Impact of the coronavirus disease 2019 pandemic on equity of access to hip and knee replacements: a population-level study.

PURPOSE: The COVID-19 pandemic had innumerable impacts on healthcare delivery. In Canada, this included limitations on inpatient capacity, which resulted in an increased focus on outpatient surgery for non-emergent cases such as joint replacements. The objective of this study was to assess whether the pandemic and the shift towards outpatient surgery had an impact on access to joint replacement for marginalized patients. METHODS: Data from Ontario's administrative healthcare databases were obtained for all patients undergoing an elective hip or knee replacement between January 1, 2018 and August 31, 2021. All surgeries performed before March 15, 2020 were classified as "pre-COVID," while all procedures performed after that date were classified as "post-COVID." The Ontario Marginalization Index domains were used to analyze proportion of marginalized patients undergoing surgery pre- and post-COVID. RESULTS: A total of 102,743 patients were included-42,812 hip replacements and 59,931 knee replacements. There was a significant shift towards outpatient surgery during the post-COVID period (1.1% of all cases pre-COVID to 13.2% post-COVID, p < 0.001). In the post-COVID cohort, there were significantly fewer patients from some marginalized groups, as well as fewer patients with certain co-morbidities, such as congestive heart failure and chronic obstructive pulmonary disease. CONCLUSION: The most important finding of this population-level database study is that, compared to before the COVID-19 pandemic, there has been a change in the profile of patients undergoing hip and knee replacements in Ontario, specifically across a range of indicators. Fewer marginalized patients are undergoing joint replacement surgery since the COVID-19 pandemic. Further monitoring of access to joint replacement surgery is required in order to ensure that surgery is provided to those who are most in need.

Quantifying COPD as a risk factor for cardiac disease in a primary prevention cohort.

BACKGROUND: Despite COPD being a risk factor for cardiovascular disease (CVD) and knowing that risk stratification for CVD primary prevention is important, little is known about the real-world risk of CVD among people with COPD with no history of CVD. This knowledge would inform CVD management for people with COPD. The current study aimed to examine the risk of major adverse cardiovascular events (MACE) (including acute myocardial infarction, stroke or cardiovascular death) in a large, complete real-world population with COPD without previous CVD. METHODS: We conducted a retrospective population cohort study using health administrative, medication, laboratory, electronic medical record and other data from Ontario, Canada. People without a history of CVD with and without physician-diagnosed COPD were followed between 2008 and 2016, and cardiac risk factors and comorbidities compared. Sequential cause-specific hazard models adjusting for these factors determined the risk of MACE in people with COPD. RESULTS: Among ∼5.8 million individuals in Ontario aged ≥40 years without CVD, 152 125 had COPD. After adjustment for cardiovascular risk factors, comorbidities and other variables, the rate of MACE was 25% higher in persons with COPD compared with those without COPD (hazard ratio 1.25, 95% CI 1.23-1.27). CONCLUSIONS: In a large real-world population without CVD, people with physician-diagnosed COPD were 25% more likely to have a major CVD event, after adjustment for CVD risk and other factors. This rate is comparable to the rate in people with diabetes and calls for more aggressive CVD primary prevention in the COPD population.

Opioid toxicity deaths in Black persons who experienced provincial incarceration in Ontario, Canada 2015-2020: A population-based study.

OBJECTIVE: In the context of mass incarceration and the opioid toxicity crisis in North America, there is a lack of data on the burden of opioid toxicity deaths in Black persons who experience incarceration. We aimed to describe absolute and relative opioid toxicity mortality for Black persons who experienced incarceration in Ontario, Canada between 2015 and 2020. METHODS: We linked data for all persons incarcerated in provincial correctional facilities and all persons who died from opioid toxicity in Ontario between 2015 and 2020, and accessed public data on population sizes. We described the characteristics of Black persons who were incarcerated and died from opioid toxicity, and calculated absolute mortality rates, as well as age-standardized mortality rates compared with all persons in Ontario not incarcerated during this period. RESULTS: Between 2015 and 2020, 0.9% (n = 137) of 16,177 Black persons who experienced incarceration died from opioid toxicity in custody or post-release, for an opioid toxicity death rate of 0.207 per 100 person years. In the two weeks post-release, the opioid toxicity death rate was 1.34 per 100 person years. Standardized for age and compared with persons not incarcerated, the mortality ratio (SMR) was 17.8 (95%CI 16.4-23.1) for Black persons who experienced incarceration. CONCLUSIONS: We identified a large, inequitable burden of opioid toxicity death for Black persons who experience incarceration in Ontario, Canada. Work is needed to support access to culturally appropriate prevention and treatment in custody and post-release for persons who are Black, and to prevent incarceration and improve determinants of health.

