Hospital-treated serious and invasive aspergillosis and candidiasis infections during the COVID-19 pandemic: a retrospective analysis of Hospital Episode Statistics data from England.

OBJECTIVES: To investigate the impact of COVID-19 on the burden of hospital-treated Aspergillus and Candida infections in England. DESIGN: A retrospective study using Hospital Episodes Statistics data to estimate the burden of serious and invasive fungal infections (SIFIs) in all patients admitted in England during March 2018-February 2020 (pre-COVID-19) and during March 2020-October 2021 (the COVID-19 period). SETTING: Hospitals in England. POPULATION: All patients with codes corresponding to serious and invasive aspergillosis and candidiasis in any diagnosis position during their admission pre-COVID-19 and during the COVID-19 period. OUTCOME MEASURES: Age, spells, patient counts, mean length of stay, admission to critical care unit (CCU), length of stay in CCU, 30-day readmissions, failed discharges (readmission within 7 days) and comorbidities. RESULTS: During the COVID-19 period, hospitalisation spells with an invasive candidiasis code fell by 3.2% and spells with an aspergillosis code by 24.8%. Mean length of stay was higher for patients with aspergillosis with or without COVID-19 and candidiasis with or without COVID-19 during the pandemic than before the pandemic. During the pandemic, mean length of stay was higher for patients with aspergillosis with COVID-19 than those with aspergillosis alone but slightly lower for patients with candidiasis with COVID-19 than for those with candidiasis alone. Of patients with a diagnosis of COVID-19, 52.5% with aspergillosis and 60.0% with candidiasis were treated in CCU compared with 13.2% and 37.1%, respectively, without a COVID-19 diagnosis. The percentage of 30-day readmissions and failed discharges for patients with SIFI was higher for those with COVID-19 than for those without. CONCLUSIONS: The burden of aspergillosis and candidiasis has been affected by COVID-19. Aspergillosis diagnoses fell among hospitalised patients during the pandemic, while candidiasis continued to fluctuate in patterns similar to pre-COVID-19. A higher burden for patients with SIFI was observed, whether or not they also had a diagnosis of COVID-19. Our findings highlight extra considerations and burden on management of serious SIFI as a result of the COVID-19 pandemic.

COVID-19-associated pulmonary aspergillosis in immunocompetent patients: a virtual patient cohort study.

The opportunistic fungus Aspergillus fumigatus infects the lungs of immunocompromised hosts, including patients undergoing chemotherapy or organ transplantation. More recently however, immunocompetent patients with severe SARS-CoV2 have been reported to be affected by COVID-19 Associated Pulmonary Aspergillosis (CAPA), in the absence of the conventional risk factors for invasive aspergillosis. This paper explores the hypothesis that contributing causes are the destruction of the lung epithelium permitting colonization by opportunistic pathogens. At the same time, the exhaustion of the immune system, characterized by cytokine storms, apoptosis, and depletion of leukocytes may hinder the response to A. fumigatus infection. The combination of these factors may explain the onset of invasive aspergillosis in immunocompetent patients. We used a previously published computational model of the innate immune response to infection with Aspergillus fumigatus. Variation of model parameters was used to create a virtual patient population. A simulation study of this virtual patient population to test potential causes for co-infection in immunocompetent patients. The two most important factors determining the likelihood of CAPA were the inherent virulence of the fungus and the effectiveness of the neutrophil population, as measured by granule half-life and ability to kill fungal cells. Varying these parameters across the virtual patient population generated a realistic distribution of CAPA phenotypes observed in the literature. Computational models are an effective tool for hypothesis generation. Varying model parameters can be used to create a virtual patient population for identifying candidate mechanisms for phenomena observed in actual patient populations.

[New characteristics of COVID-19 caused by the Omicron variant in Guangzhou].

