An Fgf-Shh positive feedback loop drives growth in developing unpaired fins.

The origin and diversification of appendage types is a central question in vertebrate evolution. Understanding the genetic mechanisms that underlie fin and limb development can reveal relationships between different appendages. Here we demonstrate, using chemical genetics, a mutually agonistic interaction between Fgf and Shh genes in the developing dorsal fin of the channel catfish, Ictalurus punctatus. We also find that Fgf8 and Shh orthologs are expressed in the apical ectodermal ridge and zone of polarizing activity, respectively, in the median fins of representatives from other major vertebrate lineages. These findings demonstrate the importance of this feedback loop in median fins and offer developmental evidence for a median fin-first scenario for vertebrate paired appendage origins.

Declining Comprehensiveness of Services Delivered by Canadian Family Physicians Is Not Driven by Early-Career Physicians.

We describe changes in the comprehensiveness of services delivered by family physicians in 4 Canadian provinces (British Columbia, Manitoba, Ontario, Nova Scotia) during the periods 1999-2000 and 2017-2018 and explore if changes differ by years in practice. We measured comprehensiveness using province-wide billing data across 7 settings (home, long-term care, emergency department, hospital, obstetrics, surgical assistance, anesthesiology) and 7 service areas (pre/postnatal care, Papanicolaou [Pap] testing, mental health, substance use, cancer care, minor surgery, palliative home visits). Comprehensiveness declined in all provinces, with greater changes in number of service settings than service areas. Decreases were no greater among new-to-practice physicians.

Changes in comprehensiveness of services delivered by Canadian family physicians: Analysis of population-based linked data in 4 provinces.

OBJECTIVE: To describe changes in the comprehensiveness of services delivered by family physicians across service settings and service areas in 4 Canadian provinces, to identify which settings and areas have changed the most, and to compare the magnitude of changes by physician characteristics. DESIGN: Descriptive analysis of province-wide, population-based billing data linked to population and physician registries. SETTING: British Columbia, Manitoba, Ontario, and Nova Scotia. PARTICIPANTS: Family physicians registered to practise in the 1999-2000 and 2017-2018 fiscal years. MAIN OUTCOME MEASURES: Comprehensiveness was measured across 7 service settings (home care, long-term care, emergency departments, hospitals, obstetric care, surgical assistance, anesthesiology) and in 7 service areas consistent with office-based practice (prenatal and postnatal care, Papanicolaou testing, mental health, substance use, cancer care, minor surgery, palliative home visits). The proportion of physicians with activity in each setting and area are reported and the average number of service settings and areas by physician characteristics is described (years in practice, sex, urban or rural practice setting, and location of medical degree training). RESULTS: Declines in comprehensiveness were observed across all provinces studied. Declines were greater for comprehensiveness of settings than for areas consistent with office-based practice. Changes were observed across all physician characteristics. On average across provinces, declines in the number of service settings and service areas were highest among physicians in practice 20 years or longer, male physicians, and physicians practising in urban areas. CONCLUSION: Declining comprehensiveness was observed across all physician characteristics, pointing to changes in the practice and policy contexts in which all family physicians work.

Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine. METHODS: We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9-12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638. FINDINGS: Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9-12. The change from the observation period in mean number of migraine days per month during weeks 9-12 was -4·3 days (95% CI -4·8 to -3·9) with rimegepant and -3·5 days (-4·0 to -3·0) with placebo (least squares mean difference -0·8 days, 95% CI -1·46 to -0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died. INTERPRETATION: Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted. FUNDING: Biohaven Pharmaceuticals.

Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine.

