Prenatal triphenyl phosphate exposure impairs placentation and induces preeclampsia-like symptoms in mice.

Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is widely used in many commercial products. The United States Environmental Protection Agency has listed TPhP as a priority compound that requires health risk assessment. We previously found that TPhP could accumulate in the placentae of mice and impair birth outcomes by activating peroxisome proliferator-activated receptor gamma (PPARγ) in the placental trophoblast. However, the underlying mechanism remains unknown. In this study, we used a mouse intrauterine exposure model and found that TPhP induced preeclampsia (PE)-like symptoms, including new on-set gestational hypertension and proteinuria. Immunofluorescence analysis showed that during placentation, PPARγ was mainly expressed in the labyrinth layer and decidua of the placenta. TPhP significantly decreased placental implantation depth and impeded uterine spiral artery remodeling by activating PPARγ. The results of the in vitro experiments confirmed that TPhP inhibited extravillous trophoblast (EVT) cell migration and invasion by activating PPARγ and inhibiting the PI3K-AKT signaling pathway. Overall, our data demonstrated that TPhP could activate PPARγ in EVT cells, inhibit cell migration and invasion, impede placental implantation and uterine spiral artery remodeling, then induce PE-like symptom and impair birth outcomes. Although the exposure doses used in this study was several orders of magnitude higher than human daily intake, our study highlights the placenta as a potential target organ of TPhP worthy of further research.

Triphenyl phosphate interferes with the synthesis of steroid hormones through the PPARγ/CD36 pathway in human trophoblast JEG-3 cells.

Triphenyl phosphate (TPhP), a chemical commonly found in human placenta and breast milk, has been shown to disturb the endocrine system. Our previous study confirmed that TPhP could accumulate in the placenta and interference with placental lipid metabolism and steroid hormone synthesis, as well as induce endoplasmic reticulum (ER) stress through PPARγ in human placental trophoblast JEG-3 cells. However, the molecular mechanism underlying this disruption remains unknown. Our study aimed to identify the role of the PPARγ/CD36 pathway in TPhP-induced steroid hormone disruption. We found that TPhP increased lipid accumulation, total cholesterol, low- and high-density protein cholesterol, progesterone, estradiol, glucocorticoid, and aldosterone levels, and genes related to steroid hormones synthesis, including 3ßHSD1, 17ßHSD1, CYP11A, CYP19, and CYP21. These effects were largely blocked by co-exposure with either a PPARγ antagonist GW9662 or knockdown of CD36 using siRNA (siCD36). Furthermore, an ER stress inhibitor 4-PBA attenuated the effect of TPhP on progesterone and glucocorticoid levels, and siCD36 reduced ER stress-related protein levels induced by TPhP, including BiP, PERK, and CHOP. These findings suggest that ER stress may also play a role in the disruption of steroid hormone synthesis by TPhP. As our study has shed light on the PPARγ/CD36 pathway's involvement in the disturbance of steroid hormone biosynthesis by TPhP in the JEG-3 cells, further investigations of the potential impacts on the placental function and following birth outcome are warranted.

Susceptibility of immature spiral ganglion neurons to aminoglycoside-induced ototoxicity is mediated by the TRPV1 channel in mice.

Aminoglycoside antibiotics are among the most common agents that can cause sensorineural hearing loss. From clinical experience, premature babies, whose inner ear is still developing, are more susceptible to aminoglycoside-induced ototoxicity, which is echoed by our previous study carried out in organotypic cultures. This study aimed to investigate whether a nonselective cation channel, TRPV1, contributes to the susceptibility of immature spiral ganglion neurons (SGNs) to the damage caused by aminoglycosides. Through western blotting and immunofluorescence, we found that the TRPV1 expression levels were much higher in immature SGNs than in their mature counterparts. In postnatal day 7 cochlear organotypic cultures, AMG-517 reduced reactive oxygen species generation and inhibited SGN apoptosis under aminoglycoside challenge. However, in adult mice, AMG-517 did not ameliorate the ABR threshold increase at high frequencies (16 kHz and 32 kHz) after aminoglycoside administration, and the SGNs within the cochleae had no morphological changes. By further regulating the function of TRPV1 in primary cultured SGNs with its inhibitor AMG-517 and agonist capsaicin, we demonstrated that TRPV1 is a major channel for aminoglycoside uptake: AMG-517 can significantly reduce, while capsaicin can significantly increase, the uptake of GTTR. In addition, TRPV1 knockdown in SGNs can also significantly reduce the uptake of GTTR. Taken together, our results demonstrated that aminoglycosides can directly enter immature SGNs through the TRPV1 channel. High expression of TRPV1 contributes to the susceptibility of immature SGNs to aminoglycoside-induced damage. The TRPV1 inhibitor AMG-517 has the potential to be a therapeutic agent for preventing aminoglycoside-induced ototoxicity in immature SGNs.

