Assessing the role of dental insurance in oral health care disparities in Canadian adults.

Background: This study examines the association of dental insurance with oral health care access and utilization in Canada while accounting for income and sociodemographic factors. It contributes to a baseline of oral health care disparities before the implementation of the Canadian Dental Care Plan (CDCP). Data and methods: This retrospective study of Canadians aged 18 to 64 years is based on data from the 2022 Canadian Community Health Survey. Multivariable logistic regression was employed to evaluate the association of dental insurance with the recency and frequency of dental visits, as well as avoidance of dental care because of cost. Results: Overall, 65.7% of Canadians reported visiting a dental professional in the previous year: 74.6% of those with private insurance, 62.8% with public insurance, and 49.8% uninsured. Cost-related avoidance of dental care was 16.0%, 20.9%, and 47.4% for the privately insured, publicly insured, and uninsured, respectively. After adjustment, adults with private (odds ratio [OR]=2.54; 95% confidence interval [CI]: 2.32 to 2.78) and public (OR=2.17; 95% CI: 1.75 to 2.68) insurance were more likely to have visited a dental professional in the last year compared with those without insurance. Similarly, both private (OR=0.22; 95% CI: 0.20 to 0.25) and public (OR=0.22; 95% CI: 0.17 to 0.29) insurance holders showed a significantly lower likelihood of avoiding dental visits because of cost when compared with uninsured individuals. Interpretation: This study showed the significant association of dental insurance with access to oral health care in Canada, contributing to setting a critical benchmark for assessments of the CDCP's effectiveness in addressing oral health disparities.

Systemic quinolones and risk of retinal detachment III: a nested case-control study using a US electronic health records database.

BACKGROUND: Quinolones are popular antibiotics that are known for their potency, broad coverage, and reasonable safety. Concerns have been raised about a possible association between quinolones and retinal detachment (RD). METHODS: We conducted a nested case-control study using electronic health records (EHR) from the Health Facts® Database. The initial cohort included all patients who were admitted between 2000 and 2016, with no history of eye disease, and had a minimum medical history of one year. Eligible cases comprised inpatients who were first admitted with a primary diagnosis of RD between 2010 and 2015. Each eligible case was matched without replacement to five unique controls by sex, race, age, and period-at-risk. We used conditional logistic regression to calculate RD risk, adjusting for exposure to other medications, and major risk factors. RESULTS: We identified 772 cases and 3860 controls. Whereas our primary analysis of all subjects revealed no quinolone-associated RD risk, elevated but non-significant risks were noted in African Americans (ciprofloxacin and levofloxacin), those aged 56-70 years old (moxifloxacin), and women (ciprofloxacin). CONCLUSION: Our study did not identify an elevated RD risk within 30 days following systemic administration of quinolone antibiotics. Suggestions of increased risk observed in some population subgroups warrant further investigation.

Systemic quinolones and risk of acute liver failure III: A nested case-control study using a US electronic health records database.

BACKGROUND AND AIM: Quinolones are globally popular antibiotics with proven potency, broad coverage, and reasonable safety. However, some concerns were raised as to their possible association with acute liver failure (ALF). The aim of this study is to assess ALF risk within 30 days of receiving a systemically administered quinolone antibiotic, in individuals with no history of liver/diseases. METHODS: We conducted a nested case-control study using electronic health records from the Cerner Health Facts. The initial cohort (n = 35 349 943) included all patients who were admitted between 2000 and 2016, with no history of liver diseases, and had a minimum medical history of one year. Eligible cases were inpatients who were first diagnosed with ALF between 2010 and 2015. Using incidence density sampling, each case was matched with up to five unique controls by sex, race, age at index encounter, and period-at-risk. We used conditional logistic regression to calculate the odds ratio and 95% confidence interval for ALF risk, upon adjusting for exposure to other medications, and major confounders (diabetes mellitus and alcohol abuse). We used the STROBE Statement for reporting on our study. RESULTS: We identified 3151 cases and 15 657 controls. Our primary analysis did not reveal an association between quinolones and ALF risk. However, some risk was identified among those with no or few comorbidities, those ≤ 60 years of age, women, men, African Americans, and Caucasians. CONCLUSION: Although our study does not suggest an overall association between quinolones and ALF, elevated risks seen in some subgroups warrant further investigation.