We investigated the types of novel coronavirus strains present during the Omicron epidemic from late 2022 to early 2023, COVID-19 co-infections with other pathogens, and clinical characteristics of patients with novel coronavirus infections. Adult patients hospitalized due to SARS CoV-2 infection in six hospitals in Guangzhou city were included in the study from November 2022 to February 2023. Clinical information was collected and analyzed, and bronchoalveolar lavage fluid was obtained for pathogen detection using a variety of techniques, including standard methods and mNGS, tNGS. The results showed that the main strain circulating in Guangzhou was Omicron BA.5.2, and the overall detection rate of potentially pathogenic pathogens combined with Omicron COVID-19 infection was 49.8%. In patients with severe COVID-19 infection, special attention should be paid to aspergillosis and combined Mycobacterium tuberculosis infection. In additon, Omicron strain infection could cause viral sepsis, which led to a worse prognosis for COVID-19 patients. Diabetic patients with SARS-CoV-2 infection did not benefit from glucocorticoid treatment, and caution was necessary when using glucocorticoids. These findings highlighted some new features of severe Omicron coronavirus infection that should be noted.

How to lose resistance to Aspergillus infections.

The distinct risk factors to deadly infections by Aspergillus fumigatus (Af) in intensive care unit (ICU) patients are well known; however, so far, the mechanistic link between these predisposing conditions has been unknown. Sarden et al. recently unraveled a shared B1a lymphocyte-natural antibody-neutrophil defense pathway to Af, opening new perspectives in diagnostics and therapeutics.

Targeting Sterylglucosidase A to Treat Aspergillus fumigatus Infections.

Invasive fungal infections are a leading cause of death in immunocompromised patients. Current therapies have several limitations, and innovative antifungal agents are critically needed. Previously, we identified the fungus-specific enzyme sterylglucosidase as essential for pathogenesis and virulence of Cryptococcus neoformans and Aspergillus fumigatus (Af) in murine models of mycoses. Here, we developed Af sterylglucosidase A (SglA) as a therapeutic target. We identified two selective inhibitors of SglA with distinct chemical scaffolds that bind in the active site of SglA. Both inhibitors induce sterylglucoside accumulation and delay filamentation in Af and increase survival in a murine model of pulmonary aspergillosis. Structure-activity relationship (SAR) studies identified a more potent derivative that enhances both in vitro phenotypes and in vivo survival. These findings support sterylglucosidase inhibition as a promising antifungal approach with broad-spectrum potential. IMPORTANCE Invasive fungal infections are a leading cause of death in immunocompromised patients. Aspergillus fumigatus is a fungus ubiquitously found in the environment that, upon inhalation, causes both acute and chronic illnesses in at-risk individuals. A. fumigatus is recognized as one of the critical fungal pathogens for which a substantive treatment breakthrough is urgently needed. Here, we studied a fungus-specific enzyme, sterylglucosidase A (SglA), as a therapeutic target. We identified selective inhibitors of SglA that induce accumulation of sterylglucosides and delay filamentation in A. fumigatus and increase survival in a murine model of pulmonary aspergillosis. We determined the structure of SglA, predicted the binding poses of these inhibitors through docking analysis, and identified a more efficacious derivative with a limited SAR study. These results open several exciting avenues for the research and development of a new class of antifungal agents targeting sterylglucosidases.

Ramification of COVID-19 pandemic : Occurrence and impact of fungal infections in a tertiary care hospital (preprint)

Coronavirus disease 2019 (COVID-19) pandemic has been prevailing for more than a year associated with increased number of opportunistic invasive fungal infections in patients who have been critically ill or immunocompromised. In this retrospective study, details of various clinical specimens received from suspected patients of fungal infections were processed according to standard protocol were studied. The fungal infections were present in 64% (51/79) COVID-19 positive patients and 43% (163/381) COVID-19 negative patients) during the year 2021 during the second wave of COVID-19. Among COVID-19 infected patients, the fungal infection mostly observed was Candidiasis (63%) followed by Aspergillosis (15% ) and Mucormycosis (6%). The maximum samples positive in COVID-19 patients were urine samples followed by Serum (for Aspergillus Galactomannan). Among the urine and respiratory samples (BAL, Tracheal aspirate, Sputum) in COVID-19 positive patients, maximum positivity of Candida species was seen. Mucormycosis in COVID-19 positive patients was isolated in Nasal samples followed by tissue sample with Rhizopus arrhizus and Rhizopus homothallicus. There has been an increase in fungal co-infections during the COVID-19 pandemic which is a matter of great concern. Early diagnosis is essential for effective management of these patients.