"Bring the Hoses to Where the Fire Is!": Differential Impacts of Marginalization and Socioeconomic Status on COVID-19 Case Counts and Healthcare Costs.

OBJECTIVES: Local health leaders and the Director General of the World Health Organization alike have observed that COVID-19 "does not discriminate." Nevertheless, the disproportionate representation of people of low socioeconomic status among those infected resembles discrimination. This population-based retrospective cohort study examined COVID-19 case counts and publicly funded healthcare costs in Ontario, Canada, with a focus on marginalization. METHODS: Individuals with their first positive severe acute respiratory syndrome coronavirus 2 test from January 1, 2020 to June 30, 2020, were linked to administrative databases and matched to negative/untested controls. Mean net (COVID-19-attributable) costs were estimated for 30 days before and after diagnosis, and differences among strata of age, sex, comorbidity, and measures of marginalization were assessed using analysis of variance tests. RESULTS: We included 28 893 COVID-19 cases (mean age 54 years, 56% female). Most cases remained in the community (20 545, 71.1%) or in long-term care facilities (4478, 15.5%), whereas 944 (3.3%) and 2926 (10.1%) were hospitalized, with and without intensive care unit, respectively. Case counts were skewed across marginalization strata with 2 to 7 times more cases in neighborhoods with low income, high material deprivation, and highest ethnic concentration. Mean net costs after diagnosis were higher for males ($4752 vs $2520 for females) and for cases with higher comorbidity ($1394-$7751) (both P < .001) but were similar across levels of most marginalization dimensions (range $3232-$3737, all P ≥ .19). CONCLUSIONS: This study suggests that allocating resources unequally to marginalized individuals may improve equality in outcomes. It highlights the importance of reducing risk of COVID-19 infection among marginalized individuals to reduce overall costs and increase system capacity.

Early invasive coronary angiography and acute ischaemic heart failure outcomes.

AIMS: While myocardial ischaemia plays a major role in the pathogenesis of heart failure (HF), the indications for coronary angiography during acute HF are not established. We determined the association of early coronary angiography during acute HF hospitalization with 2-year mortality, cardiovascular death, HF readmissions, and coronary revascularization. METHODS AND RESULTS: In a two-stage sampling process, we identified acute HF patients who presented to 70 emergency departments in Ontario (April 2010 to March 2013) and determined whether they underwent early coronary angiography within 14 days after presentation using administrative databases. After clinical record review, we defined a cohort with acute ischaemic HF as patients with at least one factor suggesting underlying ischaemic heart disease, including previous myocardial infarction, troponin elevation, or angina on presentation. We oversampled patients undergoing angiography. We used inverse-probability-of-treatment weighting (IPTW) to adjust for baseline differences. Of 7239 patients with acute HF, 2994 met inclusion criteria [median age 75 (interquartile range 65-83) years; 40.9% women]. Early angiography was performed in 1567 patients (52.3%) and was associated with lower all-cause mortality [hazard ratio (HR) 0.74, 95% confidence interval (CI) 0.61-0.90, P = 0.002], cardiovascular death (HR 0.72, 95% CI 0.56-0.93, P = 0.012), and HF readmissions (HR 0.84, 95% CI 0.71-0.99, P = 0.042) after IPTW. Those undergoing early angiography experienced higher rates of percutaneous coronary intervention (HR 2.58, 95% CI 1.73-3.86, P < 0.001) and coronary artery bypass grafting (HR 2.94, 95% CI 1.75-4.93, P < 0.001) within 2 years. CONCLUSIONS: Early coronary angiography was associated with lower all-cause mortality, cardiovascular death, HF readmissions, and higher rates of coronary revascularization in acute HF patients with possible ischaemia.

Real-world, population-based cohort study of toxicity and resource utilization of second-line ipilimumab for metastatic melanoma in Ontario, Canada.

