Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.

Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.

Current issues in the prevalence, diagnosis and management of hepatocellular carcinoma in Australia.

Hepatocellular carcinoma (HCC) is the commonest primary liver cancer encountered in the community and a leading cause of cancer morbidity and mortality. In Australia, there are several current important issues that need to be addressed in HCC management. There is a dramatically rising incidence of HCC in Australia with comparatively poorer outcomes in remote regions and in socioeconomic disadvantaged groups. Aboriginal people have a greater incidence of HCC on a background of increased liver disease prevalence and face several barriers to delivery of better healthcare outcomes compared to other Australians. The previously adopted use of imaging alone to diagnose HCC is now being challenged with biopsy likely to become increasingly necessary with the increased uptake of personalised medicine management. Managing HCC is complex involving many disciplines with the multidisciplinary team approach being the current accepted standard of care for patients. New immunotherapy combinations promise to offer patients with advanced HCC promising novel management options. However, the Australian inequities in prevalence, diagnosis and service provision, especially in Aboriginal people, need to be redressed concurrently with the adoption of new HCC management options.

Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor.

Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1-5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.

Dermatology consultation service at a large metropolitan hospital system serving minority populations.

BACKGROUND: Dermatology consultations in the inpatient hospital setting can improve diagnostic accuracy and management. OBJECTIVE: Characterize dermatologic diagnostic and treatment trends in the hospital setting and identify variables that may affect patient care. METHODS: Retrospective chart review from 1 January 2012 to 31 December 2017 at Jackson Memorial Hospital (JMH) (Miami, Florida, USA), an academic non-profit tertiary care centre affiliated with University of Miami Miller School of Medicine, was performed. Patients who received dermatology consultations in the emergency department (ED) or inpatient settings were included. Patient demographics, admission information, provisional diagnosis and management plans by primary teams, final diagnosis, management plans and testing recommendations by the dermatology consults team, and follow-up information were collected. Analysis using Microsoft Excel of how time to consultation, admission length, inpatient versus ED setting and primary team affected diagnostic accuracy was also performed. RESULTS: The 1004 consultations for 812 patients (n = 812) were reviewed (359 women, 453 men). Most patients were Hispanic (n = 359; 44.2%) or African American (n = 273; 33.6%). Mean admission length was 20.6 days (range 0-439; median 6). The most common consulting service was internal medicine (n = 452). In 387 cases (47.6%), primary teams did not give a provisional diagnosis. The most common provisional diagnoses were bacterial infection (n = 93), viral infection (n = 49) and drug reaction (n = 44). The most common diagnoses by dermatology were viral infection (n = 93), bacterial infection (n = 90) and drug reaction (n = 80). Dermatology consultation changed the provisional diagnosis in 55.7% of cases, more often in cases where consultation took place ≥2 days after admission (P < 0.05). Primary teams followed dermatology treatment recommendations in 85.2% of cases. CONCLUSION: Dermatology consultation improves diagnostic accuracy in skin disorders in the hospital setting and serves as a valuable resource for inpatient care. A notable aspect of data from this study is the unique patient population, predominantly comprised of underrepresented racial and ethnic minorities including Hispanics and African Americans.

Combining Pseudopotential and All Electron Density Functional Theory for the Efficient Calculation of Core Spectra Using a Multiresolution Approach.

Broadly speaking, the calculation of core spectra such as electron energy loss spectra (EELS) at the level of density functional theory (DFT) usually relies on one of two approaches: conceptually more complex but computationally efficient projector augmented wave based approaches or more straightforward but computationally more intensive all electron (AE) based approaches. In this work we present an alternative method, which aims to find a middle ground between the two. Specifically, we have implemented an approach in the multiwavelet madness molecular DFT code that permits a combination of atoms treated at the AE and pseudopotential (PSP) level. Atoms for which one wishes to calculate the core edges are thus treated at an AE level, while the remainder can be treated at the PSP level. This is made possible thanks to the multiresolution approach of madness, which permits accurate and efficient calculations at both the AE and PSP level. Through examples of a small molecule and a carbon nanotube, we demonstrate the potential applications of our approach.

