Initiation of opioid agonist therapy after hospital visits for opioid poisonings in Ontario.

BACKGROUND: Emergency department visits and hospital admissions for opioid toxicity are opportunities to initiate opioid agonist therapy (OAT), which reduces morbidity and mortality in patients with opioid use disorder (OUD). The study objectives were to evaluate OAT initiation rates after a hospital encounter for opioid toxicity in Ontario, Canada, and determine whether publication of a 2018 Canadian OUD management guideline was associated with increased initiation. METHODS: We conducted a retrospective, population-based serial cross-sectional study of hospital encounters for opioid toxicity among patients with OUD between Jan. 1, 2013, and Mar. 31, 2020, in Ontario, Canada. The primary outcome was OAT initiation (methadone, buprenorphine-naloxone, or slow-release oral morphine) within 7 days of discharge, measured quarterly. We examined the impact of the release of the OUD management guideline on OAT initiation rates using Autoregressive Integrated Moving Average models. RESULTS: Among 20 702 hospital visits for opioid toxicity among patients with OUD, the median age was 35 years, and 65.1% were male. Over the study period, the percentage of visits leading to OAT initiation within 7 days rose from 1.7% or less (Q1 2013) to 5.6% (Q1 2020); however, the publication of the Canadian OUD management guideline was not associated with a significant increase in these rates (0.14% slope change, 95% confidence interval -0.11% to 0.38%; p = 0.3). INTERPRETATION: Among hospital encounters for opioid toxicity, despite rising prevalence over time, only 1 in 18 patients were dispensed OAT within a week of discharge in early 2020. These findings highlight missed opportunities to initiate therapies proven to reduce mortality in patients with OUD.

Characteristics of Pediatric Patients With Celiac Disease Identified Due to an Affected First-Degree Family Member.

The incidence of celiac disease in first-degree relatives of affected individuals is higher than in the general population, yet the clinical characteristics of this unique subset of patients has not been well described. Through a retrospective review of patients seen in a tertiary care pediatric celiac disease clinic, we identified 49 patients diagnosed with celiac disease following screening due to an affected first-degree relative. Although 51% of patients screened due to an affected first-degree relative were asymptomatic, their disease histology was as severe as those screened for symptoms suggestive of celiac disease. These findings support current recommendations to screen all first-degree relatives of patients with celiac disease regardless of clinical symptoms.

Cinacalcet increases renal calcium excretion in PTHrP-mediated hypercalcemia: a case report.

BACKGROUND: In the acute setting, PTH-independent hypercalcemia is typically treated with anti-resorptive agents such as zoledronic acid or denosumab. When these agents are no longer able to control hypercalcemia, several case reports have shown the utility of cinacalcet. However, it is not known if cinacalcet can be effective in patients naïve to anti-resorptive therapy or how cinacalcet ameliorates the hypercalcemia. CASE PRESENTATION: A 47-year-old male with a history of alcohol-induced cirrhosis was admitted for left cheek bleeding and swelling from an infiltrative squamous cell carcinoma of the oral cavity. On admission, he was found to have an elevated albumin-corrected serum calcium of 13.6 mg/dL, a serum phosphorus of 2.2 mg/dL and an intact PTH of 6 pg/mL (normal 18-90) with a PTHrP of 8.1 pmol/L (normal < 4.3), consistent with PTHrP-dependent hypercalcemia. Aggressive intravenous saline hydration and subcutaneous salmon calcitonin were initiated, but his serum calcium remained elevated. Given tooth extractions scheduled for the next day and possible irradiation to the jaw in the near future, alternatives to antiresorptive therapy were sought. Cinacalcet was initiated at 30 mg twice daily then increased to 60 mg twice daily the following day. The albumin-corrected serum calcium level decreased from 13.2 to 10.9 mg/dL within 48 h. The fractional excretion of calcium increased from 3.7 to 7.0%. CONCLUSIONS: This case demonstrates the utility of cinacalcet for the treatment of PTHrP-mediated hypercalcemia without prior anti-resorptive therapy via increased renal clearance of calcium.

The association between pediatric mental health disorders and type 1 diabetes-related outcomes.

