Costs Associated with Nontuberculous Mycobacteria Infection, Ontario, Canada, 2001-2012.

To determine incidence-based healthcare costs attributable to nontuberculous mycobacterial (NTM) pulmonary disease (PD) and NTM pulmonary isolation (PI), from the healthcare payer perspective, we conducted a population-based matched cohort study in Ontario, Canada. We established cohorts of patients with incident NTM-PD and NTM-PI during 2001-2012 by using individually linked laboratory data and health administrative data, matched to unexposed persons from the general population. To estimate attributable costs for acute and long-term illness, we used a phase-of-care approach. Costs were stratified by age, sex, and healthcare resource, and reported in 2018 Canadian dollars (CAD) and US dollars (USD), standardized to 10 days. Costs were highest during the before-death phase (NTM-PD CAD $1,352 [USD $1,044]; NTM-PI CAD $731 [USD $565]). The cumulative mean attributable 1-year costs were CAD $14,953 (USD $11,541) for NTM-PD and CAD $8,729 (USD $6,737) for NTM-PI. Costs for patients with NTM-PD and NTM-PI were higher than those for unexposed persons.

Prevalence and management of aspirin hypersensitivity in a cardiology practice.

Background: Data are lacking with concern to the prevalence and management of aspirin (ASA) hypersensitivity. Objective: To study the prevalence, different types of reactions, and implications for clinical management of ASA hypersensitivity in a cardiology practice. Methods: We conducted an electronic medical record review of 11,375 individuals, 5052 (44%) in the ambulatory setting, and 6323 (56%) admitted for percutaneous coronary intervention (PCI), from January 2012 to December 2013. Results: The prevalence of ASA hypersensitivity was 1.88% (n = 214). Skin reactions were the most common (40 [19%]), followed by angioedema (10 [4.6%]), respiratory (9 [4.2%]), and anaphylaxis (6 [2.8%]). No records were found for 74 patients (34.5%), and 69 patients (32.2%) were mistakenly labeled as allergic for having gastrointestinal symptoms. Of the 214 patients who had documented ASA hypersensitivity, 108 individuals (50.46%) had coronary artery disease. The medications at discharge were the following: ASA (30 [14%]), thienopyridine (48 [22%]), a combination of ASA and thienopyridine (13 [6%]), anticoagulation only (26 [12%]), and no antiplatelet (97 [43%]). Conclusion: ASA hypersensitivity is often not documented correctly or is often misdiagnosed or not appropriately managed. There is a need for improved management of ASA hypersensitivity, including appropriate referral for ASA desensitization and combating unnecessary avoidance in patients with intolerance due to adverse effects.

The direct healthcare costs attributable to West Nile virus illness in Ontario, Canada: a population-based cohort study using laboratory and health administrative data.

BACKGROUND: West Nile virus (WNV) is a mosquito-borne flavivirus, first detected in the Western Hemisphere in 1999 and spread across North America over the next decade. Though endemic in the most populous areas of North America, few studies have estimated the healthcare costs associated with WNV. The objective of this study was to determine direct healthcare costs attributable to WNV illness in Ontario, Canada. METHODS: We conducted a cost-of-illness study on incident laboratory confirmed and probable WNV infected subjects identified from the provincial laboratory database from Jan 1, 2002 through Dec 31, 2012. Infected subjects were linked to health administrative data and matched to uninfected subjects. We used phase-of-care methods to calculate costs for 3 phases of illness: acute infection, continuing care, and final care prior to death. Mean 10-day attributable costs were reported in 2014 Canadian dollars, per capita. Sensitivity analysis was conducted to test the impact of WNV neurologic syndromes on healthcare costs. RESULTS: One thousand five hundred fifty-one laboratory confirmed and probable WNV infected subjects were ascertained; 1540 (99.3%) were matched to uninfected subjects. Mean age of WNV infected subjects was 49.1 ± 18.4 years, 50.5% were female. Mean costs attributable to WNV were $1177 (95% CI: $1001, $1352) for acute infection, $180 (95% CI: $122, $238) for continuing care, $11,614 (95% CI: $5916, $17,313) for final care - acute death, and $3199 (95% CI: $1770, $4627) for final care - late death. Expected 1-year costs were $13,648, adjusted for survival. Three hundred seventeen infected subjects were diagnosed with at least one neurologic syndrome and greatest healthcare costs in acute infection were associated with encephalitis ($4710, 95% CI: $3770, $5650). CONCLUSIONS: WNV is associated with increased healthcare resource utilization across all phases of care. High-quality studies are needed to understand the health system impact of vector-borne diseases and evaluate the cost effectiveness of novel WNV interventions.