Risk of Adverse Cardiovascular Events Following a Myocardial Infarction in Patients Receiving Combined Clopidogrel and Proton Pump Inhibitor Treatment: A Nested Case-Control Study.

BACKGROUND: The clinical implications of potential interactions between proton pump inhibitors (PPIs) and clopidogrel have been debated for over a decade. OBJECTIVE: We assessed the association between combined clopidogrel-PPI treatment and the risk of recurrent myocardial infarction (MI) and three secondary outcomes. PATIENTS AND METHODS: A nested case-control study was conducted within Cerner Corporation's Health Facts® database. A retrospective cohort of patients who experienced a first MI and started clopidogrel treatment was created. Within this cohort, patients experiencing a second MI (cases) were matched with up to five controls. Logistic regression was used to estimate adjusted odds ratios (aORs). Findings were compared with those obtained from models with three negative control exposure drugs: H2 receptor antagonists, prasugrel, and ticagrelor. RESULTS: In total, 2890 recurrent MI cases were identified within 12 months following entry into the cohort of clopidogrel users (N = 52,006). aOR for PPI use versus non-use among clopidogrel users was 1.08 [95% confidence interval (CI) 0.95-1.23]. Similar ORs were obtained for secondary endpoints. A positive association between combined use of clopidogrel/PPIs and increased risk of MI was seen in the group aged 80-89 years (aOR 1.26; 95% CI 1.05-1.51). No associations with MI were observed for (1) H2 receptor antagonist use versus non-use among clopidogrel users or (2) PPI use versus non-use among prasugrel users or among ticagrelor users. CONCLUSIONS: Overall, our findings do not support a significant adverse clinical impact of concomitant clopidogrel/PPI use by patients with MI. Nonetheless, investigation of the possible association seen in those aged 80-89 years may be warranted.

Systematic review and meta-analysis of adverse cardiovascular events associated with proton pump inhibitors used alone or in combination with antiplatelet agents.

The potential association between major adverse cardiovascular events (MACE) and concomitant treatment with proton pump inhibitors (PPIs) and clopidogrel has been debated since 2009. Recent reports, however, suggest that PPIs may increase the risk of MACE independently of clopidogrel. This review evaluates epidemiological findings relevant to the association between PPIs, taken alone or concomitantly with antiplatelets, and the risk of MACE. A systematic review and meta-analysis were conducted. Relevant studies were identified from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and then screened. Included studies were categorized into three groups: Group A: PPIs versus no PPIs; Group B: combined PPIs and clopidogrel versus clopidogrel alone; Group C: combined PPIs and other drugs versus other drugs. Pooled risk ratios (RRs) were calculated for each outcome of interest in each comparison group. Of the 1667 studies identified, 118 were included in the systematic review, of which 66 were included in the meta-analyses. Among Group A observational studies, RRs for MACE outcomes were statistically significant for some patient populations but not others. Pooled RRs from Group A RCTs were not statistically significant for any outcome. Pooled RRs for Group B observational studies were statistically significant for all-cause mortality and MI, but were diminished in magnitude when pooling was restricted to propensity score matched studies or post hoc analyses of RCTs. Group C studies did not demonstrate an association with MACE. Findings do not consistently support an association between MACE and PPIs when taken alone, or concomitantly with antiplatelets.

Association between medication-related adverse events and non-elective readmission in acute ischemic stroke.

