732 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.
- Author
-
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
- Subjects
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
- Published
- 2019
- Full Text
- View/download PDF
3. Predictors of sperm recovery after cryopreservation in testicular cancer
- Author
-
James M Hotaling, Darshan P Patel, Christopher Vendryes, Natalya A Lopushnyan, Angela P Presson, Chong Zhang, Charles H Muller, and Thomas J Walsh
- Subjects
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.
- Published
- 2016
- Full Text
- View/download PDF
4. Testicular fine-needle aspiration for the assessment of intratesticular hormone concentrations
- Author
-
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
- Subjects
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.
- Published
- 2016
- Full Text
- View/download PDF
5. Testosterone treatment and the risk of aggressive prostate cancer in men with low testosterone levels.
- Author
-
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
- Subjects
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.
- Published
- 2018
- Full Text
- View/download PDF
6. Multiple roles for hypoxia inducible factor 1-alpha in airway epithelial cells during mucormycosis
- Author
-
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
- Subjects
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.
- Published
- 2024
- Full Text
- View/download PDF
7. Role of NADPH oxidase versus neutrophil proteases in antimicrobial host defense.
- Author
-
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
- Subjects
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.
- Published
- 2011
- Full Text
- View/download PDF
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
- Author
-
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
- Subjects
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.
- Published
- 2024
- Full Text
- View/download PDF
9. 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
- Author
-
Ruta Petraitiene, Vidmantas Petraitis, Myo H. Zaw, Kaiser Hussain, Rodolfo J. Ricart Arbona, Emanuel Roilides, and Thomas J. Walsh
- Subjects
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.
- Published
- 2024
- Full Text
- View/download PDF
10. Does Type 1 Diabetes Affect Male Infertility: Type 1 Diabetes Exchange Registry-Based Analysis
- Author
-
Omer A. Raheem, Marah C. Hehemann, Marc J. Rogers, Judy N. Fustok, Irl B. Hirsch, Thomas J. Walsh
- Subjects
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.
- Published
- 2021
- Full Text
- View/download PDF
11. Novel antifungal agents in clinical trials [version 2; peer review: 2 approved]
- Author
-
Samantha E. Jacobs, Panagiotis Zagaliotis, and Thomas J. Walsh
- Subjects
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.
- Published
- 2022
- Full Text
- View/download PDF
12. Novel antifungal agents in clinical trials [version 1; peer review: 1 approved, 1 approved with reservations]
- Author
-
Samantha E. Jacobs, Panagiotis Zagaliotis, and Thomas J. Walsh
- Subjects
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.
- Published
- 2021
- Full Text
- View/download PDF
13. Therapeutic Bacteriophages for Gram-Negative Bacterial Infections in Animals and Humans
- Author
-
Panagiotis, Zagaliotis, Jordyn, Michalik-Provasek, Jason J, Gill, and Thomas J, Walsh
- Subjects
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.
- Published
- 2022
14. Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients
- Author
-
Silke Gastine, Georg Hempel, Michael N Neely, Thomas J Walsh, and Andreas H Groll
- Subjects
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.
- Published
- 2022
15. Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity
- Author
-
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
- Subjects
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
- Published
- 2023
16. One size does not fit all: variations by ethnicity in demographic characteristics of men seeking fertility treatment across North America
- Author
-
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
- Subjects
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.
- Published
- 2021
17. Candida auris Pan-Drug-Resistant to Four Classes of Antifungal Agents
- Author
-
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
- Subjects
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.
- Published
- 2022
18. Osteoarticular Mycoses
- Author
-
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
- Subjects
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.
- Published
- 2022
19. Meeting the Challenges of Sepsis in Severe Coronavirus Disease 2019: A Call to Arms
- Author
-
Thomas J Walsh, Rick A Bright, Aparna Ahuja, Matthew W McCarthy, Richard A Marfuggi, and Steven Q Simpson
- Subjects
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.
- Published
- 2022
20. Focused multivector ultraviolet (FMUV) technology rapidly eradicates SARS-CoV-2 in-vitro: Implications for hospital disinfection of COVID-19 environments
- Author
-
Steven Park, David S. Perlin, Sean Fitzgerald, Vidmantas Petraitis, and Thomas J. Walsh
- Subjects
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
21. Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits
- Author
-
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
- Subjects
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 .
- Published
- 2022
22. Multicenter Collaborative Study of the Interaction of Antifungal Combinations against Candida Spp. by Loewe Additivity and Bliss Independence-Based Response Surface Analysis
- Author
-
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
- Subjects
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.
- Published
- 2022
- Full Text
- View/download PDF
23. Are Nutraceuticals Effective in COVID-19 and Post-COVID Prevention and Treatment?
- Author
-
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
- Subjects
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
24. Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy
- Author
-
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
- Subjects
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
25. Histoplasmosis in an off-trail Hiker receiving ustekinumab: Implications for Preventive and diagnostic strategies for patients receiving anti-IL-12/23 therapy
- Author
-
Yun-Han Huang, Harjot K. Singh, Thomas J. Walsh, Rema Rao, and Reed Magleby
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Medicine (General) ,QH301-705.5 ,medicine.medical_treatment ,030106 microbiology ,030231 tropical medicine ,Case Report ,Microbiology ,Inflammatory bowel disease ,Histoplasmosis ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,Psoriasis ,Histoplasma ,Ustekinumab ,medicine ,Biology (General) ,biology ,business.industry ,Immunosuppression ,medicine.disease ,biology.organism_classification ,Dermatology ,Clinical trial ,Infectious Diseases ,Methotrexate ,business ,medicine.drug - Abstract
Ustekinumab, an IL-12/23 inhibitor, is an important agent in treatment of inflammatory bowel disease and psoriasis. Clinical trials have not demonstrated significantly increased infection risk with ustekinumab. We report a case of disseminated histoplasmosis in the setting of ustekinumab and methotrexate following a hike in the Catskill Mountains, a region not commonly associated with Histoplasma encapsulatum. To our knowledge, this is the first reported case of newly acquired histoplasmosis complicating treatment with ustekinumab., Highlights • Histoplasma is a widely distributed organism present in the environment distant from regions where it may be considered widely endemic. • Immunosuppressive regimens that include ustekinumab may increase risk of histoplasmosis. • Tissue diagnosis is valuable when suspicion is high and antigenic tests are negative.