OBJECTIVE: Transition from pediatric to adult healthcare systems is a difficult process for young adults with Type 1 Diabetes (T1D) and most patients experience a deterioration in disease control. Mental health (MH) disorders are common in individuals with T1D and are believed to play a role in disease control and transition of care. We evaluated the association between the presence of pediatric MH disorder and measures of success in diabetes care in young adults who recently transitioned to adult care. RESEARCH DESIGN AND METHODS: Retrospective cohort study of young adults in a large adult endocrinology system who transitioned from a pediatric hospital system after 2009. MH disorders were diagnosed by clinical pediatric psychologists during routine care at the pediatric hospital. Measurements of Hemoglobin A1c, diabetes-related emergencies, clinic attendance and intervals in transition were assessed and compared between the pediatric and adult hospital systems. RESULTS: 237 young adults were identified and 100 (42%) of these were diagnosed with a MH disorder during pediatric care. Presence of a MH disorder was associated with higher Hemoglobin A1c levels prior to transition and increased rates of diabetes-related hospitalizations during the transition interval. Patients with a MH disorder were less likely to establish a pattern of consistent follow up after transition (p = 0.021). CONCLUSIONS: MH disorders are common and predict greater challenges with diabetes management and less effective transition into the adult endocrinology system. Early recognition of MH disorders may allow for allocation of more proactive and intensive support for affected patients.

Transformative learning in an interprofessional student-run clinic: a qualitative study.

Student-run free clinics are increasingly seen as a way for students in health professions to have early authentic exposures to providing care to marginalized populations, often in the context of interprofessional teams. However, few studies characterize what and how students may learn from volunteering at a student-run free clinic. We aimed to examine shifts in attitude or practice that volunteers report after completing a placement at an interprofessional student-run clinic in Toronto, Ontario, Canada. Transcripts from semi-structured reflective focus groups were analyzed in an exploratory thematic manner and from the perspective of transformative learning theory. Volunteers reported attitude shifts toward greater self-awareness of assumptions, recognition of the need for systemic interventions, and seeing themselves as learning and contributing meaningfully in a team even without direct-client contact. Practice shifts emerged of individualizing assessment and treatment of patients as well as increased comfort working in interprofessional teams. Attitude and practice shifts were facilitated by authentic interactions with individuals from marginalized populations, taking a patient-centered approach, and an interprofessional context. Interprofessional student-run free clinics are suited to triggering disorienting dilemmas that set the stage for transformative learning, particularly when volunteers are guided to reflect.

A Genomic Map of the Effects of Linked Selection in Drosophila.

Natural selection at one site shapes patterns of genetic variation at linked sites. Quantifying the effects of "linked selection" on levels of genetic diversity is key to making reliable inference about demography, building a null model in scans for targets of adaptation, and learning about the dynamics of natural selection. Here, we introduce the first method that jointly infers parameters of distinct modes of linked selection, notably background selection and selective sweeps, from genome-wide diversity data, functional annotations and genetic maps. The central idea is to calculate the probability that a neutral site is polymorphic given local annotations, substitution patterns, and recombination rates. Information is then combined across sites and samples using composite likelihood in order to estimate genome-wide parameters of distinct modes of selection. In addition to parameter estimation, this approach yields a map of the expected neutral diversity levels along the genome. To illustrate the utility of our approach, we apply it to genome-wide resequencing data from 125 lines in Drosophila melanogaster and reliably predict diversity levels at the 1Mb scale. Our results corroborate estimates of a high fraction of beneficial substitutions in proteins and untranslated regions (UTR). They allow us to distinguish between the contribution of sweeps and other modes of selection around amino acid substitutions and to uncover evidence for pervasive sweeps in untranslated regions (UTRs). Our inference further suggests a substantial effect of other modes of linked selection and of adaptation in particular. More generally, we demonstrate that linked selection has had a larger effect in reducing diversity levels and increasing their variance in D. melanogaster than previously appreciated.

Preliminary Experience in Combined Somatic and Cerebral Oximetry Monitoring in Liver Transplantation.