Second-line ipilimumab has been publicly funded in Ontario for metastatic melanoma (MM) since September 2012. We examined real-world toxicity of second-line ipilimumab compared to standard second-line treatments prior to funding. MM patients who received systemic treatment from April 2005 to March 2015 were included. Patients receiving second-line ipilimumab after September 2012 were considered as cases, and those who received second-line treatment prior to the funding date were included as historical controls. Outcomes assessed include treatment-related mortality, any-cause hospital visits, ipilimumab-related hospital visits and specialist visits (eg, endocrinologists, ophthalmologists, gastroenterologists, rheumatologists and respirologists), which were captured from up to 30 and/or 90 days after end of second-line treatment. Inverse probability of treatment weighting was used to adjust for baseline differences between groups. Odds ratios (ORs) from logistic regressions and rate ratios (RRs) from rate regressions were used to assess differences between groups. We identified 329 MM patients who received second-line treatments (ipilimumab: 189; controls: 140). Ipilimumab was associated greater any-cause (60.1% vs 45.7%; OR = 1.81; P value = .019) and ipilimumab-related (47.2% vs 31.9%; OR = 1.91; P value = .011) hospital visits. Adjusting for different follow-up days, ipilimumab was associated with higher rates of all-cause (RR = 1.56 [95%CI: 1.12-2.16]), and ipilimumab-related (RR = 2.18 [95% CI: 1.45-3.27]) hospital visits. Patients receiving ipilimumab were more likely to visit specialist involved in immunotherapy toxicity management (23.5% vs 13.7%; P value = .04). Compared to historical second-line treatments, second-line ipilimumab was associated with more health service utilization (specifically hospital visits and specialist visits), suggestive of potentially increased toxicity in the real world.

Shorter Diagnosis-to-Treatment Interval in Diffuse Large B-Cell Lymphoma is Associated With Inferior Overall Survival in a Large, Population-Based Registry.

BACKGROUND: Because of prolonged screening requirements, patient and time-dependent selection have been proposed as potential biases in clinical trials. The screening process may exclude patients with a need for emergent treatment (and a short period from diagnosis to treatment initiation [DTI]). We explored the impact of DTI on overall survival (OS) in a population-based cohort of patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Using population-based administrative databases in Ontario, Canada, we identified adults aged ≥18 years with DLBCL treated with rituximab-based chemotherapy for curative intent between January 2005 and December 2015. Cox regression and multivariable analyses were presented to evaluate the impact of time from DTI on OS, controlling for relevant covariates. RESULTS: We identified 9,441 patients with DLBCL in Ontario; median age was 66 years, 53.6% were male, median number of comorbidities (Johns Hopkins aggregated diagnosis groups) was 10 (interquartile range [IQR], 8-13), and median DTI was 37 days (IQR, 22-61). Between treatment initiation and study end, 43% of patients died (median OS, 1 year; IQR, 0.4-2.8 years). Shorter DTI was a significant predictor of mortality (P<.001). Compared with the shortest DTI period of 0-18 days, those who commenced therapy at 19-29 days (hazard ratio [HR], 0.75; 95% CI, 0.68-0.84), 30-41 days (HR, 0.70; 95% CI, 0.63-0.78), 42-57 days (HR, 0.52; 95% CI, 0.46-0.58), and 58-180 days (HR, 0.52; 95% CI, 0.47-0.58) had improved survival. Increasing age (HR, 1.03; 95% CI, 1.03-1.04), male sex (HR, 1.23; 95% CI, 1.14-1.32), and increasing number of comorbidities (HR, 1.12; 95% CI, 1.11-1.13) were associated with inferior survival. CONCLUSIONS: Among patients with DLBCL, shorter DTI was associated with inferior OS. Therefore, DTI may represent a surrogate marker for aggressive biology. Clinical trials with lengthy screening periods are likely creating a time-dependent patient selection bias.

Statin and cyclooxygenase-2 inhibitors improve survival in newly diagnosed diffuse large B-cell lymphoma: a large population-based study of 4913 subjects.

Preclinical data suggests anti-lymphoma potential for statins, metformin and cyclooxygenase-2 (COX-2) inhibitors. We performed a retrospective population-based study of all adults aged ≥66 years diagnosed with diffuse large B-cell lymphoma (DLBCL) or transformed lymphoma treated with a rituximab containing regimen, between 2005 and 2015 in Ontario, Canada. Using administrative databases, we assessed the impact of medication exposures, prior to chemo-immunotherapy, on lymphoma survival. Cox regression analyses, controlling for sociodemographic factors and comorbidities, examined the relationship between medication exposure and survival. In total, 4913 patients were treated with curative intent (median age 75 years, 51% male) and 52·2% died at a median of 1 year from treatment initiation (67% due to DLBCL). In the year prior to commencing treatment, 45·7% received statins, 16·3% metformin, and 25·0% a COX-2 inhibitor. Adjusting for confounders, exposure to statin and COX-2 inhibitors prior to chemo-immunotherapy independently conferred a survival advantage: statin exposure for 30 days (hazard ratio [HR] 0·97, 95% confidence interval [CI] 0·96-0·98), 180 days (HR 0·84, 95% CI 0·80-0·89) and 365 days (HR 0·71, 95% CI 0·63-0·79) and COX-2 inhibitor exposure for 30 days (HR 0·95, 95% CI 0·95-0·98), 180 days (HR 0·76, 95% CI 0·66-0·86) and 365 days (HR 0·57, 95% CI 0·43-0·74). Metformin had no significant impact. This population-based study found a dose-related survival benefit of exposure to statins and COX-2 inhibitors prior to chemo-immunotherapy for newly diagnosed DLBCL.

