Aspergillus nodules: Natural history and the effect of antifungals.

BACKGROUND: Aspergillus nodules are classified as a subset of chronic pulmonary aspergillosis. The optimal management approach is not known as their natural evolution following biopsy, the rate of progression to chronic cavitary pulmonary aspergillosis (CCPA) and the effect of antifungal treatment have not been described. OBJECTIVES: To describe the clinical course of patients diagnosed with Aspergillus nodules and the effect of antifungal treatment. PATIENTS/METHODS: We present a series of 23 patients with histologically confirmed Aspergillus nodules and describe serial imaging, antifungal treatment and progression to other diagnoses. RESULTS: Thirteen patients were diagnosed after a CT-guided biopsy and 10 after surgical resection. Among those who had CT-guided biopsy, 8 did not receive antifungal treatment; the nodule was stable or smaller in all cases on subsequent CT scan after a mean of 15.5 months. However, one patient developed squamous cell carcinoma after 16 months and another developed CCPA after 7 months. Among the 5 patients who received antifungals for at least 4 weeks, the nodule was smaller in 1 and stable in 4. One patient developed CCPA 3 years after the biopsy. No patient who had a surgical resection subsequently had a CCPA diagnosis. CONCLUSION: Most Aspergillus nodules remained stable or improved following biopsy, irrespective of the effect of antifungals. However, CCPA can develop occasionally in patients with Aspergillus nodules and ongoing radiological follow-up may be warranted when the nodule is not resected.

Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer.

Small cell lung cancer (SCLC) is a devastating neuroendocrine carcinoma. MYCL (L-Myc) is frequently amplified in human SCLC, but its roles in SCLC progression are poorly understood. We isolated preneoplastic neuroendocrine cells from a mouse model of SCLC and found that ectopic expression of L-Myc, c-Myc, or N-Myc conferred tumor-forming capacity. We focused on L-Myc, which promoted pre-rRNA synthesis and transcriptional programs associated with ribosomal biogenesis. Deletion of Mycl in two genetically engineered models of SCLC resulted in strong suppression of SCLC. The high degree of suppression suggested that L-Myc may constitute a therapeutic target for a broad subset of SCLC. We then used an RNA polymerase I inhibitor to target rRNA synthesis in an autochthonous Rb/p53-deleted mouse SCLC model and found significant tumor inhibition. These data reveal that activation of RNA polymerase I by L-Myc and other MYC family proteins provides an axis of vulnerability for this recalcitrant cancer.

Predictive factors for treatment response and mortality in chronic pulmonary aspergillosis.

OBJECTIVES: Chronic pulmonary aspergillosis (CPA) is associated with significant mortality, and suboptimal antifungal treatment response. We describe predictive factors for treatment response and survival. METHODS: We retrospectively analysed clinical, serological and radiological parameters at baseline and following antifungal treatment in patients with CPA and correlated with clinical and radiological response and survival. RESULTS: Fifty-nine patients were included with a mean age of 61 years. Thirty (51%) had a diagnosis of COPD. On clinical assessment at 6 months, 21 (36%) had clinically improved, 20 (34%) were clinically stable and 15 (25%) had deteriorated. Radiological improvement was observed in 30 (53%), stability in 11 (19%) and deterioration in 16 (28%). Only a lower C-reactive protein (CRP) at baseline was associated with a favourable clinical-radiological response. On univariate analysis, lower CRP, higher albumin, lower Aspergillus IgG and use of inhaled steroids were associated with lower mortality. An overall favourable response at 6 months was associated with lower mortality. CONCLUSION: Inflammatory markers and Aspergillus IgG were predictors of mortality in CPA. This suggests that mortality in CPA is driven mainly by the chronic fungal infection itself rather than the underlying disease, therefore early optimised treatment of CPA may lead to improved outcomes.

On the role of exploitation and exploration strategies in the maintenance of cognitive biases: Beyond the pursuit of instrumental rewards.

