Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Investigation of Fusobacterium Nucleatum in saliva and colorectal mucosa: a pilot study.

As evidence has been linking the oral bacterium Fusobacterium nucleatum (F. nucleatum) to colorectal tumorigenesis, we aimed to produce preliminary data on the expression of F. nucleatum in both oral and colorectal body sites in cases diagnosed with colorectal neoplasms (CRN) and CRN-free controls. We conducted a pilot hospital-based case-control study among patients who underwent colonoscopy examination. Saliva samples and biopsies from healthy colon mucosa from CRN cases and CRN-free controls, and from tumors in cases, were collected, as well as data on periodontal condition and potential CRN risk factors. A total of 22 CRN cases and 21 CRN-free controls participated in this study, with a total of 135 biospecimens collected and analyzed by qPCR for detection and quantification of F. nucleatum. The detection rate of F. nucleatum was 95% in saliva samples and 18% in colorectal mucosa specimens. The median (95% CI) salivary F. nucleatum level was 0.35 (0.15-0.82) and 0.12 (0.05-0.65) in case and control groups, respectively, with a Spearman correlation of 0.64 (95% CI 0.2-0.94) between F. nucleatum level in saliva and healthy colorectal mucosa in controls. Our study results support the need for and the feasibility of further studies that aim to investigate the association between oral and colorectal levels of F. nucleatum in CRN cases and controls.Clinical Relevance: Considering the current evidence linking F. nucleatum to colorectal carcinogenesis, investigating the role of oral F. nucleatum expression in its colorectal enrichment is crucial for colorectal cancer screening and prevention avenues.

Targeting cancer stem cells with antibiotics inducing mitochondrial dysfunction as an alternative anticancer therapy.

Traditional cancer treatments based on chemo- and/or radiotherapy effectively kill only differentiated cancer cells, while metastasis and recurrences are caused by surviving cancer resistant cells (CRC) or a special subpopulation of cancer cells known as cancer stem cells (CSC). Both of these cell types compromise anticancer treatment through various mechanisms, including withdrawal of the anticancer drug through ATP-binding cassette transporters, increased expression of DNA repair genes, or transition to a quiescent phenotype. In contrast to many cancers, where energy consumption is due to glycolysis (Warburg effect), the bioenergetics of CSC and CRC is most often related to oxidative phosphorylation, that is, dependent on mitochondrial function. Therefore, compounds that induce mitochondrial dysfunction (MDF), such as some antibiotics, may represent an alternative approach to anticancer therapy. This review summarizes the major recent works on the use of antibiotics to target tumors via CSC and suggests next steps for developing this approach.

Periodontal disease as a risk factor for sporadic colorectal cancer: results from COLDENT study.

Colorectal cancer remains the top leading cancer worldwide. Accumulating evidence suggests periodontal pathogens are involved in colorectal carcinogenesis, indicating the need for high-quality epidemiological evidence linking periodontal disease (PD) and colorectal cancer (CRC). Thus, we conducted the first population-based case-control study that was specifically designed to investigate the association between compromised oral health and sporadic CRC. A total of 348 incident cases of colon or rectal cancer, and 310 age and sex frequency-matched controls, from the Montreal island and Laval population participated in the study. Data were collected on PD and on several CRC risk factors using validated questionnaires. A life-course approach was used to document long-term history regarding lifestyle factors. Multivariable unconditional logistic regression analysis was used to estimate the rate ratio (RR) quantifying the association between CRC and PD. Results showed that the rate of new diagnosis of CRC in persons with a positive history of PD was 1.45 times higher than in those with a negative history of PD adjusting for age, sex, BMI, education, income, diabetes, family history of CRC, regular use of non-steroidal anti-inflammatory drugs, lifetime cumulative smoking, lifetime consumption of red meats, processed meats, and alcoholic drinks, and lifetime total physical activity score (adjusted RR = 1.45; 95% CI 1.04-2.01; p = 0.026). Our results support the hypothesis of an association between PD and sporadic CRC risk.

