Seasonality of primary care utilization for respiratory diseases in Ontario: A time-series analysis

<p>Abstract</p> <p>Background</p> <p>Respiratory diseases represent a significant burden in primary care. Determining the temporal variation of the overall burden of respiratory diseases on the health care system and their potential causes are keys to understanding disease dynamics in populations and can contribute to the rational management of health care resources.</p> <p>Methods</p> <p>A retrospective, cross-sectional time series analysis was used to assess the presence and strength of seasonal and temporal patterns in primary care visits for respiratory diseases in Ontario, Canada, for a 10-year period from January 1, 1992 to December 31, 2002. Data were extracted from the Ontario Health Insurance Plan database for people who had diagnosis codes for chronic obstructive pulmonary disease, asthma, pneumonia, or upper respiratory tract infections.</p> <p>Results</p> <p>The results illustrate a clear seasonal pattern in visits to primary care physicians for all respiratory conditions, with a threefold increase in visits during the winter. Age and sex-specific rates show marked increases in visits of young children and in female adults. Multivariate time series methods quantified the interactions among primary care visits, and Granger causality criterion test showed that the respiratory syncytial virus (RSV) and influenza virus influenced asthma (p = 0.0060), COPD (p = 0.0038), pneumonia (p = 0.0001), and respiratory diseases (p = 0.0001).</p> <p>Conclusion</p> <p>Primary care visits for respiratory diseases have clear predictable seasonal patterns, driven primarily by viral circulations. Winter visits are threefold higher than summer troughs, indicating a short-term surge on primary health service demands. These findings can aid in effective allocation of resources and services based on seasonal and specific population demands.</p

Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

Incomplete functional recovery after delirium in elderly people: a prospective cohort study

BACKGROUND: Delirium often has a poor outcome, but why some people have incomplete recovery is not well understood. Our objective was to identify factors associated with short-term (by discharge) and long-term (by 6 month) incomplete recovery of function following delirium. METHODS: In a prospective cohort study of elderly patients with delirium seen by geriatric medicine services, function was assessed at baseline, at hospital discharge and at six months. RESULTS: Of 77 patients, vital and functional status at 6 months was known for 71, of whom 21 (30%) had died. Incomplete functional recovery, defined as ≥10 point decline in the Barthel Index, compared to pre-morbid status, was present in 27 (54%) of the 50 survivors. Factors associated with death or loss of function at hospital discharge were frailty, absence of agitation (hypoactive delirium), a cardiac cause and poor recognition of delirium by the treating service. Frailty, causes other than medications, and poor recognition of delirium by the treating service were associated with death or poor functional recovery at 6 months. CONCLUSION: Pre-existing frailty, cardiac cause of delirium, and poor early recognition by treating physicians are associated with worse outcomes. Many physicians view the adverse outcomes of delirium as intractable. While in some measure this might be true, more skilled care is a potential remedy within their grasp

Unravelling the molecular basis of high affinity nanobodies against HIV p24: in vitro functional, structural and in silico insights

Preventing the spread of infectious diseases remains an urgent priority worldwide and this is driving the development of advanced nanotechnology to diagnose infections at the point of care. Herein we report the creation of a library of novel nanobody capture ligands to detect p24, one of the earliest markers of HIV infection. We demonstrate that these nanobodies, one tenth the size of conventional antibodies, exhibit high sensitivity and broad specificity to global HIV-1 subtypes. Biophysical characterisation indicates strong 690pM binding constants and fast kinetic on-rates, one to two orders of magnitude better than monoclonal antibody comparators. A crystal structure of the lead nanobody and p24 was obtained, and used alongside molecular dynamics simulations to elucidate the molecular basis of these enhanced performance characteristics. They indicate that binding occurs at C-terminal helices 10 and 11 of p24, a negatively charged region of p24 complemented by the positive surface of the nanobody binding interface involving CDR1, CDR2 and CDR3 loops. Our findings have broad implications on the design of novel antibodies and a wide range of advanced biomedical applications

Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988

Production of a reference transcriptome and transcriptomic database (PocilloporaBase) for the cauliflower coral, Pocillopora damicornis