BACKGROUND: There is limited data on the effects of medication-related adverse events occurring during inpatient stays for stroke. The objectives of our study were to characterize reasons for acute readmission after acute ischemic stroke (AIS) and determine if medication-related adverse events occuring during AIS hospitalization were associated with 30-day readmission. Secondary objectives examined whether demographic, clinical, and hospital characterisitcs were associated with post-AIS readmission. METHODS: We used the Nationwide Readmission Database to identify index AIS hospitalizations in the United States between January and November 2014. Inpatient records were screened for diagnostic and external causes of injury codes indicative of medication-related adverse events, including adverse effects of prescribed drugs, unintentional overdosing, and medication errors. Nationally representative estimates of AIS hospitalizations, medication-related adverse events, and acute non-elective readmissions were computed using survey weighting methods. Adjusted odds of readmission for medication-related adverse events and select characteristics were estimated using unconditional logistic regression. RESULTS: We identified 439,682 individuals who were hospitalized with AIS, 4.7% of whom experienced a medication-related adverse event. Overall, 10.7% of hospitalized individuals with AIS were readmitted within 30 days of discharge. Reasons for readmission were consistent with those observed among older adults. Inpatients who experienced medication-related adverse events had significantly greater odds of being readmitted within 30 days (adjusted odds ratio (AOR): 1.22; 95% CI: 1.14-1.30). Medication-related adverse events were associated with readmission for non-AIS conditions (AOR, 1.26; 95% CI: 1.17-1.35), but not with readmission for AIS (AOR, 0.91; 95% CI: 0.75-1.10). Several factors, including but not limited to being younger than 40 years (AOR, 1.12; 95% CI: 1.00-1.26), Medicare insurance coverage (AOR, 1.33; 95% CI: 1.26-1.40), length of stay greater than 1 week (AOR, 1.38; 95% CI: 1.33-1.42), having 7 or more comorbidites (AOR, 2.20; 95% CI: 2.08-2.34), and receiving care at a for-profit hospital (AOR, 1.20; 95% CI: 1.12-1.29), were identified as being associated with all-cause 30-day readmission. CONCLUSIONS: In this nationally representative sample of AIS hospitalizations, medication-related adverse events were positively associated with 30-day readmission for non-AIS causes. Future studies are necessary to determine whether medication-related adverse events and readmissions in AIS are avoidable.

Inpatient care for stiff person syndrome in the United States: a nationwide readmission study.

BACKGROUND: Stiff person syndrome (SPS) is a progressive neurological disorder characterized by axial muscle rigidity and involuntary spasms. Autoimmune and neoplastic diseases are associated with SPS. Our study objectives were to describe inpatient care for SPS in the United States and characterize 30-day readmissions. METHODS: We queried the 2014 Nationwide Readmission Database for hospitalizations where a diagnosis of SPS was recorded. For readmission analyses, we excluded encounters with missing length of stay, hospitalization deaths, and out-of-state and December discharges. National estimates of index hospitalizations and 30-day readmissions were computed using survey weighting methods. Unconditional logistic regression was used to examine associations between demographic, clinical, and hospital characteristics and readmission. RESULTS: There were 836 patients with a recorded diagnosis of SPS during a 2014 hospitalization. After exclusions, 703 patients remained, 9.4% of which were readmitted within 30 days. Frequent reasons for index hospitalization were SPS (27.8%) and diabetes with complications (5.1%). Similarly, readmissions were predominantly for diabetes complications (24.2%) and SPS. Most readmissions attributed to diabetes complications (87.5%) were to different hospitals. Female sex (OR, 3.29; CI: 1.22-8.87) and routine discharge (OR, 0.26; CI: 0.10-0.64) were associated with readmission, while routine discharge (OR, 0.18; CI: 0.04-0.89) and care at for-profit hospitals (OR, 10.87; CI: 2.03-58.25) were associated with readmission to a different hospital. CONCLUSIONS: Readmissions in SPS may result from disease complications or comorbid conditions. Readmissions to different hospitals may reflect specialty care, gaps in discharge planning, or medical emergencies. Studies are required to determine if readmissions in SPS are preventable.

The Direct Economic and Opportunity Costs of the Medical College Admissions Test (MCAT) for Canadian Medical Students.