Acetylcholinesterase inhibitors and risk of bleeding and acute ischemic events in non-hypertensive Alzheimer's patients.

INTRODUCTION: Acetylcholinesterase inhibitors (AChEIs) are commonly used to treat mild to moderate cases of Alzheimer disease (AD). To the best of our knowledge, there has been no study estimating the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Therefore, this study aimed to estimate the association between AChEIs and the risk of bleeding and cardiovascular ischemic events in patients with non-hypertensive AD. METHODS: A nested case-control study was conducted to estimate the risk of bleeding and ischemic events (angina, myocardial infarction [MI], and stroke) in patients with AD. This study was conducted using the UK Clinical Practice Research Datalink and Hospital Episode Statistics (HES) databases. The study cohort consisted of AD patients ≥65 years of age. The case groups included all AD subjects in the database who had a bleeding or ischemic event during the cohort follow-up. Four controls were selected for each case. Patients were classified as current users or past users based on a 60-day threshold of consuming the drug. Simple and multivariable conditional logistic regression analyses were used to calculate the adjusted odds ratio for bleeding events and cardiovascular events. RESULTS: We identified 507 cases and selected 2028 controls for the bleeding event cohort and 555 cases and 2220 controls for the ischemic event cohort. The adjusted odds ratio (OR) (95% confidence interval [CI]) for the association of AChEI use was 0.93 (0.75 to 1.16) for bleeding events, 2.58 (1.01 to 6.59) for angina, and 1.89 (1.07 to 3.33) for MI. Past users of AChEIs were also at increased risk of stroke (1.51 [1.00 to 2.27]). DISCUSSION: This is the first study assessing the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Our findings could be of great interest for clinicians and researchers working on AD.

Propensity score matching versus coarsened exact matching in observational comparative effectiveness research.

Aim & methods: We compared propensity score matching (PSM) and coarsened exact matching (CEM) in balancing baseline characteristics between treatment groups using observational data obtained from a pan-Canadian prostate cancer radiotherapy database. Changes in effect estimates were evaluated as a function of improvements in balance, using results from randomized clinical trials to guide interpretation. Results: CEM and PSM improved balance between groups in both comparisons, while retaining the majority of original data. Improvements in balance were associated with effect estimates closer to those obtained in randomized clinical trials. Conclusion: CEM and PSM led to substantial improvements in balance between comparison groups, while retaining a considerable proportion of original data. This could lead to improved accuracy in effect estimates obtained using observational data in a variety of clinical situations.

Biochemistry tests in hospitalized COVID-19 patients: Experience from a Canadian tertiary care centre.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) has variable clinical presentation, from asymptomatic to severe disease leading to death. Biochemical markers may help with management and prognostication of COVID-19 patients; however, their utility is still under investigation. METHODS: A retrospective study was conducted to evaluate alanine aminotransferase, C-reactive protein (CRP), ferritin, lactate, and high sensitivity troponin T (TnT) levels in 67 patients who were admitted to a Canadian tertiary care centre for management of COVID-19. Logistic, cause-specific Cox proportional-hazards, and accelerated failure time regression modelling were performed to assess the associations of initial analyte concentrations with in-hospital death and length of stay in hospital; joint modelling was performed to assess the associations of the concentrations over the course of the hospital stay with in-hospital death. RESULTS: Initial TnT and CRP concentrations were associated with length of stay in hospital. Eighteen patients died (27%), and the median initial TnT concentration was higher in patients who died (55 ng/L) than those who lived (16 ng/L; P < 0.0001). There were no survivors with an initial TnT concentration > 64 ng/L. While the initial TnT concentration was predictive of death, later measurements were not. Only CRP had prognostic value with both the initial and subsequent measurements: a 20% increase in the initial CRP concentration was associated with a 14% (95% confidence interval (CI): 1-29%) increase in the odds of death, and the hazard of death increased 14% (95% CI: 5-25%) for each 20% increase in the current CRP value. While the initial lactate concentration was not predictive of death, subsequent measurements were. CONCLUSION: CRP, lactate and TnT were associated with poorer outcomes and appear to be useful biochemical markers for monitoring COVID-19 patients.

