TREM1 regulates antifungal immune responses in invasive pulmonary aspergillosis.

Pattern recognition receptors (PRRs) are responsible for Aspergillus fumigatus recognition by innate immunity and its subsequent immune signaling. The triggering receptor expressed on myeloid cells 1 (TREM1) is a recently characterized pro-inflammatory receptor constitutively expressed on the surface of neutrophils and macrophages. A soluble form (sTREM1) of this protein that can be detected in human body fluids has been identified. Here we investigated the role of TREM1 during invasive pulmonary aspergillosis (IPA). IPA patients displayed significantly higher levels of sTREM1 in bronchoalveolar lavages when compared to control patients. Functional analysis in TREM1 showed that the levels of sTREM1 and TREM1 pathway-related cytokines were influenced by single nucleotide polymorphisms in TREM1. In addition, we confirmed a role of TREM1 on antifungal host defense against A. fumigatus in a murine model of IPA. TREM1 deficiency increased susceptibility to infection in the immunosuppressed murine host. Deletion of TREM1 showed delayed innate and adaptive immune responses and impaired pro-inflammatory cytokine responses. The absence of TREM1 in primary macrophages attenuated the TLR signaling by altering the expression of both receptor and effector proteins that are critical to the response against A. fumigatus. In this study, and for the first time, we demonstrate the key role for the TREM1 receptor pathway during IPA.This work was supported by the Fundação para a Ciência e a Tecnologia [PTDC/SAU-SER/29635/2017]; Fundação para a Ciência e a Tecnologia [UIDB/50026/2020 and UIDP/50026/2020]; Fundação para a Ciência e a Tecnologia [PTDC/MED-GEN/28778/2017]; H2020 Excellent Science [NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023)]; Instituto de Salud Carlos III [RD16/CIII/0004/0003]; Instituto de Salud Carlos III [PI18CIII/00045]; Instituto de Salud Carlos III [MPY 1277/15]; Ministerio de Ciencia, Innovación y Universidades [RTI2018-099114-B-I00]; Associação Viver a Ciência (PT) [SFRH/BD/136814/2018]; “la Caixa” Foundation [ID 100010434].S

Correction to: Epidemiology of Dermatophytes in Belgium: A 5 Years’ Survey (Mycopathologia, (2021), 186, 3, (399-409), 10.1007/s11046-021-00542-4)

peer reviewedIn the original publication of the article, the authors first and last name were swapped and incorrectly published as ‘‘Sacheli Rosalie, Cuypers Lize, Seidel Laurence, Darfouf Rajae, Adjetey Caroline, Lagrou Katrien and Hayette Marie-Pierre’’. The correct first and last name of the authors should be ‘‘Rosalie Sacheli, Lize Cuypers, Laurence Seidel, Rajae Darfouf, Caroline Adjetey, Katrien Lagrou and Marie-Pierre Hayette’’. The original article has been corrected. © 2021, Springer Nature B.V

Pharmacokinetic variability and target attainment of fluconazole in critically ill patients

peer reviewedBackground: Fluconazole is one of the oldest antifungal drugs. Previous studies have raised concerns considering variability in exposure and inadequate target attainment in critically ill pa-tients. The current study aims to define variability and target attainment for fluconazole exposure in a large group of critically ill patients. Methods: In this pharmacokinetic study, daily plasma trough samples and, if possible, 24 h urine samples were collected to determine fluconazole concentration. A minimum target trough concentration of 10–15 mg/L was selected, corresponding to a free area under the concentration–time curve above the minimum inhibitory concentration (fAUC/MIC) of at least 100 for an MIC of 4 mg/L. Covariates that significantly influenced fluconazole exposure were identified. Results: In total, 288 plasma samples from 43 patients, with a median age of 66 years, were included. The median fluconazole trough concentration was 22.9 mg/L. A notable component of the measured concentrations was below the target trough concentrations (13% <10 mg/L and 27% <15 mg/L). The intra-and intersubject variability were 28.3% and 50.5%, respectively. The main covariates determining fluconazole exposure were the administered dose (mg/kg), augmented renal clearance, and renal replacement therapy. Conclusions: Fluconazole trough concentrations are variable in critically ill patients and a considerable number of these concentrations was below the pre-defined target trough concentrations. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.

BACKGROUND: Invasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential. METHODS: To achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved. RESULTS: There is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses. CONCLUSIONS: These updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk

The one health problem of azole resistance in Aspergillus fumigatus: current insights and future research agenda

Azole resistance is a concern for the management of diseases caused by Aspergillus fumigatus in humans. Azole fungicide use in the environment has been identified as a possible cause for development of resistance, which increases the complexity and number of stakeholders involved in this emerging problem. A workshop was held in Amsterdam early 2019 in which stakeholders, including medical and agricultural researchers, representatives from the government, public health, fungicide producers and end-users, reviewed the current evidence supporting environmental selection for resistance and to discuss which research and measures are needed to retain the effectiveness of the azole class for environmental and medical applications. This paper provides an overview of the latest insights and understanding of azole resistance development in the clinical setting and the wider environment. A One Health problem approach was undertaken to list and prioritize which research will be needed to provide missing evidence and to enable preventive intervention

Health and psychosocial status of patients with Turner syndrome after transition to adulthood: The Belgian experience