Assessment of population immunity to measles in Ontario, Canada: a Canadian Immunization Research Network (CIRN) study.

Canada eliminated measles in 1998. We conducted a sero-epidemiology study to estimate population immunity to measles in the province of Ontario, Canada and to identify groups at higher risk of outbreaks. We used a previously developed modified enzyme immunoassay to test 1,199 residual sera from patients aged 1-39 years. We re-tested negative and equivocal sera using a plaque reduction neutralization assay. We interpreted our results in the context of Ontario's immunization program and vaccine coverage data. Of 1,199 sera, 1035 (86.3%, 95% confidence interval (CI) 84.4, 88.2) were above the measles threshold for protection, 70 (5.8%, 95% CI 4.5, 7.2) were equivocal and 94 (7.8%, 95% CI 6.3, 9.4) were negative. The proportion of positive sera was highest for those 1-5 years, with 180/199 (90.5%, 95% CI 86.4, 94.5) positive sera, and lowest for those age 12-19 years, at 158/199 (79.4%, 95% CI 73.8, 85.0). Adjusted for age, females were more likely than males to have antibody titers above the threshold of protection (odds ratio = 1.60, 95% CI 1.14, 2.24). Most of the study cohort were eligible for two measles vaccine doses, and vaccine uptake in Ontario is >90% for school-aged cohorts. We observed a higher than expected proportion of sera with antibody levels below the threshold of protection, suggesting that immunity in some Ontario age-groups may be waning, despite high vaccine coverage. Alternatively, the traditional measles correlates of protection may not be an appropriate measure of population protection in measles-eliminated settings.

Small-vessel PCI outcomes in men, women, and minorities following platinum chromium everolimus-eluting stents: Insights from the pooled PLATINUM Diversity and PROMUS Element Plus Post-Approval studies.

OBJECTIVE: We evaluated 1-year outcomes after platinum chromium everolimus-eluting stents (PtCr-EES) in small versus non-small coronary arteries within a large, diverse sample of men, women, and minorities. BACKGROUND: There exists limited outcomes data on the use of second-generation drug-eluting stent to treat small diameter coronary arteries. METHODS: We pooled patients from the PLATINUM Diversity and PROMUS Element Plus stent registries. Small-vessel percutaneous coronary intervention (SV-PCI) was defined as ≥1 target lesion with reference vessel diameter (RVD) ≤2.5 mm. Endpoints included major adverse cardiac event (MACE; death, myocardial infarction [MI] or target vessel revascularization [TVR]), target vessel failure (TVF; death related to the target vessel, target vessel MI or TVR) and definite/probable stent thrombosis (ST). Multivariable Cox regression was used to risk-adjust outcomes. RESULTS: We included 4,155/4,182 (99%) patients with available RVD, of which 1,607 (39%) underwent small-vessel PCI. SV-PCI was not associated with increased MACE (adjHR 1.02; 95%CI 0.81-1.30) or TVF (adjHR 1.07; 95%CI 0.82-1.39). MI risk was lower in white men compared to women and minorities, both in the setting of SV-PCI (adjHR 0.41; 95%CI 0.23-0.74 and adjHR 0.39; 95%CI 0.20-0.75, respectively) and for non-SV-PCI (adjHR 0.61; 95%CI 0.38-0.99 and adjHR 0.45; 95%CI 0.27-0.74, respectively). There was no significant interaction between RVD and sex or minority status for any endpoint. CONCLUSION: In a large diverse contemporary PCI outcomes database, SV-PCI with PtCr-EES was not associated with increased MACE or TVR and did not account for the increased MI risk noted in women and minorities compared to white men.

Estimating direct healthcare costs attributable to laboratory-confirmed Lyme disease in Ontario, Canada: A population-based matched cohort study using health administrative data.