Effects of nocturnal wearing of dentures on the quality of sleep and oral-health-related quality in edentate elders with untreated sleep apnea: a randomized cross-over trial.

STUDY OBJECTIVES: This study aims to assess whether the nocturnal wear of dentures has an effect on the quality of sleep and oral-health-related quality of life of the edentulous elderly with untreated sleep apnea. METHODS: A single-blind randomized cross-over design with two sequences and two periods was used. Participants (n = 77) were randomly assigned either to sequence 1 (nocturnal wear followed by nocturnal nonwear of the denture for 30-30 days) or sequence 2 (nocturnal nonwear followed by nocturnal wear of denture for 30-30 days). The primary sleep outcome was the quality of sleep, assessed through sleep fragmentation measured as Apnea-Hypopnea Index (AHI) and respiratory arousal from portable polysomnography. Secondary outcomes were daytime sleepiness, sleep quality (Pittsburgh Sleep Quality Index, PSQI) and oral-health-related quality of life measured by validated questionnaires. RESULTS: The mean paired difference in AHI scores for the period of wearing versus not wearing dentures at night was small 1.0 event per hour (p = 0.50; 95% confidence interval (CI) = -2.0 to 4.1). The mean respiratory arousal index was higher when wearing dentures at night than when not wearing dentures at night, with a mean paired difference of 2.3 events per hour (p = 0.05; 95% CI = 0.0 to 4.6). No difference in sleepiness and PSQI were noted. Wearing dentures at night resulted in a statistically significantly higher mean score of psychological discomfort when compared to not wearing dentures at night. CONCLUSIONS: The results provide some support to usual practice guidelines to remove dentures at night in edentulous elders suffering from sleep apnea. CLINICAL TRIAL REGISTRATION: NCT01868295.

The effect of gestational diabetes mellitus on the risk of asthma in offspring.

PURPOSE: To examine the effect of maternal gestational diabetes mellitus on the risk of asthma in the offspring. METHODS: This cohort study used data from 19,933 children in the National Longitudinal Survey of Children and Youth (NLSCY), 1994/1995-2008/2009, Canada. Children were followed until the first-time report of having health professional-diagnosed asthma (hereafter incident asthma), loss to follow-up, or end of the NLSCY follow-up, whichever occurred first. As a surrogate for Cox proportional hazards regression, pooled logistic regression models, crude and adjusted for potential confounders, were fitted to estimate the effect of gestational diabetes mellitus on the risk of asthma in the offspring. RESULTS: Among the 19,933 children, 1,178 (5.9%) had mothers with gestational diabetes mellitus. The median duration of follow-up was 4 (interquartile range: 4) years. A total of 1639 children in the cohort had reported incident asthma during the follow-up, and 119 of them had mothers with gestational diabetes mellitus. The adjusted hazard ratio for the association between gestational diabetes mellitus and incident asthma in offspring was 1.25 (95% confidence interval [CI] 1.03, 1.51). CONCLUSIONS: Our findings suggest that gestational diabetes mellitus increases the risk of asthma in the offspring.

