Clinical use of voriconazole, posaconazole, and itraconazole revealed the need for therapeutic drug monitoring (TDM) of plasma concentrations of these antifungal agents. This need for TDM was not ...evident from clinical trials. In order to establish whether this requirement also applies to isavuconazole, we examined the plasma concentrations of 283 samples from patients receiving isavuconazole in clinical practice and compared the values with those from clinical trials. The concentration distributions from real-world use and clinical trials were nearly identical (>1 μg/ml in 90% of patients). These findings suggest that routine TDM may not be necessary for isavuconazole in most instances.
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.
The epidemiology of male infertility Winters, Brian R; Walsh, Thomas J
Urologic clinics of North America,
02/2014, Letnik:
41, Številka:
1
Journal Article
Recenzirano
The purpose of this review is to integrate understanding of epidemiology and infertility. A primer on epidemiologic science and an example disease for which the design of epidemiologic investigations ...is readily apparent are provided. Key features of infertility that limit epidemiologic investigation are described and a survey of available data on the epidemiology of infertility provided. Finally, the work that must be completed to move this area of research forward is proposed, and, with this new perspective of "infertility as a disease," improvements envisioned in public health that may be gained through improved understanding of the epidemiology of male infertility.
Recent therapeutic advances have the potential to improve outcomes of mucormycosis. Lipid formulations of amphotericin B (LFAB) have evolved as the cornerstone of primary therapy for mucormycosis. ...Posaconazole may be useful as salvage therapy, but it cannot be recommended as primary therapy for mucormycosis on the basis of available data. Preclinical and limited retrospective clinical data suggest that combination LFAB-echinocandin therapy may improve survival during mucormycosis. A definitive trial is needed to confirm these results. Combination therapy with LFAB and the iron chelator, deferasirox, also improved outcomes in animal models of mucormycosis. In contrast, combination polyene-posaconazole therapy was of no benefit in preclinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered for selected patients. Early initiation of therapy is critical to maximizing outcomes; recent developments in polymerase chain reaction technology are advancing early diagnostic strategies. Prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis.
Hematopoietic stem cell transplant (HSCT) recipients are uniquely threatened by the emergence of multidrug‐resistant (MDR) bacteria because these patients rely on immediate active antimicrobial ...therapy to combat bacterial infections. This review describes the epidemiology and treatment considerations for three challenging MDR bacterial pathogens in HSCT recipients: MDR Enterobacteriaceae, including extended‐spectrum β‐lactamase (ESBL)‐producing and carbapenem‐resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa, and vancomycin‐resistant Enterococcus (VRE). These bacteria are common causes of infection in this population and bacteremias caused by these organisms are associated with high mortality rates. Carbapenems remain the treatments of choice for serious infections due to ESBL‐producing Enterobacteriaceae in HSCT recipients. Administration of β‐lactam agents as an extended infusion is associated with improved outcomes in patients with severe infections caused by P. aeruginosa. Older agents used for the treatment of CRE and MDR P. aeruginosa infections, such as polymyxins and aminoglycosides, have major limitations. Newer agents, such as ceftazidime‐avibactam and ceftolozane‐tazobactam have great potential for the treatment of Klebsiella pneumoniae carbapemenase‐producing CRE and MDR P. aeruginosa, respectively, but more pre‐clinical and clinical data are needed to better evaluate their efficacy. Daptomycin dosages ≥8 mg/kg/day are recommended to treat VRE infections in this population, particularly in the setting of increasing daptomycin resistance. Strategies to prevent these infections include strict adherence to recommended infection control practices and multidisciplinary antimicrobial stewardship. Last, gastrointestinal screening to guide empirical therapy and the use of polymerase chain reaction‐based rapid diagnostics may decrease the time to administration of appropriate therapy for these infections, thereby leading to improved outcomes.
Introduction: Therapeutic drug monitoring (TDM) has been shown to optimize the management of invasive fungal infections (IFIs), particularly for select antifungal agents with a well-defined ...exposure-response relationship and an unpredictable pharmacokinetic profile or a narrow therapeutic index. Select triazoles (itraconazole, voriconazole, and posaconazole) and flucytosine fulfill these criteria, while the echinocandins, fluconazole, isavuconazole, and amphotericin B generally do not do so. Given the morbidity and mortality associated with IFIs and the challenges surrounding the use of currently available antifungal agents, TDM plays an important role in therapy.
Areas covered: This review seeks to describe the rationale for TDM of antifungal agents, summarize their pharmacokinetic and pharmacodynamic properties, identify treatment goals for efficacy and safety, and provide recommendations for optimal dosing and therapeutic monitoring strategies.
Expert opinion: Several new antifungal agents are currently in development, including compounds from existing antifungal classes with enhanced pharmacokinetic or safety profiles as well as agents with novel targets for the treatment of IFIs. Given the predictable pharmacokinetics of these newly developed agents, use of routine TDM is not anticipated. However, expanded knowledge of exposure-response relationships of these compounds may yield a role for TDM to improve outcomes for adult and pediatric patients.
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
. Racing simulations, such as the PlayStation game Gran Turismo, faithfully reproduce the non-linear control challenges of real race cars while also encapsulating the complex multi-agent interactions. Here we describe how we trained agents for Gran Turismo that can compete with the world's best e-sports drivers. We combine state-of-the-art, model-free, deep reinforcement learning algorithms with mixed-scenario training to learn an integrated control policy that combines exceptional speed with impressive tactics. In addition, we construct a reward function that enables the agent to be competitive while adhering to racing's important, but under-specified, sportsmanship rules. We demonstrate the capabilities of our agent, Gran Turismo Sophy, by winning a head-to-head competition against four of the world's best Gran Turismo drivers. By describing how we trained championship-level racers, we demonstrate the possibilities and challenges of using these techniques to control complex dynamical systems in domains where agents must respect imprecisely defined human norms.
Background. The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from ...single-institution retrospective studies. Methods. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. Results. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versushost disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelvemonth cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matchedrelated allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. Conclusions. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.
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