The objective of this study was to determine healthcare costs attributable to laboratory-confirmed Lyme disease (LD) from the healthcare payer perspective in Ontario, Canada. A cost-of-illness study was conducted for incident LD subjects from 1 January 2006 through 31 December 2013 ascertained from provincial laboratory and reportable disease databases, linked to health administrative data. All LD subjects included were laboratory-confirmed, according to provincial case definitions. Incident LD subjects were propensity-score matched to uninfected subjects on age, sex, comorbidities and urban/rural status. We used phase-of-care methods to calculate attributable costs for two phases of illness: initial care (≤30 days following "index date") and continuing care (>30 days after index date to the end of the follow-up period). A total of 663 incident, confirmed LD subjects were identified from 2006 through 2013. Mean age was 44.2 ± 20.1 years; 339 (51.1%) were female; and 31 (4.7%) were hospitalized ≤30 days after index date. Six hundred fifty-eight (99.2%) LD subjects were matched to uninfected subjects; mean follow-up time was 3.3 years. Mean attributable costs per case during the initial care phase and continuing care were $277 (95% CI: $197, $357) and -$5 (-$27, $17), respectively. Attributable costs per LD subject aged 5-14 years were $440 ($132, $747), greater than the costs observed for other age strata. Expected 1-year attributable costs were $832, given continuing care costs were negligible. Limitations to our study include estimating costs using a cohort of only laboratory-confirmed LD cases, introducing selection bias for diagnosed and treated patients who may have a lower risk of developing sequelae. In conclusion, the initial care phase of LD is associated with increased healthcare costs, but without significant costs attributable to LD infection after 30 days. Estimates of costs attributable to LD are important for healthcare resource prioritization and the evaluation of novel interventions.

Doublesex Evolution Is Correlated with Social Complexity in Ants.

The Dmrt (doublesex and mab-3-related transcription factor) genes are transcription factors crucial for sex determination and sexual differentiation. In some social insects, doublesex (dsx) exhibits widespread caste-specific expression across different tissues and developmental stages and has been suggested as a candidate gene for regulating division of labor in social insects. We therefore conducted a molecular evolution analysis of the Dmrt gene family in 20 ants. We found that the insect-specific oligomerization domain of DSX, oligomerization domain 2, was absent in all ants, except for the two phylogenetically basal ant species (Ponerinae), whose social structure and organization resemble the presumed ancestral condition in ants. Phylogenetic reconstruction and selection analysis revealed that dsx evolved faster than the other three members of the Dmrt family. We found evidence for positive selection for dsx in the ant subfamilies with more advanced social organization (Myrmicinae and Formicinae), but not in the Ponerinae. Furthermore, we detected expression of two Dmrt genes, dsx and DMRT11E, in adult ants, and found a clear male-biased expression pattern of dsx in most species for which data are available. Interestingly, we did not detect male-biased expression of dsx in the two ant species that possess a genetic caste determination system. These results possibly suggest an association between the evolution of dsx and social organization as well as reproductive division of labor in ants.

Outcomes in Women and Minorities Compared With White Men 1 Year After Everolimus-Eluting Stent Implantation: Insights and Results From the PLATINUM Diversity and PROMUS Element Plus Post-Approval Study Pooled Analysis.

Importance: There exist limited outcomes data for women and minorities after contemporary percutaneous coronary intervention (PCI). Objective: To examine 1-year outcomes in women and minorities vs white men after PCI with everolimus-eluting stents. Design, Settings, and Participants: The PLATINUM Diversity study was a single-arm study enrolling women and minorities. Patient-level pooling with the PROMUS Element Plus Post-Approval Study was prespecified. Data on social determinants of health and language were collected in the PLATINUM Diversity cohort, which included 1501 patients at 52 US sites. The PROMUS Element Plus Post-Approval study enrolled 2681 patients at 52 US sites with some site overlap and included an "all-comers" population. All patients were enrolled beginning in October 2014 and were followed for 12 months. Analyses began in August 2016. Interventions: Patients received 1 or more everolimus-eluting stent implantation. Main Outcomes and Measures: The primary end point was 1-year major adverse cardiac events (MACE), which included death/myocardial infarction (MI)/target vessel revascularization. Secondary ischemic end points were also evaluated. Results: The pooled study consisted of 4182 patients: 1635 white men (39.1%), 1863 women (white and minority) (44.5%), and 1059 minority patients (women and men) (25.3%). Women and minorities had a higher prevalence of diabetes, prior stroke, hypertension, renal disease, and congestive heart failure than white men but lower rates of multivessel disease, prior coronary artery bypass graft surgery, prior MI, and smoking. Unadjusted 1-year MACE rates (white men, 7.6%; women, 8.6%; minorities, 9.6%) were similar between groups with no significant differences after risk adjustment. The adjusted risk of death/MI was higher among women (odds ratio, 1.6; 95% CI, 1.1-2.4) and minorities (odds ratio, 1.9; 95% CI, 1.2-2.8) compared with white men and the adjusted risk of MI was higher in minorities (odds ratio, 2.6; 95% CI, 1.4-4.8). These differences were driven primarily by nonstent-related MIs. Within the PLATINUM Diversity cohort, the independent predictors of MACE were cardiogenic shock, renal disease, history of peripheral vascular disease, multivessel disease, widowhood, and lack of private insurance. Conclusions and Relevance: After contemporary everolimus-eluting stent implantation, women and minorities experience a similar risk of 1-year MACE but a higher adjusted risk of recurrent ischemic events primarily because of nonstent-related MIs. Both clinical and angiographic factors and social determinants of health, including widowhood and insurance status, contribute to 1-year MACE among women and minorities.