Real-world comparative effectiveness of second-line ipilimumab for metastatic melanoma: a population-based cohort study in Ontario, Canada.

BACKGROUND: For novel cancer treatments, effectiveness in clinical practice is not always aligned with clinical efficacy results. As such it is important to understand a treatment's real-world effectiveness. We examined real-world population-based comparative effectiveness of second-line ipilimumab versus non-ipilimumab treatments (chemotherapy or targeted treatments). METHODS: We used a cohort of melanoma patients receiving systemic treatment for advanced disease since April 2005 from Ontario, Canada. Patients were identified from provincial drug databases and the Ontario Cancer Registry who received second-line ipilimumab from 2012 to 2015 (treated) or second-line non-ipilimumab treatment prior to 2012 (historical controls). Historical controls were chosen, to permit the most direct comparison to pivotal trial findings. The cohort was linked to administrative databases to identify baseline characteristics and outcomes. Kaplan-Meier curves and multivariable Cox regression models were used to assess overall survival (OS). Observed potential confounders were adjusted for using inverse probability of treatment weighting (IPTW). RESULTS: We identified 329 patients with metastatic melanoma (MM) who had received second-line treatments (189 treated; 140 controls). Patients receiving second-line ipilimumab were older (61.7 years vs 55.2 years) compared to historical controls. Median OS were 6.9 (95% CI: 5.4-8.3) and 4.95 (4.3-6.0) months for ipilimumab and controls, respectively. The crude 1-year, 2-year, and 3-year OS probabilities were 34.3% (27-41%), 20.6% (15-27%), and 15.2% (9.6-21%) for ipilimumab and 17.1% (11-23%), 7.1% (2.9-11%), and 4.7% (1.2-8.2%) for controls. Ipilimumab was associated with improved OS (IPTW HR = 0.62; 95% CI: 0.49-0.78; p < 0.0001). CONCLUSIONS: This real-world analysis suggests second-line ipilimumab is associated with an improvement in OS for MM patients in routine practice.

Maternal and Cord Blood Folate Concentrations Are Inversely Associated with Fetal DNA Hydroxymethylation, but Not DNA Methylation, in a Cohort of Pregnant Canadian Women.

BACKGROUND: Aberrancies in fetal DNA methylation programming may modify disease susceptibility of the offspring. Maternal folate status has potential to alter fetal DNA methylation. OBJECTIVES: We examined the association of maternal and cord blood concentrations of folate and unmetabolized folic acid (UMFA), vitamin B-12, vitamin B-6, and choline with fetal DNA methylation and hydroxymethylation and assessed potential modifying effects of 38 fetal genetic variants in 22 genes. METHODS: Nutrient blood concentrations were measured in 368 pregnant women in early pregnancy (12-16 wk of gestation) and at delivery (37-42 wk of gestation) and in cord blood. DNA methylation and hydroxymethylation in cord blood mononuclear cells were quantified by LC-MS/MS. Pearson partial correlations were used to determine the association between individual nutrients and DNA methylation and hydroxymethylation. RESULTS: Serum and RBC folate and plasma UMFA concentrations (primary outcomes) in early pregnancy, at delivery, and in cord blood were not significantly associated with fetal DNA methylation. In contrast, maternal RBC folate in early pregnancy (r = -0.16, P = 0.04) and cord plasma UMFA (r = -0.23, P = 0.004) were inversely correlated with fetal DNA hydroxymethylation. Neither maternal and cord blood concentrations of other nutrients nor fetal genotypes (secondary outcomes) were significantly associated with fetal DNA methylation or hydroxymethylation. Infants born to mothers with RBC folate concentrations in the highest quartile and serum vitamin B-12 concentrations in the lowest quartile in early pregnancy had significantly lower fetal DNA methylation and higher birth weight compared with those born to mothers with lower RBC folate and higher serum vitamin B-12 concentrations (P = 0.01). CONCLUSIONS: Maternal and cord blood folate concentrations are associated with fetal DNA hydroxymethylation, but not DNA methylation, in a cohort of pregnant Canadian women. The observation that high folate and low vitamin B-12 maternal status in early pregnancy may be associated with decreased fetal DNA methylation and higher birth weight warrants further investigation. This trial was registered at clinicaltrials.gov as NCT02244684.

