male infertility. Mean age at questionnaire was 38 and 56 years in the fertile and infertile groups, respectively (P < 0.001). There was no statistically significant difference in the mean age at T1D diagnosis (16 and 27 years), mean duration of T1D at questionnaire (22 and 30 years), white non-Hispanic ethnicity (1906/2138, 89% versus 30/33, 91%), private insurance (1509/2138, 79% versus 30/33, 91%), and annual household income in US dollars ≥ $100 000 (757/2138, 45% versus 16/33, 55%) in the fertile and infertile men, respectively. On multivariate analysis, for each year of advancing age, men were 5% more likely to experience infertility. Age at questionnaire was the only significant predictor of infertility (OR 1.05; 95%CI 1.03 to 1.08). Age at T1D diagnosis (OR 1.01; 95%CI 0.99 to 1.04), duration of T1D (OR 0.99; 95%CI 0.96 to 1.01), mean HbA1C (OR 1.03; 95%CI 0.77 to 1.37), diabetic retinopathy (OR 1.04; 95%CI 0.50 to 2.15), and mean LDL (OR 1.01; 95%CI 0.99 to 1.02) failed to independently predict infertility; however, presence of renal failure (OR 3.38; 95%CI 0.94 to 12.13) and micro/macroalbuminuria (OR 1.27; 95%CI 0.42 to 3.82) trended toward increased odds of i n fer t i l it y. ConclusionsThis study highlights the prevalence of male infertility among men with T1D. Beyond age, there were no independent clinical predictors for male infertility among men with T1D; however, men with clinical evidence of diabetes-associated renal compromise trended toward greater odds of infertility. Further studies of fertility in this growing, at-risk population are warranted.
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- 2021
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13. Novel antifungal agents in clinical trials [version 2; peer review: 2 approved]
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Samantha E. Jacobs, Panagiotis Zagaliotis, and Thomas J. Walsh
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Review ,Articles ,Antifungal Agents ,novel treatments ,pharmacokinetic and pharmacodynamic ,clinical trials - Abstract
Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics. The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics. This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim. We discuss three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties.
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- 2022
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14. Larone's Medically Important Fungi: A Guide to Identification
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Thomas J. Walsh, Randall T. Hayden, Davise H. Larone and Thomas J. Walsh, Randall T. Hayden, Davise H. Larone
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- 2020
15. Novel antifungal agents in clinical trials [version 1; peer review: 1 approved, 1 approved with reservations]
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Samantha E. Jacobs, Panagiotis Zagaliotis, and Thomas J. Walsh
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Review ,Articles ,Antifungal Agents ,novel treatments ,pharmacokinetic and pharmacodynamic ,clinical trials - Abstract
Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics. The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics. This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim. We examine three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties.
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- 2021
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16. Development of a Corticosteroid-Immunosuppressed Mouse Model to Study the Pathogenesis and Therapy of Influenza-Associated Pulmonary Aspergillosis
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Sebastian Wurster, Jezreel Pantaleón García, Nathaniel D Albert, Ying Jiang, Keerthi Bhoda, Vikram V Kulkarni, Yongxing Wang, Thomas J Walsh, Scott Evans, and Dimitrios P Kontoyiannis
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Infectious Diseases ,Immunology and Allergy - Abstract
Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.