State mandates regarding postpartum depression.

OBJECTIVE: Postpartum depression continues to be undertreated. This project identified state policies that have been enacted regarding peripartum mental health and assessed how effective they might be. METHODS: A systematic search strategy was used to detect state-level legislative initiatives. Legislative tracking resources were used to determine which were enacted. Policies were sorted into categories. Related evidence was reviewed to gauge the impact of each category. RESULTS: Thirteen states have enacted one or more state-level peripartum mental health policies. Categories include patient education mandates, depression screening mandates, mandated task force, and public awareness campaigns. Those mandating screening include Illinois, Massachusetts, New Jersey, and West Virginia. Related outcomes evidence suggests a very limited impact. CONCLUSIONS: Several states have enacted policies addressing peripartum mental health, but these are probably not influencing clinical outcomes. Home visits with a mental health component are effective for postpartum depression; state policies could support home visits.

Total synthesis of 6-deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 cancer cell line.

A total synthesis of the natural product 6-deoxypladienolide D (1) has been achieved. Two noteworthy attributes of the synthesis are (1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and (2) the development of a scalable and cost-effective synthetic route to support drug discovery efforts. 6-Deoxypladienolide D (1) demonstrates potent growth inhibition in a mutant SF3B1 cancer cell line, high binding affinity to the SF3b complex, and inhibition of pre-mRNA splicing.

Did the fire ant supergene evolve selfishly or socially?

The genetic basis for animal social organization is poorly understood. Fire ants provide one of the rare cases where variation in social organization has been demonstrated to be under genetic control, which amazingly, segregates as a single Mendelian locus. A recent genetic, genomic, and cytological analysis revealed that this locus actually consists of over 600 genes locked together in a supergene that possesses many characteristics of sex chromosomes. The fire ant social supergene also behaves selfishly, and an interesting evolutionary question is whether the genes incorporated first into the social supergene were those for social adaptation, selfish genetic drive, or something else. In depth, functional molecular genetic analysis in fire ants and comparative genomics in other closely related socially polymorphic species will be required to resolve this question.

A simple genetic basis for complex social behaviour mediates widespread gene expression differences.

A remarkable social polymorphism is controlled by a single Mendelian factor in the fire ant Solenopsis invicta. A genomic element marked by the gene Gp-9 determines whether workers tolerate one or many fertile queens in their colony. Gp-9 was recently shown to be part of a supergene with two nonrecombining variants, SB and Sb. SB/SB and SB/Sb queens differ in how they initiate new colonies, and in many physiological traits, for example odour and maturation rate. To understand how a single genetic element can affect all these traits, we used a microarray to compare gene expression patterns between SB/SB and SB/Sb queens of three different age classes: 1-day-old unmated queens, 11-day-old unmated queens and mated, fully reproductive queens collected from mature field colonies. The number of genes that were differentially expressed between SB/SB and SB/Sb queens of the same age class was smallest in 1-day-old queens, maximal in 11-day-old queens and intermediate in reproductive queens. Gene ontology analysis showed that SB/SB queens upregulate reproductive genes faster than SB/Sb queens. For all age classes, genes inside the supergene were overrepresented among the differentially expressed genes. Consistent with the hypothesized greater number of transposons in the Sb supergene, 13 transposon genes were upregulated in SB/Sb queens. Viral genes were also upregulated in SB/Sb mature queens, consistent with the known greater parasite load in colonies headed by SB/Sb queens compared with colonies headed by SB/SB queens. Eighteen differentially expressed genes between reproductive queens were involved in chemical signalling. Our results suggest that many genes in the supergene are involved in regulating social organization and queen phenotypes in fire ants.