This article was migrated. The article was marked as recommended. Background The Association of Faculties of Medicine of Canada, Future of Medical Education in Canada report shared a collective vision to improve social accountability, including a review of admissions policies to enhance student diversity. This study explored if and how the Medical College Admissions Test (MCAT) might mediate the socioeconomic diversity of Canadian medical schools by quantifying the costs and other cost-related factors of preparing for the exam. Methods A 34-question anonymous and bilingual (English and French) online questionnaire was sent to the 2015 first-year cohort of Canadian medical students. Developed collaboratively, the survey content focused on MCAT preparation and completion activities, associated costs, and students' perceptions of MCAT costs. Findings The survey response rate was 32%. First-year medical students were more likely than the Canadian population to belong to high-income families (63% vs. 36%) and less likely to be from rural locations (4.5% vs. 19%). Use of MCAT preparation materials was reported by nearly every MCAT test-taker (95.3%): of those, 76.4% used free practice tests; 59.8% paid for practice tests; 45.1% registered for preparation courses; and 3.3% hired a private tutor. In terms of writing the MCAT, the total economic costs per respondent are estimated at $6,357 ($4,755-$7,958) and total direct costs per respondent are estimated at $2,970 ($1,882- $4,058). Opportunity costs represented the majority of economic costs, at $3,387 ($2,872 - $3,901), or 53.2%. MCAT preparation costs are estimated to be $2,372 ($1,373-$3,372), or 79.9% of total direct costs and 37.3% of economic costs. Most respondents agreed, 76%, that the MCAT posed a financial hardship. Conclusion The financial demands of preparing for and completing the MCAT quantified in this study highlight an admissions requirement that is likely contributing to the current student diversity challenges in Canadian medical schools. In the spirit of social accountability, perhaps it is time to prioritize equitable alternative for assessing applicants' academic readiness for medical school.

Determinants of neurological disease: Synthesis of systematic reviews.

Systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 neurological conditions, prioritized as a component of the National Population Health Study of Neurological Conditions. These systematic reviews provided a basis for evaluating the weight of evidence of evidence for risk factors for the onset and progression of the 14 individual neurological conditions considered. A number of risk factors associated with an increased risk of onset for more than one condition, including exposure to pesticides (associated with an increased risk of AD, amyotrophic lateral sclerosis, brain tumours, and PD; smoking (AD, MS); and infection (MS, Tourette syndrome). Coffee and tea intake was associated with a decreased risk of onset of both dystonia and PD. Further understanding of the etiology of priority neurological conditions will be helpful in focusing future research initiatives and in the development of interventions to reduce the burden associated with neurological conditions in Canada and internationally.

External validation and comparison of two variants of the Elixhauser comorbidity measures for all-cause mortality.

Assessing prevalent comorbidities is a common approach in health research for identifying clinical differences between individuals. The objective of this study was to validate and compare the predictive performance of two variants of the Elixhauser comorbidity measures (ECM) for inhospital mortality at index and at 1-year in the Cerner Health Facts® (HF) U.S. DATABASE: We estimated the prevalence of select comorbidities for individuals 18 to 89 years of age who received care at Cerner contributing health facilities between 2002 and 2011 using the AHRQ (version 3.7) and the Quan Enhanced ICD-9-CM ECMs. External validation of the ECMs was assessed with measures of discrimination [c-statistics], calibration [Hosmer-Lemeshow goodness-of-fit test, Brier Score, calibration curves], added predictive ability [Net Reclassification Improvement], and overall model performance [R2]. Of 3,273,298 patients with a mean age of 43.9 years and a female composition of 53.8%, 1.0% died during their index encounter and 1.5% were deceased at 1-year. Calibration measures were equivalent between the two ECMs. Calibration performance was acceptable when predicting inhospital mortality at index, although recalibration is recommended for predicting inhospital mortality at 1 year. Discrimination was marginally better with the Quan ECM compared the AHRQ ECM when predicting inhospital mortality at index (cQuan = 0.887, 95% CI: 0.885-0.889 vs. cAHRQ = 0.880, 95% CI: 0.878-0.882; p < .0001) and at 1-year (cQuan = 0.884, 95% CI: 0.883-0.886 vs. cAHRQ = 0.880, 95% CI: 0.878-0.881, p < .0001). Both the Quan and the AHRQ ECMs demonstrated excellent discrimination for inhospital mortality of all-causes in Cerner Health Facts®, a HIPAA compliant observational research and privacy-protected data warehouse. While differences in discrimination performance between the ECMs were statistically significant, they are not likely clinically meaningful.

A systematic review of the risks factors associated with the onset and natural progression of epilepsy.