The impact of hip and knee osteoarthritis on the subsequent risk of incident diabetes: a population-based cohort study.

AIMS/HYPOTHESIS: This study examined the relationship between hip/knee osteoarthritis and incident diabetes. We hypothesised that hip/knee osteoarthritis would be independently related to an increased risk of incident diabetes and that this relationship would be due, at least in part, to walking difficulty. We also hypothesised a stronger relationship with incident diabetes for knee than hip osteoarthritis because of the higher prevalence in the former of obesity/the metabolic syndrome. METHODS: A population cohort aged ≥55 years recruited from 1996 to 1998 was followed through provincial health administrative data to 2014. Participants with baseline diabetes were excluded. Hip/knee osteoarthritis was defined as swelling, pain or stiffness in any joint lasting 6 weeks in the past 3 months and indication on a joint homunculus that a hip/knee was 'troublesome'. Walking limitation was defined as self-reported difficulty standing or walking in the last 3 months (yes/no). Using Cox regressions, we examined the relationship of baseline hip/knee osteoarthritis with incident diabetes as defined from health administrative data, controlling for age, sex, BMI, income, prior hypertension, cardiovascular disease and primary care exposure. We tested whether the observed effect was mediated through walking limitation. RESULTS: In total, 16,362 participants were included: median age 68 years and 61% female. Of these, 1637 (10%) individuals met the criteria for hip osteoarthritis, 2431 (15%) for knee osteoarthritis and 3908 (24%) for walking limitation. Over a median follow-up of 13.5 years (interquartile range 7.3-17.8), 3539 individuals (22%) developed diabetes. Controlling for confounders, a significant relationship was observed between number of hip/knee joints with osteoarthritis and incident diabetes: HR for two vs no osteoarthritic hips 1.25 (95% CI 1.08, 1.44); HR for two vs no osteoarthritic knees 1.16 (95% CI 1.04, 1.29). From 37% to 46% of this relationship was explained by baseline walking limitation. CONCLUSIONS/INTERPRETATION: In a large population cohort aged ≥55 years who were free of diabetes at baseline, and controlling for confounders, the presence and burden of hip/knee osteoarthritis was a significant independent predictor of incident diabetes. This association was partially explained by walking limitation. Increased attention to osteoarthritis and osteoarthritis-related functional limitations has the potential to reduce diabetes risk.

Suboptimal maternal and cord plasma pyridoxal 5' phosphate concentrations are uncommon in a cohort of Canadian pregnant women and newborn infants.

Vitamin B6 is important in fetal development, but little is known of the vitamin B6 status of pregnant women and newborns in North America and potential modifying factors. This prospective study determined maternal and cord plasma concentrations of pyridoxal 5' phosphate (PLP; an indicator of vitamin B6 status) in a convenience sample of 368 Canadian pregnant women and their newborns. The association of maternal intake of vitamin B6 and fetal genetic variants with cord plasma PLP and homocysteine concentrations was also examined. Dietary and supplemental intakes of vitamin B6 were assessed in early and mid to late pregnancy. PLP concentrations were measured in maternal plasma in early pregnancy and at delivery, and in cord plasma. Six fetal variants of the MTHFR and CßS genes were assessed for their association with cord plasma PLP and homocysteine concentrations. Geometric mean (95% CI) PLP concentrations were 107 (98, 116) nmol/L in early pregnancy and 58 (53, 62) nmol/L at delivery, respectively, and 296 (275, 319) nmol/L in cord blood (p < .0001). During early pregnancy and at delivery, 3.6% and 5.5% of women had plasma PLP concentrations <20 nmol/L, respectively. Ninety eight percent of the women with supplemental B6 intake of at least the recommended dietary allowance had PLP concentrations >20 nmol/L. Fetal genetic variants were not associated with cord PLP and homocysteine concentrations. Vitamin B6 deficiency is uncommon in a cohort of Canadian pregnant women due largely to prevalent vitamin B6 supplement use.

