Costs associated with invasive Scedosporium and Lomentospora prolificans infections: a case-control study.

BACKGROUND: Little is known about the short- and long-term healthcare costs of invasive Scedosporium/Lomentospora prolificans infections, particularly in patient groups without haematological malignancy. This study investigated excess index hospitalization costs and cumulative costs of these infections. The predictors of excess cost and length of stay (LOS) of index hospitalization were determined. These estimates serve as valuable inputs for cost-effectiveness models of novel antifungal agents. METHODS: A retrospective case-control study was conducted at six Australian hospitals. Cases of proven/probable invasive Scedosporium/L. prolificans infections between 2011 and 2021 (n = 34) were matched with controls (n = 66) by predefined criteria. Cost data were retrieved from activity-based costing systems and analysis was performed from the Australian public hospital perspective. All costs were presented in 2022 Australian dollars (AUD). Median regression analysis was used to adjust excess costs of index hospitalization whereas cumulative costs up to 1.5 years follow-up were estimated using interval-partitioned survival probabilities. RESULTS: Invasive Scedosporium/L. prolificans infections were independently associated with an adjusted median excess cost of AUD36 422 (P = 0.003) and LOS of 16.27 days (P < 0.001) during index hospitalization. Inpatient stay was the major cost driver (42.7%), followed by pharmacy cost, of which antifungal agents comprised 23.8% of the total cost. Allogeneic haematopoietic stem cell transplant increased the excess cost (P = 0.013) and prolonged LOS (P < 0.001) whereas inpatient death within ≤28 days reduced both cost (P = 0.001) and LOS (P < 0.001). The median cumulative cost increased substantially to AUD203 292 over 1.5 years in cases with Scedosporium/L. prolificans infections. CONCLUSIONS: The economic burden associated with invasive Scedosporium/L. prolificans infections is substantial.

When to change treatment of acute invasive aspergillosis: an expert viewpoint.

Invasive aspergillosis (IA) is an acute infection affecting patients who are immunocompromised, as a result of receiving chemotherapy for malignancy, or immunosuppressant agents for transplantation or autoimmune disease. Whilst criteria exist to define the probability of infection for clinical trials, there is little evidence in the literature or clinical guidelines on when to change antifungal treatment in patients who are receiving prophylaxis or treatment for IA. To try and address this significant gap, an advisory board of experts was convened to develop criteria for the management of IA for use in designing clinical trials, which could also be used in clinical practice. For primary treatment failure, a change in antifungal therapy should be made: (i) when mycological susceptibility testing identifies an organism from a confirmed site of infection, which is resistant to the antifungal given for primary therapy, or a resistance mutation is identified by molecular testing; (ii) at, or after, 8 days of primary antifungal treatment if there is increasing serum galactomannan, or galactomannan positivity in serum, or bronchoalveolar lavage fluid when the antigen was previously undetectable, or there is sudden clinical deterioration, or a new clearly distinct site of infection is detected; and (iii) at, or after, 15 days of primary antifungal treatment if the patient is clinically stable but with ≥2 serum galactomannan measurements persistently elevated compared with baseline or increasing, or if the original lesions on CT or other imaging, show progression by >25% in size in the context of no apparent change in immune status.

Hippo pathway elements Co-localize with Occludin: A possible sensor system in pancreatic epithelial cells.

External adherens junction-based cell-cell contacts involving E-cadherin interactions function to sense planar cell status and modulate epithelial cell proliferation through Hippo (Hpo) and non-canonical Wnt pathways signaling. We hypothesized these regulatory processes should also be sensitive to a similar cell-cell contact sensor associated with apical-basal polarity events at epithelial surfaces. We used 2 human pancreatic cancer cell lines to explore this hypothesis: one with the capacity to form functional tight junction structures and polarize (HPAFII) and one lacking this capacity (AsPc1). Occludin (Ocln), a tetraspanning protein associated with TJ structures and capable of establishing external cell-cell contacts, was observed to partially co-localize with Hpo elements YAP (c-yes associated protein) and TEAD (TEA-dependent), which function to drive a proliferative transcription program. Treatment with dobutamine, known to affect YAP, was shown to suppress proliferation in an Ocln-dependent manner. Blockade of protein kinase C-zeta (PKC-ζ) diminished transepithelial electrical resistance (TER) of HPAFII monolayers that was not corrected by dobutamine treatment while the loss of TER resulting from inhibition of ROCK1 could be partially recovered. Examination of normal and cancerous human pancreatic biopsies showed that the cellular localization of Ocln, c-Yes, YAP, and TEAD were similar to HPAFII for normal cells and AsPc1 for cancerous cells. Together, these results suggest a link between Hpo and signals emanating from cell-cell contacts involving Ocln that may regulate pancreatic cell proliferation through the coordination of planar cell polarity with apical-basal polarity events.