BACKGROUND: Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin gene-related peptide receptor antagonist that may be effective in acute migraine treatment. METHODS: In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least a 1-year history of migraine and two to eight migraine attacks of moderate or severe intensity per month to receive rimegepant orally at a dose of 75 mg or matching placebo for the treatment of a single migraine attack. The primary end points were freedom from pain and freedom from the most bothersome symptom (other than pain) identified by the patient, both of which were assessed 2 hours after the dose of rimegepant or placebo was administered. RESULTS: A total of 1186 patients were randomly assigned to receive rimegepant (594 patients) or placebo (592 patients); of these, 537 patients in the rimegepant group and 535 patients in the placebo group could be evaluated for efficacy. The overall mean age of the patients evaluated for efficacy was 40.6 years, and 88.7% were women. In a modified intention-to-treat analysis, the percentage of patients who were pain-free 2 hours after receiving the dose was 19.6% in the rimegepant group and 12.0% in the placebo group (absolute difference, 7.6 percentage points; 95% confidence interval [CI], 3.3 to 11.9; P<0.001). The percentage of patients who were free from their most bothersome symptom 2 hours after the dose was 37.6% in the rimegepant group and 25.2% in the placebo group (absolute difference, 12.4 percentage points; 95% CI, 6.9 to 17.9; P<0.001). The most common adverse events were nausea and urinary tract infection. CONCLUSIONS: Treatment of a migraine attack with the oral calcitonin gene-related peptide receptor antagonist rimegepant resulted in a higher percentage of patients who were free of pain and free from their most bothersome symptom than placebo. (Funded by Biohaven Pharmaceuticals; ClinicalTrials.gov number, NCT03237845.).

Changes over time in patient visits and continuity of care among graduating cohorts of family physicians in 4 Canadian provinces.

BACKGROUND: Lack of patient access to family physicians in Canada is a concern. The role of recent physician graduates in this problem of supply of primary care services has not been established. We sought to establish whether career stage or graduation cohort were related to family physician practice volume and continuity of care over time. METHODS: We conducted a retrospective cohort study of family physician practice from 1997/98 to 2017/18. We collected administrative health and physician claims data in British Columbia, Manitoba, Ontario and Nova Scotia. We included all physicians who registered with their respective provincial regulatory colleges as having a medical specialty of family practice or who had billed the provincial health insurance system for patient care as family physicians, or both. We used regression models to isolate the effects of 3-year categories of years in practice (at all career stages), time period and cohort on patient contacts and physician-level continuity of care. RESULTS: Between 1997/98 and 2017/18, the median number of patient contacts per provider per year fell by between 515 and 1736 contacts in the 4 provinces examined. Median contacts peaked at 27-29 years in practice in all provinces, and median physician-level continuity of care increased until 30 or more years in practice. We found no association between graduation cohort and patient contacts or physician-level continuity of care. INTERPRETATION: Recent cohorts of family physicians practise similarly to their predecessors in terms of practice volumes and continuity of care. Because family physicians of all career stages showed declining patient contacts, we suggest that system-wide solutions to recent challenges in the accessibility of primary care in Canada are needed.

Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial.

OBJECTIVE: Evaluate the efficacy, safety, and tolerability of zavegepant nasal spray in the acute treatment of migraine. BACKGROUND: Calcitonin gene-related peptide-targeting agents are a novel class of therapeutics for migraine, but none are currently available as a nonoral option for acute treatment. Zavegepant, a high-affinity, selective, and structurally unique calcitonin gene-related peptide-receptor antagonist in late-stage development, is formulated as a nasal spray for the acute treatment of migraine. METHODS: This randomized, dose-ranging, placebo-controlled, Phase 2/3 trial in adults aged ≥18 years with migraine (NCT03872453) was conducted at US study sites. Participants were randomized by an interactive web response system and treated a single attack of moderate to severe pain intensity with zavegepant nasal spray 5, 10, 20 mg, or placebo. Coprimary efficacy endpoints were pain freedom and freedom from the most bothersome symptom at 2 h postdose. RESULTS: Of the 1673 participants aged 18 to 79 years who were randomized, 1588 were treated with study medication, and 1581 (mean age 40.8 years, 85.5% female) were analyzed for efficacy: zavegepant 5 mg (n = 387), 10 mg (n = 391), 20 mg (n = 402), and placebo (n = 401). Zavegepant 10 and 20 mg were more effective than placebo on the coprimary endpoints of pain freedom at 2 h postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6; p = 0.0113]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2; p = 0.0055]) and freedom from the most bothersome symptom at 2 h postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3]; 10 mg: 41.9% [98.3% CI, 36.0, 47.9; p = 0.0155]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4; p = 0.0094]). Findings for the 5 mg dose were not significant. The most common treatment-emergent adverse events with zavegepant 10 and 20 mg and placebo were dysgeusia (13.5% to 16.1% vs. 3.5%), nausea (2.7% to 4.1% vs. 0.5%), and nasal discomfort (1.3% to 5.2% vs. 0.2%). Most adverse events were mild or moderate and resolved without treatment. There was no signal of hepatotoxicity. CONCLUSION: Zavegepant nasal spray, in single doses of 10 or 20 mg, was effective for the acute treatment of migraine, with a favorable safety profile. Additional research is needed to confirm its potential as a nonoral medication for the acute treatment of migraine.