Detection of Fusobaterium nucleatum in feces and colorectal mucosa as a risk factor for colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer deaths worldwide. Accumulating evidence suggests a potentially important role of colorectal infection with Fusobacterium nucleatum (F. nucleatum) in colorectal carcinogenesis. We conducted a systematic review, including both a qualitative synthesis and a meta-analysis, to synthesize the evidence from the epidemiological literature on the association between F. nucleatum detection in the colon/rectum and CRC. METHODS: A systematic literature search of Ovid MEDLINE(R), Embase, Web of Science Core Collection, EBM Reviews-Cochrane Database of Systematic Reviews, and CINAHL Plus with Full Text was conducted using earliest inclusive dates up to 4 October 2020. Eligible studies were original, comparative observational studies that reported results on colorectal F. nucleatum detection and CRC. Two independent reviewers extracted the relevant information. Odds ratio (OR) estimates were pooled across studies using the random effects model. Newcastle-Ottawa scale was used to critically appraise study quality. RESULTS: Twenty-four studies were included in the systematic review, of which 12 were included in the meta-analysis. Studies investigated F. nucleatum in feces, colorectal tissue samples, or both. In most studies included in the systematic review, the load of F. nucleatum was higher, on average, in specimens from CRC patients than in those from CRC-free controls. Meta-analysis showed a positive association between F. nucleatum detection in colorectal specimens and CRC (OR = 8.3; 95% confidence interval (95% CI) 5.2 to 13.0). CONCLUSIONS: The results of this systematic review suggest that F. nucleatum in the colon/rectum is associated with CRC. SYSTEMATIC REVIEW REGISTRATION: This systematic review protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) on July 10, 2018 (registration number CRD42018095866).

Age, period, and cohort effects on asthma prevalence in Canadian adults, 1994-2011.

PURPOSE: To examine the age, period, and cohort effects on asthma prevalence among Canadian adults from 1994/1995 to 2010/2011. METHODS: Using data from the National Population Health Survey, 13,616 Canadian adults were followed for 16 years. Age was limited to 18-80 years during follow-up. Modified Poisson regression models with generalized estimating equations were used to estimate age, period, and cohort effects on asthma and active asthma prevalence after accounting for sociodemographic factors. Model-based standardization was performed to estimate standardized rates. RESULTS: Overall asthma prevalence increased from 5% in 1994/1995 to 11% in 2010/2011; decreasing from 12% for 20-year-olds to 6% for 50-60-year-olds and then increased to 8% for 80-year-olds. Individuals aged 20 years had the steepest increase in prevalence between 1994/1995 and 2010/2011. Active asthma prevalence increased from 5% in 1994/1995 to 8% in 2010/2011; decreasing from 8% for 20-year-olds to 5% for 50-60-year-olds and then increased to 6% for 80-year-olds. CONCLUSIONS: Our findings suggest the presence of age, period, and cohort effects on prevalence of asthma overall and presence of age and period effects on active asthma prevalence in Canadian adults.

Asthma exacerbation trajectories and their predictors in children with incident asthma.

BACKGROUND: Asthma exacerbation trajectories in children after incident asthma diagnosis are understudied. OBJECTIVE: To identify trajectories of asthma exacerbation and predictors of these trajectories in children with incident asthma. METHODS: Children from the National Longitudinal Survey of Children and Youth, Canada, with incident asthma were followed-up for up to 12 years during childhood. Latent class growth modeling was used to identify distinct asthma exacerbation trajectory groups. Multinomial logistic regression was performed to identify predictors of trajectory group membership. RESULTS: The mean age at asthma diagnosis among 403 children was 5.9 years. Three distinct trajectories were identified: low increasing (21.3% of children), medium decreasing (45.8% of children), and high decreasing (32.8% of children). Asthma attack probability increased gradually after diagnosis in low increasing group, decreased from moderate level after diagnosis to almost zero probability at the end of follow-up in the medium decreasing group, and decreased after diagnosis but remained higher in the high decreasing group than the other 2 groups at 12 years after diagnosis. Children having more siblings at home were more likely to belong to the medium decreasing and high decreasing trajectory groups, whereas children older at asthma diagnosis were less likely to belong to the medium decreasing and high decreasing trajectory groups than the low increasing trajectory group. CONCLUSION: Our results suggest that children with incident asthma follow 3 distinct trajectories of asthma exacerbations after asthma diagnosis. The trajectory group with initial moderate exacerbation probability has better long-term prognosis.

Is a fusobacterium nucleatum infection in the colon a risk factor for colorectal cancer?: a systematic review and meta-analysis protocol.