Invasive cerebral aspergillosis in non-neutropenic patients: A case series from Western India.

PURPOSE: Invasive cerebral aspergillosis (ICA) is a rare but fatal infection affecting neutropenic immunocompromised patients. Recently cases have been reported in non-neutropenic settings also. We hereby present a series of ICA cases in non-neutropenic patients diagnosed at our tertiary care centre in Western India between March to October 2021. METHODS: All patients with clinico-radiological suspicion of CNS infections were analysed. Data regarding Clinico-radiological features, diagnosis, treatment and outcome were collected. After ruling out bacterial, viral and mycobacterial causes, appropriate samples were sent for KOH (potassium hydroxide) wet mount, fungal culture, histopathology and serum/CSF galactomannan. RESULTS: A total of four patients were diagnosed with ICA with a mean age of 43.5 years. Three patients had significant comorbidities; Diabetes mellitus, chronic liver disease and COVID-19 pneumonia treated with dexamethasone, respectively. One patient had no known predisposing factor. Radiologically, one patient presented with a frontal brain abscess and two patients had multiple subcortical hyperintensities. Three patients were diagnosed based on CSF galactomannan (Platelia™ Aspergillus antigen, Bio-Rad, France) with OD >1 and one patient had high serum galactomannan (OD >2). CSF culture grew Aspergillus species in two patients. All patients were treated with Voriconazole. One patient recovered, and the remaining three succumbed due to delayed presentation and extensive cerebral involvement. CONCLUSION: Even in non-neutropenic patients, a high index of suspicion is warranted for cerebral aspergillosis. CSF galactomannan can be considered a reliable marker for diagnosing ICA in non-neutropenic settings. Early diagnosis allows timely antifungal therapy, which could be a key to improving the outcomes.

Metagenomic Next-Generation Sequencing of Plasma for Diagnosis of COVID-19-Associated Pulmonary Aspergillosis.

Timely diagnosis remains an unmet need in non-neutropenic patients at risk for aspergillosis, including those with COVID-19-associated pulmonary aspergillosis (CAPA), which in its early stages is characterized by tissue-invasive growth of the lungs with limited angioinvasion. Currently available mycological tests show limited sensitivity when testing blood specimens. Metagenomic next-generation sequencing (mNGS) to detect microbial cell-free DNA (mcfDNA) in plasma might overcome some of the limitations of conventional diagnostics. A two-center cohort study involving 114 COVID-19 intensive care unit patients evaluated the performance of plasma mcfDNA sequencing for the diagnosis of CAPA. Classification of CAPA was performed using the European Confederation for Medical Mycology (ECMM)/International Society for Human and Animal Mycoses (ISHAM) criteria. A total of 218 plasma samples were collected between April 2020 and June 2021 and tested for mcfDNA (Karius test). Only 6 patients were classified as probable CAPA, and 2 were classified as possible, while 106 patients did not fulfill CAPA criteria. The Karius test detected DNA of mold pathogens in 12 samples from 8 patients, including Aspergillus fumigatus in 10 samples from 6 patients. Mold pathogen DNA was detected in 5 of 6 (83% sensitivity) cases with probable CAPA (A. fumigatus in 8 samples from 4 patients and Rhizopus microsporus in 1 sample), while the test did not detect molds in 103 of 106 (97% specificity) cases without CAPA. The Karius test showed promising performance for diagnosis of CAPA when testing plasma, being highly specific. The test detected molds in all but one patient with probable CAPA, including cases where other mycological tests from blood resulted continuously negative, outlining the need for validation in larger studies.