A Y-like social chromosome causes alternative colony organization in fire ants.

Intraspecific variability in social organization is common, yet the underlying causes are rarely known. In the fire ant Solenopsis invicta, the existence of two divergent forms of social organization is under the control of a single Mendelian genomic element marked by two variants of an odorant-binding protein gene. Here we characterize the genomic region responsible for this important social polymorphism, and show that it is part of a pair of heteromorphic chromosomes that have many of the key properties of sex chromosomes. The two variants, hereafter referred to as the social B and social b (SB and Sb) chromosomes, are characterized by a large region of approximately 13 megabases (55% of the chromosome) in which recombination is completely suppressed between SB and Sb. Recombination seems to occur normally between the SB chromosomes but not between Sb chromosomes because Sb/Sb individuals are non-viable. Genomic comparisons revealed limited differentiation between SB and Sb, and the vast majority of the 616 genes identified in the non-recombining region are present in the two variants. The lack of recombination over more than half of the two heteromorphic social chromosomes can be explained by at least one large inversion of around 9 megabases, and this absence of recombination has led to the accumulation of deleterious mutations, including repetitive elements in the non-recombining region of Sb compared with the homologous region of SB. Importantly, most of the genes with demonstrated expression differences between individuals of the two social forms reside in the non-recombining region. These findings highlight how genomic rearrangements can maintain divergent adaptive social phenotypes involving many genes acting together by locally limiting recombination.

Genome-wide expression patterns and the genetic architecture of a fundamental social trait.

Explaining how interactions between genes and the environment influence social behavior is a fundamental research goal, yet there is limited relevant information for species exhibiting natural variation in social organization. The fire ant Solenopsis invicta is characterized by a remarkable form of social polymorphism, with the presence of one or several queens per colony and the expression of other phenotypic and behavioral differences being completely associated with allelic variation at a single Mendelian factor marked by the gene Gp-9. Microarray analyses of adult workers revealed that differences in the Gp-9 genotype are associated with the differential expression of an unexpectedly small number of genes, many of which have predicted functions, implying a role in chemical communication relevant to the regulation of colony queen number. Even more surprisingly, worker gene expression profiles are more strongly influenced by indirect effects associated with the Gp-9 genotypic composition within their colony than by the direct effect of their own Gp-9 genotype. This constitutes an unusual example of an "extended phenotype" and suggests a complex genetic architecture with a single Mendelian factor, directly and indirectly influencing the individual behaviors that, in aggregate, produce an emergent colony-level phenotype.

An evidence-based approach to the use of drug-eluting stents in clinical practice.

Less than a year after their release, drug-eluting stents are being used in more than 70% of patients who undergo percutaneous intervention for obstructive coronary disease in the United States. This unprecedented quick adoption was fueled by results of several randomized trials that demonstrated a profound reduction in restenosis rates compared with bare-metal stents. Subset analysis of the drug-eluting stent trials shows a strong restenosis reduction rate across a wide range of patient characteristics; however, these broad beneficial effects are based on randomized subjects who may not represent the actual population currently being treated with coronary stents. This review presents an analysis of the available data on the approved drug-eluting stents, including patient subsets that may or may not benefit; potential stent-specific complications; and a discussion of costs, risks, and cost-effectiveness.

Bank robberies by an Asian gang: an assessment of the routine activities theory.

It was reported for the first time that a series of bank robberies were committed by an Asian gang group in a major southern city. The bank robberies showed a variety of operational methods. The purpose of this descriptive study is to apply the routine activities theory to explain the causal factors of the robberies. The analysis shows that the six Asian bank robberies resulted from a supply of motivated offenders, the availability of suitable targets, and a low level of capable guardians against crime. Findings suggest that crime-specific measures are an appropriate method for examining the merits of the routine activities theory.