Short-term effects of intravenous batroxobin in treatment of sudden sensorineural hearing loss: a propensity score-matched study.

Background: Sudden sensorineural hearing loss (SSNHL) can cause great panic in patients. Whether it is advantageous to add intravenous batroxobin in the treatment of SSNHL remains to be determined. This study aimed to compare the short-term efficacy of therapy combined with intravenous batroxobin and that without intravenous batroxobin in SSNHL patients. Methods: This retrospective study harvested the data of SSNHL patients hospitalized in our department from January 2008 to April 2021. The hearing levels on the admitted day (before treatment) and the discharge day were considered pre-treatment hearing and post-treatment hearing, respectively. The hearing gain was the difference value of pre-treatment hearing and post-treatment hearing. We used Siegel's criteria and the Chinese Medical Association of Otolaryngology (CMAO) criteria to evaluate hearing recovery. The complete recovery rate, overall effective rate, and hearing gain at each frequency were considered outcomes. Propensity score matching (PSM) was conducted to balance the baseline characteristics between the batroxobin group and the non-batroxobin group. Sensitivity analysis was carried out in flat-type and total-deafness SSNHL patients. Results: During the study period, 657 patients with SSNHL were admitted to our department. Among them, a total of 274 patients met the enrolled criteria of our study. After PSM, 162 patients (81 in each group) were included in the analysis. Once the hospitalized treatment was completed, the patients would be discharged the next day. Logistic regression analysis of the propensity score-matched cohort indicated that both the complete recovery rates [Siegel's criteria, OR: 0.734, 95% CI: 0.368-1.466, p = 0.381; CMAO criteria, OR: 0.879, 95% CI: 0.435-1.777, p = 0.720] and the overall effective rates [Siegel's criteria and CMAO criteria, OR: 0.741, 95% CI: 0.399-1.378, p = 0.344] were not significantly different between the two treatment groups. Sensitivity analysis has shown similar results. For flat-type and total-deafness SSNHL patients, no significant difference was found in post-treatment hearing gain at each frequency between the two groups after PSM. Conclusion: There was no significant difference in short-term hearing outcomes between treatment with batroxobin and treatment without batroxobin in SSNHL patients by Siegel's and CMAO criteria after PSM. Future studies for better therapy regimens of SSNHL are still needed.

Novel ZnFe2O4/BC/ZnO photocatalyst for high-efficiency degradation of tetracycline under visible light irradiation.

Developing broad-spectrum light reactions, effective charge separation, and easily recoverable photocatalysts were considered cost-effective pollution remediation methods. The ZnFe2O4/BC/ZnO composite was prepared to achieve these objectives, where biochar (BC) was used as a conductive channel and ZnFe2O4 as a magnetic substance. Among them, the 0.6-ZBO composite performed the best, with photocatalytic removal of tetracycline (TC) reaching 85.6%. The photocatalytic degradation rated constant of 0.6-ZBO composite was 23.36 × 10-3 min-1, which was 7.6, 4.1, and 2.5 times higher than that of ZnFe2O4/BC, ZnO, and ZnFe2O4/ZnO samples, respectively. According to several characterization data, it was demonstrated that successful Z-scheme heterojunctions were constructed between ZnFe2O4 and ZnO. The 0.6-ZBO complex increased the range of light absorption and strengthened the separation of electron-hole pairs, thus improving the redox ability of the complex. In the different water matrices, the stability of 0.6-ZBO was excellent and its ability to remove TC decreased slightly to about 11% after 5 cycles. This work provided a valuable approach to design a novel and efficient system for degrading organic pollutants in wastewater using magnetic biochar.

