Performance of the clarus Aspergillus galactomannan enzyme immunoassay prototype for the diagnosis of invasive pulmonary aspergillosis in serum.

BACKGROUND: Serum galactomannan (GM) testing is essential for diagnosing invasive aspergillosis (IA), particularly in immunocompromised individuals. The global lack of on-site GM testing capacities necessitates cost-effective alternatives, such as .the clarus Aspergillus GM enzyme immunoassay prototype (clarus AGM prototype). METHODS: This single-centre, cross-sectional study compared the diagnostic performance of the clarus AGM prototype (IMMY, Norman, Oklahoma) with the serological gold standard (=Platelia AGM assay; Bio-Rad, Marnes-la-Cocquette, France). IA was classified according to modified 2020 EORTC/MSG consensus and 2024 FUNDICU criteria. In total, 300 prospectively (May-Dec 2023) and retrospectively (2012-2015) collected samples were included. RESULTS: Among 300 samples from 232 patients, 49 (16%) were classified as proven (n = 1) or probable IA (n = 48). In non-IA cases (n = 250), one patient was classified as possible IA. With the manufacturer recommended cut-off of ≥0.2, sensitivity and specificity of the clarus AGM prototype were 27% (13/49; 95% confidence interval [CI]: 15%-41%) and 99% (248/250; 95% CI: 97%-100%), respectively, while sensitivity and specificity were 78% and 79% when using the optimised Youden's cut-off of 0.0045 ODI. ROC curve analysis demonstrated an area under the curve (AUC) of 0.829 (95% CI: 0.760-0.898) for the clarus AGM prototype in distinguishing between proven/probable IA and non-IA. The AUC for the Platelia AGM was 0.951 (95% CI: 0.909-994). Spearman's correlation analysis showed a weak correlation between the two assays (0.382; p < .001). CONCLUSIONS: The weak correlation between the clarus AGM prototype and Platelia AGM highlights the need for further investigation into the clinical performance of the clarus AGM prototype, giving the different antigen epitopes addressed.

Antifungals in Patients With Extracorporeal Membrane Oxygenation: Clinical Implications.

Extracorporeal membrane oxygenation (ECMO) is a life-saving technique used in critical care medicine for patients with severe respiratory or cardiac failure. This review examines the treatment and prophylaxis of fungal infections in ECMO patients, proposing specific regimens based on available data for different antifungals (azoles, echinocandins, amphotericin B/liposomal amphotericin B) and invasive fungal infections. Currently, isavuconazole and posaconazole have the most supported data, while modified dosages of isavuconazole are recommended in ECMO. Echinocandins are preferred for invasive candidiasis. However, choosing echinocandins is challenging due to limited and varied data on concentration loss in the ECMO circuit. Caution is likewise advised when using liposomal amphotericin B due to uncertain concentrations and potential ECMO dysfunction based on scarce data. We further conclude with the importance of further research on the impact of ECMO on antifungal drug concentrations to optimize dosing regimens in critically ill patients.

Invasive Pulmonary Aspergillosis in Critically Ill Patients with Hantavirus Infection, Austria.

We investigated a cohort of 370 patients in Austria with hantavirus infections (7.8% ICU admission rate) and detected 2 cases (cumulative incidence 7%) of invasive pulmonary aspergillosis; 1 patient died. Hantavirus-associated pulmonary aspergillosis may complicate the course of critically ill patients who have hemorrhagic fever with renal syndrome.

B cell heterogeneity in human tuberculosis highlights compartment-specific phenotype and functional roles.

B cells are important in tuberculosis (TB) immunity, but their role in the human lung is understudied. Here, we characterize B cells from lung tissue and matched blood of patients with TB and found they are decreased in the blood and increased in the lungs, consistent with recruitment to infected tissue, where they are located in granuloma associated lymphoid tissue. Flow cytometry and transcriptomics identify multiple B cell populations in the lung, including those associated with tissue resident memory, germinal centers, antibody secretion, proinflammatory atypical B cells, and regulatory B cells, some of which are expanded in TB disease. Additionally, TB lungs contain high levels of Mtb-reactive antibodies, specifically IgM, which promotes Mtb phagocytosis. Overall, these data reveal the presence of functionally diverse B cell subsets in the lungs of patients with TB and suggest several potential localized roles that may represent a target for interventions to promote immunity or mitigate immunopathology.

Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease.

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

Psychological flexibility as a mechanism of change in psilocybin-assisted therapy for major depression: results from an exploratory placebo-controlled trial.

Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions.

Implementation of an antimicrobial stewardship program for urinary tract infections in long-term care facilities: a cluster-controlled intervention study.

BACKGROUND: Widespread inappropriate use of antimicrobial substances drives resistance development worldwide. In long-term care facilities (LTCF), antibiotics are among the most frequently prescribed medications. More than one third of antimicrobial agents prescribed in LTCFs are for urinary tract infections (UTI). We aimed to increase the number of appropriate antimicrobial treatments for UTIs in LTCFs using a multi-faceted antimicrobial stewardship intervention. METHODS: We performed a non-randomized cluster-controlled intervention study. Four LTCFs of the Geriatric Health Centers Graz were the intervention group, four LTCFs served as control group. The main components of the intervention were: voluntary continuing medical education for primary care physicians, distribution of a written guideline, implementation of the project homepage to distribute guidelines and videos and onsite training for nursing staff. Local nursing staff recorded data on UTI episodes in an online case report platform. Two blinded reviewers assessed whether treatments were adequate. RESULTS: 326 UTI episodes were recorded, 161 in the intervention group and 165 in the control group. During the intervention period, risk ratio for inadequate indication for treatment was 0.41 (95% CI 0.19-0.90), p = 0.025. In theintervention group, the proportion of adequate antibiotic choices increased from 42.1% in the pre-intervention period, to 45.9% during the intervention and to 51% in the post-intervention period (absolute increase of 8.9%). In the control group, the proportion was 36.4%, 33.3% and 33.3%, respectively. The numerical difference between intervention group and control group in the post-intervention period was 17.7% (difference did not reach statistical significance). There were no significant differences between the control group and intervention group in the safety outcomes (proportion of clinical failure, number of hospital admissions due to UTI and adverse events due to antimicrobial treatment). CONCLUSIONS: An antimicrobial stewardship program consisting of practice guidelines, local and web-based education for nursing staff and general practitioners resulted in a significant increase in adequate treatments (in terms of decision to treat the UTI) during the intervention period. However, this difference was not maintained in the post-intervention phase. Continued efforts to improve the quality of prescriptions further are necessary. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov NCT04798365.

Comparison of decrease in elbow flexion strength in patients after tenotomy and tenodesis of the long head of the biceps brachii.

NTRODUCTION: The last two decades have been leading to the development of several types of surgical techniques and procedures to manage the LHB lesions. This paper analyses and compares the difference in muscle strength pre- and post-operatively in two most commonly used surgical procedures - LHB tenotomy and tenodesis. METHOD: The study includes 68 patients who underwent surgery between 2016 and 2020. The patients who had met the prospective study inclusion criteria were divided into two groups based on type of surgery they had undergone (LHB tenotomy or tenodesis); each group consisted of 34. The muscle strength during elbow flexion was measured preoperatively and postoperatively using the Commander Echo Console ultrasound muscle testing device. All patients enrolled in the study had been assessed for elbow flexion strength preoperatively. The muscle strength was measured preoperatively and then 3 years postoperatively (12 to 60 months) on average. CONCLUSION: The study confirmed that the patients who had undergone LHB tenodesis show a significantly lower decrease in elbow flexion strength and a significantly lower incidence of "Popeye" deformity than the patients after LHB tenotomy. Moreover, in the tenodesis group, it was possible to initiate rehabilitation earlier. The incidence of postoperative complications was almost identical in both groups of patients (Tab. 10, Fig. 6, Ref. 40).

New treatment options for critically important WHO fungal priority pathogens.