Outcomes of patients with chronic obstructive pulmonary disease diagnosed with or without pulmonary function testing.

BACKGROUND: A small number of people with chronic obstructive pulmonary disease (COPD) receive pulmonary function testing around the time of diagnosis. Because omitting testing increases misdiagnosis, we sought to determine whether health outcomes differed between patients whose COPD was diagnosed with or without pulmonary function testing. METHODS: We conducted a longitudinal population study of patients with physician-diagnosed COPD from 2005 to 2012 using health administrative data from Ontario, Canada. We assessed whether having pulmonary function testing around the time of diagnosis was associated with the composite outcome of admission to hospital for COPD or all-cause death, using adjusted survival analysis. RESULTS: Chronic obstructive pulmonary disease was diagnosed in 68 898 patients during the study period; 41.2% of patients received peridiagnostic pulmonary function testing. In adjusted analysis, patients who underwent testing were less likely to die or be admitted to hospital for COPD (adjusted hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.89-0.94) and were more likely to be prescribed an inhaled long-acting bronchodilator than patients who did not undergo testing. Subgroup analysis suggested that the association of testing and outcomes was confined to patients with COPD diagnosed in the ambulatory care setting (adjusted HR 0.80, 95% CI 0.76-0.84). INTERPRETATION: Confirmation of a COPD diagnosis using pulmonary function testing is associated with a decreased risk of death and admission to hospital for COPD. In ambulatory patients, this effect may be from increased use of appropriate COPD medications. The findings of this study validate current guideline recommendations that encourage pulmonary function testing for diagnosis in all patients with suspected COPD.

Low Serum Vitamin B-12 Concentrations Are Prevalent in a Cohort of Pregnant Canadian Women.

BACKGROUND: Among Canadian women of reproductive age, 5% and 20% have serum vitamin B-12 concentrations indicative of deficiency (<148 pmol/L) and marginal status (148-220 pmol/L), respectively. Given the association between suboptimal vitamin B-12 and adverse pregnancy outcomes, an understanding of vitamin B-12 status during pregnancy, and factors that influence it, is required. OBJECTIVE: This prospective analysis from the PREFORM (PREnatal FOlic acid exposuRe on DNA Methylation in the newborn infant) study investigated 1) vitamin B-12 status in a cohort of Canadian pregnant women and their newborns, 2) the association of maternal dietary vitamin B-12 intake with maternal and cord blood concentrations of vitamin B-12 and its biomarkers, and 3) the association of fetal genetic polymorphisms with cord blood concentrations of vitamin B-12 and its biomarkers. METHODS: In pregnant Canadian women (n = 368; mean ± SD age: 32 ± 5 y), vitamin B-12 intakes were assessed in early (0-16 wk) and mid- to late (23-37 wk) pregnancy. Serum vitamin B-12 and plasma total homocysteine (tHcy) and methylmalonic acid (MMA) in maternal blood at 12-16 wk of pregnancy and at delivery (28-42 wk) and in cord blood were measured and compared by using regression analyses. The associations of 28 fetal genetic variants in vitamin B-12 metabolism and cord blood vitamin B-12, tHcy, and MMA concentrations were assessed by using regression analysis, with adjustment for multiple testing. RESULTS: A total of 17% and 38% of women had deficient and 35% and 43% had marginal serum vitamin B-12 concentrations at 12-16 wk of pregnancy and at delivery, respectively. Only 1.9-5.3% had elevated MMA (>271 nmol/L), and no women had elevated tHcy (>13 µmol/L). Maternal dietary vitamin B-12 intake during pregnancy was either weakly associated or not associated with maternal and cord blood vitamin B-12 (r(2) = 0.17-0.24, P < 0.0008), tHcy (P = NS) and MMA (r(2) = 0.05-0.11, P < 0.001). Fetal genetic polymorphisms were not associated with cord blood concentrations of vitamin B-12 and its biomarkers. CONCLUSIONS: Deficient and marginal serum vitamin B-12 concentrations are prevalent in Canadian pregnant women with the use of traditional cutoffs, despite supplement use. Given the growing interest among women to adhere to a vegetarian diet that may be lower in vitamin B-12, and vitamin B-12's importance in pregnancy, the functional ramifications of these observations need to be elucidated. This trial was registered at clinicaltrials.gov as NCT02244684.

Folic Acid Supplementation Adversely Affects Chemosensitivity of Colon Cancer Cells to 5-fluorouracil.