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- 2023
17. Therapeutic Bacteriophages for Gram-Negative Bacterial Infections in Animals and Humans
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Panagiotis, Zagaliotis, Jordyn, Michalik-Provasek, Jason J, Gill, and Thomas J, Walsh
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Microbiology (medical) ,Infectious Diseases ,Immunology ,Immunology and Allergy ,Molecular Biology - Abstract
Drug-resistant Gram-negative bacterial pathogens are an increasingly serious health threat causing worldwide nosocomial infections with high morbidity and mortality. Of these, the most prevalent and severe are Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Salmonella typhimurium. The extended use of antibiotics has led to the emergence of multidrug resistance in these bacteria. Drug-inactivating enzymes produced by these bacteria, as well as other resistance mechanisms, render drugs ineffective and make treatment of such infections more difficult and complicated. This makes the development of novel antimicrobial agents an urgent necessity. Bacteriophages, which are bacteria-killing viruses first discovered in 1915, have been used as therapeutic antimicrobials in the past, but their use was abandoned due to the widespread availability of antibiotics in the 20th century. The emergence, however, of drug-resistant pathogens has re-affirmed the need for bacteriophages as therapeutic strategies. This review describes the use of bacteriophages as novel agents to combat this rapidly emerging public health crisis by comprehensively enumerating and discussing the innovative use of bacteriophages in both animal models and in patients infected by Gram-negative bacteria.
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- 2022
18. Online Regression for Data With Changepoints Using Gaussian Processes and Reusable Models.
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Robert C. Grande, Thomas J. Walsh 0001, Girish Chowdhary 0001, Sarah Ferguson, and Jonathan P. How
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- 2017
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19. New Developments in Pediatric Antifungal Pharmacology
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Andreas H, Groll, Emmanuel, Roilides, and Thomas J, Walsh
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Microbiology (medical) ,Echinocandins ,Antifungal Agents ,Infectious Diseases ,Mycoses ,Pediatrics, Perinatology and Child Health ,Humans ,Child - Published
- 2022
20. Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients
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Silke Gastine, Georg Hempel, Michael N Neely, Thomas J Walsh, and Andreas H Groll
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Pharmacology ,Microbiology (medical) ,Echinocandins ,Antifungal Agents ,Infectious Diseases ,Caspofungin ,Humans ,Pharmacology (medical) ,Child ,Monte Carlo Method ,Invasive Fungal Infections - Abstract
Background Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. Objectives Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. Methods A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0–24 h/MIC together with reported AUC0–24 h from previously reported paediatric trials were used to guide adequate exposure. Results and Conclusions A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.
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- 2022
21. Impact of a Rapid Molecular Test for Klebsiella pneumoniae Carbapenemase and Ceftazidime-Avibactam Use on Outcomes After Bacteremia Caused by Carbapenem-Resistant Enterobacterales
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Michael J, Satlin, Liang, Chen, Angela, Gomez-Simmonds, Jamie, Marino, Gregory, Weston, Tanaya, Bhowmick, Susan K, Seo, Steven J, Sperber, Angela C, Kim, Brandon, Eilertson, Sierra, Derti, Stephen G, Jenkins, Michael H, Levi, Melvin P, Weinstein, Yi-Wei, Tang, Tao, Hong, Stefan, Juretschko, Katherine L, Hoffman, Thomas J, Walsh, Lars F, Westblade, Anne-Catrin, Uhlemann, and Barry N, Kreiswirth
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Microbiology (medical) ,Infectious Diseases - Abstract
Background Patients with bacteremia due to carbapenem-resistant Enterobacterales (CRE) experience delays until appropriate therapy and high mortality rates. Rapid molecular diagnostics for carbapenemases and new β-lactam/β-lactamase inhibitors may improve outcomes. Methods We conducted an observational study of patients with CRE bacteremia from 2016 to 2018 at 8 New York and New Jersey medical centers and assessed center-specific clinical microbiology practices. We compared time to receipt of active antimicrobial therapy and mortality between patients whose positive blood cultures underwent rapid molecular testing for the Klebsiella pneumoniae carbapenemase (KPC) gene (blaKPC) and patients whose cultures did not undergo this test. CRE isolates underwent antimicrobial susceptibility testing by broth microdilution and carbapenemase profiling by whole-genome sequencing. We also assessed outcomes when ceftazidime-avibactam and polymyxins were used as targeted therapies. Results Of 137 patients with CRE bacteremia, 89 (65%) had a KPC-producing organism. Patients whose blood cultures underwent blaKPC PCR testing (n = 51) had shorter time until receipt of active therapy (median: 24 vs 50 hours; P = .009) compared with other patients (n = 86) and decreased 14-day (16% vs 37%; P = .007) and 30-day (24% vs 47%; P = .007) mortality. blaKPC PCR testing was associated with decreased 30-day mortality (adjusted odds ratio: .37; 95% CI: .16–.84) in an adjusted model. The 30-day mortality rate was 10% with ceftazidime-avibactam monotherapy and 31% with polymyxin monotherapy (P = .08). Conclusions In a KPC-endemic area, blaKPC PCR testing of positive blood cultures was associated with decreased time until appropriate therapy and decreased mortality for CRE bacteremia, and ceftazidime-avibactam is a reasonable first-line therapy for these infections.