A mechanism for temporary bioadhesion.

The flatworm Macrostomum lignano features a duo-gland adhesive system that allows it to repeatedly attach to and release from substrates in seawater within a minute. However, little is known about the molecules involved in this temporary adhesion. In this study, we show that the attachment of M. lignano relies on the secretion of two large adhesive proteins, M. lignano adhesion protein 1 (Mlig-ap1) and Mlig-ap2. We revealed that both proteins are expressed in the adhesive gland cells and that their distribution within the adhesive footprints was spatially restricted. RNA interference knockdown experiments demonstrated the essential function of these two proteins in flatworm adhesion. Negatively charged modified sugars in the surrounding water inhibited flatworm attachment, while positively charged molecules impeded detachment. In addition, we found that M. lignano could not adhere to strongly hydrated surfaces. We propose an attachment-release model where Mlig-ap2 attaches to the substrate and Mlig-ap1 exhibits a cohesive function. A small negatively charged molecule is secreted that interferes with Mlig-ap1, inducing detachment. These findings are of relevance for fundamental adhesion science and efforts to mitigate biofouling. Further, this model of flatworm temporary adhesion may serve as the starting point for the development of synthetic reversible adhesion systems for medicinal and industrial applications.

The Phytotoxin Myrigalone A Triggers a Phased Detoxification Programme and Inhibits Lepidium sativum Seed Germination via Multiple Mechanisms including Interference with Auxin Homeostasis.

Molecular responses of plants to natural phytotoxins comprise more general and compound-specific mechanisms. How phytotoxic chalcones and other flavonoids inhibit seedling growth was widely studied, but how they interfere with seed germination is largely unknown. The dihydrochalcone and putative allelochemical myrigalone A (MyA) inhibits seed germination and seedling growth. Transcriptome (RNAseq) and hormone analyses of Lepidium sativum seed responses to MyA were compared to other bioactive and inactive compounds. MyA treatment of imbibed seeds triggered the phased induction of a detoxification programme, altered gibberellin, cis-(+)-12-oxophytodienoic acid and jasmonate metabolism, and affected the expression of hormone transporter genes. The MyA-mediated inhibition involved interference with the antioxidant system, oxidative signalling, aquaporins and water uptake, but not uncoupling of oxidative phosphorylation or p-hydroxyphenylpyruvate dioxygenase expression/activity. MyA specifically affected the expression of auxin-related signalling genes, and various transporter genes, including for auxin transport (PIN7, ABCG37, ABCG4, WAT1). Responses to auxin-specific inhibitors further supported the conclusion that MyA interferes with auxin homeostasis during seed germination. Comparative analysis of MyA and other phytotoxins revealed differences in the specific regulatory mechanisms and auxin transporter genes targeted to interfere with auxin homestasis. We conclude that MyA exerts its phytotoxic activity by multiple auxin-dependent and independent molecular mechanisms.

Differences in developmental potential predict the contrasting patterns of dental diversification in characiform and cypriniform fishes.

Morphological diversification during adaptive radiation may depend on factors external or internal to the lineage. We provide evidence for the latter in characiform fishes (tetras and piranhas), which exhibit extensive dental diversity. Phylogenetic character mapping supported regain of lost teeth as contributing to this diversity. To test for latent potential for dentition that would facilitate its evolutionary expansion, we overexpressed a tooth initiation signal, the tumour necrosis factor pathway ligand ectodysplasin, in a model characiform, the Mexican tetra (Astyanax mexicanus). This manipulation resulted in extensive ectopic dentition, in contrast with its previously reported limited effect in the zebrafish (Danio rerio). Tooth location in the order Cypriniformes, to which the zebrafish belongs, is much more restricted than in characiforms, a pattern that may be explained by differences in the retention of ancestral developmental potential. Our results suggest that differences in evolvability between lineages may lead to contrasting patterns of diversification.