OBJECTIVE: The use of cerebral near-infrared spectroscopy (NIRS) has become widespread in cardiac surgery after research demonstrated an association between perioperative cerebral desaturations and postoperative complications. Somatic NIRS desaturation also is associated with an increased risk of postoperative complications and mortality. The objective of this study was to explore the trends of both somatic and cerebral NIRS during liver transplantation. DESIGN: A prospective, single-site, observational case series. SETTING: Tertiary care center. PARTICIPANTS: The study comprised 10 patients undergoing liver transplantation. INTERVENTIONS: NIRS sensors were placed on the forehead (cerebral regional oxygen saturation [rSO2]) and on the right arm and right leg (somatic rSO2) to measure tissue perfusion. Desaturation was defined as a 20% decrease of baseline values for 15 seconds. MEASUREMENTS AND MAIN RESULTS: In all patients, parallel changes in both cerebral and somatic rSO2 values were observed during phlebotomy, bleeding, transfusion, portal vein clamping, and the use of vasoactive agents. Induction of anesthesia increased cerebral rSO2 more than it did somatic values. However, ascites removal, abdominal manipulation, and clamping of the inferior vena cava (IVC) were associated with nonparallel changes in cerebral and somatic rSO2. Ascites removal was associated with increased somatic leg rSO2, and IVC clamping and abdominal hypertension were associated with a significant reduction in somatic leg rSO2. Somatic leg desaturation instead of arm or cerebral desaturation was associated with more postoperative complications. CONCLUSIONS: The use of combined NIRS monitoring allows for the identification of the source of somatic or cerebral desaturation. Compromised venous flow from the IVC from clamping or abdominal compartment syndrome typically is associated with the appearance of more pronounced leg than arm desaturation.

Investigating student perceptions at an interprofessional student-run free clinic serving marginalised populations.

Many health profession schools have student-run free clinics (SRFCs), but their educational relevance has not been well studied. The aim of this study was to evaluate the learning experiences and skills developed among interprofessional healthcare students at an SRFC serving marginalised populations, in order to provide data for ongoing programme improvement and recommendations for other SRFCs based on lessons learned. Under 1:1 supervision with a preceptor, interprofessional students completed three clinical shifts at an SRFC and attended a reflection session. A total of 101 out of 105 participants answered semi-structured pre- and post-programme surveys (response rate: 96%). Descriptive statistics and descriptive thematic analyses were used for quantitative and qualitative data, respectively. Numerous skills derived from learning objectives common to many healthcare professions were addressed while participating at the SRFC. Valued programme elements included working with and learning about inner city populations in an interprofessional care model. Interprofessional SRFCs encourage student learning about resources for inner city populations and interprofessional collaboration while providing an opportunity to develop skills related to the formal curriculum. This may provide a workable strategy to address an interprofessional education gap in the healthcare professional curriculum.

Is Age Associated With the Severity of Post-Mild Traumatic Brain Injury Symptoms?

BACKGROUND: Mild traumatic brain injury (mTBI) is a significant public health concern. Research has shown that mTBI is associated with persistent physical, cognitive, and behavioural symptoms, leading to significant direct and indirect medical costs. Our objective was to determine if age impacts the type and severity of post-mTBI symptoms experienced. METHODS: Retrospective analysis of prospectively collected data at a level 1 tertiary care outpatient head injury clinic. Participants (N=167) were patients seen at the clinic following an mTBI. The Rivermead Post-Concussion Symptoms Questionnaire was used to assess symptom severity. RESULTS: In our sample, the mean age was 44±16 years with 51% males. Compared with other age groups, patients >66 years of age were significantly more likely to report an mTBI between 6 AM to 12 PM (69%). Middle-aged patients (36-55 years) were more likely to report higher severity of certain post-mTBI symptoms (headache, nausea and vomiting, irritability, poor concentration, sleep disturbance, blurry vision, light sensitivity, and taking longer to think) compared with patients >66 years of age. CONCLUSIONS: In general, middle-aged patients reported higher severity of post-mTBI symptoms compared with the oldest patients. Thus, there was a significant association between age and the severity of specific mTBI symptoms, which highlights the need for targeted management. Additional research is needed to understand the mechanisms that could be contributing to the higher symptom severity experienced by the middle-aged group.

Child and Adolescent Emergency and Urgent Mental Health Delivery Through Telepsychiatry: 12-Month Prospective Study.