Why can initial biases persist in repeated choice tasks? Previous research has shown that frequent rewards can lure the decision maker into premature exploitation of a supposedly best option, which can result in the persistence of initial biases. Here, we demonstrate that even in the absence of rewards, initial biases can be perpetuated through a positive testing strategy. After eliciting a biased preference for one of two equally rewarding options, participants (N = 203) could sample freely from both options without the lure of any financial rewards. When participants were told to rule out alternatives in this phase, they explored the supposedly worse option and thereby managed to overcome their initial bias. When told to optimize their strategy, however, they exhibited a positive testing strategy resulting in the continued exploitation of the supposedly better option, a bias they maintained in an incentivized choice phase and later judgments. Across all participants, individual tendencies to exploit one option in earlier phases predicted biased behavior in subsequent phases. The findings highlight that not only the pursuit of instrumental rewards can lead to exploitation and the maintenance of initial biases. We discuss potential consequences for interventions.

Defective Interferon-Gamma Production Is Common in Chronic Pulmonary Aspergillosis.

BACKGROUND: Immune defects in chronic pulmonary aspergillosis (CPA) are poorly characterized. We compared peripheral blood cytokine profiles in patients with CPA versus healthy controls and explored the relationship with disease severity. METHODS: Interferon-gamma (IFNγ), interleukin (IL)-17, tumor necrosis factor-α, IL-6, IL-12, and IL-10 were measured after in vitro stimulation of whole blood with lipopolysaccharide (LPS), phytohemagglutinin, ß-glucan, zymosan (ZYM), IL-12 or IL-18, and combinations. Clinical parameters and mortality were correlated with cytokine production. RESULTS: Cytokine profiles were evaluated in 133 patients (57.1% male, mean age 61 years). In comparison to controls, patients with CPA had significantly reduced production of IFNγ in response to stimulation with ß-glucan + IL-12 (312 vs 988 pg/mL), LPS + IL-12 (252 vs 1033 pg/mL), ZYM + IL-12 (996 vs 2347 pg/mL), and IL-18 + IL-12 (7193 vs 12 330 pg/mL). Age >60 (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.00-2.91; P = .05) and chronic obstructive pulmonary disease (HR, 1.69; 95% CI, 1.03-2.78; P = .039) were associated with worse survival, whereas high IFNγ production in response to beta-glucan + IL-12 stimulation (HR, 0.48; 95% CI, .25-0.92; P = .026) was associated with reduced mortality. CONCLUSIONS: Patients with CPA show impaired IFNγ production in peripheral blood in response to stimuli. Defective IFNγ production ability correlates with worse outcomes. Immunotherapy with IFNγ could be beneficial for patients showing impaired IFNγ production in CPA.

Interferon gamma replacement as salvage therapy in chronic pulmonary aspergillosis: effects on frequency of acute exacerbation and all-cause hospital admission.

Chronic pulmonary aspergillosis (CPA) is often poorly responsive to antifungal treatment; secondary infections increase morbidity/mortality, particularly in progressive cases. Interferon gamma (IFNγ) has been implicated in not only Aspergillus control but also bacterial clearance. Clinical notes of patients with CPA treated with IFNγ (2011-2018) were retrospectively hand-searched. In patients treated for >12 months (n=20), the frequency of acute exacerbation reduced from 3.1 to 1.4 episodes/year (p=0.006) in the 12 months after treatment initiation compared with the 12 months before. A significant reduction in the frequency of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). These findings support further prospective studies.

Micafungin may be safely administered as outpatient parenteral antimicrobial therapy for chronic pulmonary aspergillosis.

BACKGROUND: Intravenous micafungin has been reported as a treatment alternative in patients with chronic pulmonary aspergillosis (CPA) where long-term oral triazole therapy is unfeasible. OBJECTIVES: We evaluated the safety and efficacy of micafungin administered via the outpatient parenteral antimicrobial therapy (OPAT) service for the treatment of CPA. METHODS: We included all CPA patients who received micafungin via OPAT between April 2016 and March 2018. Data on adverse events and line-related complications, and Quality of Life (QoL) scores at the start of micafungin course and 3 months later were extracted. Improvements in QoL were defined as an improvement of ≥4 points in at least one modality (symptom, impact, activity, total) in the St George's QoL score. A stable QoL score was defined as a change in score of <4 points in either direction whilst deterioration was defined as an increase of ≥4 points. RESULTS: There were 20 OPAT episodes involving 18 patients with a median duration of micafungin therapy of 21 (range: 4-248) days. Improvement or stability in the symptoms, activity, impact and total score was seen in 14 (78%), 12 (67%), 9 (50%) and 9 (50%) of the patients, respectively. However, half of the patients reported deterioration in the impact domain and total scores. By self-assessment, patients who categorised themselves as "poor" were comparable at the start of OPAT and at 3 months (43% vs 50%, McNemar's P = 0.7). Adverse events attributable to micafungin were recorded in 3 (14.3%) episodes. CONCLUSIONS: Micafungin may be safely administered via an OPAT service. Micafungin therapy was associated with an improvement or stability in QoL scores in at least 50% of the patients across the four domains.