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- 2022
22. Food and Drug Administration Public Workshop Summary—Development Considerations of Antifungal Drugs to Address Unmet Medical Need
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Yuliya Yasinskaya, Shukal Bala, Ursula Waack, Cheryl Dixon, Karen Higgins, Jason N Moore, Caroline J Jjingo, Elizabeth O'Shaughnessy, Philip Colangelo, Radu Botgros, Sumathi Nambiar, David Angulo, Aaron Dane, Tom Chiller, Michael R Hodges, Taylor Sandison, William Hope, Thomas J Walsh, Peter Pappas, Aspasia Katragkou, Laura Kovanda, John H Rex, Kieren A Marr, Luis Ostrosky-Zeichner, Shohko Sekine, Monika Deshpande, Sunita J Shukla, and John Farley
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Microbiology (medical) ,Infectious Diseases - Abstract
Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development.
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- 2023
23. Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity
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Nicholas M. Smith, Katie Rose Boissonneault, Liang Chen, Vidmantas Petraitis, Ruta Petraitiene, Xun Tao, Jieqiang Zhou, Yinzhi Lang, Povilas Kavaliauskas, Zackery P. Bulman, Patricia N. Holden, Raymond Cha, Jürgen B. Bulitta, Barry N. Kreiswirth, Thomas J. Walsh, and Brian T. Tsuji
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Pharmacology ,Microbial Sensitivity Tests ,Clinical Therapeutics ,Ceftazidime ,beta-Lactamases ,Anti-Bacterial Agents ,Aztreonam ,Drug Combinations ,Klebsiella pneumoniae ,Infectious Diseases ,Cell Wall ,Klebsiella ,Animals ,Pharmacology (medical) ,Rabbits ,Azabicyclo Compounds ,Polymyxin B - Abstract
Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality (P
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- 2023
24. Sample Efficient Reinforcement Learning with Gaussian Processes.
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Robert C. Grande, Thomas J. Walsh 0001, and Jonathan P. How
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- 2014
25. Reinforcement learning with multi-fidelity simulators.
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Mark Cutler, Thomas J. Walsh 0001, and Jonathan P. How
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- 2014
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26. One size does not fit all: variations by ethnicity in demographic characteristics of men seeking fertility treatment across North America
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Peter N. Kolettis, Kirk C. Lo, Robert E. Brannigan, Scott I. Zeitlin, Tung Chin M. Hsieh, Jared M. Bieniek, James M. Dupree, Edmund Y. Ko, Susan Lau, Victor Chow, James M. Hotaling, Ajay K. Nangia, Jason C. Hedges, Armand Zini, Mary K. Samplaski, Aaron Spitz, Keith Jarvi, Eugene F. Fuchs, David Shin, Andrew B. Chen, James F. Smith, Jay I. Sandlow, Thomas J. Walsh, Marc A. Fisher, Katherine Lajkosz, Marc Goldstein, Trustin Domes, Ethan D. Grober, and J. C. Trussell
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Retrospective review ,business.industry ,media_common.quotation_subject ,Ethnic group ,Outcome measures ,Obstetrics and Gynecology ,Fertility ,Race (biology) ,Reproductive Medicine ,Male fertility ,Biologic Factors ,Medicine ,Racial differences ,business ,Demography ,media_common - Abstract
Objective To compare racial differences in male fertility history and treatment. Design Retrospective review of prospectively collected data. Setting North American reproductive urology centers. Patient(s) Males undergoing urologist fertility evaluation. Intervention(s) None. Main Outcome Measure(s) Demographic and reproductive Andrology Research Consortium data. Result(s) The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, Conclusion(s) Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment.