- Published
- 2021
26. Genetic Heterogeneity and Core Clinical Features of NOG-Related-Symphalangism Spectrum Disorder
- Author
-
Kathleen A. Leppig, Thomas J. Walsh, Dawson Wells, Dror Gilony, Karen B. Avraham, Mary Claire King, Ryan J. Carlson, Jay T. Rubinstein, Suleyman Gulsuner, Zippora Brownstein, and Alicia M. Quesnel
- Subjects
Foot Deformities, Congenital ,business.industry ,Genetic heterogeneity ,Point mutation ,Tarsal Bones ,medicine.disease ,Bioinformatics ,Article ,Stapes ,Sensory Systems ,Conductive hearing loss ,Genetic Heterogeneity ,Synostosis ,Otorhinolaryngology ,Temporal bone ,medicine ,Humans ,Otosclerosis ,Missense mutation ,Neurology (clinical) ,business ,Hand Deformities, Congenital ,Carpal Bones ,Chromosomal Deletion - Abstract
Objectives To better distinguish NOG-related-symphalangism spectrum disorder (NOG-SSD) from chromosomal 17q22 microdeletion syndromes and to inform surgical considerations in stapes surgery for patients with NOG-SSD. Background Mutations in NOG cause a variety of skeletal syndromes that often include conductive hearing loss. Several microdeletions of chromosome 17q22 lead to severe syndromes with clinical characteristics that overlap NOG-SSD. Isolated deletion of NOG has not been described, and therefore the contribution of NOG deletion in these syndromes is unknown. Methods Two families with autosomal dominant NOG-SSD exhibited stapes ankylosis, facial dysmorphisms, and skeletal and joint anomalies. In each family, NOG was evaluated by genomic sequencing and candidate mutations confirmed as damaging by in vitro assays. Temporal bone histology of a patient with NOG-SSD was compared with temporal bones of 40 patients diagnosed with otosclerosis. Results Family 1 harbors a 555 kb chromosomal deletion encompassing only NOG and ANKFN1. Family 2 harbors a missense mutation in NOG leading to absence of noggin protein. The incus-footplate distance of the temporal bone was significantly longer in a patient with NOG-SSD than in patients with otosclerosis. Conclusion The chromosomal microdeletion of family 1 led to a phenotype comparable to that due to a NOG point mutation and much milder than the phenotypes due to other chromosome 17q22 microdeletions. Severe clinical findings in other microdeletion cases are likely due to deletion of genes other than NOG. Based on temporal bone findings, we recommend that surgeons obtain longer stapes prostheses before stapes surgery in individuals with NOG-SSD stapes ankylosis.
- Published
- 2021
27. Does Type 1 Diabetes Affect Male Infertility: Type 1 Diabetes Exchange Registry-Based Analysis
- Author
-
Judy N. Fustok, Thomas J. Walsh, Irl B. Hirsch, Marc J. Rogers, Marah Hehemann, and Omer A. Raheem
- Subjects
Infertility ,Type 1 diabetes ,education.field_of_study ,030219 obstetrics & reproductive medicine ,Multivariate analysis ,endocrine system diseases ,business.industry ,media_common.quotation_subject ,Population ,030209 endocrinology & metabolism ,Fertility ,Diabetic retinopathy ,medicine.disease ,Male infertility ,03 medical and health sciences ,0302 clinical medicine ,medicine ,General Earth and Planetary Sciences ,Household income ,business ,education ,General Environmental Science ,Demography ,media_common - Abstract
Introduction: The 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. Methods: We 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. Results: The 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 infertility. Conclusions: This 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.
- Published
- 2021
28. Colonization With Fluoroquinolone-Resistant Enterobacterales Decreases the Effectiveness of Fluoroquinolone Prophylaxis in Hematopoietic Cell Transplant Recipients
- Author
-
Rianna Malherbe, Michael Hovan, Stephen G. Jenkins, Koen van Besien, Lars F. Westblade, Jingmei Hsu, Alexandra Gomez-Arteaga, Thomas J. Walsh, Claire Douglass, Catherine B. Small, Michael J. Satlin, Sebastian Mayer, Rosemary Soave, Adrienne A. Phillips, Marisa La Spina, Emily Davidson, Liang Chen, and Barry N. Kreiswirth
- Subjects
0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,medicine.medical_treatment ,030106 microbiology ,Bacteremia ,Levofloxacin ,Hematopoietic stem cell transplantation ,Neutropenia ,03 medical and health sciences ,0302 clinical medicine ,Ciprofloxacin ,Neoplasms ,Internal medicine ,Enterobacterales ,medicine ,Humans ,Colonization ,030212 general & internal medicine ,Retrospective Studies ,Hematopoietic cell ,business.industry ,Broth microdilution ,Hematopoietic Stem Cell Transplantation ,Antibiotic Prophylaxis ,medicine.disease ,Transplant Recipients ,Anti-Bacterial Agents ,Transplantation ,Major Articles and Commentaries ,Infectious Diseases ,business ,Fluoroquinolones ,medicine.drug - Abstract
Background Levofloxacin prophylaxis is recommended to prevent gram-negative bloodstream infections (BSIs) in patients with prolonged chemotherapy-induced neutropenia. However, increasing fluoroquinolone resistance may decrease the effectiveness of this approach. Methods We assessed the prevalence of colonization with fluoroquinolone-resistant Enterobacterales (FQRE) among patients admitted for hematopoietic cell transplantation (HCT) from November 2016 to August 2019 and compared the risk of gram-negative BSI between FQRE-colonized and noncolonized patients. All patients received levofloxacin prophylaxis during neutropenia. Stool samples were collected upon admission for HCT and weekly thereafter until recovery from neutropenia, and underwent selective culture for FQRE. All isolates were identified and underwent antimicrobial susceptibility testing by broth microdilution. FQRE isolates also underwent whole-genome sequencing. Results Fifty-four of 234 (23%) patients were colonized with FQRE prior to HCT, including 30 of 119 (25%) allogeneic and 24 of 115 (21%) autologous HCT recipients. Recent antibacterial use was associated with FQRE colonization (P = .048). Ninety-one percent of colonizing FQRE isolates were Escherichia coli and 29% produced extended-spectrum β-lactamases. Seventeen (31%) FQRE-colonized patients developed gram-negative BSI despite levofloxacin prophylaxis, compared to only 2 of 180 (1.1%) patients who were not colonized with FQRE on admission (P Conclusions Nearly one-third of HCT recipients with pretransplant FQRE colonization developed gram-negative BSI while receiving levofloxacin prophylaxis, and infections were typically caused by their colonizing strains. In contrast, levofloxacin prophylaxis was highly effective in patients not initially colonized with FQRE.
- Published
- 2021
29. Comparison between Perianal Swab and Stool Specimens for Detecting Colonization with Extended-Spectrum Beta-Lactamase-Producing and Fluoroquinolone-Resistant Enterobacterales
- Author
-
Jeffrey M. Kubiak, Michael Hovan, Emily Davidson, Claire Douglass, Kevin Burgos, Thomas J. Walsh, Lars F. Westblade, and Michael J. Satlin
- Subjects
Gastrointestinal Tract ,Microbiology (medical) ,Enterobacteriaceae ,Hematopoietic Stem Cell Transplantation ,Humans ,Bacteriology ,beta-Lactamases ,Anti-Bacterial Agents ,Fluoroquinolones - Abstract
Stool specimens are frequently used to detect gastrointestinal tract colonization with antimicrobial-resistant enteric bacteria, but they cannot be rapidly collected. Perianal swab specimens can be collected more quickly and efficiently, but data evaluating their suitability as a specimen type for this purpose are sparse. We performed selective culture for extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) and fluoroquinolone-resistant Enterobacterales (FQRE) using paired perianal swab and stool specimens that were collected within 1 day of each other from hematopoietic cell transplant recipients and patients with acute leukemia. Nineteen (7.6%) of 251 stool specimens yielded ESBL-E and 64 (26%) of 246 stool specimens yielded FQRE. The positive percent agreement of perianal swab specimens compared to stool specimens was 95% (18/19; 95% confidence interval [CI], 74% to 100%) for detecting ESBL-E and 95% (61/64; 95% CI, 87% to 99%) for detecting FQRE. The concordance between specimen types was 98% (95% CI, 97% to 100%). Perianal swabs are a reliable specimen type for surveillance of the gastrointestinal tract for ESBL-E and FQRE.