Characterization of Aspergillus spp. isolated from patients with coronavirus disease 2019.

INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is an important complication of coronavirus disease 2019 (COVID-19), and while there are case reports and epidemiological studies, few studies have isolated Aspergillus strains from patients. Therefore, we analyzed the strains, sensitivities, and genetic homology of Aspergillus spp. Isolated from patients with COVID-19. METHODS: We investigated the Aspergillus strains detected from patients with COVID-19 hospitalized in Osaka Metropolitan University Hospital from December 2020 to June 2021. A molecular epidemiological analysis of Aspergillus spp. was performed using drug susceptibility tests and TRESPERG typing, and data on patient characteristics were collected from electronic medical records. RESULTS: Twelve strains of Aspergillus were detected in 11 of the 122 patients (9%) with COVID-19. A. fumigatus was the most common species detected, followed by one strain each of Aspergillus aureolus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus. A. aureolus was resistant to voriconazole, and no resistance was found in other strains. All A. fumigatus strains were genetically distinct strains. Six of the 11 patients that harbored Aspergillus received antifungal drug treatment and tested positive for ß-D-glucan and/or Aspergillus galactomannan antigen. The results indicated that Aspergillus infections were acquired from outside the hospital and not from nosocomial infections. CONCLUSION: Strict surveillance of Aspergillus spp. is beneficial in patients at high-risk for IPA. When Aspergillus is detected, it is important to monitor the onset of IPA carefully and identify the strain, perform drug sensitivity tests, and facilitate early administration of therapeutic agents to patients with IPA.

Prevention of acquired invasive fungal infection with decontamination regimen in mechanically ventilated ICU patients: a pre/post observational study.

BACKGROUND: Invasive fungal infections acquired in the intensive care unit (AFI) are life-threating complications of critical illness. However, there is no consensus on antifungal prophylaxis in this setting. Multiple site decontamination is a well-studied prophylaxis against bacterial and fungal infections. Data on the effect of decontamination regimens on AFI are lacking. We hypothesised that multiple site decontamination could decrease the rate of AFI in mechanically ventilated patients. METHODS: We conducted a pre/post observational study in 2 ICUs, on adult patients who required mechanical ventilation for >24 h. During the study period, multiple-site decontamination was added to standard of care. It consists of amphotericin B four times daily in the oropharynx and the gastric tube along with topical antibiotics, chlorhexidine body wash and nasal mupirocin. RESULTS: In 870 patients, there were 27 AFI in 26 patients. Aspergillosis accounted for 20/143 of ventilator-associated pneumonia and candidemia for 7/75 of ICU-acquired bloodstream infections. There were 3/308 (1%) patients with AFI in the decontamination group and 23/562 (4%) in the standard-care group (p = 0.011). In a propensity-score matched analysis, there were 3/308 (1%) and 16/308 (5%) AFI in the decontamination group and the standard-care group respectively (p = 0.004) (3/308 vs 11/308 ventilator-associated pulmonary aspergillosis, respectively [p = 0.055] and 0/308 vs 6/308 candidemia, respectively [p = 0.037]). CONCLUSION: Acquired fungal infection is a rare event, but accounts for a large proportion of ICU-acquired infections. Our study showed a preventive effect of decontamination against acquired fungal infection, especially candidemia.Take home messageAcquired fungal infection (AFI) incidence is close to 4% in mechanically ventilated patients without antifungal prophylaxis (3% for pulmonary aspergillosis and 1% for candidemia).Aspergillosis accounts for 14% of ventilator-associated pneumonia and candidemia for 9% of acquired bloodstream infections.Immunocompromised patients, those infected with SARS-COV 2 or influenza virus, males and patients admitted during the fall season are at higher risk of AFI.Mechanically ventilated patients receiving multiple site decontamination (MSD) have a lower risk of AFI.

Bilateral renal aspergillosis with a fungal cast masquerading as renal malignancy.

