Baseline characteristics and comorbidities in the CAnadian REgistry for Pulmonary Fibrosis.

BACKGROUND: The CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) is a multi-center, prospective registry designed to study the natural history of fibrotic interstitial lung disease (ILD) in adults. The aim of this cross-sectional sub-study was to describe the baseline characteristics, risk factors, and comorbidities of patients enrolled in CARE-PF to date. METHODS: Patients completed study questionnaires and clinical measurements at enrollment and each follow-up visit. Environmental exposures were assessed by patient self-report and comorbidities by the Charlson Comorbidity Index (CCI). Baseline characteristics, exposures, and comorbidities were described for the overall study population and for incident cases, and were compared across ILD subtypes. RESULTS: The full cohort included 1285 patients with ILD (961 incident cases (74.8%)). Diagnoses included connective tissue disease-associated ILD (33.3%), idiopathic pulmonary fibrosis (IPF) (24.7%), unclassifiable ILD (22.3%), chronic hypersensitivity pneumonitis (HP) (7.5%), sarcoidosis (3.2%), non-IPF idiopathic interstitial pneumonias (3.0%, including idiopathic nonspecific interstitial pneumonia (NSIP) in 0.9%), and other ILDs (6.0%). Patient-reported exposures were most frequent amongst chronic HP, but common across all ILD subtypes. The CCI was ≤2 in 81% of patients, with a narrow distribution and range of values. CONCLUSIONS: CTD-ILD, IPF, and unclassifiable ILD made up 80% of ILD diagnoses at ILD referral centers in Canada, while idiopathic NSIP was rare when adhering to recommended diagnostic criteria. CCI had a very narrow distribution across our cohort suggesting it may be a poor discriminator in assessing the impact of comorbidities on patients with ILD.

Characterization of the Trehalose Utilization Operon in Streptococcus mutans Reveals that the TreR Transcriptional Regulator Is Involved in Stress Response Pathways and Toxin Production.

Streptococcus mutans, the organism most frequently associated with the development of dental caries, is able to utilize a diverse array of carbohydrates for energy metabolism. One such molecule is trehalose, a disaccharide common in human foods, which has been recently implicated in enhancing the virulence of epidemic strains of the pathogen Clostridium difficile In this study, mutants with deletions of all three genes in the putative S. mutans trehalose utilization operon were characterized, and the genes were shown to be required for wild-type levels of growth when trehalose was the only carbohydrate source provided. Interestingly, the TreR transcriptional regulator appeared to be critical for responding to oxidative stress and for mounting a protective stress tolerance response following growth at moderately acidic pH. mRNA sequencing (RNA-seq) of a treR deletion mutant suggested that in S. mutans, TreR acts as a trehalose-sensing activator of transcription of the tre operon, rather than as a repressor, as described in other species. In addition, deletion of treR caused the downregulation of a number of genes involved in genetic competence and bacteriocin production, supporting the results of a recent study linking trehalose and the S. mutans competence pathways. Finally, deletion of treR compromised the ability of S. mutans to inhibit the growth of the competing species Streptococcus gordonii and Lactococcus lactis Taking the results together, this study solidifies the role of the S. mutans tre operon in trehalose utilization and suggests novel functions for the TreR regulator, including roles in the stress response and competitive fitness.IMPORTANCES. mutans is the primary etiologic agent of dental caries, which globally is the most common chronic disease. S. mutans must be able to outcompete commensal organisms in its dental plaque niche in order to establish persistence and pathogenesis. To that end, S. mutans metabolizes a diverse array of carbohydrates to generate acid and impede its acid-sensitive neighbors. Additionally, S. mutans utilizes quorum signaling through genetic competence-associated pathways to induce production of toxins to kill its rivals. This study definitively shows that the S. mutans trehalose utilization operon is required for growth in trehalose. Furthermore, this study suggests that the S. mutans TreR transcriptional regulator has a novel role in virulence through regulation of genes involved in genetic competence and toxin production.

Detection and function of lipopolysaccharide and its purified lipid A after treatment with auxiliary chemical substances and calcium hydroxide dressings used in root canal treatment.