BACKGROUND: The significant gap between children and adolescents presenting for emergency mental healthcare and the shortage of child and adolescent psychiatrists constitutes a major barrier to timely access for psychiatric assessment for rural and remote areas. Unlike remote areas, urban emergency departments have in-house psychiatric consultation. Telepsychiatry may be a solution to ensure the same service for remote areas. However, there is a paucity of studies on the use of telepsychiatry for child and adolescent emergency consults. Thus, the aim of our study was to (1) assess patient satisfaction with telepsychiatry and (2) compare clinical characteristics and outcome of telepsychiatry with face-to-face emergency child and adolescent assessments. METHODS: This is a prospective study of telepsychiatry emergency assessments of children and adolescents referred by emergency physicians. The comparison group was age- and gender-matched patients seen for face-to-face urgent assessments. Data were gathered on demographic and clinical variables. Telepsychiatry satisfaction was assessed using a questionnaire. Descriptive statistics and chi-square tests were used to assess group differences for each variable. Logistic regression was used to assess impact of the variables on outcome after the consult. A p value <0.05 was used to determine statistical significance. RESULTS: Sixty (n = 60) assessments were conducted through telepsychiatry in 12 months. Among the telepsychiatry group, Aboriginal patients were over-represented (50% vs. 6.7%, p < 0.001), a higher proportion received a diagnosis of adjustment disorder (22% vs. 8.3%, p = 0.004) or no diagnosis (27% vs. 6.7%, p = 0.004) compared with controls. There was no statistically significant difference between groups on other clinical variables. Patients reported a high degree of satisfaction with telepsychiatry. CONCLUSIONS: Telepsychiatry is acceptable to patients and families for safe emergency assessment and follow-up, reducing unnecessary travel to urban centers. Longer time outcomes are needed to establish validity of telepsychiatry for emergency assessments.

Effect of comorbidities and medications on frequency of primary care visits among older patients.

OBJECTIVE: To determine if comorbidities and high-risk medications affect the frequency of family physician visits among older patients. DESIGN: Retrospective chart review. SETTING: Academic family health team at Sunnybrook Health Sciences Centre in Toronto, Ont. PARTICIPANTS: Among patients aged 65 years and older who were registered patients of the family health team between July 1, 2013, and June 30, 2014, the 5% who visited their family physicians most frequently and the 5% who visited their family physicians least frequently were selected for the study (N = 265). MAIN OUTCOME MEASURES: Predictors of frequent visits to family physicians. RESULTS: The significant predictors of being a high-frequency user were female sex (odds ratio [OR] = 2.20, P = .03), age older than 85 years (OR = 5.35, P = .001), and higher total number of medications (OR = 1.49, P < .001). Age-adjusted Charlson comorbidity index score, number of Beers criteria medications, and Anticholinergic Risk Scale score were not significant predictors (P > .05). CONCLUSION: Female sex, age older than 85, and higher total number of medications were independent significant predictors of higher frequency of family physician visits among older patients. Validated tools, such as the Charlson comorbidity index, Beers criteria, and Anticholinergic Risk Scale, did not independently predict the frequency of visits, indicating that predicting frequency of visits is likely complex.

A survey of Canadian interprofessional student-run free clinics.

Student-run free clinics (SRFCs) have existed in Canada since 1971, providing interprofessional healthcare to underserved populations. SRFCs are seen as vehicles for socially accountable health professional education. Literature on how Canadian SRFC function is lacking. Web-based surveys were sent to student leaders from Canadian SRFCs regarding their 2014 activities. All six fully-functioning SRFCs responded reporting on the following: services provided, professions involved, governing structure, funding sources, clients seen, types of care sought, students and preceptors involved, as well as perceived strengths, weaknesses, opportunities and threats. In 2014, 2,159 clients were provided clinical care at Canadian SRFCs. The most common reasons for visiting included pain and infection. Strengths identified include autonomy, ability to adapt to client needs, serving the underserved, and real-world interprofessional teamwork. Weaknesses reported include high student and preceptor turnover. Threats include securing funding and liability coverage. Since there is little literature on Canadian SRFCs, we compared our results with United States (US) based SRFCs. Canadian SRFCs share core values with US-based SRFCs and report similar strengths and challenges. However, Canadian SRFCs differ in scope and appear to provide care for more acute concerns. Data from studies of US-based SRFCs may not be immediately applicable to Canadian SRFCs. Studies evaluating Canadian SRFCs are needed.

A second-generation assembly of the Drosophila simulans genome provides new insights into patterns of lineage-specific divergence.