Epilepsy is a neurological condition that affects more than 50 million individuals worldwide. It presents as unpredictable, temporary and recurrent seizures often having negative physical, psychological and social consequences. To inform disease prevention and management strategies, a comprehensive systematic review of the literature on risk factors for the onset and natural progression of epilepsy was conducted. Computerized bibliographic databases for systematic reviews, meta-analyses, observational studies and genetic association studies published between 1990 and 2013 describing etiological risk factors for epilepsy was searched. The quality of systematic reviews was validated using the AMSTAR tool and articles were reviewed by two referees. A total of 16,958 articles went through stage one review of abstracts and titles. A total of 76 articles on genetic and non-genetic risk factors for the onset and progression of epilepsy met the eligibility criteria for data extraction. Dozens of risk factors were significantly associated with onset of epilepsy. Inconsistent levels of evidence for risk of onset included family history of epilepsy, history of febrile seizures, alcohol consumption, CNS and other infections, brain trauma, head injury, perinatal stroke, preterm birth and three genetic markers. Limited evidence showed that symptomatic epilepsy, focal seizures/syndromes, slow waves on EEG, higher seizure frequency, high stress or anxiety, and lack of sleep decreased the odds of seizure remission. High quality studies were rare and while a large body of work exists, relatively few systematic reviews were found.

Factors associated with the onset and progression of neurotrauma: A systematic review of systematic reviews and meta-analyses.

Neurotrauma, including traumatic brain injury (TBI) and spinal cord injury (SCI), is a preventable condition that imposes an important burden on the Canadian society. In this study, the current evidence on risk factors for the onset and progression of neurotrauma is systematically reviewed and synthesized. Searches of the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Medline and Medline in Process (via OVID), EMBASE and PsycINFO from inception to February 2013 were conducted to identify relevant systematic reviews and meta-analyses published in English or French. Two referees screened and assessed the quality of the studies using the AMSTAR tool. Thirty-two studies examined at least one risk factor for the onset of neurotrauma. Thirteen studies passed the quality assessment and the majority evaluated the impact of protective equipment in sports. Helmets effectively reduce TBI from bicycling, skiing, snowboarding, ice hockey and motorcycling. There was no evidence of a protective effect of helmets for SCI. No studies contributed evidence on risk factors for the onset of SCI. Of two studies examining risk factors for the progression of neurotrauma, only injury severity was found to be associated with poorer post-injury outcomes. Substantial evidence supports the use of helmets for the prevention of TBI in sports and motorcycling and face shields in ice hockey. Addressing bicycle helmet legislation across Canada may be an effective option for reducing TBI caused by bicycle accidents. Limited evidence on relevant risk factors for spinal cord injuries and neurotrauma progression was available.

Associations between Anticholinergic Burden and Adverse Health Outcomes in Parkinson Disease.

BACKGROUND: Elderly adults should avoid medications with anticholinergic effects since they may increase the risk of adverse events, including falls, delirium, and cognitive impairment. However, data on anticholinergic burden are limited in subpopulations, such as individuals with Parkinson disease (PD). The objective of this study was to determine whether anticholinergic burden was associated with adverse outcomes in a PD inpatient population. METHODS: Using the Cerner Health Facts® database, we retrospectively examined anticholinergic medication use, diagnoses, and hospital revisits within a cohort of 16,302 PD inpatients admitted to a Cerner hospital between 2000 and 2011. Anticholinergic burden was computed using the Anticholinergic Risk Scale (ARS). Primary outcomes were associations between ARS score and diagnosis of fracture and delirium. Secondary outcomes included associations between ARS score and 30-day hospital revisits. RESULTS: Many individuals (57.8%) were prescribed non-PD medications with moderate to very strong anticholinergic potential. Individuals with the greatest ARS score (≥ 4) were more likely to be diagnosed with fractures (adjusted odds ratio (AOR): 1.56, 95% CI: 1.29-1.88) and delirium (AOR: 1.61, 95% CI: 1.08-2.40) relative to those with no anticholinergic burden. Similarly, inpatients with the greatest ARS score were more likely to visit the emergency department (adjusted hazard ratio (AHR): 1.32, 95% CI: 1.10-1.58) and be readmitted (AHR: 1.16, 95% CI: 1.01-1.33) within 30-days of discharge. CONCLUSIONS: We found a positive association between increased anticholinergic burden and adverse outcomes among individuals with PD. Additional pharmacovigilance studies are needed to better understand risks associated with anticholinergic medication use in PD.