AIM: To investigate the influence of auxiliary chemical substances (ACSs) and calcium hydroxide [Ca(OH)2 ] dressings on lipopolysaccharides (LPS)/lipid A detection and its functional ability in activating Toll-like receptor 4 (TLR4). METHODOLOGY: Fusobacterium nucleatum pellets were exposed to antimicrobial agents as following: (i) ACS: 5.25%, 2.5% and 1% sodium hypochlorite solutions (NaOCl), 2% chlorhexidine (CHX) (gel and solution) and 17% ethylenediaminetetraacetic acid (EDTA); (ii) intracanal medicament: Ca(OH)2 paste for various periods (1 h, 24 h, 7 days, 14 days and 30 days); (iii) combination of substances: (a) 2.5% NaOCl (1 h), followed by 17% EDTA (3 min) and Ca(OH)2 (7 days); (b) 2% CHX (1 h), afterwards, 17% EDTA (3 min) followed by Ca(OH)2 (7 days). Saline solution was the control. Samples were submitted to LPS isolation and lipid A purification. Lipid A peaks were assessed by matrix-assisted laser desorption ionization time-of-flight mass spectrom (MALDI-TOF MS) whilst LPS bands by SDS-PAGE separation and silver staining. TLR4 activation determined LPS function activities. Statistical comparisons were carried out using one-way anova with Tukey-Kramer post-hoc tests at the 5% significance level. RESULTS: Matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis of control lipid A demonstrated the ion cluster at mass/charge (m/z) 1882 and an intense band in SDS-PAGE followed by silver staining of control LPS. In parallel, LPS control induced a robust TLR4 activation when compared to ACS (P ≤ .001). 5.25% NaOCl treatment led to the absence of lipid A peaks and LPS bands, whilst no changes occurred to lipid A/LPS after treatment with others ACS. Concomitantly, 5.25% NaOCl-treated LPS did not activate TLR4 (P < .0001). As for Ca(OH)2 , lipid A was not detected by MALDI-TOF nor by gel electrophoresis within 24 h. LPS treated with Ca(OH)2 was a weak TLR4 activator (P < .0001). From 24 h onwards, no significant differences were found amongst the time periods tested (P > 0.05). The addition of Ca(OH)2 for 7 days to cells treated either with 2.5% NaOCl or 2% CHX led to the absence of lipid A peaks and LPS bands, leading to a lower activation of TLR4. CONCLUSION: 5.25% NaOCl and Ca(OH)2 dressings from 24 h onwards were able to induce both, loss of lipid A peaks and no detection of LPS bands, rendering a diminished immunostimulatory activity through TLR4.

Molecular field theory for biaxial nematics formed from liquid crystal dimers and inhibited by the twist-bend nematic.

Liquid crystal dimers with odd spacers are good candidates as materials for biaxial nematic phases (NB). The dimers are flexible molecules sustaining biaxial conformations, and couplings between the conformational and orientational distributions could be expected to stabilise NB. We apply a molecular field theory for flexible molecules developed elsewhere to study a simple system made up of dimers composed of two cylindrically symmetric mesogenic groups. Our model allows for two idealised conformations: one linear and one bent at a tetrahedral angle. For a restricted set of chain lengths, the model predicts a first-order reentrant phase transition from the NB phase into a low temperature uniaxial nematic phase (NU). However the formation of the biaxial nematic could be blocked by the appearance of a twist-bent nematic.

The school as a health promoter for children with asthma: The purpose of an education programme.

BACKGROUND: Not only is asthma one of the leading causes of hospitalisation in children under 15 years and one of the main reasons for primary care outpatient visits, it also accounts for 13 million lost days of school annually, which can affect children's learning, integration at school and overall academic achievements. MATERIAL AND METHODS: This review article highlights the important role of the school in helping children and adolescents to control and manage their asthma through integrated and coordinated actions of health professionals, school staff, family, and the community. RESULTS: We recommended key elements for a multidisciplinary team asthma school programme that can be replicated and implemented especially in developing countries where children and adolescents are in a more disadvantaged environment. CONCLUSION: This multidisciplinary asthma school intervention when demonstrated with efficacy can be applied in the context of the real world, where many children and families who need care the most currently do not receive it.

Modelling of P3HT:PCBM interface using coarse-grained forcefield derived from accurate atomistic forcefield.