<p>Abstract</p> <p>Background</p> <p>Motivated by the precarious state of the world's coral reefs, there is currently a keen interest in coral transcriptomics. By identifying changes in coral gene expression that are triggered by particular environmental stressors, we can begin to characterize coral stress responses at the molecular level, which should lead to the development of more powerful diagnostic tools for evaluating the health of corals in the field. Furthermore, the identification of genetic variants that are more or less resilient in the face of particular stressors will help us to develop more reliable prognoses for particular coral populations. Toward this end, we performed deep mRNA sequencing of the cauliflower coral, <it>Pocillopora damicornis</it>, a geographically widespread Indo-Pacific species that exhibits a great diversity of colony forms and is able to thrive in habitats subject to a wide range of human impacts. Importantly, <it>P. damicornis </it>is particularly amenable to laboratory culture. We collected specimens from three geographically isolated Hawaiian populations subjected to qualitatively different levels of human impact. We isolated RNA from colony fragments ("nubbins") exposed to four environmental stressors (heat, desiccation, peroxide, and hypo-saline conditions) or control conditions. The RNA was pooled and sequenced using the 454 platform.</p> <p>Description</p> <p>Both the raw reads (n = 1, 116, 551) and the assembled contigs (n = 70, 786; mean length = 836 nucleotides) were deposited in a new publicly available relational database called PocilloporaBase <url>http://www.PocilloporaBase.org</url>. Using BLASTX, 47.2% of the contigs were found to match a sequence in the NCBI database at an E-value threshold of ≤.001; 93.6% of those contigs with matches in the NCBI database appear to be of metazoan origin and 2.3% bacterial origin, while most of the remaining 4.1% match to other eukaryotes, including algae and amoebae.</p> <p>Conclusions</p> <p><it>P. damicornis </it>now joins the handful of coral species for which extensive transcriptomic data are publicly available. Through PocilloporaBase <url>http://www.PocilloporaBase.org</url>, one can obtain assembled contigs and raw reads and query the data according to a wide assortment of attributes including taxonomic origin, PFAM motif, KEGG pathway, and GO annotation.</p

Fine mapping of a linkage peak with integration of lipid traits identifies novel coronary artery disease genes on chromosome 5

Coronary artery disease (CAD), and one of its intermediate risk factors, dyslipidemia, possess a demonstrable genetic component, although the genetic architecture is incompletely defined. We previously reported a linkage peak on chromosome 5q31-33 for early-onset CAD where the strength of evidence for linkage was increased in families with higher mean low density lipoprotein-cholesterol (LDL-C). Therefore, we sought to fine-map the peak using association mapping of LDL-C as an intermediate disease-related trait to further define the etiology of this linkage peak. The study populations consisted of 1908 individuals from the CATHGEN biorepository of patients undergoing cardiac catheterization; 254 families (N = 827 individuals) from the GENECARD familial study of early-onset CAD; and 162 aorta samples harvested from deceased donors. Linkage disequilibrium-tagged SNPs were selected with an average of one SNP per 20 kb for 126.6-160.2 MB (region of highest linkage) and less dense spacing (one SNP per 50 kb) for the flanking regions (117.7-126.6 and 160.2-167.5 MB) and genotyped on all samples using a custom Illumina array. Association analysis of each SNP with LDL-C was performed using multivariable linear regression (CATHGEN) and the quantitative trait transmission disequilibrium test (QTDT; GENECARD). SNPs associated with the intermediate quantitative trait, LDL-C, were then assessed for association with CAD (i.e., a qualitative phenotype) using linkage and association in the presence of linkage (APL; GENECARD) and logistic regression (CATHGEN and aortas)

Asymptotic complexities of discrete logarithm algorithms in pairing-relevant finite fields

International audienceWe study the discrete logarithm problem at the boundary case between small and medium characteristic finite fields, which is precisely the area where finite fields used in pairing-based cryptosystems live. In order to evaluate the security of pairing-based protocols, we thoroughly analyze the complexity of all the algorithms that coexist at this boundary case: the Quasi-Polynomial algorithms, the Number Field Sieve and its many variants, and the Function Field Sieve. We adapt the latter to the particular case where the extension degree is composite, and show how to lower the complexity by working in a shifted function field. All this study finally allows us to give precise values for the characteristic asymptotically achieving the highest security level for pairings. Surprisingly enough, there exist special characteristics that are as secure as general ones

Granger Causality Analysis of Steady-State Electroencephalographic Signals during Propofol-Induced Anaesthesia

Changes in conscious level have been associated with changes in dynamical integration and segregation among distributed brain regions. Recent theoretical developments emphasize changes in directed functional (i.e., causal) connectivity as reflected in quantities such as ‘integrated information’ and ‘causal density’. Here we develop and illustrate a rigorous methodology for assessing causal connectivity from electroencephalographic (EEG) signals using Granger causality (GC). Our method addresses the challenges of non-stationarity and bias by dividing data into short segments and applying permutation analysis. We apply the method to EEG data obtained from subjects undergoing propofol-induced anaesthesia, with signals source-localized to the anterior and posterior cingulate cortices. We found significant increases in bidirectional GC in most subjects during loss-of-consciousness, especially in the beta and gamma frequency ranges. Corroborating a previous analysis we also found increases in synchrony in these ranges; importantly, the Granger causality analysis showed higher inter-subject consistency than the synchrony analysis. Finally, we validate our method using simulated data generated from a model for which GC values can be analytically derived. In summary, our findings advance the methodology of Granger causality analysis of EEG data and carry implications for integrated information and causal density theories of consciousness