Investigating Canadian medical school attrition metrics to inform socially accountable admissions planning.

OBJECTIVE: Attrition from Canadian medical degree programs was never described despite differences in admissions requirements at the 17 faculties of medicine. Knowledge on attrition metrics could help the faculties evaluate new avenues for addressing the Association of Faculties of Medicine's (AFMC) Future of Medical Education in Canada (FMEC MD) recommendation to enhance admissions practices with the goal to improve social accountability and student diversity. METHOD: AFMC databases were used to track medical degree completion of all Canadian M.D. students who enrolled between 2003 and 2007. Students were followed and assigned an M.D. completion status as of by July 1, 2013. Bivariate statistics were used to evaluate if demographic, admission and degree progression variables were associated with medical school attrition. RESULTS: Of 11,454 students enrolled in Canadian M.D. programs from 2003 to 2007, only 197 (1.7%) did not complete. Québec had significantly higher attrition than other jurisdictions with age, educational attainment at time of enrolment, MCAT completion and struggling academically associated with attrition. CONCLUSION: Attrition from Canadian MD programs is rare and associated with differences in admission requirements and possibly suggests an optimum life stage for medical studies. Improved knowledge of attrition-related factors may offer an additional level of evidence for improving the alignment between admissions policies and the social accountability objectives of medical schools.

Associations Between Cardiovascular Events and Nonergot Dopamine Agonists in Parkinson's Disease.

BACKGROUND: Knowledge of possible cardiovascular risks from Parkinson's disease (PD) medications is critical to informing safe and effective treatment decisions. The objective of our study was to determine whether PD patients treated with nonergot dopamine agonists (DAs) are at increased risk of adverse cardiovascular or cerebrovascular outcomes, relative to PD patients receiving other treatments. METHODS: Matched case-control studies were conducted within a cohort of 14,122 inpatients receiving treatment for PD who were identified in the Cerner Health Facts database. Primary outcomes were associations between nonergot DA use and diagnosis of adverse cardiovascular events (acute myocardial infarction, heart failure [HF], hypotension, and valvulopathy). Secondary outcomes included associations between nonergot DA use and diagnosis of adverse cerebrovascular events (cerebrovascular accident and ischemic stroke) and odds of significant exposure-outcome relationships by patient factors. RESULTS: HF was the only adverse event that demonstrated a significant association with nonergot DA use. Individuals treated with pramipexole were more likely to be diagnosed with HF, relative to no use (adjusted odds ratio [AOR]: 1.28; 95% confidence interval [CI]: 1.07-1.53). The association between pramipexole and HF was greater among individuals treated with pramipexole monotherapy (relative to levodopa monotherapy) (AOR, 1.50; 95% CI: 1.09-2.06). Compared to nonusers, men and older individuals treated with pramipexole were more likely to be diagnosed with HF. CONCLUSIONS: Results from our study suggest an association between pramipexole use and HF. Findings warrant replication; however, individuals with PD and independent risk factors for, or a history of, HF may benefit from limited use of this drug.

Trends in inpatient antiparkinson drug use in the USA, 2001-2012.

PURPOSE: Although therapeutic options and clinical guidelines for Parkinson's disease (PD) have changed significantly in the past 15 years, prescribing trends in the USA remain unknown. The purpose of this population-based cohort study was to examine patterns of inpatient antiparkinson drug use between January 2001 and December 2012 in relation to clinical guideline publication, drug introduction/withdrawal, and emerging safety concerns. METHODS: A total of 16,785 inpatients receiving pharmacological treatment for PD were identified in the Cerner Health Facts database. Our primary outcome was standardized (age, sex, race, and census region) annual prevalence of antiparkinson drug use. We also examined antiparkinson medication trends and polypharmacy by age and sex. RESULTS: The most frequently prescribed antiparkinson drugs between 2001 and 2012 were levodopa (85%) and dopamine agonists (28%). Dopamine agonist use began declining in 2007, from 34 to 27% in 2012. The decline followed publication of the American Academy of Neurology's practice parameter refuting levodopa toxicity, pergolide withdrawal, and pramipexole label revisions. Despite safety concerns for cognitive impairment and falls, individuals ≥80 years of age demonstrated stable rates of dopamine agonist use from 2001 to 2012. Polypharmacy was most common in younger patients. CONCLUSIONS: Dopamine agonist use declined from 2007 to 2012, suggesting that increased awareness of safety issues and practice guidelines influenced prescribing. These events appear to have minimally influenced treatment provided to older PD patients. Antiparkinson prescribing trends indicate that safety and best practice information may be communicated effectively.

FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A.

Mutations in the human FOXC1 transcription factor gene underlie Axenfeld-Rieger (AR) syndrome, a disorder characterized by anterior segment malformations in the eye and glaucoma. Through the use of an inducible FOXC1 protein, along with an intermediate protein synthesis blocker, we have determined direct targets of FOXC1 transcriptional regulation. FOXC1 regulates the expression of FOXO1A and binds to a conserved element in the FOXO1A promoter in vivo. The zebrafish foxO1a orthologs exhibit a robust expression pattern in the periocular mesenchyme. Furthermore, FOXO1A expression is reduced in cultured human trabecular meshwork (TM) cells and in the zebrafish developing eye when FOXC1 expression is knocked down by siRNAs and morpholino antisense oliognucleotides, respectively. We also demonstrate that reduced FOXC1 expression increases cell death in cultured TM cells in response to oxidative stress, and increases cell death in the developing zebrafish eye. These studies have uncovered a novel role for FOXC1 as an essential mediator of cellular homeostasis in the eye and indicate that a decreased resistance to oxidative stress may underlie AR-glaucoma pathogenesis. Given that FOXO1A influences cellular homeostasis when positively or negatively regulated; the dysregulation of FOXO1A activities in the eye through FOXC1 loss of function mutations and FOXC1 gene duplications provides an explanation into how seemingly similar human disorders can arise from both increases and decreases in FOXC1 gene dose.

ERK-FosB signaling in dorsal MPOA neurons plays a major role in the initiation of parental behavior in mice.

During mouse parental behavior, neurons in the dorsal medial preoptic area (MPOAd) are activated and express transcription factors such as c-Fos and FosB. FosB-knockout mice are reported to be defective in parental care. To clarify molecular signaling responsible for parental behavior, we investigated gene expression profiles in the MPOAd of parental versus nonparental mice. We identified upregulation of NGFI-B, SPRY1, and Rad in parental mice, together with c-Fos and FosB. A common inducer of these genes, the extracellular signal regulated kinase (ERK) was phosphorylated in MPOAd neurons upon pup exposure. Pharmacological blockade of ERK phosphorylation inhibited the FosB upregulation in MPOAd, and the initiation of pup retrieving in virgin female mice, but did not affect the established parenting in parous females. Furthermore, induction of SPRY1 and Rad was impaired in MPOAd of nonparental FosB-knockout mice. These results suggest the pivotal role of ERK-FosB signaling in the initiation of parental care.

Mapping cis-acting regulatory variation in recombinant congenic strains.

We present an integrated approach for the enriched detection of genes subject to cis-acting variation in the mouse genome. Gene expression profiling was performed with lung tissue from a panel of recombinant congenic strains (RCS) derived from A/J and C57BL/6J inbred mouse strains. A multiple-regression model measuring the association between gene expression level, donor strain of origin (DSO), and predominant strain background identified over 1,500 genes (P < 0.05) whose expression profiles differed according to the DSO. This model also identified over 1,200 genes whose expression showed dependence on background (P < 0.05), indicating the influence of background genetic context on transcription levels. Sequences obtained from 1-kb segments of 3'-untranslated regions identified single nucleotide polymorphisms in 64% of genes whose expression levels correlated with DSO status, compared with 29% of genes that displayed no association (P < 0.01, Fisher exact test). Allelic imbalance was identified in 50% of genes positive for expression-DSO association, compared with 22% of negative genes (P < 0.05, Fisher exact test). Together, these results demonstrate the utility of RCS mice for identifying the roles of proximal genetic determinants and background genetic context in determining gene expression levels. We propose the use of this integrated experimental approach in multiple tissues from this and other RCS panels as a means for genome-wide cataloging of genetic regulatory mechanisms in laboratory strains of mice.