Invasive isolated renal aspergilloma in an immunocompetent host is rare, and few cases have been reported in the literature. It is a unique entity encountered by a urologist that can lead to catastrophic complications like end-stage renal disease. Infective pathology may closely resemble renal mass, and timely, appropriate investigations are obligatory for early intervention. This case report highlights the importance of strong consideration of renal fungal infections in the differential diagnosis of a renal mass with atypical radiological findings in an immunocompetent host. Meticulous decision-making and appropriate management help to prevent disastrous sequelae.

Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality, but data on their pathophysiology are scarce. We aimed to explore the role of lung epithelial and myeloid innate immunity in patients with IAPA or CAPA. METHODS: In this observational study, we retrospectively recruited patients who had been admitted to the intensive care unit (ICU) of University Hospitals Leuven, Belgium, requiring non-invasive or invasive ventilation because of severe influenza or COVID-19, with or without aspergillosis, between Jan 1, 2011, and March 31, 2021, whose bronchoalveolar lavage samples were available at the hospital biobank. Additionally, biobanked in vivo tracheobronchial biopsy samples from patients with IAPA or CAPA and invasive Aspergillus tracheobronchitis admitted to ICUs requiring invasive ventilation between the same dates were collected from University Hospitals Leuven, Hospital Network Antwerp (Belgium), and Amiens-Picardie University Hospital (France). We did nCounter gene expression analysis of 755 genes linked to myeloid innate immunity and protein analysis of 47 cytokines, chemokines, and growth factors on the bronchoalveolar lavage samples. Gene expression data were used to infer cell fractions by use of CIBERSORTx, to perform hypergeometric enrichment pathway analysis and gene set enrichment analysis, and to calculate pathway module scores for the IL-1ß, TNF-α, type I IFN, and type II IFN (IFNγ) pathways. We did RNAScope targeting influenza virus or SARS-CoV-2 RNA and GeoMx spatial transcriptomics on the tracheobronchial biopsy samples. FINDINGS: Biobanked bronchoalveolar lavage samples were retrieved from 166 eligible patients, of whom 40 had IAPA, 52 had influenza without aspergillosis, 33 had CAPA, and 41 had COVID-19 without aspergillosis. We did nCounter gene expression analysis on bronchoalveolar lavage samples from 134 patients, protein analysis on samples from 162 patients, and both types of analysis on samples from 130 patients. We performed RNAScope and spatial transcriptomics on the tracheobronchial biopsy samples from two patients with IAPA plus invasive Aspergillus tracheobronchitis and two patients with CAPA plus invasive Aspergillus tracheobronchitis. We observed a downregulation of genes associated with antifungal effector functions in patients with IAPA and, to a lesser extent, in patients with CAPA. We found a downregulated expression of several genes encoding proteins with functions in the opsonisation, recognition, and killing of conidia in patients with IAPA versus influenza only and in patients with CAPA versus COVID-19 only. Several genes related to LC3-associated phagocytosis, autophagy, or both were differentially expressed. Patients with CAPA had significantly lower neutrophil cell fractions than did patients with COVID-19 only. Patients with IAPA or CAPA had downregulated IFNγ signalling compared with patients with influenza only or COVID-19 only, respectively. The concentrations of several fibrosis-related growth factors were significantly elevated in the bronchoalveolar lavage fluid from patients with IAPA versus influenza only and from patients with CAPA versus COVID-19 only. In one patient with CAPA, we visualised an active or very recent SARS-CoV-2 infection disrupting the epithelial barrier, facilitating tissue-invasive aspergillosis. INTERPRETATION: Our results reveal a three-level breach in antifungal immunity in IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytise and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils. The potential of adjuvant IFNγ in the treatment of IAPA and CAPA should be investigated. FUNDING: Research Foundation Flanders, Coronafonds, the Max Planck Society, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, "la Caixa" Foundation, and Horizon 2020.