We create a new assembly of the Drosophila simulans genome using 142 million paired short-read sequences and previously published data for strain w(501). Our assembly represents a higher-quality genomic sequence with greater coverage, fewer misassemblies, and, by several indexes, fewer sequence errors. Evolutionary analysis of this genome reference sequence reveals interesting patterns of lineage-specific divergence that are different from those previously reported. Specifically, we find that Drosophila melanogaster evolves faster than D. simulans at all annotated classes of sites, including putatively neutrally evolving sites found in minimal introns. While this may be partly explained by a higher mutation rate in D. melanogaster, we also find significant heterogeneity in rates of evolution across classes of sites, consistent with historical differences in the effective population size for the two species. Also contrary to previous findings, we find that the X chromosome is evolving significantly faster than autosomes for nonsynonymous and most noncoding DNA sites and significantly slower for synonymous sites. The absence of a X/A difference for putatively neutral sites and the robustness of the pattern to Gene Ontology and sex-biased expression suggest that partly recessive beneficial mutations may comprise a substantial fraction of noncoding DNA divergence observed between species. Our results have more general implications for the interpretation of evolutionary analyses of genomes of different quality.

Natural allelic variation underlying a major fitness trade-off in Arabidopsis thaliana.

Plants can defend themselves against a wide array of enemies, from microbes to large animals, yet there is great variability in the effectiveness of such defences, both within and between species. Some of this variation can be explained by conflicting pressures from pathogens with different modes of attack. A second explanation comes from an evolutionary 'tug of war', in which pathogens adapt to evade detection, until the plant has evolved new recognition capabilities for pathogen invasion. If selection is, however, sufficiently strong, susceptible hosts should remain rare. That this is not the case is best explained by costs incurred from constitutive defences in a pest-free environment. Using a combination of forward genetics and genome-wide association analyses, we demonstrate that allelic diversity at a single locus, ACCELERATED CELL DEATH 6 (ACD6), underpins marked pleiotropic differences in both vegetative growth and resistance to microbial infection and herbivory among natural Arabidopsis thaliana strains. A hyperactive ACD6 allele, compared to the reference allele, strongly enhances resistance to a broad range of pathogens from different phyla, but at the same time slows the production of new leaves and greatly reduces the biomass of mature leaves. This allele segregates at intermediate frequency both throughout the worldwide range of A. thaliana and within local populations, consistent with this allele providing substantial fitness benefits despite its marked impact on growth.

Genome-wide association study of 107 phenotypes in Arabidopsis thaliana inbred lines.

Although pioneered by human geneticists as a potential solution to the challenging problem of finding the genetic basis of common human diseases, genome-wide association (GWA) studies have, owing to advances in genotyping and sequencing technology, become an obvious general approach for studying the genetics of natural variation and traits of agricultural importance. They are particularly useful when inbred lines are available, because once these lines have been genotyped they can be phenotyped multiple times, making it possible (as well as extremely cost effective) to study many different traits in many different environments, while replicating the phenotypic measurements to reduce environmental noise. Here we demonstrate the power of this approach by carrying out a GWA study of 107 phenotypes in Arabidopsis thaliana, a widely distributed, predominantly self-fertilizing model plant known to harbour considerable genetic variation for many adaptively important traits. Our results are dramatically different from those of human GWA studies, in that we identify many common alleles of major effect, but they are also, in many cases, harder to interpret because confounding by complex genetics and population structure make it difficult to distinguish true associations from false. However, a-priori candidates are significantly over-represented among these associations as well, making many of them excellent candidates for follow-up experiments. Our study demonstrates the feasibility of GWA studies in A. thaliana and suggests that the approach will be appropriate for many other organisms.

Recombination and linkage disequilibrium in Arabidopsis thaliana.

Linkage disequilibrium (LD) is a major aspect of the organization of genetic variation in natural populations. Here we describe the genome-wide pattern of LD in a sample of 19 Arabidopsis thaliana accessions using 341,602 non-singleton SNPs. LD decays within 10 kb on average, considerably faster than previously estimated. Tag SNP selection algorithms and 'hide-the-SNP' simulations suggest that genome-wide association mapping will require only 40%-50% of the observed SNPs, a reduction similar to estimates in a sample of African Americans. An Affymetrix genotyping array containing 250,000 SNPs has been designed based on these results; we demonstrate that it should have more than adequate coverage for genome-wide association mapping. The extent of LD is highly variable, and we find clear evidence of recombination hotspots, which seem to occur preferentially in intergenic regions. LD also reflects the action of selection, and it is more extensive between nonsynonymous polymorphisms than between synonymous polymorphisms.