Coleorhiza-enforced seed dormancy: a novel mechanism to control germination in grasses.

How the biophysical properties of overlaying tissues control growth, such as the embryonic root (radicle) during seed germination, is a fundamental question. In eudicot seeds the endosperm surrounding the radicle confers coat dormancy and controls germination responses through modulation of its cell wall mechanical properties. Far less is known for grass caryopses that differ in tissue morphology. Here we report that the coleorhiza, a sheath-like organ that surrounds the radicle in grass embryos, performs the same role in the grass weed Avena fatua (common wild oat). We combined innovative biomechanical techniques, tissue ablation, microscopy, tissue-specific gene and enzyme activity expression with the analysis of hormones and oligosaccharides. The combined experimental work demonstrates that in grass caryopses the coleorhiza indeed controls germination for which we provide direct biomechanical evidence. We show that the coleorhiza becomes reinforced during dormancy maintenance and weakened during germination. Xyloglucan endotransglycosylases/hydrolases may have a role in coleorhiza reinforcement through cell wall remodelling to confer coat dormancy. The control of germination by coleorhiza-enforced dormancy in grasses is an example of the convergent evolution of mechanical restraint by overlaying tissues.

Determinants of Discharge Disposition From Acute Care for Survivors of Hypoxic-Ischemic Brain Injury: Results From a Large Population-Based Cohort Data Set.

OBJECTIVE: To identify determinants of discharge disposition from acute care among survivors of hypoxic-ischemic brain injury (HIBI), stratified by sex. DESIGN: Population-based retrospective cohort study using provincial data in Ontario, Canada. The determinants were grouped into predisposing, need, and enabling factors using the Anderson Behavioral Model. SETTING: Acute care. PARTICIPANTS: Survivors of HIBI aged ≥20 years at the time of hospitalization and discharged alive from acute care between April 1, 2002, and March 31, 2017. There were 7492 patients with HIBI, of whom 28% (N=2077) survived their acute care episode. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Discharge disposition from acute care, categorized as complex continuing care (CCC), long-term care (LTC), inpatient rehabilitation (IR), home with support, home without support, and transferred to another acute care. RESULTS: The discharge dispositions for the 2077 survivors were IR 23.4% (n=487), CCC 19.5% (n=404), LTC 6.2% (n=128), home without support 31.2% (n=647), home with support 15.1% (n=314), and other 4.6%. Multinomial multivariable logistic regression analysis using home without support as the reference category revealed that female patients were significantly more likely than male patients to be discharged to LTC/CCC. Those who were older, were frail, and had longer stay in acute care or special care unit (SCU) were more likely to be discharged to LTC/CCC. The only significant determinant for IR was longer stay in acute care. Survivors with cardiac-related injury were less likely to be discharged to LTC/CCC. Income was a significant factor for male patients but not for female patients in the sex-stratified analysis. The following variables were investigated but were not significant determinants in this study: need factors (comorbidity score, prior psychiatric disorders, health care utilization) and enabling factors (income quintile, rural area of residence). CONCLUSIONS: Predisposing (age, sex) and need factors (frailty, acute care days, SCU days, type of injury) were significant determinants of discharge disposition from acute care after HIBI. In spite of a system with universal coverage, sex differences were found, with more female patients being discharged to CCC/LTC rather than IR, controlling for age and other confounders. These findings should be considered in appropriate discharge planning from acute care for survivors of HIBI.

Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial.

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. METHODS: In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. FINDINGS: Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3â€ˆ× the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2â€ˆ× the upper limit of normal were reported. Treated participants reported no serious adverse events. INTERPRETATION: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. FUNDING: Biohaven Pharmaceuticals.

Predictors of in-hospital mortality following hypoxic-ischemic brain injury: a population-based study.