BACKGROUND: Most girls with Turner syndrome (TS) are intensively followed by paediatricians, but are lost to follow-up when they reach adulthood. To gain insight into the adult medical and psychosocial situation, we performed a survey in young adult TS patients. PATIENTS AND METHODS: A questionnaire concerning current health status, education, occupation and living situation was sent to 160 young adult TS women, all treated during childhood with GH and oestrogen if needed. RESULTS: We received 102 completed questionnaires. Mean +/- SD age at reception of the questionnaire was 23.4 +/- 3.3 years, height 153.3 +/- 5.2 cm, body mass index 23.7 +/- 4.9 kg/m(2). Age and auxological parameters were comparable between responders and non-responders. Thirteen (12.7%) responders were not under regular medical care; 15 (14.7%) were seen by a general practitioner, while 28 (27.4%) needed several specialists. Forty-one (40.2%) patients reported health problems. The most frequently reported problem was hypertension (10.7%), followed by hypothyroidism (5.8%) and back problems (4.9%). Twenty-four (23.5%) of the 41 patients were taking medication for the indicated health problems. Twenty-six (25.5%) women had undergone spontaneous puberty; 16 of them reported spontaneous menstruations while 10 received oestrogen replacement therapy. Of the 76 women with induced puberty, 11 (14.5%) were not taking any oestrogen anymore. Compared with the general population, more TS women attended university and more obtained higher education. Forty-six women (45.1%) were working full-time, 7 (6.9%) were unemployed, and 4 (3.9%) received an allocation. Seventy (68.6%) patients were still living with their parents, while 18 (17.6%) were living together or married, and 14 (13.7%) were living alone. CONCLUSIONS: The transition of adolescents with TS to adult medical care is not optimal in Belgium. Although 40.2% of these young women reported health problems, 12.7% did not consult any physician. Many TS women did not take oestrogen replacement therapy. A specialized multidisciplinary approach for adults with TS is needed in order to optimize health and psychosocial status in these women

Serious fungal infections in Portugal

There is a lack of knowledge on the epidemiology of fungal infections worldwide because there are no reporting obligations. The aim of this study was to estimate the burden of fungal disease in Portugal as part of a global fungal burden project. Most published epidemiology papers reporting fungal infection rates from Portugal were identified. Where no data existed, specific populations at risk and fungal infection frequencies in those populations were used in order to estimate national incidence or prevalence, depending on the condition. An estimated 1,510,391 persons develop a skin or nail fungal infection each year. The second most common fungal infection in Portugal is recurrent vulvovaginal candidiasis, with an estimated 150,700 women (15-50 years of age) suffering from it every year. In human immunodeficiency virus (HIV)-infected people, oral or oesophageal candidiasis rates were estimated to be 19.5 and 16.8/100,000, respectively. Candidaemia affects 2.19/100,000 patients, in a total of 231 cases nationally. Invasive aspergillosis is less common than in other countries as chronic obstructive pulmonary disease (COPD) is uncommon in Portugal, a total of 240 cases annually. The estimated prevalence of chronic pulmonary aspergillosis after tuberculosis (TB) is 194 cases, whereas its prevalence for all underlying pulmonary conditions was 776 patients. Asthma is common (10% in adults) and we estimate 16,614 and 12,600 people with severe asthma with fungal sensitisation and allergic bronchopulmonary aspergillosis, respectively. Sixty-five patients develop Pneumocystis pneumonia in acquired immune deficiency syndrome (AIDS) and 13 develop cryptococcosis. Overall, we estimate a total number of 1,695,514 fungal infections starting each year in Portugal.info:eu-repo/semantics/publishedVersio

How to: interpret MICs of antifungal compounds according to the revised clinical breakpoints v. 10.0 European committee on antimicrobial susceptibility testing (EUCAST)

BACKGROUND: EUCAST has revised the definition of the susceptibility category "I" from "Intermediate" to "Susceptible, Increased exposure". This implies that "I" can be used where the drug-concentration at the site of infection is high, either because of dose escalation or through other means to ensure efficacy. Consequently, "I" is no longer used as a buffer-zone to prevent technical fact

On the isoperimetric problem for the Laplacian with Robin and Wentzell boundary conditions

Doctor of PhilosophyWe consider the problem of minimising the eigenvalues of the Laplacian with Robin boundary conditions $\frac{\partial u}{\partial \nu} + \alpha u = 0$ and generalised Wentzell boundary conditions $\Delta u + \beta \frac{\partial u}{\partial \nu} + \gamma u = 0$ with respect to the domain $\Omega \subset \mathbb R^N$ on which the problem is defined. For the Robin problem, when $\alpha > 0$ we extend the Faber-Krahn inequality of Daners [Math. Ann. 335 (2006), 767--785], which states that the ball minimises the first eigenvalue, to prove that the minimiser is unique amongst domains of class $C^2$. The method of proof uses a functional of the level sets to estimate the first eigenvalue from below, together with a rearrangement of the ball's eigenfunction onto the domain $\Omega$ and the usual isoperimetric inequality. We then prove that the second eigenvalue attains its minimum only on the disjoint union of two equal balls, and set the proof up so it works for the Robin $p$-Laplacian. For the higher eigenvalues, we show that it is in general impossible for a minimiser to exist independently of $\alpha > 0$. When $\alpha < 0$, we prove that every eigenvalue behaves like $-\alpha^2$ as $\alpha \to -\infty$, provided only that $\Omega$ is bounded with $C^1$ boundary. This generalises a result of Lou and Zhu [Pacific J. Math. 214 (2004), 323--334] for the first eigenvalue. For the Wentzell problem, we (re-)prove general operator properties, including for the less-studied case $\beta 0$ establish a type of equivalence property between the Wentzell and Robin minimisers for all eigenvalues. This yields a minimiser of the second Wentzell eigenvalue. We also prove a Cheeger-type inequality for the first eigenvalue in this case