Impaired JNK signaling cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma.

The c-Jun N-terminal protein kinase (JNK) and its two direct activators, namely the mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) and MKK7, constitute a signaling node frequently mutated in human pancreatic ductal adenocarcinoma (PDAC). Here we demonstrate the cooperative interaction of endogenous expression of Kras(G12D) with loss-of-function mutations in mkk4 or both, mkk4 and mkk7 genes in the pancreas. More specifically, impaired JNK signaling in a subpopulation of Pdx1-expressing cells dramatically accelerated the appearance of Kras(G12D)-induced acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasias, which rapidly progressed to invasive PDAC within 10 weeks of age. Furthermore, inactivation of mkk4/mkk7 compromised acinar regeneration following acute inflammatory stress by locking damaged exocrine cells in a permanently de-differentiated state. Therefore, we propose that JNK signaling exerts its tumor suppressive function in the pancreas by antagonizing the metaplastic conversion of acinar cells toward a ductal fate capable of responding to oncogenic stimulation.

Osteopontin is a novel downstream target of SOX9 with diagnostic implications for progression of liver fibrosis in humans.

UNLABELLED: Osteopontin (OPN) is an important component of the extracellular matrix (ECM), which promotes liver fibrosis and has been described as a biomarker for its severity. Previously, we have demonstrated that Sex-determining region Y-box 9 (SOX9) is ectopically expressed during activation of hepatic stellate cells (HSC) when it is responsible for the production of type 1 collagen, which causes scar formation in liver fibrosis. Here, we demonstrate that SOX9 regulates OPN. During normal development and in the mature liver, SOX9 and OPN are coexpressed in the biliary duct. In rodent and human models of fibrosis, both proteins were increased and colocalized to fibrotic regions in vivo and in culture-activated HSCs. SOX9 bound a conserved upstream region of the OPN gene, and abrogation of Sox9 in HSCs significantly decreased OPN production. Hedgehog (Hh) signaling has previously been shown to regulate OPN expression directly by glioblastoma (GLI) 1. Our data indicate that in models of liver fibrosis, Hh signaling more likely acts through SOX9 to modulate OPN. In contrast to Gli2 and Gli3, Gli1 is sparse in HSCs and is not increased upon activation. Furthermore, reduction of GLI2, but not GLI3, decreased the expression of both SOX9 and OPN, whereas overexpressing SOX9 or constitutively active GLI2 could rescue the antagonistic effects of cyclopamine on OPN expression. CONCLUSION: These data reinforce SOX9, downstream of Hh signaling, as a core factor mediating the expression of ECM components involved in liver fibrosis. Understanding the role and regulation of SOX9 during liver fibrosis will provide insight into its potential modulation as an antifibrotic therapy or as a means of identifying potential ECM targets, similar to OPN, as biomarkers of fibrosis.

Excited state dynamics and activation parameters of remarkably slow photoinduced CO loss from (η6-benzene)Cr(CO)3 in n-heptane solution: a DFT and picosecond-time-resolved infrared study.

The electronic structure of (η6-benzene)Cr(CO)3 has been calculated using density functional theory and a molecular orbital interaction diagram constructed based on the Cr(CO)3 and benzene fragments. The highest occupied molecular orbitals are mainly metal based. The nature of the lowest energy excited states were determined by time-dependent density functional theory, and the lowest energy excited state was found to have significant metal to carbonyl charge transfer character. The photochemistry of (η6-benzene)Cr(CO)3 was investigated by time-resolved infrared spectroscopy with picosecond time resolution. The low energy excited state was detected following irradiation at 400 nm, and this exhibited ν(CO) bands at lower energy than the equivalent ν(CO) bands of (η6-benzene)Cr(CO)3, consistent with metal to carbonyl charge transfer character, and is formed with excess vibrational energy, relaxing to the v = 0 vibrational state within 3 ps. The resulting "cold" excited state decays to form the CO-loss species (η6-benzene)Cr(CO)2 in approximately 70% yield and to reform (η6-benzene)Cr(CO)3 within 150 ps. The rates of relaxation from the vibrationally hot state to the cold excited state and its subsequent reaction to yield (η6-benzene)Cr(CO)2 were measured over a range of temperatures from 274 to 320 K, and the activation parameters for both processes were obtained from Eyring plots. The vibrational relaxation exhibits a negative activation enthalpy ΔH(‡) (-10 (±4) kJ mol⁻¹) and a negative activation entropy ΔS(‡) (-50 (±16) J mol⁻¹ K⁻¹). A significant barrier (ΔH(‡) = +12 (±4) kJ mol⁻¹) was obtained for the formation of (η6-benzene)Cr(CO)2 with a ΔS(‡) value close to zero. These data are used to propose a model for the CO-loss process to yield (η6-benzene)Cr(CO)2 and to explain why low temperature irradiation of (η6-benzene)Cr(CO)3 with light of wavelengths greater than 400 nm produced relatively minor amounts of (η6-benzene)Cr(CO)2.