To understand the morphological evolution of P3HT:PCBM bulk heterojunction during thermal treatment process, we employed coarse-grained Molecular Dynamics (MD) simulations with a forcefield derived from atomistic model and experimental data such as crystal structure and melting temperature. The current study focuses on the differences between interfaces that PCBM forms with various P3HT orientations. Crystallinity analysis suggests that more ordered P3HT is observed near the interface for face-on and amorphous case, while no such trend is observed for edge-on and end-on configurations due to weaker interactions at the interface as evident from the considerably less negative interfacial energy. An analysis of pathways for C60 diffusion into P3HT using both an energy-based and solvent surface approach for amorphous P3HT reveals continuous chain motion-assisted pathways while for crystalline P3HT diffusion pathways remain restricted to grain boundaries. Based on these calculations, we propose a morphological evolution process for P3HT:PCBM bulk-heterojunction, which starts with nucleation crystallisation at the P3HT:PCBM interface, followed by PCBM diffusion along the grain boundaries and amorphous P3HT regions towards PCBM-rich domains.

Molecular field theory for biaxial smectic A liquid crystals.

Thermotropic biaxial nematic phases seem to be rare, but biaxial smectic A phases less so. Here we use molecular field theory to study a simple two-parameter model, with one parameter promoting a biaxial phase and the second promoting smecticity. The theory combines the biaxial Maier-Saupe and McMillan models. We use alternatively the Sonnet-Virga-Durand (SVD) and geometric mean approximations (GMA) to characterize molecular biaxiality by a single parameter. For non-zero smecticity and biaxiality, the model always predicts a ground state biaxial smectic A phase. For a low degree of smectic order, the phase diagram is very rich, predicting uniaxial and biaxial nematic and smectic phases, with the addition of a variety of tricritical and tetracritical points. For higher degrees of smecticity, the region of stability of the biaxial nematic phase is restricted and eventually disappears, yielding to the biaxial smectic phase. Phase diagrams from the two alternative approximations for molecular biaxiality are similar, except inasmuch that SVD allows for a first-order isotropic-biaxial nematic transition, whereas GMA predicts a Landau point separating isotropic and biaxial nematic phases. We speculate that the rarity of thermotropic biaxial nematic phases is partly a consequence of the presence of stabler analogous smectic phases.

Defining metabolic flexibility in hair follicle stem cell induced squamous cell carcinoma.

Among the numerous changes associated with the transformation to cancer, cellular metabolism is one of the first discovered and most prominent[1, 2]. However, despite the knowledge that nearly every cancer is associated with the strong upregulation of various metabolic pathways, there has yet to be much clinical progress on the treatment of cancer by targeting a single metabolic enzyme directly[3-6]. We previously showed that inhibition of glycolysis through lactate dehydrogenase (LDHA) deletion in cancer cells of origin had no effect on the initiation or progression of cutaneous squamous cell carcinoma[7], suggesting that these cancers are metabolically flexible enough to produce the necessary metabolites required for sustained growth in the absence of glycolysis. Here we focused on glutaminolysis, another metabolic pathway frequently implicated as important for tumorigenesis in correlative studies. We genetically blocked glutaminolysis through glutaminase (GLS) deletion in cancer cells of origin, and found that this had little effect on tumorigenesis, similar to what we previously showed for blocking glycolysis. Tumors with genetic deletion of glutaminolysis instead upregulated lactate consumption and utilization for the TCA cycle, providing further evidence of metabolic flexibility. We also found that the metabolic flexibility observed upon inhibition of glycolysis or glutaminolysis is due to post-transcriptional changes in the levels of plasma membrane lactate and glutamine transporters. To define the limits of metabolic flexibility in cancer initiating hair follicle stem cells, we genetically blocked both glycolysis and glutaminolysis simultaneously and found that frank carcinoma was not compatible with abrogation of both of these carbon utilization pathways. These data point towards metabolic flexibility mediated by regulation of nutrient consumption, and suggest that treatment of cancer through metabolic manipulation will require multiple interventions on distinct pathways.

Trends in child pedestrian motor vehicle collision injury rates by neighborhood deprivation score in Toronto, Canada.