- Published
- 2022
30. Non-Aspergillus Hyaline Molds: A Host-Based Perspective of Emerging Pathogenic Fungi Causing Sinopulmonary Diseases
- Author
-
Samantha E. Jacobs and Thomas J. Walsh
- Subjects
Microbiology (medical) ,Plant Science ,Ecology, Evolution, Behavior and Systematics - Abstract
The incidence of invasive sino-pulmonary diseases due to non-Aspergillus hyaline molds is increasing due to an enlarging and evolving population of immunosuppressed hosts as well as improvements in the capabilities of molecular-based diagnostics. Herein, we review the following opportunistic pathogens known to cause sinopulmonary disease, the most common manifestation of hyalohyphomycosis: Fusarium spp., Scedosporium spp., Lomentospora prolificans, Scopulariopsis spp., Trichoderma spp., Acremonium spp., Paecilomyces variotii, Purpureocillium lilacinum, Rasamsonia argillacea species complex, Arthrographis kalrae, and Penicillium species. To facilitate an understanding of the epidemiology and clinical features of sino-pulmonary hyalohyphomycoses in the context of host immune impairment, we utilized a host-based approach encompassing the following underlying conditions: neutropenia, hematologic malignancy, hematopoietic and solid organ transplantation, chronic granulomatous disease, acquired immunodeficiency syndrome, cystic fibrosis, and healthy individuals who sustain burns, trauma, or iatrogenic exposures. We further summarize the pre-clinical and clinical data informing antifungal management for each pathogen and consider the role of adjunctive surgery and/or immunomodulatory treatments to optimize patient outcome.
- Published
- 2023
31. Antifungal efficacy of isavuconazole and liposomal amphotericin B in a rabbit model of Exserohilum rostratum meningoencephalitis: A preclinical paradigm for management of CNS phaeohyphomycosis
- Author
-
Patriss W. Moradi, Aspasia Katragkou, Vidmantas Petraitis, Laura L. Kovanda, Ethan Naing, Bo Bo Win Maung, Malcolm Finkelman, Gittel E Sussman-Straus, Thomas J. Walsh, and Ruta Petraitiene
- Subjects
rabbits ,Antifungal Agents ,Pyridines ,Triazole ,Microbial Sensitivity Tests ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ascomycota ,Central Nervous System Diseases ,In vivo ,Amphotericin B ,Amphotericin B deoxycholate ,Nitriles ,medicine ,Animals ,Humans ,liposomal amphotericin B ,030212 general & internal medicine ,experimental CNS phaeohyphomycosis ,0303 health sciences ,030306 microbiology ,business.industry ,isavuconazole ,Exserohilum rostratum ,Micafungin ,Disease Management ,Meningoencephalitis ,General Medicine ,Triazoles ,medicine.disease ,In vitro ,Disease Models, Animal ,Phaeohyphomycosis ,Infectious Diseases ,chemistry ,AcademicSubjects/SCI00960 ,Original Article ,Drug Therapy, Combination ,Female ,AcademicSubjects/MED00010 ,business ,medicine.drug - Abstract
Treatment options for Exserohilum rostratum meningoencephalitis and other causes of phaeohyphomycosis of the central nervous system (CNS) are limited, while mortality and morbidity remain high. We therefore evaluated isavuconazole, a new antifungal triazole in comparison to liposomal amphotericin B (LAMB), in vitro and in the rabbit model of Exserohilum rostratum meningoencephalitis. We hypothesized that isavuconazole alone or in combination with LAMB or micafungin may be alternative options for treatment of CNS phaeohyphomycosis. We therefore investigated the in vitro antifungal activity of isavuconazole alone or in combination with amphotericin B deoxycholate (DAMB) or micafungin and efficacy of treatment with isavuconazole and LAMB in a rabbit model of experimental E. rostratum meningoencephalitis. Combination checkerboard plates were used to determine the minimum inhibitory concentrations, minimal lethal concentrations, fractional inhibitory concentration indices, and Bliss surface analysis of isavuconazole and amphotericin B deoxycholate (DAMB), either alone or in combination. As there were no in vitro synergistic or antagonistic interactions for either combination of antifungal agents against the E. rostratum isolates, in vivo studies were conducted with isavuconazole and LAMB as monotherapies. Rabbits were divided in following groups: treated with isavuconazole at 60 mg/kg/d (ISAV60), LAMB at 5.0 (LAMB5), 7.5 (LAMB7.5), and 10 mg/kg/d (LAMB10), and untreated controls (UC). In ISAV60-, LAMB5-, LAMB7.5-, and LAMB10-treated rabbits, significant reductions of fungal burden of E. rostratum in cerebral, cerebellar, and spinal cord tissues (P
- Published
- 2020
32. Primer on the Pathogenesis of Severe COVID-19: Part One
- Author
-
Thomas J. Walsh
- Subjects
severe acute respiratory syndrome (sars) ,cluster of differentiation 147 (cd147) ,viruses ,severe acute respiratory syndrome coronavirus-2 (sars-cov-2) ,pneumonia ,protein kinase r ,Medicine ,nrlp3 inflammasome ,coronavirus disease (covid-19) - Abstract
In Part One of this exploration of the pathogenesis of coronavirus disease (COVID-19), the author will evaluate the viral and cellular immunological basis for the condition. The virus demonstrates a remarkable capability not just to evade, but to exploit host immune characteristics to perpetuate viral replication. In this regard, severe acute respiratory syndrome (SARS)/severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disables most antiviral mechanisms, including the early interferon response, and avoids detection to permit unimpeded viral multiplication. Consequently, antigen-presenting cells fail to adequately stimulate the T-cell receptor. As a consequence, T-cell p53 remains highly expressed, which in turn disables an adequate effector T-cell response. Replicating SARS-CoV-2 double-strand RNA robustly activates protein kinase R (PKR)/PKRlike endoplasmic reticulum kinase (PERK). While the virus is grossly invulnerable to its antiviral effects, PKR is crucial for effecting the cytokine milieu in COVID-19. PERK is a component of the unfolded protein response, which eventuates in autophagy. SARS virions use double-membrane vesicles and adapt PERK signalling not only to avoid autophagy, but to facilitate replication. Viral activation of PKR/PERK is mutually exclusive to NLRP3 stimulation. The NLRP3 pathway elaborates IL-1β. This is chiefly a feature of paediatric SARS/SARS-CoV-2 cases. The difficulties encountered in predicting outcome and forging effective therapeutics speaks to the breadth of complexity of the immunopathogenesis of this virus.