F508del CFTR gene mutation in patients with allergic bronchopulmonary aspergillosis.

OBJECTIVE: The F508del mutation occurs in approximately 3.5% of Caucasian population of Northern Europe. Heterozygotes have increased risk for asthma and reduced pulmonary function. Allergic bronchopulmonary aspergillosis (ABPA) is more common in patients with cystic fibrosis (CF). We aimed to establish the frequency of F508del mutation in adult patients with ABPA. METHODS: A retrospective matched case-control study of CF genotyped patients with ABPA seen at the National Aspergillosis Centre was undertaken. Key data were collected retrospectively from medical records, including respiratory comorbidities, total IgE, Aspergillus IgG and IgE, and immunoglobulins. Cystic fibrosis transmembrane regulator (CFTR) gene mutation analysis included multiplex PCR and sequencing. RESULTS: From a cohort of 189 ABPA patients, 156 were screened for common mutations and variants in the CFTR gene. Eighteen were heterozygous for at least one CFTR mutation; 12 (7.7%) were heterozygous for the F508del, notably; 3 were heterozygous for the intron 8 5T variant; and 1 for an intronic variant of uncertain significance, c.3139 + 18C>T. Eight (67%) had asthma, 7 (58%) had CT-defined bronchiectasis, 4 (33%) hypergammaglobulinemia (>16 g/L), 3 (25%) sinusitis and 1 (8%) chronic pulmonary aspergillosis. Eight (67%) had elevated Aspergillus IgG antibodies (42-98 mg/L), and 8 (67%) had total IgE above 1,000 KIU/L. Two individuals heterozygous for the F508del mutation and the TG12T5 variant were diagnosed with CF, leading to a de novo CF discovery rate of 1.3%. CONCLUSIONS: In our ABPA patient cohort, the presence of the delta F508 mutation was higher than that seen in general population. Genetic counseling for CFTR genotyping might be appropriate for these patients.

Predictors of mortality in chronic pulmonary aspergillosis.

Chronic pulmonary aspergillosis (CPA) is a chronic progressive infection that destroys lung tissue in non-immunocompromised patients. Contemporary series suggest 50-85% 5-year mortality, with few prognostic factors identified.A cohort of 387 CPA patients referred to the UK's National Aspergillosis Centre from 1992 to June 2012 was studied until June 2015. The impact of objective and subjective variables including age, sex, previous pulmonary conditions, dyspnoea score, quality of life, serum albumin and C-reactive protein and radiological appearances were assessed using Kaplan-Meier curves, log rank tests and Cox proportional hazards modelling. In samples of patients, retrospective review of time from likely onset of CPA to referral and cause of death were also investigated.Survival was 86%, 62% and 47% at 1, 5 and 10 years, respectively. Increased mortality was associated with nontuberculous mycobacterial infection (hazard ratio 2.07, 95% CI 1.22-3.52; p<0.001) and chronic obstructive pulmonary disease (1.57, 1.05-2.36; p=0.029) as well as higher age (1.053, 1.03-1.07 per year; p<0.001), lower albumin (0.92, 0.87-0.96 per g·L-1), lower activity (1.021, 1.01-1.03 per point increase in St George's Respiratory Questionnaire activity domain; p<0.001) and having one, and especially, bilateral aspergillomas (p<0.001).Several factors impact on mortality of CPA, and can be evaluated as tools to assess CPA prognosis.

Long interspersed element-1 protein expression is a hallmark of many human cancers.