Objective: To identify predictors of in-hospital mortality following Hypoxic-Ischemic Brain Injury (HIBI) using the Anderson Behavioral Model.Design and Setting: Population based retrospective cohort study in Ontario, Canada with data collected between 1 April 2002 and 31 March 2017.Patients: Adult patients aged 20 years and older with HIBI-related acute care admission were identified in the health administrative data. Multivariable cox proportional hazard regression models were used to identify predisposing, need and enabling factors that predict in-hospital mortality.Results: Of the 7492 patients admitted to acute care with HIBI, the in-hospital mortality rate was 71%. The predisposing factors associated with mortality were female sex (HR, 1.16; 95% CI, 1.10-1.23) and older age (65-79 vs. 20-34: HR, 1.17; 95% CI, 1.02-1.35). The need factors associated with mortality were the presence of COPD (HR, 1.10; 95% CI, 1.02-1.17), psychiatric illness (HR, 1.13; 95% CI, 1.05-1.20) injury due to cardiac illness (HR, 1.19; 95% CI, 1.12-1.26) and longer emergency department length of stay. Having spending any time in an alternate level of care and the application of tracheotomy procedures were found to reduce mortality.Conclusions: The acute/critical care centers need to consider these findings to adopt prevention strategies targeting reduced in-hospital mortality.

Change in Function Over Inpatient Rehabilitation After Hypoxic Ischemic Brain Injury: A Population-Wide Cohort Study.

OBJECTIVE: To estimate change in motor, cognitive, and overall functional performance during inpatient rehabilitation (IR) and to identify potential determinants of these outcomes among patients with hypoxic-ischemic brain injury (HIBI). DESIGN: Population-based retrospective cohort study using Ontario's health administrative data. SETTING: Inpatient rehabilitation. PARTICIPANTS: Survivors of HIBI 20 years and older discharged from acute care between fiscal years 2002-2003 and 2010-2011 and admitted to IR within 1 year of acute care discharge (N=159). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Functional status as measured by FIM, total, and scores on motor and cognitive subscales. RESULTS: A higher proportion (77%) of HIBI patients in the study were male and 28% were older than 65 years. We observed material improvements in FIM total, motor, and cognitive scores from across the IR episode. Potential determinants of total FIM gain were living in rural location (ß, 10.4; 95% CI, 0.21-21), having shorter preceding acute care length of stay (15-30 vs >60 days ß, 10.4; 95% CI, 1.4-19.5), and failing to proceed directly to IR following acute care discharge (ß, 8.7; 95% CI, 1.8-15.5). Motor FIM gain had similar identified potential determinants. Identified potential determinants of cognitive FIM gain were shorter (ie, 31-60 vs >60 days) preceding acute care, longer IR and length of stay, and proceeding directly to IR. There were no sex differences in functional gain. CONCLUSIONS: Inpatient rehabilitation is beneficial to HIBI survivors. Timely access to these services may be crucial in achieving optimal outcomes for these patients.

Physiological and pathological covariates of persistent concussion-related fatigue: results from two regression methodologies.

BACKGROUND: Fatigue severity in persons with mild traumatic brain injury (mTBI) has received little research attention, despite its typically positively skewed nature. Investigation of covariates across a range of fatigue severity may provide insight into important contributors. OBJECTIVE: To assess the relative significance of a priori-hypothesized covariates of physiological and pathological (mental and physical) fatigue in persons with mTBI/concussion, applying ordinary least squares (OLS) and quantile regression (QR) approaches. METHODS: We conducted a cross-sectional investigation in 80 participants with mTBI/concussion (mean age 45.4 ± 10.1 years, 59% male). The fatigue severity scale (FSS) was used as an outcome measure. Predictors of this outcome, grouped into physiological and pathological models of fatigue were assessed using OLS and QR. RESULTS: The mean total FSS score was 46.13 ± 14.59, and the median was 49 (interquartile range 37-57), demonstrating positive skewness. Fatigue severity was associated with variables within the mental, psychological and psychiatric domains at different levels of the fatigue score distribution. CONCLUSION: Results highlighted that some covariates had a significant impact on the FSS total score at non-central parts of its distribution, while others exhibited significant impact across the entire distribution. Addressing covariates of fatigue across the severity continuum can enhance research and clinical management.