- Published
- 2020
33. Primer on the Pathogenesis of Severe COVID-19: Part Two
- Author
-
Thomas J. Walsh
- Subjects
severe acute respiratory syndrome (sars) ,protein kinase r (pkr) ,angiotensin-converting enzyme 2 (ace2) ,cluster of differentiation (cd) 147 ,pneumonia ,Medicine ,myocarditis ,nadph oxidase ,coronavirus disease (covid-19) - Abstract
In the following continuation article, the author will expand on how the mechanisms discussed in Part One capitalise on host characteristics to produce the organ specific damage seen in severe coronavirus disease (COVID-19), with specific reference to pulmonary and cardiac manifestations. Pneumonia is the primary manifestation of COVID-19; presentation varies from a mild, self-limiting pneumonitis to a fulminant and progressive respiratory failure. Features of disease severity tend to directly correlate with patient age, with elderly populations faring poorest. Advancing age parallels an increasingly pro-oxidative pulmonary milieu, a consequence of increasing host expression of phospholipase A2 Group IID. Virally induced expression of NADPH oxidase intensifies this pro-oxidant environment. The virus avails of the host response by exploiting caveolin-1 to assist in disabling host defenses and adopting a glycolytic metabolic pathway to self-replicate. Although not a cardiotropic virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can induce arrhythmias, a myocarditis-like syndrome, and myocardial infarction. Monocyte activation as a consequence of a surge of cytokine expression is the driver of these processes. Induced expression of cluster of differentiation 147 (CD147) and TNF-α may also have a role. SARS-CoV-2 fluently harnesses the immune mechanisms of the host to its advantage, rendering it a formidable systemic pathogen. Future effective treatments are contingent upon improved aetiological understanding.
- Published
- 2020
34. Bloodstream Infections in Hematologic Malignancy Patients With Fever and Neutropenia: Are Empirical Antibiotic Therapies in the United States Still Effective?
- Author
-
Andrea J Zimmer, Erica Stohs, Jane Meza, Christopher Arnold, John W Baddley, Pranatharthi Chandrasekar, Zeinab El Boghdadly, Carlos A Gomez, Eileen K Maziarz, Jose G Montoya, Steven Pergam, Kenneth V Rolston, Michael J Satlin, Gowri Satyanarayana, Shmuel Shoham, Lynne Strasfeld, Randy Taplitz, Thomas J Walsh, Jo-Anne H Young, Yuning Zhang, and Alison G Freifeld
- Subjects
Infectious Diseases ,Oncology - Abstract
Background Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant. Methods In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation. Results Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall. Conclusions In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes.
- Published
- 2022
35. Outcome Disparities Among Men and Women With COVID-19: An Analysis of the New York City Population Cohort
- Author
-
Joseph P. Alukal, Thomas J. Walsh, Joseph M. Caputo, Nahid Punjani, Mary Ann Chiasson, Lisa Wiechmann, James M. Hotaling, Philip S. Li, Albert S. Ha, and Vinson Wang
- Subjects
Adult ,Male ,Databases, Factual ,Coronavirus disease 2019 (COVID-19) ,Pneumonia, Viral ,Disease ,Risk Assessment ,Cohort Studies ,COVID-19 Testing ,Sex Factors ,Cause of Death ,Outcome Assessment, Health Care ,Case fatality rate ,Humans ,Medicine ,Hospital Mortality ,Healthcare Disparities ,Pandemics ,Aged ,Retrospective Studies ,Cause of death ,Clinical Laboratory Techniques ,business.industry ,COVID-19 ,Retrospective cohort study ,Health Status Disparities ,General Medicine ,Middle Aged ,Hospitalization ,Relative risk ,Female ,New York City ,Coronavirus Infections ,business ,Risk assessment ,Demography ,Cohort study - Abstract
Background Growing evidence suggests a possible sex disparity in COVID-19 disease related outcomes. Objective To explore the sex disparity in COVID-19 cases and outcomes using New York City (NYC) population level data. Setting NYC surveillance data from February 29 to June 12, 2020. Participants Individuals tested for COVID-19 in metropolitan NYC.Outcome Measurements and Statistical Analysis: Outcomes of interest included rates of COVID-19 case positivity, hospitalization and death. Relative risks and case fatality rates were computed for all outcomes based on sex and were stratified by age groups. Results and limitations 911,310 individuals were included, of whom 434,273 (47.65%) were male and 477,037 (52.35%) were female. Men represented the majority of positive cases (n=106,275, 51.36%), a majority of hospitalizations (n=29,847, 56.44%), and a majority of deaths (n=13,054, 59.23%). Following population level adjustments for age and sex, testing rates of men and women were equivalent. The majority of positive cases and hospitalizations occurred in men for all age groups except age g75 years, and death was more likely in men of all age groups. Men were at a statistically significant greater relative risk of case positivity, hospitalization, and death across all age groups except those l18 years of age. The most significant difference for case positivity was observed in the 65n74 age group (RR 1.22, 95%CI 1.19n1.24), for hospitalization in the 45n65 age group (RR 1.85, 95% 1.80n1.90), and for death in the 18n44 age group (RR 3.30, 95% CI 2.82n3.87). Case fatality rates were greater for men in all age-matched comparisons to women. Limitations include the use of an evolving surveillance data set and absence of further demographic characteristics such as ethnographic data. Conclusion Men have higher rates of COVID-19 positivity, hospitalization, and death despite greater testing of women; this trend remains after stratification by age. J Drugs Dermatol. 2020;19(10):960-967. doi:10.36849/JDD.2020.5590.
- Published
- 2020
36. Dalbavancin Reduces Hospital Stay and Improves Productivity for Patients with Acute Bacterial Skin and Skin Structure Infections: The ENHANCE Trial
- Author
-
Justin J Choi, Thomas J. Walsh, Nicholas Pickell, Patrick Gillard, Ronald Copp, Katelyn R. Keyloun, and Matthew W. McCarthy
- Subjects
0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,Activities of daily living ,Acute bacterial skin and skin structure infection ,Cost ,medicine.drug_class ,030106 microbiology ,Antibiotics ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Intensive care ,Long-acting antibiotic ,Medicine ,lcsh:RC109-216 ,In patient ,030212 general & internal medicine ,Original Research ,business.industry ,Dalbavancin ,Pragmatic trial ,Infectious Diseases ,Skin structure ,business ,Hospital stay - Abstract
Introduction Admissions for acute bacterial skin and skin structure infections (ABSSSI) are often prolonged because of intravenous (IV) antibiotics. Use of a long-acting IV antibiotic may reduce length of stay (LOS) on a hospitalist service. The ENHANCE ABSSSI trial sought to determine the impact on LOS and work productivity in patients treated with a long-acting IV antibiotic, dalbavancin, vs. usual care at an urban tertiary-care center. Methods A single-center, pre- vs. post-period pragmatic trial at Weill-Cornell Medical Center assessed usual care for consecutively enrolled admitted ABSSSI patients during an observational period (pre-period). Identification and treatment of eligible admitted ABSSSI patients with dalbavancin were implemented in the post-period. Those with life-threatening infections, requiring multiple antibiotics/intensive care, or with unstable comorbidities were excluded. Outcomes were assessed over a 44-day follow-up period. Results Of 48 and 43 patients enrolled, respectively, in the pre- and post-periods, mean infection-related LOS was reduced in the post-period (3.2 days vs. 4.8 days; P = 0.003). Similar results were found in an adjusted LOS analysis. Work productivity and activity impairment outcomes significantly improved in the post-period (P ≤ 0.01). Complete response rates were similar: 50% (pre-period) and 57% (post-period). Among AEs identified, 17% (n = 7) were found to have possible causal relation to dalbavancin in the post-period. Few AEs were serious (n = 3; 7% post-period versus n = 1; 2% pre-period). Conclusion After implementing the ENHANCE ABSSSI pathway, LOS was significantly reduced by almost 2 days, with potential improvements in work productivity and ability to complete daily activities. Trial Registration ClinicalTrials.gov identifier, NCT03233438. Funding Allergan plc. Electronic supplementary material The online version of this article (10.1007/s40121-019-00275-4) contains supplementary material, which is available to authorized users.