Cancers comprise a heterogeneous group of human diseases. Unifying characteristics include unchecked abilities of tumor cells to proliferate and spread anatomically, and the presence of clonal advantageous genetic changes. However, universal and highly specific tumor markers are unknown. Herein, we report widespread long interspersed element-1 (LINE-1) repeat expression in human cancers. We show that nearly half of all human cancers are immunoreactive for a LINE-1-encoded protein. LINE-1 protein expression is a common feature of many types of high-grade malignant cancers, is rarely detected in early stages of tumorigenesis, and is absent from normal somatic tissues. Studies have shown that LINE-1 contributes to genetic changes in cancers, with somatic LINE-1 insertions seen in selected types of human cancers, particularly colon cancer. We sought to correlate this observation with expression of the LINE-1-encoded protein, open reading frame 1 protein, and found that LINE-1 open reading frame 1 protein is a surprisingly broad, yet highly tumor-specific, antigen.

Regulation of pyruvate metabolism in metabolic-related diseases.

Pyruvate is an obligatory intermediate in the oxidative disposal of glucose and a major precursor for the synthesis of glucose, glycerol, fatty acids, and non-essential amino acids. Stringent control of the fate of pyruvate is critically important for cellular homeostasis. The regulatory mechanisms for its metabolism are therefore of great interest. Recent advances include the findings that (a) the mitochondrial pyruvate carrier is sensitive to inhibition by thiazolidinediones; (b) pyruvate dehydrogenase kinases induce the Warburg effect in many disease states; and (c) pyruvate carboxylase is an important determinate of the rates of gluconeogenesis in humans with type 2 diabetes. These enzymes are potential therapeutic targets for several diseases.

A hub and spokes approach to building community capacity for eating disorders in rural Western Australia.

OBJECTIVE: To determine whether an outreach community-based training program on eating disorders enhances perceived capacity of rural health and education professionals to respond to and manage eating disorders. DESIGN: Survey conducted upon completion of outreach training. SETTING: Rural Western Australia. PARTICIPANTS: Health and education professionals working in rural Western Australia. MAIN OUTCOME MEASURES: Questionnaire responses analysed via descriptive statistics and inferential tests. RESULTS: There was a significant increase in perceived ability to identify, support and/or treat people with eating disorders among health and education professionals. CONCLUSIONS: Outreach training up-skilled rural gatekeepers and introduced systemic health system benefits of increased consultation and liaison, a fine-tuning of referral processes, a reduction in hospital admissions and better uptake of local services by patients discharged from hospital.

Deep Cascade Gradient RBF Networks With Output-Relevant Feature Extraction and Adaptation for Nonlinear and Nonstationary Processes.

The main challenge for industrial predictive models is how to effectively deal with big data from high-dimensional processes with nonstationary characteristics. Although deep networks, such as the stacked autoencoder (SAE), can learn useful features from massive data with multilevel architecture, it is difficult to adapt them online to track fast time-varying process dynamics. To integrate feature learning and online adaptation, this article proposes a deep cascade gradient radial basis function (GRBF) network for online modeling and prediction of nonlinear and nonstationary processes. The proposed deep learning method consists of three modules. First, a preliminary prediction result is generated by a GRBF weak predictor, which is further combined with raw input data for feature extraction. By incorporating the prior weak prediction information, deep output-relevant features are extracted using a SAE. Online prediction is finally produced upon the extracted features with a GRBF predictor, whose weights and structure are updated online to capture fast time-varying process characteristics. Three real-world industrial case studies demonstrate that the proposed deep cascade GRBF network outperforms existing state-of-the-art online modeling approaches as well as deep networks, in terms of both online prediction accuracy and computational complexity.

Adaptive Multioutput Gradient RBF Tracker for Nonlinear and Nonstationary Regression.

Multioutput regression of nonlinear and nonstationary data is largely understudied in both machine learning and control communities. This article develops an adaptive multioutput gradient radial basis function (MGRBF) tracker for online modeling of multioutput nonlinear and nonstationary processes. Specifically, a compact MGRBF network is first constructed with a new two-step training procedure to produce excellent predictive capacity. To improve its tracking ability in fast time-varying scenarios, an adaptive MGRBF (AMGRBF) tracker is proposed, which updates the MGRBF network structure online by replacing the worst performing node with a new node that automatically encodes the newly emerging system state and acts as a perfect local multioutput predictor for the current system state. Extensive experimental results confirm that the proposed AMGRBF tracker significantly outperforms existing state-of-the-art online multioutput regression methods as well as deep-learning-based models, in terms of adaptive modeling accuracy and online computational complexity.