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- 2021
27. Candida auris Pan-Drug-Resistant to Four Classes of Antifungal Agents
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Samantha E. Jacobs, Jonathan L. Jacobs, Emily K. Dennis, Sarah Taimur, Meenakshi Rana, Dhruv Patel, Melissa Gitman, Gopi Patel, Sarah Schaefer, Kishore Iyer, Jang Moon, Victoria Adams, Polina Lerner, Thomas J. Walsh, YanChun Zhu, Mohammed Rokebul Anower, Mayuri M. Vaidya, Sudha Chaturvedi, and Vishnu Chaturvedi
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Pharmacology ,Infectious Diseases ,Antifungal Agents ,Drug Resistance, Fungal ,Mechanisms of Resistance ,Humans ,Pharmacology (medical) ,Microbial Sensitivity Tests ,Candida auris ,Phylogeny - Abstract
Candida auris is an urgent antimicrobial resistance threat due to its global emergence, high mortality, and persistent transmissions. Nearly half of C. auris clinical and surveillance cases in the United States are from the New York and New Jersey Metropolitan area. We performed genome, and drug-resistance analysis of C. auris isolates from a patient who underwent multi-visceral transplantation. Whole-genome comparisons of 19 isolates, collected over 72 days, revealed closed similarity (Average Nucleotide Identity > 0.9996; Aligned Percentage > 0.9764) and a distinct subcluster of NY C. auris South Asia Clade I. All isolates had azole-linked resistance in ERG11(K143R) and CDR1(V704L). Echinocandin resistance first appeared with FKS1(S639Y) mutation and then a unique FKS1(F635C) mutation. Flucytosine-resistant isolates had mutations in FCY1, FUR1, and ADE17. Two pan-drug-resistant C. auris isolates had uracil phosphoribosyltransferase deletion (FUR1[1Δ33]) and the elimination of FUR1 expression, confirmed by a qPCR test developed in this study. Besides ERG11 mutations, four amphotericin B-resistant isolates showed no distinct nonsynonymous variants suggesting unknown genetic elements driving the resistance. Pan-drug-resistant C. auris isolates were not susceptible to two-drug antifungal combinations tested by checkerboard, Etest, and time-kill methods. The fungal population pattern, discerned from SNP phylogenetic analysis, was consistent with in-hospital or inpatient evolution of C. auris isolates circulating locally and not indicative of a recent introduction from elsewhere. The emergence of pan-drug-resistance to four major classes of antifungals in C. auris is alarming. Patients at high risk for drug-resistant C. auris might require novel therapeutic strategies and targeted pre-and/or posttransplant surveillance.