Household food security and breast-feeding duration among Canadian Inuit.

OBJECTIVE: There have been few studies investigating the association between food security and breast-feeding duration and none have been conducted among Canadian Inuit, a population disproportionately burdened with food insecurity. We evaluated the association between household food security and breast-feeding duration in Canadian Inuit children. DESIGN: Data were obtained from the Nunavut Inuit Child Health Survey, a population-based cross-sectional survey. SETTING: The Canadian Territory of Nunavut in 2007 and 2008. SUBJECTS: Caregivers of Inuit children aged 3-5 years. Participating children were randomly sampled from community medical centre lists. RESULTS: Out of 215 children, 147 lived in food-insecure households (68·4 %). Using restricted mean survival time models, we estimated that children in food-secure households were breast-fed for 16·8 (95 % CI 12·5, 21·2) months and children in food-insecure households were breast-fed for 21·4 (95 % CI 17·9, 24·8) months. In models adjusting for social class, traditional knowledge and child health, household food security was not associated with breast-feeding duration (hazard ratio=0·82, 95 % CI 0·58, 1·14). CONCLUSIONS: Our research does not support the hypothesis that children living in food-insecure households were breast-fed for a longer duration than children living in food-secure households. However, we found that more than 50 % of mothers in food-insecure households continued breast-feeding well beyond 1 year. Many mothers in food-secure households also continued to breast-feed beyond 1 year. Given the high prevalence of food insecurity in Inuit communities, we need to ensure infants and their caregivers are being adequately nourished to support growth and breast-feeding, respectively.

Selection and constraint underlie irreversibility of tooth loss in cypriniform fishes.

The apparent irreversibility of the loss of complex traits in evolution (Dollo's Law) has been explained either by constraints on generating the lost traits or the complexity of selection required for their return. Distinguishing between these explanations is challenging, however, and little is known about the specific nature of potential constraints. We investigated the mechanisms underlying the irreversibility of trait loss using reduction of dentition in cypriniform fishes, a lineage that includes the zebrafish (Danio rerio) as a model. Teeth were lost from the mouth and upper pharynx in this group at least 50 million y ago and retained only in the lower pharynx. We identified regional loss of expression of the Ectodysplasin (Eda) signaling ligand as a likely cause of dentition reduction. In addition, we found that overexpression of this gene in the zebrafish is sufficient to restore teeth to the upper pharynx but not to the mouth. Because both regions are competent to respond to Eda signaling with transcriptional output, the likely constraint on the reappearance of oral teeth is the alteration of multiple genetic pathways required for tooth development. The upper pharyngeal teeth are fully formed, but do not exhibit the ancestral relationship to other pharyngeal structures, suggesting that they would not be favored by selection. Our results illustrate an underlying commonality between constraint and selection as explanations for the irreversibility of trait loss; multiple genetic changes would be required to restore teeth themselves to the oral region and optimally functioning ones to the upper pharynx.

National position statement for the management of latent tuberculosis infection.

The primary role of any tuberculosis (TB) control program is to ensure the prompt identification and effective treatment of active disease. The host immune system often succeeds in containing the initial (or primary) infection with Mycobacterium tuberculosis (Mtb), but may fail to eliminate the pathogen. The persistence of viable organisms explains the potential for the development of active disease years or even decades after infection. This is known as latent tuberculosis infection (LTBI) although, rather than a distinct entity, this probably represents part of a dynamic spectrum. Individuals with LTBI are asymptomatic and it is therefore clinically undetectable. The World Health Organization (WHO) estimates that one-third of the global population has been infected with Mtb, with highest prevalence of LTBI in countries/regions with the highest prevalence of active disease. In 2013, 88% of 1322 notifications in Australia were in the overseas-born population (incidence 19.5 per 100,000 v. 1.0 per 100,000), with this proportion rising over the course of the last decade. Combined with epidemiological evidence of low local transmission, this strongly implies that the vast majority resulted from reactivation of latent infection acquired prior to immigration. Contrasting trends in TB incidence in other developed countries probably reflect differences in policy regarding LTBI. CONCLUSION: The diagnosis and treatment of LTBI represents an important opportunity for intervention by jurisdictional TB control programs.