- Published
- 2019
37. Pharmacokinetics, Tissue Distribution, and Efficacy of VIO-001 (Meropenem/Piperacillin/Tazobactam) for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia in Immunocompetent Rabbits with Chronic Indwelling Vascular Catheters
- Author
-
Nicholas K. Goldner, Thomas J. Walsh, Ethan Naing, Christina A. Sutherland, Aki Yoneda Kau, Vidmantas Petraitis, Andrew Garcia, Ruta Petraitiene, David P. Nicolau, Christopher Bulow, and Povilas Kavaliauskas
- Subjects
Methicillin-Resistant Staphylococcus aureus ,medicine.medical_specialty ,Bacteremia ,Microbial Sensitivity Tests ,medicine.disease_cause ,Meropenem ,Gastroenterology ,Tazobactam ,Internal medicine ,medicine ,Animals ,Tissue Distribution ,Experimental Therapeutics ,Pharmacology (medical) ,Pharmacology ,business.industry ,Staphylococcal Infections ,medicine.disease ,Methicillin-resistant Staphylococcus aureus ,Anti-Bacterial Agents ,Piperacillin, Tazobactam Drug Combination ,Infectious Diseases ,Pharmacodynamics ,Piperacillin/tazobactam ,Vancomycin ,Rabbits ,business ,Vascular Access Devices ,Piperacillin ,medicine.drug - Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infections of surgically implanted subcutaneous vascular catheters (SISVCs) cause serious morbidity in patients with chronic illnesses. Previous in vitro and murine models demonstrated the synergistic interaction of equimolar concentrations of meropenem/piperacillin/tazobactam (MPT) (VIO-001) against MRSA infection. We investigated the pharmacokinetics (PK) and efficacy of VIO-001 for the treatment of MRSA bacteremia in immunocompetent rabbits with SISVCs. In PK studies, we determined that optimal dosing to achieve a time above 4× MIC (T(>4×MIC)) of a duration of 3 to 3.30 h required a 1-h infusion with every-4-h (Q4h) dosing. Study groups in efficacy experiments consisted of MPT combinations of 100/150/100 mg/kg of body weight (MPT100), 200/300/200 mg/kg (MPT200), and 400/600/400 mg/kg (MPT400); vancomycin (VAN) at 15 mg/kg; and untreated controls (UC). The inoculum of MRSA isolate USA300-TCH1516 (1 × 10(3) organisms) was administered via the SISCV on day 1 and locked for 24 h. The 8-day therapy started at 24 h postinoculation. There was a significant reduction of MRSA in blood cultures from the SISVCs in all treatment groups, with full clearance on day 4, versus UCs (P
- Published
- 2021
38. Association Between Testosterone Treatment and Risk of Incident Cardiovascular Events Among US Male Veterans With Low Testosterone Levels and Multiple Medical Comorbidities
- Author
-
Chloe Krakauer, Alexandra E. Fox, Alvin M. Matsumoto, Nicholas L. Smith, Molly M. Shores, Thomas J. Walsh, Kathryn P. Moore, Mary Lou Thompson, Susan R. Heckbert, Christopher W. Forsberg, and Anna Korpak
- Subjects
Male ,medicine.medical_specialty ,Epidemiology ,Comorbidity ,Low testosterone levels ,Risk Factors ,Internal medicine ,Testosterone treatment ,Cardiovascular Disease ,medicine ,cohort study ,Humans ,Diseases of the circulatory (Cardiovascular) system ,Myocardial infarction ,Stroke ,thrombosis ,Aged ,Ischemic Stroke ,Veterans ,Original Research ,business.industry ,Testosterone (patch) ,Venous Thromboembolism ,Middle Aged ,medicine.disease ,Thrombosis ,stroke ,myocardial infarction ,Cardiovascular Diseases ,RC666-701 ,testosterone ,Cardiology and Cardiovascular Medicine ,business ,Cohort study - Abstract
Background Testosterone treatment is common in men, although risks for major cardiovascular events are unclear. Methods and Results A study was conducted in US male veterans, aged ≥40 years, with low serum testosterone and multiple medical comorbidities and without history of myocardial infarction, stroke, venous thromboembolism, prostate cancer, or testosterone treatment in the prior year. For the primary outcome, we examined if testosterone treatment was associated with a composite cardiovascular outcome (incident myocardial infarction, ischemic stroke, or venous thromboembolism). Testosterone use was modeled as intramuscular or transdermal and as current use, former use, and no use. Current testosterone users were compared with former users to reduce confounding by indication. The cohort consisted of 204 857 men with a mean (SD) age of 60.9 (9.9) years and 4.7 (3.5) chronic medical conditions. During follow‐up of 4.3 (2.8) years, 12 645 composite cardiovascular events occurred. In adjusted Cox regression analyses, current use of transdermal testosterone was not associated with risk for the composite cardiovascular outcome (hazard ratio [HR], 0.89; 95% CI, 0.76–1.05) in those without prevalent cardiovascular disease, and in those with prevalent cardiovascular disease was associated with lower risk (HR, 0.80; 95% CI, 0.70–0.91). In similar analyses, current use of intramuscular testosterone was not associated with risk for the composite cardiovascular outcome in men without or with prevalent cardiovascular disease (HR, 0.91; 95% CI, 0.80–1.04; HR, 0.98; 95% CI, 0.89–1.09, respectively). Conclusions In a large cohort of men without a history of myocardial infarction, stroke, or venous thromboembolism, testosterone treatment was not associated with increased risk for incident composite cardiovascular events.