Folic acid (FA) fortification and widespread supplemental use have significantly increased folate status in North America. Furthermore, >50% of colorectal cancer patients use FA supplement. The increased folate status may interfere with cancer chemotherapy. We investigated the effect of FA supplementation on chemosensitivity of human colon cancer cells to 5-fluorouracil (5-FU) using a xenograft model. Mice harboring human HCT116 colon cancer xenografts were randomized to receive the control, or 4× or 12.5× supplemental levels of FA. Within each diet group, mice were randomized to receive 5-FU+leucovorin or saline and xenograft growth and characteristics were determined. The expression of genes involved in folate metabolism and cancer treatment was determined. FA supplementation and 5-FU significantly interacted to influence xenograft growth (P < 0.007). At the control level, 5-FU significantly inhibited the growth of the xenografts (P < 0.0001). However, at the 4× supplemental level, 5-FU-treated xenografts grew faster than untreated xenografts (P = 0.048) while at the 12.5× supplemental level, 5-FU exhibited no effect. Cell proliferation, degree of necrosis, and expression of the selected genes did not significantly differ by the supplemental levels of FA. Our data suggest that FA supplementation may be detrimental to 5-FU chemotherapy of colon cancer and pose public health concern.

Pregnant Canadian Women Achieve Recommended Intakes of One-Carbon Nutrients through Prenatal Supplementation but the Supplement Composition, Including Choline, Requires Reconsideration.

BACKGROUND: Folate, vitamin B-6, vitamin B-12, and choline are involved in one-carbon metabolism and play critical roles in pregnancy including prevention of birth defects and promotion of neurodevelopment. However, excessive intakes may adversely affect disease susceptibility in offspring. Intakes of these nutrients during pregnancy are not well characterized. OBJECTIVE: Our aim was to determine dietary and supplemental intakes and major dietary sources of one-carbon nutrients during pregnancy. METHODS: In pregnant women (n = 368) at ≤16 wk postconception, supplement use >30 d before pregnancy was assessed by maternal recall and supplement and dietary intakes in early (0-16 wk) and late pregnancy (23-37 wk) were assessed by food-frequency questionnaire. RESULTS: Preconception, 60.1% (95% CI: 55.8, 64.3) of women used B vitamin-containing supplements. This increased to 92.8% (95% CI: 89.6, 95.2) in early and 89.0% (95% CI: 85.0, 92.3) in late pregnancy. Median supplemental folic acid, vitamin B-12, and vitamin B-6 were 1000 µg/d, 2.6 µg/d, and 1.9 mg/d, respectively. Forty-one percent and 50% of women had dietary intakes of folate and vitamin B-6 less than the estimated average requirement (520 mg/d dietary folate equivalents and 1.6 mg/d, respectively). Eight-seven percent of women had choline intakes less than the Adequate Intake (450 mg/d). Dietary intakes did not change appreciably during pregnancy. Fruits and vegetables and fortified foods contributed ∼57% to total dietary folate intake. Fruits and vegetables contributed ∼32% to total dietary vitamin B-6 intake and dairy and egg products contributed ∼37% to total dietary vitamin B-12 intake. CONCLUSIONS: Vitamin supplements were an important source of one-carbon nutrients during pregnancy in our sample. Without supplements, many women would not have consumed quantities of folate and vitamin B-6 consistent with recommendations. Given the importance of choline in pregnancy, further research to consider inclusion in prenatal supplements is warranted. This trial was registered at clinicaltrials.gov as NCT02244684.

Maternal Choline Status, but Not Fetal Genotype, Influences Cord Plasma Choline Metabolite Concentrations.