The impact of seasonal operating room closures on wait times for oral cancer surgery.

BACKGROUND: Operating room slowdowns occur at specific intervals in the year as a cost-saving measure. We aim to investigate the impact of these slowdowns on the care of oral cavity cancer patients at a Canadian tertiary care centre. METHODS: A total of 585 oral cavity cancer patients seen between 1999 and 2015 at the London Health Science Centre (lhsc) Head and Neck Multidisciplinary Clinic were included in this study. Operating room hours and patient load from 2006 to 2014 were calculated. Our primary endpoint was the wait time from consultation to definitive surgery. Exposure variables were defined according to wait time intervals occurring during time periods with reduced operating room hours. RESULTS: Overall case volume rose significantly from 2006 to 2014 (p < 0.001), while operating room hours remained stable (p = 0.555). Patient wait times for surgery increased from 16.3 days prior to 2003 to 25.5 days in 2015 (p = 0.008). Significant variability in operating room hours was observed by month, with lowest reported for July and August (p = 0.002). The greater the exposure to these months, the more likely patients were to wait longer than 28 days for surgery (odds ratio per day [or]: 1.07, 95% confidence interval [ci]: 1.05 to 1.10, p < 0.001). Individuals seen in consultation preceding a month with below average operating room hours had a higher risk of disease recurrence and/or death (hazard ratio [hr]: 1.59, 95% ci: 1.10 to 2.30, p = 0.014). CONCLUSIONS: Scheduled reductions in available operating room hours contribute to prolonged wait times and higher disease recurrence. Further work is needed to identify strategies maximizing efficient use of health care resources without negatively affecting patient outcomes.

Isospin Symmetry at High Spin Studied via Nucleon Knockout from Isomeric States.

One-neutron knockout reactions have been performed on a beam of radioactive ^{53}Co in a high-spin isomeric state. The analysis is shown to yield a highly selective population of high-spin states in an exotic nucleus with a significant cross section, and hence represents a technique that is applicable to the planned new generation of fragmentation-based radioactive beam facilities. Additionally, the relative cross sections among the excited states can be predicted to a high level of accuracy when reliable shell-model input is available. The work has resulted in a new level scheme, up to the 11^{+} band-termination state, of the proton-rich nucleus ^{52}Co (Z=27, N=25). This has in turn enabled a study of mirror energy differences in the A=52 odd-odd mirror nuclei, interpreted in terms of isospin-nonconserving (INC) forces in nuclei. The analysis demonstrates the importance of using a full set of J-dependent INC terms to explain the experimental observations.

Lewis acid-promoted [2 + 2] cycloadditions of alkenes with aryl ketenes.

A method for the [2 + 2] cycloaddition of aryl ketenes and alkenes is presented. The process involves the in situ generation of a ketene in the presence of a Lewis acid. The utility of products is demonstrated towards the synthesis of a common scaffold found in several natural product families.

Defining the genomic landscape of head and neck cancers through next-generation sequencing.

Next-generation sequencing (NGS) has revolutionized the field of genomics and improved our understanding of cancer biology. Advances have been achieved by sequencing tumor DNA and using matched normal DNA to filter out germ line variants to identify cancer-specific changes. The identification of high incidences of activating mutations in head and neck squamous cell carcinoma (HNSCC) amenable to drug targeting has been made, with clear distinctions between the mutational profile of HPV-positive and HPV-negative tumors. This wealth of new understanding undoubtedly ameliorates our understanding of HNSCC cancer biology and elucidates clear targets for drug targeting which will guide future personalized medicine.

Secular trends in the survival of patients with laryngeal carcinoma, 1995-2007.