We examined trends from 2000 to 2019 in child pedestrian motor vehicle collision (PMVC) injury rates in Toronto, Canada, to see if injury trends varied by neighbourhood deprivation. This 20-year period was associated with major road safety policy changes in the City. A Poisson regression analysis examined police-reported data on children (age 1-19 years), killed or seriously injured (KSI) PMVC rates, by deprivation status (using the Ontario Marginalization Index), over the period 2000-2019. Models controlled for location (urban core v. inner suburbs) and evaluated potential interactions. There were 523 child pedestrian KSI collisions from 2000 to 2019. Over this period, KSI rates decreased by more than 50 % across all neighbourhood deprivation levels. Steep declines from 2000 to 2010 were followed by level or increasing child PMVC rates from 2010 to 2019. Higher deprivation was associated with slightly elevated KSI rates; although not statistically significant. It is important to learn from road safety policy "successes" and ensure that future road safety interventions are applied equitably across areas, accounting for deprivation and location.

Issue 1 - "Update on adverse respiratory effects of outdoor air pollution" Part 2): Outdoor air pollution and respiratory diseases: Perspectives from Angola, Brazil, Canada, Iran, Mozambique and Portugal.

OBJECTIVE: To analyse the GARD perspective on the health effects of outdoor air pollution, and to synthesise the Portuguese epidemiological contribution to knowledge on its respiratory impact. RESULTS: Ambient air pollution has deleterious respiratory effects which are more apparent in larger, densely populated and industrialised countries, such as Canada, Iran, Brazil and Portugal, but it also affects people living in low-level exposure areas. While low- and middle-income countries (LMICs), are particularly affected, evidence based on epidemiological studies from LMICs is both limited and heterogeneous. While nationally, Portugal has a relatively low level of air pollution, many major cities face with substantial air pollution problems. Time series and cross-sectional epidemiological studies have suggested increased respiratory hospital admissions, and increased risk of respiratory diseases in people who live in urban areas and are exposed to even a relatively low level of air pollution. CONCLUSIONS: Adverse respiratory effects due to air pollution, even at low levels, have been confirmed by epidemiological studies. However, evidence from LMICs is heterogeneous and relatively limited. Furthermore, longitudinal cohort studies designed to study and quantify the link between exposure to air pollutants and respiratory diseases are needed. Worldwide, an integrated approach must involve multi-level stakeholders including governments (in Portugal, the Portuguese Ministry of Health, which hosts GARD-Portugal), academia, health professionals, scientific societies, patient associations and the community at large. Such an approach not only will garner a robust commitment, establish strong advocacy and clear objectives, and raise greater awareness, it will also support a strategy with adequate measures to be implemented to achieve better air quality and reduce the burden of chronic respiratory diseases (CRDs).

Family history, BRCA mutations and breast cancer in Vietnamese women.

The purpose of this report is to estimate the proportions of familial and hereditary breast cancers among unselected cases of breast cancer in Vietnam. Two hundred and ninety-two unselected cases of incident breast cancer were recruited from the National Cancer Hospital, Hanoi, the largest cancer centre in Vietnam. Family histories were collected for 292 cases and a DNA sample was obtained for 259 cases. DNA samples were screened for mutations in the large exons of BRCA1 and BRCA2 using the protein truncation test and by allele-specific testing for 17 founder mutations which have been reported in other Asian populations. Complete gene sequencing was performed on two cases of familial breast cancer. Seven of 292 cases reported a relative with breast cancer and one patient reported a relative with ovarian cancer. A pathogenic BRCA mutation was detected in 2 of 259 cases; one BRCA1 carrier was diagnosed at age 51 and one BRCA2 carrier was diagnosed at age 42. Neither case reported a relative with breast or ovarian cancer. A family history of breast cancer is very uncommon among Vietnamese breast cancer patients. The frequency of pathogenic BRCA mutations in Vietnamese breast cancer patients is among the lowest reported worldwide.

A point prevalence survey of hospital inpatients to define the proportion with palliation as the primary goal of care and the need for specialist palliative care.

The direct burden of people whose goal of care is a palliative approach has not been estimated in the acute care setting. Using a single time point, cross-sectional survey of all inpatient beds, an estimate was generated across a network of three South Australian public hospitals. One in three inpatients had a palliative approach as the goal of care and of these, only one in five had been referred to specialist palliative care services. Those referred were significantly more likely to have cancer and be younger men. Active recognition and documentation that a palliative approach frames the goals of care for this person needs to be incorporated more systematically into clinical practice in the acute care setting. At the same time, triggers for needs-based referral for specialist assessment should be implemented. Specialist palliative care services must also provide direct care for a wider range of patients than just those with cancer.