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- 2022
28. Osteoarticular Mycoses
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Maria N. Gamaletsou, Blandine Rammaert, Barry Brause, Marimelle A. Bueno, Sanjeet S. Dadwal, Michael W. Henry, Aspasia Katragkou, Dimitrios P. Kontoyiannis, Matthew W. McCarthy, Andy O. Miller, Brad Moriyama, Zoi Dorothea Pana, Ruta Petraitiene, Vidmantas Petraitis, Emmanuel Roilides, Jean-Pierre Sarkis, Maria Simitsopoulou, Nikolaos V. Sipsas, Saad J. Taj-Aldeen, Valérie Zeller, Olivier Lortholary, Thomas J. Walsh, Laiko General Hospital, University of Athens School of Medicine, Pharmacologie des anti-infectieux et antibiorésistance (PHAR2), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Hospital for Special Surgery, Far Eastern Federal University (FEFU), City of Hope National Medical Center, Nationwide Children's Hospital, The Ohio State University School of Medicine, The University of Texas M.D. Anderson Cancer Center [Houston], Weill Medical College of Cornell University [New York], New York Presbyterian Hospital, NIH Clinical Center, Bethesda, Maryland, Hippokration General Hospital, Aristotle University of Thessaloniki, Hamad Medical Corporation [Doha, Qatar], Groupe Hospitalier Diaconesses Croix Saint-Simon, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génomique évolutive, modélisation et santé (GEMS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Center for Innovative Therapeutics and Diagnostics, Richmond, Virginia
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Microbiology (medical) ,cryptococcosis ,phaeohyphomycosis ,General Immunology and Microbiology ,histoplasmosis ,Epidemiology ,coccidioidomycosis ,Public Health, Environmental and Occupational Health ,osteomyelitis ,candidiasis ,mucormycosis ,antifungal therapy ,Infectious Diseases ,aspergillosis ,mycoses ,[SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology - Abstract
Osteoarticular mycoses are chronic debilitating infections that require extended courses of antifungal therapy and may warrant expert surgical intervention. As there has been no comprehensive review of these diseases, the International Consortium for Osteoarticular Mycoses prepared a definitive treatise for this important class of infections. Among the etiologies of osteoarticular mycoses are Candida spp., Aspergillus spp., Mucorales, dematiaceous fungi, non-Aspergillus hyaline molds, and endemic mycoses, including those caused by Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides species. This review analyzes the history, epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, inflammatory biomarkers, diagnostic imaging modalities, treatments, and outcomes of osteomyelitis and septic arthritis caused by these organisms. Candida osteomyelitis and Candida arthritis are associated with greater events of hematogenous dissemination than those of most other osteoarticular mycoses. Traumatic inoculation is more commonly associated with osteoarticular mycoses caused by Aspergillus and non-Aspergillus molds. Synovial fluid cultures are highly sensitive in the detection of Candida and Aspergillus arthritis. Relapsed infection, particularly in Candida arthritis, may develop in relation to an inadequate duration of therapy. Overall mortality reflects survival from disseminated infection and underlying host factors.
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- 2022
29. Meeting the Challenges of Sepsis in Severe Coronavirus Disease 2019: A Call to Arms
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Thomas J Walsh, Rick A Bright, Aparna Ahuja, Matthew W McCarthy, Richard A Marfuggi, and Steven Q Simpson
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Infectious Diseases ,Oncology - Abstract
Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. Sepsis may be caused by bacterial, fungal, or viral pathogens. The clinical manifestations exhibited by patients with severe coronavirus disease 2019 (COVID-19)-related sepsis overlap with those exhibited by patients with sepsis from secondary bacterial or fungal infections and can include an altered mental status, dyspnea, reduced urine output, tachycardia, and hypotension. Critically ill patients hospitalized with severe acute respiratory syndrome coronavirus 2 infections have increased risk for secondary bacterial and fungal infections. The same risk factors that may predispose to sepsis and poor outcome from bloodstream infections (BSIs) converge in patients with severe COVID-19. Current diagnostic standards for distinguishing between (1) patients who are critically ill, septic, and have COVID-19 and (2) patients with sepsis from other causes leave healthcare providers with 2 suboptimal choices. The first choice is to empirically administer broad-spectrum, antimicrobial therapy for what may or may not be sepsis. Such treatment may not only be ineffective and inappropriate, but it also has the potential to cause harm. The development of better methods to identify and characterize antimicrobial susceptibility will guide more accurate therapeutic interventions and reduce the evolution of new antibiotic-resistant strains. The ideal diagnostic test should (1) be rapid and reliable, (2) have a lower limit of detection than blood culture, and (3) be able to detect a specific organism and drug sensitivity directly from a clinical specimen. Rapid direct detection of antimicrobial-resistant pathogens would allow targeted therapy and result in improved outcomes in patients with severe COVID-19 and sepsis.