- Published
- 2021
39. Outracing champion Gran Turismo drivers with deep reinforcement learning
- Author
-
Peter R. Wurman, Samuel Barrett, Kenta Kawamoto, James MacGlashan, Kaushik Subramanian, Thomas J. Walsh, Roberto Capobianco, Alisa Devlic, Franziska Eckert, Florian Fuchs, Leilani Gilpin, Piyush Khandelwal, Varun 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
- Subjects
Automobile Driving ,Competitive Behavior ,Multidisciplinary ,Deep Learning ,Reward ,Video Games ,Autonomous racing ,Reinforcement Learning ,Humans ,Reinforcement, Psychology ,Sports - Abstract
Many potential applications of artificial intelligence involve making real-time decisions in physical systems while interacting with humans. Automobile racing represents an extreme example of these conditions; drivers must execute complex tactical manoeuvres to pass or block opponents while operating their vehicles at their traction limits
- Published
- 2021
40. Ibrexafungerp, a Novel Triterpenoid Antifungal in Development for the Treatment of Mold Infections
- Author
-
David A. Angulo, Barbara Alexander, Riina Rautemaa-Richardson, Ana Alastruey-Izquierdo, Martin Hoenigl, Ashraf S. Ibrahim, Mahmoud A. Ghannoum, Thomas R. King, Nkechi E. Azie, Thomas J. Walsh, and NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos)
- Subjects
Microbiology (medical) ,Prevention ,ibrexafungerp ,Evaluation of treatments and therapeutic interventions ,Plant Science ,invasive fungal infection ,molds ,new antifungal agents ,Emerging Infectious Diseases ,Infectious Diseases ,Rare Diseases ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,triterpenoid ,Development of treatments and therapeutic interventions ,Infection ,Ecology, Evolution, Behavior and Systematics - Abstract
Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician's armamentarium against these difficult-to-treat infections. Experiments reported in this manuscript were funded by Scynexis and support for mucormycosis research was provided by the NIH/NIAID under Contract No. HHSN272201700039I (Task order A34-HHSN27200003). Sí
- Published
- 2022
41. Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients
- Author
-
J. Christopher Day, Haydar Frangoul, Christopher Lademacher, Lara Danziger-Isakov, William J Muller, Inci Yildirim, Amit Desai, William J. Steinbach, Mark E. Jones, Julie Chu, Paul K. Sue, Laura L. Kovanda, Tempe K. Chen, Susan R. Rheingold, Dwight E Yin, Michael Neely, Thomas J. Walsh, Antonio Arrieta, Victoria A. Statler, Desiree Leiva Phillips, Kelley Micklus, Grace A. McComsey, and Kamal Hamed
- Subjects
0301 basic medicine ,Adolescent ,Pyridines ,030106 microbiology ,Administration, Oral ,Population pharmacokinetics ,Clinical Therapeutics ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,population pharmacokinetics ,Oral administration ,Nitriles ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Child ,invasive fungal infections ,business.industry ,isavuconazole ,Infant ,Safety tolerability ,Triazoles ,Prodrug ,Isavuconazonium ,triazole ,pediatric ,Infectious Diseases ,Tolerability ,Child, Preschool ,business ,medicine.drug - Abstract
Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to 80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).
- Published
- 2021
42. Comparison of clinician and patient users of a mobile phone application to assess penile curvature in Peyronie’s disease
- Author
-
Saneal Rajanahally, Thomas J. Walsh, George R. Schade, Marc J. Rogers, Hunter Wessells, Ryan S. Hsi, Wayne Brisbane, Lauren Trew, and Kevin A. Ostrowski
- Subjects
medicine.medical_specialty ,030219 obstetrics & reproductive medicine ,Home environment ,business.industry ,Urology ,Girth measurements ,Gold standard ,030232 urology & nephrology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Disease severity ,Patient experience ,Physical therapy ,Medicine ,Pearson Correlation Test ,Penile curvature ,Peyronie's disease ,business - Abstract
Assessment of Peyronie’s disease with penile injection is invasive and uncomfortable. We developed a smartphone application (UWPEN) to assess penile angulation in the home environment. The purpose of this study was to compare clinician and patient measurements and assess the patient experience with UWPEN in a clinical setting. We prospectively enrolled patients with Peyronie’s disease undergoing intracavernosal injection of alprostadil. Penile angulation and narrowing were then assessed by patients and clinicians using UWPEN and compared to values obtained via a goniometer and a ruler (gold standard). Measurements were compared using the Pearson correlation test. Upon completion of measurements, patients were surveyed regarding the ease of use, confidence with use, and measurement preferences. Twenty patients were enrolled in the study; two patients were excluded for poor penile turgidity after a maximum dosage of intracavernosal alprostadil. Correlation between UWPEN and gold standard measurements by patients and clinicians was R = 0.55 (p = 0.01) and R = 0.87 (p
- Published
- 2019
43. The expanding use of matrix-assisted laser desorption/ionization-time of flight mass spectroscopy in the diagnosis of patients with mycotic diseases
- Author
-
Matthew W. McCarthy and Thomas J. Walsh
- Subjects
0301 basic medicine ,Materials science ,Fungi ,Analytical chemistry ,Matrix assisted laser desorption ionization time of flight ,Mass spectrometry ,Laser ,Pathology and Forensic Medicine ,law.invention ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Molecular Diagnostic Techniques ,Mycoses ,law ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,030220 oncology & carcinogenesis ,Desorption ,Genetics ,Humans ,Molecular Medicine ,Molecular Biology - Abstract
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a powerful new tool to identify human fungal pathogens and has radically altered the diagnostic mycology workflow at many medical centers around the world. Areas covered: While most experience is with the identification of yeasts, including species of Candida and Cryptococcus, there is ongoing work investigating the role of MALDI-TOF MS to detect molds, including species of Aspergillus, Fusarium, Scedosporium, and Mucormyctes as well as thermally dimorphic fungi. Expert commentary: In this paper, we review the current knowledge about this important new platform and examine how its expanding use may impact molecular diagnostics and patient care in the years ahead.