BACKGROUND: Recent reports suggest a decline over time in the survival of patients newly diagnosed with laryngeal cancer in spite of developments in treatment practices. Our study set out to determine whether the survival of patients with laryngeal cancer in Ontario has changed over time. METHODS: This population-based cohort study of patients diagnosed with laryngeal cancer in the province of Ontario between 1995 and 2007 used data extracted from linked provincial administrative and registry databases. Its main outcomes were overall survival, laryngectomy-free survival, and survival ratio relative to an age- and sex-matched general population. RESULTS: The 4298 patients newly diagnosed with laryngeal cancer during the period of interest were predominantly men (n = 3615, 84.1%) with glottic cancer (n = 2787, 64.8%); mean age in the group was 66 years (interquartile range: 59-74 years). Patient demographics did not significantly change over time. Overall, 5-year survival was 57.4%; laryngectomy-free survival was 45.4%. Comparing patients from three eras (1995-1998, 1999-2003, 2004-2007) and adjusting for age, sex, and comorbidity status, we observed no differences in overall survival or laryngectomy-free survival over time. The 5-year relative survival ratio for patients with laryngeal cancer compared with an age- and sex-matched group from the general population was 81.1% for glottic cancer and 44.5% for supraglottic cancer. CONCLUSIONS: In patients with a new diagnosis of laryngeal cancer, overall and laryngectomy-free survival have remained unchanged since the mid-1990s. New methods to improve survival and the rate of laryngeal preservation in this patient population are needed.

The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population.

BACKGROUND: Sexually transmitted infection with the human papillomavirus (hpv) is responsible for a significant burden of human cancers involving the cervix, anogenital tract, and oropharynx. Studies in the United States and Europe have demonstrated an alarming increase in the frequency of hpv-positive oropharyngeal cancer, but the same direct evidence does not exist in Canada. METHODS: Using the London Health Sciences Centre pathology database, we identified tonsillar cancers diagnosed between 1993 and 2011. Real-time polymerase chain reaction was then used on pre-treatment primary-site biopsy samples to test for dna from the high-risk hpv types 16 and 18. The study cohort was divided into three time periods: 1993-1999, 2000-2005, and 2006-2011. RESULTS: Of 160 tumour samples identified, 91 (57%) were positive for hpv 16. The total number of tonsillar cancers significantly increased from 1993-1999 to 2006-2011 (32 vs. 68), and the proportion of cases that were hpv-positive substantially increased (25% vs. 62%, p < 0.002). Those changes were associated with a marked improvement in 5-year overall survival (39% in 1993-1999 vs. 84% in 2006-2011, p < 0.001). When all factors were included in a multivariable model, only hpv status predicted treatment outcome. INTERPRETATION: The present study is the first to provide direct evidence that hpv-related oropharyngeal cancer is increasing in incidence in a Canadian population. Given the long lag time between hpv infection and clinically apparent malignancy, oropharyngeal cancer will be a significant clinical problem for the foreseeable future despite vaccination efforts.

Establishment of four head and neck squamous cell carcinoma cell lines: importance of reference DNA for accurate genomic characterisation.

OBJECTIVE: There is significant interest in developing early passage cell lines with matched normal reference DNA to facilitate a precision medicine approach in assessing drug response. This study aimed to establish early passage cell lines, and perform whole exome sequencing and short tandem repeat profiling on matched normal reference DNA, primary tumour and corresponding cell lines. METHODS: A cell culture based, in vitro study was conducted of patients with primary human papillomavirus positive and human papillomavirus negative tumours. RESULTS: Four early passage cell lines were established. Two cell lines were human papillomavirus positive, confirmed by sequencing and p16 immunoblotting. Short tandem repeat profiling confirmed that all cell lines were established from their index tumours. Whole exome sequencing revealed that the matched normal reference DNA was critical for accurate mutational analysis: a high rate of false positive mutation calls were excluded (87.6 per cent). CONCLUSION: Early passage cell lines were successfully established. Patient-matched reference DNA is important for accurate cell line mutational calls.

Genomic glucocorticoid action in embryonic mouse neural stem cells.