BACKGROUND: Yet often overlooked in public health discourse, fungal infections pose a crucial global disease burden associated with annual mortality rates approximately equal to tuberculosis and HIV. In response, the WHO published its first global priority list of fungal pathogens in 2022 assigning Aspergillus fumigatus, Candida albicans, Candida auris, and Cryptococcus neoformans to the critical group. OBJECTIVES: This review provides succinct insights into novel antifungals in development, aiming to contribute valuable information and perspectives with a focus on recent clinical findings and new treatment approaches for critical members of the WHO fungal pathogen priority list. SOURCES: PubMed literature search using 'Aspergillus fumigatus', 'Cryptococcus neoformans', 'Candida auris', and 'Candida albicans', along with the names of novel antifungal substances, including 'fosmanogepix', 'ibrexafungerp', 'opelconazole', 'oteseconazole', 'MAT2203', 'olorofim', and 'rezafungin' was conducted. CONTENT: For each critical pathogen, current issues and global clinical data from recent trials are covered. The remarkable development of three new antifungal therapeutics recently receiving Food and Drug Administration approval (ibrexafungerp-June 2021, oteseconazole -April 2022, and rezafungin-March 2023) is outlined, with two more exciting new antifungal substances, namely, olorofim and fosmanogepix expecting approval within the next years. Ibrexafungerp, fosmanogepix, and rezafungin have additionally been granted orphan drug status by the European Medicines Agency in Europe (ibrexafungerp-November 2021, fosmanogepix-July 2022, and rezafungin-January 2024). IMPLICATIONS: Although the limited number of targets and the emergence of resistance have posed challenges to antifungal treatment, new drugs such as ibrexafungerp, rezafungin, fosmanogepix, or olorofim have shown promising clinical efficacy. These drugs not only provide alternative options for invasive fungal infections but also alleviate treatment in outpatient settings. More clinical data, implementation of stewardship programmes, and surveillance, including utilization of drugs in agriculture, are necessary to prevent resistance development and to ensure the safety and efficacy of these new agents.

Ruxolitinib, IV Immunoglobulin, and High-Dose Glucocorticoids for Critically Ill Adults With Secondary Hemophagocytic Lymphohistiocytosis: A Single-Center Observational Pilot Study.

OBJECTIVES: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently leads to ICU admission. Overall survival in adults with sHLH remains poor, especially in those requiring intensive care. Classical chemotherapeutic treatment exhibits myelosuppression and toxicity. Recently, inhibition of Janus kinase signaling by ruxolitinib has shown efficacy in pediatric HLH. We therefore aimed to determine the activity and safety of a ruxolitinib-based regimen, in critically ill adults with sHLH. DESIGN: Observational pilot study. SETTING: Single-center tertiary academic ICU. PATIENTS: Nine adults (≥ 18 yr) who fulfilled at least five of the eight HLH-2004 criteria. INTERVENTION: Triplet regimen combining: 1) ruxolitinib, 2) polyvalent human IV immunoglobulins (IVIG) at a dose of 1 g/kg bodyweight for 5 days, and 3) high-dose corticosteroids (CSs, dexamethasone 10 mg/m² body surface area, or methylprednisolone equivalent) with subsequent tapering according to the HLH-2004 protocol. MEASUREMENT AND MAIN RESULTS: Nine patients (median age: 42 yr [25th-75th percentile: 32-54]; male: n = 6 males, median H-score: 299 [255-304]) were treated with the triplet regimen. The median Sequential Organ Failure Assessment score at HLH diagnosis was 9 (median; 25th-75th percentile: 7-12), indicating multiple-organ dysfunction in all patients. Within 10 days a significant decrease of the inflammatory parameters soluble interleukin-2 receptor and ferritin as well as a stabilization of the blood count could be shown. All patients were alive at ICU discharge (100% ICU survival), 1 patient died after ICU discharge because of traumatic intracerebral hemorrhage that might be related to HLH or treatment, corresponding to an overall survival of 86% in a 6 months follow-up period. CONCLUSION: In this small case series, a triplet regimen of ruxolitinib in combination with IVIG and CS was highly effective and save for treating critically ill adults with sHLH.