- Published
- 2019
44. 123. Oral Ibrexafungerp Outcomes by Fungal Disease in Patients from an Interim Analysis of a Phase 3 Open-label Study (FURI)
- Author
-
Peter G Pappas, Oliver Cornely, Philipp Koehler, Todd P McCarty, Barbara D Alexander, Rachel Miller, Jose A Vazquez, John W Sanders, Caryn Morse, Luis Ostrosky-Zeichner, Robert Krause, Jürgen Prattes, Andrej Spec, Riina Rautemaa-Richardson, Rohit Bazaz, Thomas J Walsh, Francisco M Marty, Isabel H Gonzalez-Bocco, Marisa Miceli, Martin Hoenigl, Thomas F Patterson, Nkechi Azie, and David A Angulo
- Subjects
Infectious Diseases ,AcademicSubjects/MED00290 ,Oncology ,Oral Abstracts ,education ,health care economics and organizations - Abstract
Background Candida species are a major cause of invasive and mucocutaneouls infections. There are limited oral treatment options available for patients with Candida infections who are unresponsive to or who are intolerant of currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. We present an analysis of patient outcomes from the FURI study by fungal disease type. Table 1: FURI Outcomes by Fungal Disease Methods FURI patients were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis,other fungal diseases and evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy is clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 patients enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total of 39 (52.7%) patients had invasive candidiasis, 32 (43.2%) had mucocutaneous candidiasis and 3 (4.5%) patients had invasive aspergillosis. The percent of patients who were determined to have a complete response (CR), partial response (PR), clinical improvement (CI) was 63.5%, stable disease (SD) was 23.0%, patients with progression of disease 6.8% and 4 patients were indeterminate. Additionally, there was 1 death in the FURI study that was not related to fungal disease. Table 1 shows outcomes by fungal disease type as determined by the DRC. Conclusion Analysis of 74 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker's Bureau)Astellas Pharma (Speaker's Bureau)Euopean Confederation of Medical Mycology (Speaker's Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker's Bureau)MSD (Speaker's Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker's Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Consultant) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker's Bureau)Pfizer (Scientific Research Study Investigator, Speaker's Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker's Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, Astellas (Grant/Research Support)Gilead (Grant/Research Support)Pfizer (Grant/Research Support) Martin Hoenigl, MD, Astellas (Individual(s) Involved: Self): Grant/Research Support; F2G (Individual(s) Involved: Self): Grant/Research Support; Gilead (Individual(s) Involved: Self): Grant/Research Support; Pfiyer (Individual(s) Involved: Self): Grant/Research Support; Scýnexis (Individual(s) Involved: Self): Grant/Research Support Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)
- Published
- 2021
45. 992. Oral Ibrexafungerp Outcomes in Patients with Oropharyngeal and Esophageal Candidiasis from an Interim Analysis of a Phase 3 Open-label Study (FURI)
- Author
-
Jose A Vazquez, Oliver Cornely, Philipp Koehler, Riina Rautemaa-Richardson, Rohit Bazaz, G Marshall Lyon, Francisco M Marty, Isabel H Gonzalez-Bocco, Rachel Miller, Thomas J Walsh, Peter Pappas, Todd P McCarty, John W Sanders, Caryn Morse, Luis Ostrosky-Zeichner, Robert Krause, Jürgen Prattes, Andrej Spec, David Andes, Oliver Witzke, Nkechi Azie, and David A Angulo
- Subjects
Infectious Diseases ,Oncology ,education - Abstract
Background Candida albicans is the predominant organism causing esophageal candidiasis (EC) and oropharyngel candidiasis (OPC). These infections may arise from subjects colonized with Candida who are predisposed due to illness, debility or a local reduction in host resistance to an overgrowth of their own indigenous flora. Patients with mucocutaneous Candida infections can be treated in the outpatient setting, yet there are limited oral treatment options available for patients who are unresponsive to or who are intolerant to currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. Table 1. FURI Outcomes in OPC and EC Methods FURI subjects were eligible for enrollment if they had proven or probable severe mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, or other fungal diseases with evidence of treatment failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment or if they were unable to receive an approved oral antifungal option (e.g., susceptibility of the organism) and a continued IV antifungal therapy was clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total 32 subjects (43.2%) had mucocutaneous candidiasis and 24 subjects were diagnosed with OPC or EC. The percent of patients who were determined to have a complete response (CR) or partial response (PR) was 62.5%, stable disease (SD), 20.8%, and progression of disease, 16.7%. Table 1 shows outcomes by EC and OPC as determined by the DRC. Conclusion Analysis of 24 EC and OPC patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging mucocutaneous fungal disease and limited treatment options. Disclosures Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) G. Marshall Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Peter Pappas, MD, Astellas (Grant/Research Support)Cidara (Grant/Research Support, Advisor or Review Panel member)Mayne (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)SCYNEXIS, Inc. (Consultant, Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker’s Bureau)Pfizer (Scientific Research Study Investigator, Speaker’s Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, SCYNEXIS, Inc. (Consultant, Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Oliver Witzke, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)
- Published
- 2021
46. Targeted long-read sequencing identifies missing disease-causing variation
- Author
-
Tim Cherry, Seth J. Perlman, Rando Allikmets, Christina Lam, Katrina M Dipple, Alexias Safi, Hailey Loucks, Penny M Chow, Ian A. Glass, Xue Zou, Heather C Mefford, Angela Sun, Deborah A. Nickerson, Danny E. Miller, Dawn L. Earl, James T. Bennett, Alexandra P. Lewis, Stephanie Austin, Margaret P Adam, Apoorva K Iyengar, Arvis Sulovari, Edith P Almanza Fuerte, Andrew S. Allen, Audrey Squire, Karynne E. Patterson, Erin Huggins, Winston Lee, William H. Majoros, Emily S Bonkowski, Tianyun Wang, Priya S. Kishnani, Robin L. Bennett, Mary Claire King, Tara L. Wenger, Erika Beckman, Kendra Hoekzema, Gregory E. Crawford, Timothy E. Reddy, Evan E. Eichler, Irene Chang, Anne V. Hing, Zoe Nelson, Thomas J. Walsh, Dan Doherty, Megan C. Sikes, Michael J. Bamshad, Catherine R Paschal, Jessica X. Chong, Jenny Thies, and Katherine M. Munson
- Subjects
Male ,DNA Copy Number Variations ,Computational biology ,Disease ,Biology ,Article ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Gene ,Genetics (clinical) ,030304 developmental biology ,Sequence (medicine) ,Data source ,Chromosome Aberrations ,0303 health sciences ,Genome, Human ,Genetic Diseases, Inborn ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Phenotype ,Karyotyping ,Mutation (genetic algorithm) ,Cytogenetic Analysis ,Mutation ,Mendelian inheritance ,symbols ,Female ,Nanopore sequencing ,030217 neurology & neurosurgery - Abstract
Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.
- Published
- 2021
47. Cisplatin +/− rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer
- Author
-
Susan M. Perkins, Cynthia X. Ma, Thomas J. Walsh, Michael A. Danso, Kathy D. Miller, Maitri Kalra, Paula Silverman, Yan Tong, David R. Jones, Sunil Badve, and Mary Claire King
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,Pharmacology (medical) ,Radiology, Nuclear Medicine and imaging ,education ,Rucaparib ,Lymph node ,Cancer genetics ,RC254-282 ,Neoadjuvant therapy ,Cisplatin ,education.field_of_study ,Chemotherapy ,business.industry ,BRCA mutation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Translational research ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0–11.5 cm) with 1 (0–38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82–4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.
- Published
- 2021
48. Efficacy and Pharmacokinetics of Fosmanogepix (APX001) in the Treatment of Candida Endophthalmitis and Hematogenous Meningoencephalitis in Nonneutropenic Rabbits
- Author
-
Thomas J. Walsh, Robert Mansbach, Ruta Petraitiene, Bo Bo Win Maung, Michael R. Hodges, Karen Joy Shaw, Vidmantas Petraitis, and Malcolm Finkelman
- Subjects
medicine.medical_specialty ,Antifungal Agents ,Microbial Sensitivity Tests ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Endophthalmitis ,Pharmacokinetics ,Meningoencephalitis ,In vivo ,Internal medicine ,Candida albicans ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,030212 general & internal medicine ,Candida ,Pharmacology ,0303 health sciences ,biology ,030306 microbiology ,business.industry ,medicine.disease ,Disseminated Candidiasis ,biology.organism_classification ,Corpus albicans ,Infectious Diseases ,Rabbits ,business - Abstract
Candida endophthalmitis is a serious sight-threatening complication of candidemia that may occur before or during antifungal therapy. Hematogenous Candida meningoencephalitis (HCME) is also a serious manifestation of disseminated candidiasis in premature infants, immunosuppressed children, and immunocompromised adults. We evaluated the antifungal efficacy and pharmacokinetics of the prodrug fosmanogepix (APX001) in a rabbit model of endophthalmitis/HCME. Manogepix (APX001A), the active moiety of prodrug fosmanogepix, inhibits the fungal enzyme Gwt1 and is highly active in vitro and in vivo against Candida spp., Aspergillus spp., and other fungal pathogens. Plasma pharmacokinetics of manogepix after oral administration of fosmanogepix on day 6 at 25, 50, and 100 mg/kg resulted in maximum concentration of drug in plasma (C(max)) of 3.96 ± 0.41, 4.14 ± 1.1, and 11.5 ± 1.1 μg/ml, respectively, and area under the concentration-time curve from 0 to 12 h (AUC(0–12)) of 15.8 ± 3.1, 30.8 ± 5.0, 95.9 ± 14 μg·h/ml, respectively. Manogepix penetrated the aqueous humor, vitreous, and choroid with liquid-to-plasma ratios ranging from 0.19 to 0.52, 0.09 to 0.12, and 0.02 to 0.04, respectively. These concentrations correlated with a significant decrease in Candida albicans burden in vitreous (>10(1) to 10(3) log CFU/g) and choroid (>10(1) to 10(3) log CFU/g) (P ≤ 0.05 and P ≤ 0.001, respectively). The aqueous humor had no detectable C. albicans in treatment and control groups. The tissue/plasma concentration ratios of manogepix in meninges, cerebrum, cerebellum, and spinal cord were approximately 1:1, which correlated with a >10(2) to 10(4) decline of C. albicans in tissue versus control (P ≤ 0.05). Serum and cerebrospinal fluid (CSF) (1→3)-β-d-glucan levels demonstrated significant declines in response to fosmanogepix treatment. These findings provide an experimental foundation for fosmanogepix in treatment of Candida endophthalmitis and HCME and derisk the clinical trials of candidemia and invasive candidiasis.