Prenatal exposure to synthetic glucocorticoids (sGCs) reprograms brain development and predisposes the developing fetus towards potential adverse neurodevelopmental outcomes. Using a mouse model of sGC administration, previous studies show that these changes are accompanied by sexually dimorphic alterations in the transcriptome of neural stem and progenitor cells (NSPCs) derived from the embryonic telencephalon. Because cell type-specific gene expression profiles tightly regulate cell fate decisions and are controlled by a flexible landscape of chromatin domains upon which transcription factors and enhancer elements act, we multiplexed data from four genome-wide assays: RNA-seq, ATAC-seq (assay for transposase accessible chromatin followed by genome wide sequencing), dual cross-linking ChIP-seq (chromatin immunoprecipitation followed by genome wide sequencing), and microarray gene expression to identify novel relationships between gene regulation, chromatin structure, and genomic glucocorticoid receptor (GR) action in NSPCs. These data reveal that GR binds preferentially to predetermined regions of accessible chromatin to influence gene programming and cell fate decisions. In addition, we identify SOX2 as a transcription factor that impacts the genomic response of select GR target genes to sGCs (i.e., dexamethasone) in NSPCs.

Recent performance improvements to the DFT and TDDFT in GAMESS.

The general atomic and molecular electronic structure system (GAMESS) is a quantum chemistry package used in the first-principles modeling of complex molecular systems using density functional theory (DFT) as well as a number of other post-Hartree-Fock methods. Both DFT and time-dependent DFT (TDDFT) are of particular interest to the materials modeling community. Millions of CPU hours per year are expended by GAMESS calculations on high-performance computing systems; any substantial reduction in the time-to-solution for these calculations represents a significant saving in CPU hours. As part of this work, three areas for improvement were identified: (1) the exchange-correlation (XC) integration grid, (2) profiling and optimization of the DFT code, and (3) TDDFT parallelization. We summarize the work performed in these task areas and present the resulting performance improvement. These software enhancements are available in 12JAN2009R3 or later versions of GAMESS.

Hyperthermic isolated limb perfusion for extremity soft tissue sarcomas: systematic review of clinical efficacy and quality assessment of reported trials.

BACKGROUND AND OBJECTIVES: Extremity soft tissue sarcomas (STS) are managed with radiotherapy and limb-sparing surgery however aggressive or recurrent cases require amputation. Hyperthermic isolated limb perfusion (HILP) has been proposed as an alternative. Our aim was to systematically review phase II HILP trials, assess tumor response, limb salvage (LS), and quality of scientific publications on this technique. METHODS: We conducted a literature search of electronic databases (MEDLINE, EMBASE, Scopus, Cochrane Library) and clinical trial registries for phase II HILP trials on non-resectable extremity STS. Outcomes of interest were complete response (CR), partial response (PR), and LS rates. Quality of published trials was assessed using a quality checklist. RESULTS: Of 518 patients across 12 studies, 408 had some response (CR or PR), and 428 had the limb spared. Median CR, PR, and LS rates were 31%, 53.5%, and 82.5%, respectively. Median Wieberdink loco-regional toxicity rates were 3.8%, 45.5%, 17%, 1%, and 0% for levels 1-5, respectively. No trial fulfilled either all ideal or essential quality criteria. Seven trials did not include statistical methodology. CONCLUSION: HILP seems effective in treating advanced extremity STS. However, poor publication quality hinders results validity. Technical and methodological standardization, well-designed, multi-institutional trials are warranted.

The use of autologous platelet and plasma products in salvage neck dissections: a prospective clinical study evaluating early and late wound healing.