Geographic disparities in performance of pediatric polysomnography to diagnose obstructive sleep apnea in a universal access health care system.

BACKGROUND: Diagnostic polysomnography (PSG) is recommended prior to adenotonsillectomy (AT) for children with obstructive sleep apnea (OSA) and certain high-risk characteristics, but resource limitations often prevent this practice. OBJECTIVE: We performed a population-based assessment of children across Ontario, Canada to describe and quantify disparities in PSG. METHODS AND MATERIALS: This retrospective cohort study was performed using provincial health administrative data held at ICES. We identified children 0-10 years old who underwent PSG and AT between 2009 and 2018, and those with a PSG within 18 months prior to and/or 12 months following AT. We calculated the odds of PSG prior to/following AT after adjustment for demographics, medical comorbidities, geographic and socioeconomic characteristics. Our main predictor was driving time/distance to the nearest pediatric sleep centre ascertained using spatial analysis and geographic information systems. RESULTS: We identified 27,837 children <10 years old who underwent AT for OSA in Ontario. Only 12.8% had a PSG within 18 months prior and 5.7% had a PSG within 12 months following AT. Shorter driving time/distance, older age, male sex and certain comorbidities were associated with increased odds of PSG. CONCLUSION: Only a small proportion of children in our cohort underwent PSG prior to or following AT surgery despite universal access to healthcare. This study suggests a need to increase overall PSG access, particularly for those living distant from existing pediatric sleep centres. Future studies could determine if increased PSG testing in 'underserviced areas' would reduce overall surgery rates and/or improve health outcomes.

Prioritised research agenda for prevention and control of chronic respiratory diseases.

The 2008-2013 World Health Organization (WHO) action plan on noncommunicable diseases (NCDs) includes chronic respiratory diseases as one of its four priorities. Major chronic respiratory diseases (CRDs) include asthma and rhinitis, chronic obstructive pulmonary disease, occupational lung diseases, sleep-disordered breathing, pulmonary hypertension, bronchiectiasis and pulmonary interstitial diseases. A billion people suffer from chronic respiratory diseases, the majority being in developing countries. CRDs have major adverse effects on the life and disability of patients. Effective intervention plans can prevent and control CRDs, thus reducing morbidity and mortality. A prioritised research agenda should encapsulate all of these considerations in the frame of the global fight against NCDs. This requires both CRD-targeted interventions and transverse NCD programmes which include CRDs, with emphasis on health promotion and disease prevention.

Referral patterns to a palliative care service in rural Australia servicing indigenous Australians.

BACKGROUND: Territory palliative care (TPC) of the Northern Territory covers a population of 150000 over 400000 km² in urban, rural and remote settings. Thirty-two per cent of the population are indigenous Australians. There is little documentation of palliative services to the indigenous Australians. METHODS: We retrospectively reviewed the referral characteristics of patients who died in or were discharged from the TPC over 6 months in order to define unique characteristics of palliative care of such a population. RESULTS: The records of 151 consecutive patients were analysed, with a mean age 63 ± 17 years, 62% male, 59% non-indigenous, 70% urban dwellers and 71% referred for malignancies. Median time to separation was 69 days, with 33% discharged within 30 days, while 28% survived beyond 6 months. Eighty-two per cent of patients died, and of these 52% in the hospice. indigenous patients were more likely to be younger (54 vs 70 years), female (52% vs 29%), living rurally (52% vs 12%) and to die at home (47% vs 11%). CONCLUSION: These data showed major differences from the largest Australian study published so far, based on a population of predominantly non-indigenous Australians. This study identifies for the first time how TPC needs to have an encompassing service plan and delivery model to cater for indigenous patients and people in remote locations.

Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data.