BACKGROUND: Choline deficiency during pregnancy can lead to adverse birth outcomes, including impaired neurodevelopment and birth defects. Genetic variants of choline and one-carbon metabolism may also influence birth outcomes by altering plasma choline concentrations. The effects of maternal ad libitum choline intake during pregnancy and fetal genetic variants on maternal and cord concentrations of choline and its metabolites are unknown. OBJECTIVES: This prospective study sought to assess the effect of 1) maternal dietary choline intake on maternal and cord plasma concentrations of choline and its metabolites, and 2) fetal genetic polymorphisms on cord plasma concentrations. METHODS: The dietary choline intake of 368 pregnant Canadian women was assessed in early (0-16 wk) and late (23-37 wk) pregnancy with the use of a food frequency questionnaire. Plasma concentrations of free choline and its metabolites were measured in maternal samples at recruitment and delivery, and in the cord blood. Ten fetal genetic variants in choline and one-carbon metabolism were assessed for their association with cord plasma concentrations of free choline and its metabolites. RESULTS: Mean maternal plasma free choline, dimethylglycine, and trimethylamine N-oxide (TMAO) concentrations increased during pregnancy by 49%, 17%, and 13%, respectively (P < 0.005), whereas betaine concentrations decreased by 21% (P < 0.005). Cord plasma concentrations of free choline, betaine, dimethylglycine, and TMAO were 3.2, 2.0, 1.3, and 0.88 times corresponding maternal concentrations at delivery, respectively (all P < 0.005). Maternal plasma concentrations of betaine, dimethylglycine, and TMAO (r(2) = 0.19-0.51; P < 0.0001) at delivery were moderately strong, whereas maternal concentrations of free choline were not significant (r(2) = 0.12; P = 0.06), predictors of cord plasma concentrations of these metabolites. Neither maternal dietary intake nor fetal genetic variants predicted maternal or cord plasma concentrations of choline and its metabolites. CONCLUSION: These data collectively indicate that maternal choline status, but not fetal genotype, influences cord plasma concentrations of choline metabolites. This trial was registered at clinicaltrials.gov as NCT02244684.

Socioeconomic Status, Sex, Age and Access to Medications for COPD in Ontario, Canada.

Disparities in COPD health outcomes have been found with older individuals, men and those of lower socioeconomic status doing worse. We sought to determine if this was due to differences in access to COPD medications. We conducted a retrospective cohort study using population health administrative data from Ontario, Canada, a province with universal prescription drug coverage for older adults. All individuals with COPD aged 67 years and older in 2008 who were not taking inhaled long-acting bronchodilators or inhaled corticosteroids were followed for 2 years. Poisson regression was used to determine the effects of age, sex, and socioeconomic status on the likelihood of initiating one of these medications, after adjusting for potential confounders. Over the study period, 54,050 of 185,698 (29.1%) older individuals with COPD not previously taking any inhaled long-acting bronchodilators or corticosteroids were initiated on one or more of these medications. After adjustment, individuals of low socioeconomic status, measured using neighborhood income level quintiles, were slightly more likely to initiate COPD medications than those of high socioeconomic status (relative risk (RR) 1.05; 95% confidence interval (95% CI) 1.02-1.08). While men received COPD medication at a consistent rate across all age groups, the likelihood that a woman received medication decreased with increasing age. With the exception of older women, there was minimal disparity in prescription for COPD medications. Disparity in health outcomes among Ontario COPD patients is not clearly explained by differences in medication access by socioeconomic status, sex or age.

Which patients are most likely to benefit from total joint arthroplasty?

OBJECTIVE: To evaluate patient predictors of good outcome following total joint arthroplasty (TJA). METHODS: A population cohort with hip/knee arthritis (osteoarthritis [OA] or inflammatory arthritis) ages ≥55 years was recruited between 1996 and 1998 (baseline) and assessed annually for demographics, troublesome joints, health status, and overall hip/knee arthritis severity using the Western Ontario and McMaster Universities OA Index (WOMAC). Survey data were linked with administrative databases to identify primary TJAs. Good outcome was defined as an improvement in WOMAC summary score greater than or equal to the minimal important difference (MID; 0.5 SD of the mean change). Logistic regression and Akaike's information criterion were used to determine the optimal number of predictors and the best model of that size. Log Poisson regression was used to determine the relative risk (RR) for a good outcome. RESULTS: Primary TJA was performed in 202 patients (mean age 71.0 years; 79.7% female; 82.7% with >1 troublesome hip/knee; 65.8% knee replacements). Mean improvement in WOMAC summary score was 10.2 points (SD 18.05; MID 9 points). Of these patients, 53.5% experienced a good outcome. Four predictors were optimal. The best 4-variable model included pre-TJA WOMAC, comorbidity, number of troublesome hips/knees, and arthritis type (C statistic 0.80). The probability of a good outcome was greater with worse (higher) pre-TJA WOMAC summary scores (adjusted RR 1.32 per 10-point increase; P < 0.0001), fewer troublesome hips/knees (adjusted RR 0.82 per joint; P = 0.002), OA (adjusted RR for rheumatoid arthritis versus OA 0.33; P = 0.009), and fewer comorbidities (adjusted RR per condition 0.88; P = 0.01). CONCLUSION: In an OA cohort with a high prevalence of multiple troublesome joints and comorbidity, only half achieved a good TJA outcome, defined as improved pain and disability. A more comprehensive assessment of the benefits and risks of TJA is warranted.