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- 2022
30. Focused multivector ultraviolet (FMUV) technology rapidly eradicates SARS-CoV-2 in-vitro: Implications for hospital disinfection of COVID-19 environments
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Steven Park, David S. Perlin, Sean Fitzgerald, Vidmantas Petraitis, and Thomas J. Walsh
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Disinfection ,Technology ,Infectious Diseases ,SARS-CoV-2 ,Ultraviolet Rays ,Epidemiology ,Health Policy ,Public Health, Environmental and Occupational Health ,COVID-19 ,Humans ,Hospitals - Abstract
Focused Multivector Ultraviolet technology rapidly killed the SARS-CoV-2 coronavirus in-vitro. Plates were inoculated with a mean of greater than 10
- Published
- 2022
31. Real-World Reinforcement Learning via Multifidelity Simulators.
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Mark Cutler, Thomas J. Walsh 0001, and Jonathan P. How
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- 2015
- Full Text
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32. Bayesian Nonparametric Reward Learning From Demonstration.
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Bernard Michini, Thomas J. Walsh 0001, Ali-akbar Agha-mohammadi, and Jonathan P. How
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- 2015
- Full Text
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33. Dynamic Teaching in Sequential Decision Making Environments.
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Thomas J. Walsh 0001 and Sergiu Goschin
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- 2012
34. Adenovirus viremia after in vivo T-cell depleted allo-transplant in adults: low lymphocyte counts are associated with uncontrolled viremia and fatal outcomes
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Markus Plate, Thomas J. Walsh, Koen van Besien, Sebastian Mayer, Alexandra Gomez-Arteaga, Alex Drelick, Hanna Rennert, Michael J. Satlin, Tsiporah B. Shore, Ok-Kyong Chaekal, Catherine B. Small, Rosemary Soave, Zhengming Chen, Rosy Priya L. Kodiyanplakkal, Jingmei Hsu, Nina Orfali, and Adrienne A. Phillips
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Cancer Research ,business.industry ,Incidence (epidemiology) ,T cell ,Lymphocyte ,virus diseases ,Viremia ,Hematology ,medicine.disease ,Cell therapy ,medicine.anatomical_structure ,Oncology ,In vivo ,Cord blood ,Immunology ,Medicine ,Cumulative incidence ,business - Abstract
The incidence of adenovirus viremia and the role of screening in preventing adenovirus disease in adult transplant recipients are not well defined. Between January 2017 and May 2020, 262 allogeneic transplants were performed using in vivo T-cell depletion. Adenovirus viremia was found in 59 patients for a cumulative incidence of 10% by one hundred days and 23% (95% CI 20-26%) by one year. There was a higher incidence of viremia associated with cord blood transplant (p = .04). No other patient, donor or transplant characteristics were identified that predicted for viremia. In 47 patients (80%), viremia remained well below 200,000 copies/mL and resolved. Twelve patients developed high level viremia. Treatment with antivirals and in some cases adoptive cell therapy, was often ineffective and only two survived. Low lymphocyte count at initial detection of adenovirus viremia was the best predictor of uncontrolled disease.
- Published
- 2021
35. Blending Autonomous Exploration and Apprenticeship Learning.
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Thomas J. Walsh 0001, Daniel Hewlett, and Clayton T. Morrison
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- 2011
36. Teaching and executing verb phrases.
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Daniel Hewlett, Thomas J. Walsh 0001, and Paul R. Cohen
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- 2011
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37. Challenges to decoding the intention behind natural instruction.
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Raquel Torres Peralta, Tasneem Kaochar, Ian R. Fasel, Clayton T. Morrison, Thomas J. Walsh 0001, and Paul R. Cohen
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- 2011
- Full Text
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38. Gender Differences and the Value of Choice in Intelligent Tutoring Systems.