OBJECTIVES: To evaluate the effect of autologous platelet and plasma adhesives (APA) on postoperative drainage and soft-tissue fibrosis following neck dissections. DESIGN: This was a blinded comparative prospective cohort study done as two parts: part one evaluated early post-surgical outcomes and part two evaluated late tissue fibrosis. METHOD: Salvage neck dissections were stratified into two groups based on severity of prior treatment. High risk patients were defined as those who had previously undergone chemoradiation therapy and autologous platelet adhesives were administered to the surgical wound intraoperatively. The low risk group consisted of patients undergoing salvage neck dissections following radiation only and acted as controls. Part one evaluated postsurgical wound drainage as the primary outcome as well as length of hospital stay and complications. Part two evaluated late postoperative tissue fibrosis by comparing neck skin using the Cutometer. R2 and F0 were the specific Cutometer parameters for quantifying the viscoelastic properties of the skin. RESULTS: Postoperative wound drainage was significantly less (253.7 vs. 345.8) in the autologous platelet adhesive group as compared to the control group (p less than 0.03). Length of stay in the APA group versus the control group was 3.13 and 3.86 days respectively (p less than 0.004). Both R2 and F0 measurements showed improved viscoelastic properties of the skin in the APA group (R2 p less than 0.05, F0 p less than 0.05). CONCLUSIONS: APA application following salvage neck dissections may reduce early postperative wound drainage and improve long-term skin quality.

Synergistic inhibition of the lethal fungal pathogen Batrachochytrium dendrobatidis: the combined effect of symbiotic bacterial metabolites and antimicrobial peptides of the frog Rana muscosa.

A powerful mechanism for protection against disease in animals is synergy between metabolites present in the natural microbiota of the host and antimicrobial peptides (AMPs) produced by the host. We studied this method of protection in amphibians in regard to the lethal disease chytridiomycosis, which is caused by Batrachochytrium dendrobatidis (Bd). In this study, we show that the AMPs of Rana muscosa, as well as the metabolite 2,4-diacetylphloroglucinol (2,4-DAPG) from Pseudomonas fluorescens, a bacterial species normally found on the skin of R. muscosa, were inhibitory to the growth of Bd in vitro. When both AMPs and 2,4-DAPG were used in growth inhibition assays, they worked synergistically to inhibit the growth of Bd. This synergy resulted in reduced minimum concentrations necessary for inhibition by either 2,4-DAPG or AMPs. This inhibitory concentration of AMPs did not inhibit the growth of a P. fluorescens strain that produced 2,4-DAPG in vitro, although its growth was inhibited at higher peptide concentrations. These data suggest that the AMPs secreted onto frog skin and the metabolites secreted by the resident beneficial bacteria may work synergistically to enhance protection against Bd infection on amphibian skin. These results may aid conservation efforts to augment amphibian skins' resistance to chytridiomycosis by introducing anti-Bd bacterial species that work synergistically with amphibian AMPs.

Do transition towns have the potential to promote health and well-being? A health impact assessment of a transition town initiative.

OBJECTIVES: Climate change and energy vulnerability present significant challenges for the development and sustainability of our communities. The adverse effects will most likely impact on those already experiencing poverty, as energy and food costs will rise, thus increasing inequalities in health. Transition town initiatives seek to build cohesive sustainable communities to prepare for a future with limited oil and a changing climate. Increasingly, public health practitioners are interested in the role of transition towns as a community development initiative, and their potential to support the wider public health agenda. Health impact assessment (HIA) is an evidence-based process that aims to predict the positive and negative impacts of a strategy, proposal or development. The HIA process provides an opportunity to promote sustainable communities by ensuring that new strategies and developments are considered in the context of their contribution to the health and well-being of local populations. The aim of this study was to use an HIA to examine the potential health and well-being benefits of two related transition town initiatives. STUDY DESIGN: A rapid HIA to consider the potential lifestyle changes and health and well-being impacts of Transition Together/Transition Streets (TT/TS) projects. METHODS: An HIA template was used to assess key documents related to the TT/TS initiatives and those related to the characteristics of the community. Additionally, meetings with 12 key informants (four involved in TT/TS and eight purposively selected for their local knowledge) were held using the HIA template to focus the discussion. RESULTS: The findings highlight the associated lifestyle changes such as increased physical activity and healthy eating, and possible social and well-being benefits of engagement in such an initiative. Engagement may be limited to those already concerned about environmental issues. CONCLUSION: This paper illustrates the important links between transition towns and the wider public health agenda, and demonstrates how an HIA can be applied to a community-based initiative. It provides a means by which transition town initiatives can demonstrate health and well-being benefits, whilst raising concerns about inclusivity and equity.