Gestation and lactation triphenyl phosphate exposure disturbs offspring gut microbiota in a sex-dependent pathway.

Triphenyl phosphate (TPhP) is an Organophosphate flame retardant (OPFR) that has been widely used in many commercial products. Following its widely usage, its health risk has been concerned. In this study, mice were exposed to TPhP (1 mg/kg) during pregnancy and lactation (E0-PND21), the effect of TPhP on gut microbiota and its role in TPhP mediated lipid metabolism disturbance of offspring was investigated. Our results showed that TPhP disturbed the gut microbiota in dam or offspring at different extent, with male offspring experiencing major effects. Both the composition, abundance or network of gut microbiome was affected in male offspring. In male offspring, expression of genes along gut-liver axis including FXR, CYP7A1, SREBP-1c and ChREBP was significantly up-regulated, and expression of SHP, FGF15 and ASBT was significantly down-regulated. Consistent with this, lipid accumulation in the liver, and increased level of triglyceride, total cholestrol and total bile acid in the serum was observed. The changed abundance of Ruminococcaceae, Clostridiaceae, and Bacteroidaceae shows strong correlation with disturbed lipid metabolism in male offspring. Our research showed that indirect TPhP exposure during early life stage could affect the gut microbiota and gene expression along gut-liver axis in offspring at sex-dependent pathways, with males experiencing more effects.

Triphenyl phosphate disturbs placental tryptophan metabolism and induces neurobehavior abnormal in male offspring.

Epidemiological studies have shown that prenatal triphenyl phosphate (TPhP) exposure is related to abnormal neurobehavior in children. However, the neurodevelopmental toxicity of TPhP in mammals is limited. To study the neurodevelopmental toxicity of TPhP in mammals and investigate the underlying mechanism, we used a mouse intrauterine TPhP exposure model. We measured the inflammatory factors (IL-6, TNFα) and NFκB levels, and tryptophan metabolism in placentae, detected the fetal brain transcriptome, hippocampal neuron development and neurobehavioral in the male offspring. The results showed that the protein level of IL-6, TNFα and NFκB in the placenta of the TPhP treatment group (1, 5 mg/kg) were significantly increased. Change of the protein level of these pro-inflammatory factors in maternal serum or fetal brain was not observed. Expression of genes along tryptophan-serotonin metabolism pathway were significantly decreased. While, the concentration of 5-HT levels in the placenta or fetal brain were significantly increased. Consistent with the increased 5-HT, the Nissl body was reduced in the hippocampus of treatment group. The expression of serotonergic neuron gene markers including Tph2, Htr1A, Htr2A, Pet1 and Lmx1b in the hippocampus of treatment group was significantly decreased. The neurobehavioral test showed that TPhP decreased center time that represent anxiety-like behavior, and reduced learning and memory in male offspring. Meanwhile, expression of genes along tryptophan-kynurenine metabolism pathway were significantly increased. The result of the transcriptome analysis of fetal brain showed that the differentially expressed genes are mainly involved in the transcription regulation of DNA as a template in the nucleus, and the enriched pathways are mainly signal pathways regulated by axon guidance and neurotrophic factors, dopaminergic and cholinergic synapses, suggest that not only serotonergic neuronal was affected. Overall, this study demonstrates that TPhP has the potential to induce placental inflammatory response in the placenta, disturb placental tryptophan metabolism, compromise the neuronal development and synaptic transmission, and cause abnormal neurobehavior in male offspring.

Establishment of a risk index for early complications after trans-canal endoscopic ear surgery.