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Derek T. Green, Thomas J. Walsh 0001, Paul R. Cohen, Carole R. Beal, and Yu-Han Chang
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- 2011
- Full Text
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39. Towards Understanding How Humans Teach Robots.
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Tasneem Kaochar, Raquel Torres Peralta, Clayton T. Morrison, Ian R. Fasel, Thomas J. Walsh 0001, and Paul R. Cohen
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- 2011
- Full Text
- View/download PDF
40. Learning a Skill-Teaching Curriculum with Dynamic Bayes Nets.
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Derek T. Green, Thomas J. Walsh 0001, Paul R. Cohen, and Yu-Han Chang
- Published
- 2011
- Full Text
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41. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits
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Vidmantas Petraitis, Ruta Petraitiene, Povilas Kavaliauskas, Ethan Naing, Andrew Garcia, Benjamin N. Georgiades, Roger Echols, Robert A. Bonomo, Yoshinori Yamano, Michael J. Satlin, and Thomas J. Walsh
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Pharmacology ,Adult ,Stenotrophomonas maltophilia ,Siderophores ,Pneumonia ,Microbial Sensitivity Tests ,Anti-Bacterial Agents ,Cephalosporins ,Infectious Diseases ,Trimethoprim, Sulfamethoxazole Drug Combination ,Humans ,Animals ,Pharmacology (medical) ,Rabbits ,Gram-Negative Bacterial Infections - Abstract
Stenotrophomonas maltophilia is an important cause of pneumonia in immunocompromised patients. Cefiderocol is a parenteral siderophore cephalosporin with potent in vitro activity against S. maltophilia .
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- 2022
42. Multicenter Collaborative Study of the Interaction of Antifungal Combinations against Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis
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Joseph Meletiadis, David R. Andes, Shawn R. Lockhart, Mahmoud A. Ghannoum, Cindy C. Knapp, Luis Ostrosky-Zeichner, Michael A. Pfaller, Vishnu Chaturvedi, and Thomas J. Walsh
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Microbiology (medical) ,pharmacodynamic interactions ,Loewe additivity ,Bliss independence ,synergy ,antagonism ,Candida ,antifungal drugs ,Plant Science ,Ecology, Evolution, Behavior and Systematics - Abstract
Combination antifungal therapy is widely used but not well understood. We analyzed the spectrophotometric readings from a multicenter study conducted by the New York State Department of Health to further characterize the in vitro interactions of the major classes of antifungal agents against Candida spp. Loewe additivity-based fractional inhibitory concentration index (FICi) analysis and Bliss independence-based response surface (BIRS) analysis were used to analyze two-drug inter- and intraclass combinations of triazoles (AZO) (voriconazole, posaconazole), echinocandins (ECH) (caspofungin, micafungin, anidulafungin), and a polyene (amphotericin B) against Candida albicans, C. parapsilosis, and C. glabrata. Although mean FIC indices did not differ statistically significantly from the additivity range of 0.5–4, indicating no significant pharmacodynamic interactions for all of the strain–combinations tested, BIRS analysis showed that significant pharmacodynamic interactions with the sum of percentages of interactions determined with this analysis were strongly associated with the FIC indices (Χ2 646, p < 0.0001). Using a narrower additivity range of 1–2 FIC index analysis, statistically significant pharmacodynamic interactions were also found with FICi and were in agreement with those found with BIRS analysis. All ECH+AB combinations were found to be synergistic against all Candida strains except C. glabrata. For the AZO+AB combinations, synergy was found mostly with the POS+AB combination. All AZO+ECH combinations except POS+CAS were synergistic against all Candida strains although with variable magnitude; significant antagonism was found for the POS+MIF combination against C. albicans. The AZO+AZO combination was additive for all strains except for a C. parapsilosis strain for which antagonism was also observed. The ECH+ECH combinations were synergistic for all Candida strains except C. glabrata for which they were additive; no antagonism was found.