BACKGROUND: Despite a considerable amount of epidemiological research for identification of risk factors involved in the development of colorectal cancer, the current understanding of the etiology of this disease remains rather poor. Accumulating evidence suggests a potentially important role of infection with Fusobacterium nucleatum in the colon in colorectal carcinogenesis. The objective of this systematic review is to synthesize the epidemiological evidence on the association between infection with Fusobacterium nucleatum in the colon and colorectal cancer. METHODS: This systematic review will include observational studies (cohort, case-control, cross-sectional) in humans in which the role of Fusobacterium nucleatum in the etiology of colorectal cancer was investigated. MEDLINE, EMBASE, Web of Science, and Cochrane Database of Systematic Reviews will be searched using a comprehensive search strategy and manual screening of references. Two reviewers will independently identify eligible studies and extract the data from the included studies. The quality of studies will be assessed by using the Newcastle-Ottawa scale. Random-effects models will be used to estimate pooled measures of association (where feasible). Meta-regression and subgroup analyses will be conducted to explore the potential sources of heterogeneity. The Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement will be followed for reporting. DISCUSSION: Deepening knowledge regarding the etiology of colorectal cancer and the potential implications of Fusobacterium nucleatum in this disease is instrumental for prevention, diagnosis, and treatment of this often-fatal disease. This review will produce summarized current evidence on this topic. SYSTEMATIC REVIEW REGISTRATION: This systematic review protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 10 July 2018 (registration number CRD42018095866).

Does the use of incretin-based medications increase the risk of cancer in patients with type-2 diabetes mellitus?

PURPOSE: Incretin-based medications are a novel class of agents for the treatment of type-2 diabetes mellitus (DM2). The safety profile of these medications is not firmly established, and concerns have been raised about their potential carcinogenicity. The objective of our study was to produce new evidence on the effect of incretin-based medications on cancer risk in patients with DM2. METHODS: We conducted a "retrospective cohort" study with data from the Clinical Practice Research Datalink and the Hospital Episodes Statistics in the UK. New users of either an incretin-based medication (n = 18 885) or a sulfonylurea medication (n = 36 929) between 2007 and 2013 were identified and followed for up to 8 years. Cox proportional-hazards models were used to estimate the quasi-intention-to-treat and quasi-per-protocol hazard-ratios for the association between incretin-based medications with cancer while adjusting for potential confounders. RESULTS: The adjusted hazard ratio (95% confidence interval) for use of incretin-based medications versus use of sulfonylurea medications for the overall-cancer outcome was 0.97 (0.90, 1.05) in the quasi-intention-to-treat analysis and 0.90 (0.81, 1.00) in the quasi-per-protocol analysis. In both analyses, the hazard-ratio functions over the 8-year follow-up seemed fairly constant, and the 8-year cumulative-risk functions in the two subcohorts were similar. CONCLUSIONS: Our study suggests that the use of incretin-based medications in patients with DM2 does not increase the risk of cancer relative to the use of sulfonylurea medications, at least in the first several years of the use. Further research is needed to assess long-term effects of the use of incretin-based medications on cancer risk.

Missing single nucleotide polymorphisms in Genetic Risk Scores: A simulation study.

Using a genetic risk score (GRS) to predict a phenotype in a target sample can be complicated by missing data on the single nucleotide polymorphisms (SNPs) that comprise the GRS. This is usually addressed by imputation, omission of the SNPs or by replacing the missing SNPs with proxy SNPs. To assess the impact of the omission and proxy approaches on effect size estimation and predictive ability of weighted and unweighted GRS with small numbers of SNPs, we simulated a dichotomous phenotype conditional on real genotype data. We considered scenarios in which the proportion of missing SNPs ranged from 20-70%. We assessed the impact of omitting or replacing missing SNPs on the association between the GRS and phenotype, the corresponding statistical power and the area under the receiver operating curve. Omission resulted in a larger bias towards the null value of the effect size, a smaller predictive ability and greater loss of statistical power than proxy approaches. The predictive ability of a weighted GRS that includes SNPs with large weights depends of the availability of these large-weight SNPs.