PURPOSE: This study aimed to determine the risk factors associated with early postoperative complications of trans-canal endoscopic ear surgery (TEES), then to develop a risk index. MATERIALS AND METHODS: This single-institution retrospective study reviewed TEESs from January 1, 2017, to December 31, 2019 in a tertiary hospital. In the derivation cohort, univariable and multivariable logistic regression were performed to identify factors significantly associated with early postoperative complications of TEES. Then these parameters were integrated into a trans-canal endoscopic ear surgery risk index (TEESRI). The performance of TEESRI was compared with that of the American Society of Anesthesiologists (ASA) classification using the validation cohort. RESULTS: 932 TEESs were enrolled in total and 151 (16.2%) developed early postoperative complications. In the derivation set, 8 factors including state of the opposite ear and presence of nasal or pharyngeal diseases were found to be independently associated with the occurrence of early postoperative complications on multivariable regression analysis [area under the curve (AUC), 0.806; 95% confidence interval (CI), 0.765-0.848]. Using the validation cohort, the AUC of the TEESRI was 0.776 [95%CI, 0.711-0.842], with a sensitivity of 82.2% and specificity of 65.5%, while the AUC of the ASA classification was 0.512 (95%CI, 0.421-0.603). The TEESRI outperformed the ASA classification when evaluating the risk for early postoperative complications of TEES. CONCLUSIONS: Based on the 8 risk factors, the TEESRI was established with satisfactory predicting capacity. Surgeons should pay extra attention to the risk factors in the TEESRI, when treating patients.

Effects of long-term exposure to TDCPP in zebrafish (Danio rerio) - Alternations of hormone balance and gene transcriptions along hypothalamus-pituitary axes.

BACKGROUND: TDCPP is one of the major chemical of organophosphate flame retardants (OPFRs) that has been detected ubiquitously in both the environment and biota. Previously we observed that it influenced the concentrations of sex and thyroid hormones in a sex-dependent pattern, leading to reproductive impairments after short-term exposure in zebrafish. Here we investigate the consequences of longer-term exposure to TDCPP on the hypothalamic-pituitary-gonad (HPG), hypothalamic-pituitary-interrenal (HPI), and hypothalamic-pituitary-thyroid (HPT) axes of zebrafish (Danio rerio). METHODS: A 120-day exposure test to 0.005, 0.05 and 0.5 mg/L TDCPP was initiated with fertilized eggs. Sex steroid hormones in the treated fishes were measured and transcriptional changes were analyzed. RESULTS: In female fish, exposure to TDCPP resulted in increases in plasma cortisol, follicle stimulating hormone (FSH), luteinizing hormone (LH), 17ß-estradiol (E2), cortisol, thyroxine (T4), and triiodothyronine (T3). Transcription of most target genes along HPG, HPI and HPT axes were increased by the exposure. While in male fish the exposure led to decreases in cortisol, FSH, LH, T4, T3, testosterone (T), and 11-ketotestosterone (11-KT). Transcription of genes along HPG, HPI and HPT axes, especially steroidogenic genes, were inhibited in male zebrafish. While, E2/T or E2/11-KT ratio was increased in both female and females. The sex-dependent changes in hormones might be due to differential responses to TDCPP induced stresses. An increase in cortisol level coincided with increases in E2 and THs in female fish, while in males decreases in cortisol as well as T, 11-KT and THs were observed. Long-term exposure to TDCPP at very low (µg/L) concentrations could disrupt hormone balances in a sex dependent way. CONCLUSION: This study revealed that TDCPP could affect endocrine axes - HPG, HPI and HPT - in zebrafish, and impair zebrafish development.

Prenatal exposure to triphenyl phosphate activated PPARγ in placental trophoblasts and impaired pregnancy outcomes.

The health risks of triphenyl phosphate (TPhP) have increased since its widespread application. Using placental trophoblast cell line JEG-3, we demonstrated that TPhP could induce endoplasmic reticulum stress (ERS) and cell apoptosis through PPARγ-mediated lipid metabolism. However, the developmental toxicity of TPhP through the placenta is not known. In this study, prenatal TPhP exposure to mice was investigated. Pregnant mice were orally exposed to TPhP (1 and 5 mg/kg) from embryonic day 0 (E0) until delivery. The results showed that TPhP could accumulate in placenta and impair pregnancy outcomes. After exposure, at E18, placental hormone chorionic gonadotrophin and testosterone levels were significantly decreased, but progesterone and estradiol levels were significantly increased, and placental angiogenesis was activated in the low-dose exposure group. While, in the high-dose exposure group, only estradiol levels were significantly increased. Different with the effect on hormone level or angiogenesis, TPhP significantly increased PPARγ and its regulated lipid transport proteins FABP, FATP, and CD36, and induced lipid accumulation in placental trophoblasts of both low- and high-exposure group. RNA-seq analysis of the placenta identified differentially expressed genes that were mainly involved in the ERS and MAPK signaling pathways. Western blot analysis verified that the protein levels related to ERS stress and apoptosis were significantly increased. To further confirm the role of PPARγ in TPhP mediated placental toxicity, pregnant mice were orally exposed to TPhP (1 mg/kg) or TPhP (1 mg/kg) + GW9662 (PPARγ inhibitor, 2 mg/kg) from E0 until delivery. The results showed that GW9662 could ameliorate the effect of TPhP on placental lipid accumulation, ERS and cell apoptosis, suggesting that PPARγ mediated the placental toxicity of TPhP. Overall, our results indicated that prenatal TPhP exposure impaired pregnancy outcomes, at least partly through PPARγ regulated function of trophoblast.