A Multiplex PCR and DNA-Sequencing Workflow on Serum for the Diagnosis and Species Identification for Invasive Aspergillosis and Mucormycosis.

There has been significant increase in the use of molecular tools for the diagnosis of invasive aspergillosis (IA) and mucormycosis. However, their range of detection may be too limited as species diversity and coinfections are increasing. Here, we aimed to evaluate a molecular workflow based on a new multiplex PCR assay detecting the whole Aspergillus genus and the Mucorales order followed by a species-specific PCR or a DNA-sequencing approach for IA and/or mucormycosis diagnosis and species identification on serum. Performances of the MycoGENIE Aspergillus spp./Mucorales spp. duplex PCR kit were analyzed on a broad range of fungal strains and on sera from high-risk patients prospectively over a 12-month period. The kit allowed the detection of nine Aspergillus species and 10 Mucorales (eight genera) strains assessed. No cross-reactions between the two targets were observed. Sera from 744 patients were prospectively analyzed, including 35 IA, 16 mucormycosis, and four coinfections. Sensitivity varies from 85.7% (18/21) in probable/proven IA to 28.6% (4/14) in COVID-19-associated pulmonary aspergillosis. PCR-positive samples corresponded to 21 A. fumigatus, one A. flavus, and one A. nidulans infections. All the disseminated mucormycosis were positive in serum (14/14), including the four Aspergillus coinfections, but sensitivity fell to 33.3% (2/6) in localized forms. DNA sequencing allowed Mucorales identification in serum in 15 patients. Remarkably, the most frequent species identified was Rhizomucor pusillus (eight cases), whereas it is barely found in fungal culture. This molecular workflow is a promising approach to improve IA and mucormycosis diagnosis and epidemiology.

Invasive Mucormycosis and Aspergillosis Coinfection Associated with Post-COVID-19 Pneumonia in a Tertiary Care Hospital.

Acute invasive fungal rhinosinusitis is a rare infection primarily affecting patients with co-morbidities like immunosuppression and poorly controlled diabetes. Mucormycosis is increasingly being reported in patients with SARS-CoV-2 (COVID-19). However, reports of coinfection of aspergillosis and mucormycosis involving nose, paranasal sinuses, orbit, and brain are rare in literature. We aimed to evaluate the patient demographics, clinical presentation, and management of cases presenting with mixed infection. We carried out retrospective analysis of 12 patients with confirmed diagnosis of mixed invasive fungal infections post-COVID-19 disease out of 70 cases of COVID-19-associated mucormycosis (CAM) presenting to a tertiary-level hospital in North India from May to June 2021. All patients had diabetes mellitus; the mean age was 48 years. The common presenting features were headache, nasal congestion, palatal ulcer, and vision loss accompanied by facial pain and swelling. Two patients developed cerebral abscess during the course of treatment; three patients had concurrent COVID-19 pneumonia. All patients received systemic liposomal amphotericin B and serial surgical debridements. The overall mortality rate was 16.7%. Our study demonstrates that mucormycosis and aspergillosis are angioinvasive mycoses that are clinically and radiologically identical. KOH direct mount of clinical sample showing septate hyphae should be extensively searched for aseptate hyphae after digestion and clearing of the tissue. A high index of suspicion of mixed infection post-COVID-19 and early initiation of liposomal amphotericin B followed by prompt surgical intervention can reduce the overall morbidity and mortality among patients with this condition.

A rare case report of tracheobronchial aspergillosis with endobronchial aspergilloma in a patient clinically recovered from COVID-19.

The novel coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 has led to an increased incidence of fungal infections. However, pulmonary infections are rare. COVID-associated pulmonary aspergillosis has been reported; however, there is no prior report of tracheobronchial aspergillosis with endobronchial aspergilloma as per the authors' literature search. We report such a case of a 65-year-old male with radiology and biopsy-proven endobronchial aspergilloma upon a background of tracheobronchial and pulmonary aspergillosis after having recovered clinically from severe COVID-19 disease.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.