Comparison of diagnoses of early-onset sepsis associated with use of Sepsis Risk Calculator versus NICE CG149: a prospective, population-wide cohort study in London, UK, 2020-2021.

OBJECTIVE: We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks' gestation identified >24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance. DESIGN AND SETTING: Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE). PARTICIPANTS: All live births ≥34 weeks' gestation between September 2020 and August 2021. OUTCOME MEASURES: EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age. We evaluated the incidence of EOS identified by culture obtained >24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced >24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures. RESULTS: Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (<72 hours) was 0.64/1000 live births. The incidence of EOS identified >24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced >24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals. CONCLUSION: There was no significant difference in the incidence of EOS identified >24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life.

Netrin-1 feedforward mechanism promotes pancreatic cancer liver metastasis via hepatic stellate cell activation, retinoid, and ELF3 signaling.

The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.

Multi-Output Selective Ensemble Identification of Nonlinear and Nonstationary Industrial Processes.

A key characteristic of biological systems is the ability to update the memory by learning new knowledge and removing out-of-date knowledge so that intelligent decision can be made based on the relevant knowledge acquired in the memory. Inspired by this fundamental biological principle, this article proposes a multi-output selective ensemble regression (SER) for online identification of multi-output nonlinear time-varying industrial processes. Specifically, an adaptive local learning approach is developed to automatically identify and encode a newly emerging process state by fitting a local multi-output linear model based on the multi-output hypothesis testing. This growth strategy ensures a highly diverse and independent local model set. The online modeling is constructed as a multi-output SER predictor by optimizing the combining weights of the selected local multi-output models based on a probability metric. An effective pruning strategy is also developed to remove the unwanted out-of-date local multi-output linear models in order to achieve low online computational complexity without scarifying the prediction accuracy. A simulated two-output process and two real-world identification problems are used to demonstrate the effectiveness of the proposed multi-output SER over a range of benchmark schemes for real-time identification of multi-output nonlinear and nonstationary processes, in terms of both online identification accuracy and computational complexity.

They Told Me "This Isn't a Hotel": Young People's Experiences and Perceptions of Care When Presenting to the Emergency Department with Suicide-Related Behaviour.

In Australia, the number of young people presenting to the emergency department with mental health concerns, in particular, suicidal behaviour (defined here as suicidal ideation, thoughts, intent and attempts) is increasing. Little is known about the experiences of Australian young people who present to hospital emergency departments with suicidal behaviour. In this qualitative study, we conducted a series of focus groups with 55 young people aged 16-25 years, with a view to developing a framework for youth suicide prevention for Western Australia. The data were analysed using a general inductive analysis approach. We explored the experiences and perceptions of the care and management of 35 young people presenting to Western Australian hospital emergency departments. Participants described a range of negative experiences relating to the emergency department environment, staff attitudes and their treatment by staff. We argue that adapting ED practices and approaches to young people presenting with suicidal thoughts and behaviours based on these findings will result in lower rates of repeated presentations and admissions to hospital and lower rates of suicide attempts and deaths by suicide.

Tumor microbiome links cellular programs and immunity in pancreatic cancer.

Microorganisms are detected in multiple cancer types, including in putatively sterile organs, but the contexts in which they influence oncogenesis or anti-tumor responses in humans remain unclear. We recently developed single-cell analysis of host-microbiome interactions (SAHMI), a computational pipeline to recover and denoise microbial signals from single-cell sequencing of host tissues. Here we use SAHMI to interrogate tumor-microbiome interactions in two human pancreatic cancer cohorts. We identify somatic-cell-associated bacteria in a subset of tumors and their near absence in nonmalignant tissues. These bacteria predominantly pair with tumor cells, and their presence is associated with cell-type-specific gene expression and pathway activities, including cell motility and immune signaling. Modeling results indicate that tumor-infiltrating lymphocytes closely resemble T cells from infected tissue. Finally, using multiple independent datasets, a signature of cell-associated bacteria predicts clinical prognosis. Tumor-microbiome crosstalk may modulate tumorigenesis in pancreatic cancer with implications for clinical management.