Removal efficiencies and risk assessment of endocrine-disrupting chemicals at two wastewater treatment plants in South China.

Endocrine-disrupting chemicals (EDCs) in the effluent from wastewater treatment plants (WWTPs) are an important pollutant sources of the aquatic system. In this study, the removal efficiencies of eight typical EDCs at two domestic WWTPs in Dongguan City, China, are reported based on instrumental analysis and bioassay results. Bioactivities, including steroidogenesis-disrupting effects, estrogen receptor (ER)-binding activity, and aryl hydrocarbon receptor (AhR)-binding activity were evaluated using the H295R, MVLN, and H4IIE cell bioassays, respectively. The potential environmental risks of these residual EDCs were also evaluated. The results of instrumental analysis showed that nonylphenol was the major chemical type present among the eight tested EDCs. Meanwhile, concentrations of estrogen compounds including estrone, 17ß-estradiol (E2), estriol, 17α-ethinyl estradiol, and diethylstilbestrol were relatively low. The removal rates of all eight EDCs were relatively high. Although the chemical analysis indicated high removal efficiency, the bioassay results showed that steroidogenesis-disrupting effects as well as ER-binding and AhR-binding activities remained, with E2-equivalent values of effluent samples ranging from 0.16 to 0.9 ng·L-1, and 2,3,7,8-tetrachlorodibenzo-p-dioxin-equivalent values ranging from 0.61 to 4.09 ng L-1. Principal component analysis combined with regression analysis suggests that the chemicals analyzed in this study were partly responsible for these ER and AhR activities. Ecological risk assessment of the residual EDCs showed that estrone was the most hazardous chemical among the eight EDCs tested, with a risk quotient of 1.44-5.50. Overall, this study suggests that, despite high apparent removal efficiencies of typical EDCs, their bioactivities and potential ecological risks cannot be ignored.

Impact of physician-based palliative care delivery models on health care utilization outcomes: A population-based retrospective cohort study.

BACKGROUND: Increasing involvement of palliative care generalists may improve access to palliative care. It is unknown, however, if their involvement with and without palliative care specialists are associated with different outcomes. AIM: To describe physician-based models of palliative care and their association with healthcare utilization outcomes including: emergency department visits, acute hospitalizations and intensive care unit (ICU) admissions in last 30 days of life; and, place of death. DESIGN: Population-based retrospective cohort study using linked health administrative data. We used descriptive statistics to compare outcomes across three models (generalist-only palliative care; consultation palliative care, comprising of both generalist and specialist care; and specialist-only palliative care) and conducted a logistic regression for community death. SETTING/PARTICIPANTS: All adults aged 18-105 who died in Ontario, Canada between April 1, 2012 and March 31, 2017. RESULTS: Of the 231,047 decedents who received palliative services, 40.3% received generalist, 32.3% consultation and 27.4% specialist palliative care. Across models, we noted minimal to modest variation for decedents with at least one emergency department visit (50%-59%), acute hospitalization (64%-69%) or ICU admission (7%-17%), as well as community death (36%-40%). In our adjusted analysis, receipt of a physician home visit was a stronger predictor for increased likelihood of community death (odds ratio 9.6, 95% confidence interval 9.4-9.8) than palliative care model (generalist vs consultation palliative care 2.0, 1.9-2.0). CONCLUSION: The generalist palliative care model achieved similar healthcare utilization outcomes as consultation and specialist models. Including a physician home visit component in each model may promote community death.