OBJECTIVE: Health administrative databases can be used to track chronic diseases. The aim of this study was to validate a case ascertainment definition of paediatric-onset inflammatory bowel disease (IBD) using administrative data and describe its epidemiology in Ontario, Canada. METHODS: A population-based clinical database of patients with IBD aged <15 years was used to define cases, and patient information was linked to health administrative data to compare the accuracy of various patterns of healthcare use. The most accurate algorithm was validated with chart data of children aged <18 years from 12 medical practices. Administrative data from the period 1991-2008 were used to describe the incidence and prevalence of IBD in Ontario children. Changes in incidence were tested using Poisson regression. RESULTS: Accurate identification of children with IBD required four physician contacts or two hospitalisations (with International Classification of Disease (ICD) codes for IBD) within 3 years if they underwent colonoscopy and seven contacts or three hospitalisations within 3 years in those without colonoscopy (children <12 years old, sensitivity 90.5%, specificity >99.9%; children <15 years old, sensitivity 89.6%, specificity >99.9%; children <18 years old, sensitivity 91.1%, specificity 99.5%). Age- and sex-standardised prevalence per 100 000 population of paediatric IBD has increased from 42.1 (in 1994) to 56.3 (in 2005). Incidence per 100 000 has increased from 9.5 (in 1994) to 11.4 (in 2005). Statistically significant increases in incidence were noted in 0-4 year olds (5.0%/year, p = 0.03) and 5-9 year olds (7.6%/year, p<0.0001), but not in 10-14 or 15-17 year olds. CONCLUSION: Ontario has one of the highest rates of childhood-onset IBD in the world, and there is an accelerated increase in incidence in younger children.

Insights Obtained by Culturing Saccharibacteria With Their Bacterial Hosts.

Oral microbiome research has moved from asking "Who's there?" to "What are they doing?" Understanding what microbes "do" involves multiple approaches, including obtaining genomic information and examining the interspecies interactions. Recently we isolated a human oral Saccharibacteria (TM7) bacterium, HMT-952, strain TM7x, which is an ultrasmall parasite of the oral bacterium Actinomyces odontolyticus. The host-parasite interactions, such as phage-bacterium or Saccharibacteria-host bacterium, are understudied areas with large potential for insight. The Saccharibacteria phylum is a member of Candidate Phyla Radiation, a large lineage previously devoid of cultivated members. However, expanding our understanding of Saccharibacteria-host interactions requires examining multiple phylogenetically distinct Saccharibacteria-host pairs. Here we report the isolation of 3 additional Saccharibacteria species from the human oral cavity in binary coculture with their bacterial hosts. They were obtained by filtering ultrasmall Saccharibacteria cells free of other larger bacteria and inoculating them into cultures of potential host bacteria. The binary cocultures obtained could be stably passaged and studied. Complete closed genomes were obtained and allowed full genome analyses. All have small genomes (<1 Mb) characteristic of parasitic species and dramatically limited de novo synthetic pathway capabilities but include either restriction modification or CRISPR-Cas systems as part of an innate defense against foreign DNA. High levels of gene synteny exist among Saccharibacteria species. Having isolates growing in coculture with their hosts allowed time course studies of growth and parasite-host interactions by phase contrast, fluorescence in situ hybridization, and scanning electron microscopy. The cells of the 4 oral Saccharibacteria species are ultrasmall and could be seen attached to their larger Actinobacteria hosts. Parasite attachment appears to lead to host cell death and lysis. The successful cultivation of Saccharibacteria species has significantly expanded our understanding of these ultrasmall Candidate Phyla Radiation bacteria.

Phylogenetic and biological characterization of highly pathogenic H5N1 avian influenza viruses (Vietnam 2005) in chickens and ducks.

Analysis of Asian H5N1 avian influenza (AI) virus hemagglutinin (HA) genes shows a common origin, but the virus has evolved into at least three major clades (clades 0, 1, and 2) over the last 13 years. Previous reports of Vietnam viruses have documented predominantly clade 1 viruses. Unexpectedly, 19 viruses from northern Vietnam isolated in December 2005 fell into clade 2. These viruses further clustered into two distinct sublineages. Representative viruses from each sublineage were chosen for antigenic and pathogenic evaluation. Two distinct antigenic groups correlating with the genetic information were present when comparing hemagglutination inhibition (HI) titers. All viruses were highly virulent not only in chickens, killing them within 2 days of experimental inoculation, but also in 2- and 5-week-old Pekin ducks, causing 100% mortality within 4 days of challenge. The information gained about these viruses provides insight with regards to implementing control programs, including vaccine seed strain selection.