Printed educational materials: effects on professional practice and health care outcomes.

BACKGROUND: Printed educational materials (PEMs) are widely used passive dissemination strategies to improve knowledge, awareness, attitudes, skills, professional practice and patient outcomes. Traditionally they are presented in paper formats such as monographs, publication in peer-reviewed journals and clinical guidelines and appear to be the most frequently adopted method for disseminating information. OBJECTIVES: To determine the effectiveness of PEMs in improving process outcomes (including the behaviour of healthcare professionals) and patient outcomes. To explore whether the effect of characteristics of PEMs (e.g., source, content, format, mode of delivery, timing/frequency, complexity of targeted behaviour change) can influence process outcomes (including the behaviour of healthcare professionals and patient outcomes). SEARCH STRATEGY: The following electronic databases were searched up to July 2006: (a) The EPOC Group Specialised Register (including the database of studies awaiting assessment (see 'Specialised Register'under 'Group Details'); (b) The Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effectiveness; (c) MEDLINE, EMBASE, CINAHL and CAB Health. An updated search of MEDLINE was done in March 2007. SELECTION CRITERIA: We included randomised controlled trials (RCTs) , controlled clinical trials (CCT), controlled before and after studies (CBAs) and interrupted time series analyses (ITS) that evaluated the impact of printed educational materials on healthcare professionals' practice and/or patient outcomes. There was no language restriction. Any objective measure of professional performance (sch as number of tests ordered, prescriptions for a particular drug), or patient health outcomes (e.g., blood pressure, number of caesarean sections) were included. DATA COLLECTION AND ANALYSIS: Four reviewers undertook data abstraction independently using a modified version of the EPOC data collection checklist. Any disagreement was resolved by discussion among the reviewers and arbitrators. Statistical analysis was based upon consideration of dichotomous process outcomes, continuous process outcomes, patient outcome dichotomous measures and patient outcome continuous measures. We presented the results for all comparisons using a standard method of presentation where possible. We reported separately for each study the median effect size for each type of outcome, and the median of these effect sizes across studies. MAIN RESULTS: Twenty-three studies were included for this review. Evidence from this review showed that PEMs appear to have small beneficial effects on professional practice. RCTs comparing PEMs to no intervention observed an absolute risk difference median: +4.3% on categorical process outcomes (e.g., x-ray requests, prescribing and smoking cessation activities) (range -8.0% to +9.6%, 6 studies), and a relative risk difference +13.6% on continuous process outcomes (e.g., medication change, x-rays requests per practice) (range -5.0% to +26.6%, 4 studies). These findings are similar to those reported for the ITS studies, although significantly larger effect sizes were observed (relative risk difference range from 0.07% to 31%). In contrast, the median effect size was -4.3% for patient outcome categorical measures (e.g., screening, return to work, quit smoking) (range -0.4% to -4.6%, 3 studies)). Two studies reported deteriorations in continuous patient outcome data (e.g., depression score, smoking cessation attempts) of -10.0% and -20.5%. One study comparing PEMs with educational workshops observed minimal differences. Two studies comparing PEMs and education outreach did not have statistically significant differences between the groups. It was not possible to explore potential effect modifiers across studies. AUTHORS' CONCLUSIONS: The results of this review suggest that when compared to no intervention, PEMs when used alone may have a beneficial effect on process outcomes but not on patient outcomes. Despite this wide of range of effects reported for PEMs, clinical significance of the observed effect sizes is not known. There is insufficient information about how to optimise educational materials. The effectiveness of educational materials compared to other interventions is uncertain.