Does the public feel prepared to be substitute decision-makers? Gaps in preparedness and support for a high school curriculum: a national survey.

BACKGROUND: Substitute decision-makers (SDMs) make decisions on behalf of patients who do not have capacity, in line with previously expressed wishes, values and beliefs. However, miscommunications and poor awareness of previous wishes often lead to inappropriate care. Increasing public preparedness to communicate on behalf of loved ones may improve care in patients requiring an SDM. METHODS: We conducted an online survey in January 2019 with a representative sample of the Canadian population. The primary outcome was self-reported preparedness to be an SDM. The secondary outcome was support for a high school curriculum on the role of SDMs. The effect of socio-demographics, known enablers and barriers to acting as an SDM, and attitudes towards a high school curriculum were assessed using multivariate analysis. RESULTS: Of 1,000 participants, 53.1% felt prepared to be an SDM, and 75.4% stated they understood their loved one's values. However, only 55.6% reported having had a meaningful conversation with their loved one about values and wishes, and only 61.7% reported understanding the SDM role. Engagement in advance care planning for oneself was low (23.1%). Age, experience, training and comfort with communication were associated with preparedness in our multivariate analysis. A high school curriculum was supported by 61.1% of respondents, with 28.3% neutral and 10.6% against it. INTERPRETATION: There is a gap between perceived and actual preparedness to be an SDM. Many report understanding their loved one's values yet have not asked them about wishes in illness or end of life. The majority of respondents support high school education to improve preparedness.

Gaps in public preparedness to be a substitute decision-maker and the acceptability of high school education on resuscitation and end-of-life care: a mixed-methods study.

BACKGROUND: When a patient is incapable of making medical decisions for him- or herself, a substitute decision-maker makes choices according to the patient's previously expressed wishes, values and beliefs; however, little is known about public readiness to act as a substitute decision-maker in Canada. Our primary objective was to measure public self-reported preparedness to act as a substitute decision-maker, and explore the attitudes, barriers and enablers associated with preparedness. METHODS: From November 2017 to June 2018, we conducted a mixed-methods street intercept survey at 12 pedestrian areas in Ottawa, Ontario. We used descriptive statistics and logistic regression analysis to assess predictors of perceived preparedness to be a substitute decision-maker and determine support for high school education. We analyzed qualitative interview questions using inductive thematic analysis. RESULTS: Of the 626 eligible respondents, 196 refused to participate, leaving 430 participants (response rate 68.7%). A total of 404 surveys (94.0%) were fully complete with no missing data. The respondents were mostly female (243 [56.5%]) and residents of Ontario (364 [84.6%]). The average age was 33.9 years. Although 314 respondents (73.0%) felt prepared to be a substitute decision-maker, 194 (45.1%) reported never having had meaningful conversations with loved ones to understand their wishes in the event of critical illness. A total of 293 participants (68.1%) identified important barriers to feeling prepared. Most respondents (309 [71.9%]) agreed that high school students should learn about being a substitute decision-maker, citing age appropriateness, potential societal benefit and improved decision-making, while cautioning the need to respect different maturity levels, cultures and experiences. INTERPRETATION: he lack of conversation between loved ones reveals a gap between perceived and actual preparedness to be a substitute decision-maker for a loved one with a critical illness. The overall acceptability of high school education warrants further exploration.

Epidemiologic Evaluation of Human Papillomavirus Type Competition and the Potential for Type Replacement Post-Vaccination.

BACKGROUND: Millions of women have been vaccinated with one of two first-generation human papillomavirus (HPV) vaccines. Both vaccines remain in use and target two oncogenic types (HPVs 16 and 18); however, if these types naturally compete with others that are not targeted, type replacement may occur following reductions in the circulating prevalence of targeted types. To explore the potential for type replacement, we evaluated natural HPV type competition in unvaccinated females. METHODS: Valid HPV DNA typing information was available from five epidemiological studies conducted in Canada and Brazil (n = 14,685; enrollment across studies took place between1993 and 2010), which used similar consensus-primer PCR assays, capable of detecting up to 40 HPV types. A total of 38,088 cervicovaginal specimens were available for inclusion in our analyses evaluating HPV type-type interactions involving vaccine-targeted types (6, 11, 16, and 18), and infection with each of the other HPV types. RESULTS: Across the studies, the average age of participants ranged from 21.0 to 43.7 years. HPV16 was the most common type (prevalence range: 1.0% to 13.8%), and in general HPV types were more likely to be detected as part of a multiple infection than as single infections. In our analyses focusing on each of the vaccine-targeted HPV types separately, many significant positive associations were observed (particularly involving HPV16); however, we did not observe any statistically significant negative associations. CONCLUSIONS: Our findings suggest that natural HPV type competition does not exist, and that type replacement is unlikely to occur in vaccinated populations.