An evaluation of wait-times at an interprofessional student-run free clinic.

Student-run free clinics (SRFCs) are becoming increasingly popular programmes in schools for promoting interprofessional education and service learning. Despite their prevalence, little research has been done surrounding SRFCs and wait-times. SRFCs may experience long wait-times because patients are often seen on a drop-in basis and time has to be allotted for interprofessional case discussion and teaching. The purpose of this study was to evaluate the wait-times for patients being seen at an interprofessional SRFC and determine potential improvements. Wait-times, total treatment room times, total time per patient, and whether a referral and/or prescription was given were tracked from May 2014 to July 2015 at an SRFC. A total of 268 patients were seen in 52 clinics. On average, five patients were seen per clinic. Patients waited for an average time of 21 minutes before they were seen by the team. Average treatment time per patient was 69 minutes. Patients were generally at the clinic for a total of 91 minutes before being discharged. Several improvements for managing client flow at interprofessional SRFCs are discussed.

Landscape of standing variation for tandem duplications in Drosophila yakuba and Drosophila simulans.

We have used whole genome paired-end Illumina sequence data to identify tandem duplications in 20 isofemale lines of Drosophila yakuba and 20 isofemale lines of D. simulans and performed genome wide validation with PacBio long molecule sequencing. We identify 1,415 tandem duplications that are segregating in D. yakuba as well as 975 duplications in D. simulans, indicating greater variation in D. yakuba. Additionally, we observe high rates of secondary deletions at duplicated sites, with 8% of duplicated sites in D. simulans and 17% of sites in D. yakuba modified with deletions. These secondary deletions are consistent with the action of the large loop mismatch repair system acting to remove polymorphic tandem duplication, resulting in rapid dynamics of gain and loss in duplicated alleles and a richer substrate of genetic novelty than has been previously reported. Most duplications are present in only single strains, suggesting that deleterious impacts are common. Drosophila simulans shows larger numbers of whole gene duplications in comparison to larger proportions of gene fragments in D. yakuba. Drosophila simulans displays an excess of high-frequency variants on the X chromosome, consistent with adaptive evolution through duplications on the D. simulans X or demographic forces driving duplicates to high frequency. We identify 78 chimeric genes in D. yakuba and 38 chimeric genes in D. simulans, as well as 143 cases of recruited noncoding sequence in D. yakuba and 96 in D. simulans, in agreement with rates of chimeric gene origination in D. melanogaster. Together, these results suggest that tandem duplications often result in complex variation beyond whole gene duplications that offers a rich substrate of standing variation that is likely to contribute both to detrimental phenotypes and disease, as well as to adaptive evolutionary change.

Multiplexed shotgun genotyping for rapid and efficient genetic mapping.

We present a new approach to genotyping based on multiplexed shotgun sequencing that can identify recombination breakpoints in a large number of individuals simultaneously at a resolution sufficient for most mapping purposes, such as quantitative trait locus (QTL) mapping and mapping of induced mutations. We first describe a simple library construction protocol that uses just 10 ng of genomic DNA per individual and makes the approach accessible to any laboratory with standard molecular biology equipment. Sequencing this library results in a large number of sequence reads widely distributed across the genomes of multiplexed bar-coded individuals. We develop a Hidden Markov Model to estimate ancestry at all genomic locations in all individuals using these data. We demonstrate the utility of the approach by mapping a dominant marker allele in D. simulans to within 105 kb of its true position using 96 F1-backcross individuals genotyped in a single lane on an Illumina Genome Analyzer. We further demonstrate the utility of our method by genetically mapping more than 400 previously unassembled D. simulans contigs to linkage groups and by evaluating the quality of targeted introgression lines. At this level of multiplexing and divergence between strains, our method allows estimation of recombination breakpoints to a median of 38-kb intervals. Our analysis suggests that higher levels of multiplexing and/or use of strains with lower levels of divergence are practicable.