- Published
- 2021
49. Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology
- Author
-
George Dimopoulos, Thomas Lehrnbecher, Sanjay G. Revankar, Chin Fen Neoh, Patrick C. Y. Woo, Retno Wahyuningsih, Sayoki Mfinanga, Rosanne Sprute, Petr Hamal, Abdullah M. S. Al-Hatmi, Birgit Spiess, Anil Kumar, Galia Rahav, Saad J. Taj-Aldeen, Oliver A. Cornely, Jean-Philippe Bouchara, Kerstin Albus, Michaela Lackner, Valentina Arsic-Arsenijevic, Martin Hoenigl, Jacques F. Meis, Philipp Koehler, Malcolm Richardson, Jo Anne H. Young, Tomáš Freiberger, Coleman Rotstein, Jon Salmanton-García, Anuradha Chowdhary, Matteo Bassetti, Rafael F. Duarte, G. Sybren de Hoog, Jannik Stemler, Monica A Slavin, Dorothee Arenz, Juergen Prattes, Marcio Nucci, Adilia Warris, Danila Seidel, Thomas J. Walsh, Thomas R. Rogers, Jeffrey D. Jenks, Thomas F. Patterson, Terrence Rohan Chinniah, Flavio Queiroz-Telles, Fabianne Carlesse, Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Laboratoire de Parasitologie-Mycologie (CHU d'Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)
- Subjects
0301 basic medicine ,medicine.medical_specialty ,food.ingredient ,Medical mycology ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,Mycology ,03 medical and health sciences ,0302 clinical medicine ,food ,All institutes and research themes of the Radboud University Medical Center ,Intensive care ,Epidemiology ,Medicine ,Animals ,Humans ,030212 general & internal medicine ,Disease management (health) ,Intensive care medicine ,ComputingMilieux_MISCELLANEOUS ,Societies, Medical ,biology ,business.industry ,Dematiaceous ,Fungi ,Disease Management ,Guideline ,biology.organism_classification ,3. Good health ,Infectious Diseases ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Mycoses ,Scopulariopsis ,Practice Guidelines as Topic ,business ,Rasamsonia - Abstract
With increasing numbers of patients needing intensive care or who are immunosuppressed, infections caused by moulds other than Aspergillus spp or Mucorales are increasing. Although antifungal prophylaxis has shown effectiveness in preventing many invasive fungal infections, selective pressure has caused an increase of breakthrough infections caused by Fusarium, Lomentospora, and Scedosporium species, as well as by dematiaceous moulds, Rasamsonia, Schizophyllum, Scopulariopsis, Paecilomyces, Penicillium, Talaromyces and Purpureocillium species. Guidance on the complex multidisciplinary management of infections caused by these pathogens has the potential to improve prognosis. Management routes depend on the availability of diagnostic and therapeutic options. The present recommendations are part of the One World-One Guideline initiative to incorporate regional differences in the epidemiology and management of rare mould infections. Experts from 24 countries contributed their knowledge and analysed published evidence on the diagnosis and treatment of rare mould infections. This consensus document intends to provide practical guidance in clinical decision making by engaging physicians and scientists involved in various aspects of clinical management. Moreover, we identify areas of uncertainty and constraints in optimising this management.
- Published
- 2021
50. Navigating the Uncertainties of COVID-19-Associated Aspergillosis: A Comparison With Influenza-Associated Aspergillosis
- Author
-
Dimitrios P. Kontoyiannis, Thomas J. Walsh, Russell E. Lewis, and Frédéric Lamoth
- Subjects
0301 basic medicine ,Aspergillus fumigates ,SARS-CoV-2 ,acute respiratory distress syndrome ,corticosteroids ,flu ,intensive care unit ,mechanical ventilation ,pneumonia ,Antifungal Agents ,Review ,medicine.disease_cause ,Aspergillosis ,law.invention ,Aspergillus fumigatus ,03 medical and health sciences ,Galactomannan ,chemistry.chemical_compound ,0302 clinical medicine ,law ,Pandemic ,Influenza, Human ,Immunology and Allergy ,Medicine ,Humans ,030212 general & internal medicine ,skin and connective tissue diseases ,Invasive Pulmonary Aspergillosis ,biology ,business.industry ,Incidence (epidemiology) ,COVID-19 ,medicine.disease ,biology.organism_classification ,Intensive care unit ,respiratory tract diseases ,Pneumonia ,030104 developmental biology ,Infectious Diseases ,AcademicSubjects/MED00290 ,chemistry ,Superinfection ,Immunology ,Pulmonary Aspergillosis ,business - Abstract
Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a life-threatening superinfection of severe respiratory viral infections, such as influenza. The pandemic of Coronavirus Disease 2019 (COVID-19) due to emerging SARS-CoV-2 rose concern about the eventuality of IPA complicating COVID-19 in intensive care unit mechanically-ventilated patients. While the association between severe influenza and IPA has been demonstrated, it remains unclear whether SARS-CoV-2 infection represents a specific risk factor for IPA. A variable incidence of such complication has been previously reported, which can be partly attributed to differences in diagnostic strategy and IPA definitions, and possibly local environmental/epidemiological factors. In this article, we discuss the similarities and differences between influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA). Compared to IAPA, the majority of CAPA cases have been classified as putative rather than proven/probable IPA, in the absence of positive serum galactomannan or histopathologic evidence of angio-invasion. Discrimination between Aspergillus airways colonization and CAPA is difficult. Distinct physiopathology and cytokine profiles of influenza and COVID-19 may explain these discrepancies. Whether CAPA represents a distinct entity is still debatable and many questions remain unanswered, such as its actual incidence, the predisposing role of corticosteroids or immunomodulatory drugs, and the indications for antifungal therapy.
- Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.