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- 2022
- Full Text
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43. Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment?
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Alessia Catalano, Domenico Iacopetta, Jessica Ceramella, Azzurra Chiara De Maio, Giovanna Basile, Federica Giuzio, Maria Grazia Bonomo, Stefano Aquaro, Thomas J. Walsh, Maria Stefania Sinicropi, Carmela Saturnino, Athina Geronikaki, and Giovanni Salzano
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Health (social science) ,Plant Science ,Health Professions (miscellaneous) ,Microbiology ,Food Science - Abstract
The beginning of the end or the end of the beginning? After two years mastered by coronavirus disease 19 (COVID-19) pandemic, we are now witnessing a turnaround. The reduction of severe cases and deaths from COVID-19 led to increasing importance of a new disease called post-COVID syndrome. The term post-COVID is used to indicate permanency of symptoms in patients who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immune, antiviral, antimicrobial therapies, as well as ozone therapy have been used to treat COVID-19 disease. Vaccines have then become available and administered worldwide to prevent the insurgence of the disease. However, the pandemic is not over yet at all given the emergence of new omicron variants. New therapeutic strategies are urgently needed. In this view, great interest was found in nutraceutical products, including vitamins (C, D, and E), minerals (zinc), melatonin, probiotics, flavonoids (quercetin), and curcumin. This review summarizes the role of nutraceuticals in the prevention and/or treatment of COVID-19 disease and post-COVID syndrome.
- Published
- 2022
44. Generalizing Apprenticeship Learning across Hypothesis Classes.
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Thomas J. Walsh 0001, Kaushik Subramanian, Michael L. Littman, and Carlos Diuk
- Published
- 2010
45. Integrating Sample-Based Planning and Model-Based Reinforcement Learning.
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Thomas J. Walsh 0001, Sergiu Goschin, and Michael L. Littman
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- 2010
- Full Text
- View/download PDF
46. Exploring compact reinforcement-learning representations with linear regression.
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Thomas J. Walsh 0001, Istvan Szita, Carlos Diuk, and Michael L. Littman
- Published
- 2009
47. Democratic approximation of lexicographic preference models.
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Fusun Yaman, Thomas J. Walsh 0001, Michael L. Littman, and Marie desJardins
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- 2008
- Full Text
- View/download PDF
48. Knows what it knows: a framework for self-aware learning.
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Lihong Li 0001, Michael L. Littman, and Thomas J. Walsh 0001
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- 2008
- Full Text
- View/download PDF
49. Efficient Learning of Action Schemas and Web-Service Descriptions.
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Thomas J. Walsh 0001 and Michael L. Littman
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- 2008
50. Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy
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Alla Kuzminsky, Liora Sagi, Adi Aran, Luba Blumkin, Tehila Klopstock, Dorit Lev, Dafna Guttman, Lilach Shemer Meiri, Reeval Segel, Suleyman Gulsuner, Michal Yechieli, Mary Claire King, Varda Gross-Tsur, Aviva Fattal, Paul Renbaum, Hilla Ben-Pazi, Ephrat Lahad Levy, Sharon Zeligson, Nira Schneebaum Sender, Dorit Shmueli, Thomas J. Walsh, and Amnon Lahad
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0301 basic medicine ,medicine.medical_specialty ,Candidate gene ,Movement disorders ,DNA Copy Number Variations ,Microarray ,medicine.disease_cause ,Cerebral palsy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Exome Sequencing ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Exome sequencing ,Genetic testing ,Mutation ,medicine.diagnostic_test ,business.industry ,Cerebral Palsy ,Point mutation ,Microarray Analysis ,medicine.disease ,030104 developmental biology ,Child, Preschool ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveTo determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).MethodsTrio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.ResultsGiven both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3.ConclusionsCryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.
- Published
- 2021
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