Screening polypectomy rates below quality benchmarks: a prospective study.

AIM: To estimate and compare sex-specific screening polypectomy rates to quality benchmarks of 40% in men and 30% in women. METHODS: A prospective cohort study was undertaken of patients aged 50-75, scheduled for colonoscopy, and covered by the Québec universal health insurance plan. Endoscopist and patient questionnaires were used to obtain screening and non-screening colonoscopy indications. Patient self-report was used to obtain history of gastrointestinal conditions/symptoms and prior colonoscopy. Sex-specific polypectomy rates (PRs) and 95%CI were calculated using Bayesian hierarchical logistic regression. RESULTS: In total, 45 endoscopists and 2134 (mean age = 61, 50% female) of their patients participated. According to patients, screening PRs in males and females were 32.4% (95%CI: 23.8-41.8) and 19.4% (95%CI: 13.1-25.4), respectively. According to endoscopists, screening PRs in males and females were 30.2% (95%CI: 27.0-41.9) and 16.6% (95%CI: 16.3-28.6), respectively. Sex-specific PRs did not meet quality benchmarks at all ages except for: males aged 65-69 (patient screening indication), and males aged 70-74 (endoscopist screening indication). For all patients aged 50-54, none of the CI included the quality benchmarks. CONCLUSION: Most sex-specific screening PRs in Québec were below quality benchmarks; PRs were especially low for all 50-54 year olds.

Feasibility of a call-in centre to deliver colorectal cancer screening in primary care.

OBJECTIVE: To evaluate the feasibility of a call-in centre to deliver colorectal cancer (CRC) screening in primary care through self-administered fecal occult blood testing (FOBT). DESIGN: Four-month intervention study (September 2010 to January 2011) with randomly selected follow-up interviews. SETTING: The family medicine clinics of 3 hospitals in Montreal, Que. PARTICIPANTS: Letters from doctors invited their patients to contact the call-in centre (N = 761). Eligible patients agreeing to FOBT were sent testing kits that could be returned by mail (N = 100). Randomly selected patients (N = 36) were interviewed to explore the reasons why they did not contact the call-in centre, or why they did or did not adhere to FOBT. MAIN OUTCOME MEASURES: Feasibility was assessed by the proportions of patients who contacted the call-in centre, who were eligible for FOBT, and who adhered to FOBT; and by the time between invitation mail-out and contact with the call-in centre, initial telephone contact and receipt of the signed consent form, and FOBT kit mail-out and receipt of the kit by the laboratory. Hierarchical logistic regression evaluated the effect of patient characteristics on feasibility indicators, adjusting for clustering by physician and centre. RESULTS: Of 761 patients (61.6% female, mean age 61.0 years), 250 (32.9%) contacted the call-in centre, of whom 100 (40.0%) were eligible for and consented to FOBT; 62 (62.0%) of these patients adhered to FOBT. Median (interquartile range) time from invitation mail-out to call-in centre contact was 21 (7 to 29) days, from initial telephone contact to receipt of the signed consent form was 24 (10 to 38) days, and from FOBT kit mail-out to receipt at the laboratory was 23 (18 to 32) days. With the exception of previous cancer diagnosis, patient characteristics were not associated with feasibility indicators. Of the 115 (46.0%) patients determined to be ineligible for FOBT screening, 111 (96.5%) were up to date with or already scheduled for screening. CONCLUSION: Feasibility of the call-in centre was demonstrated. Targeting screening-eligible individuals or coupling a call-in service with another evidence-based CRC screening improvement strategy might further improve uptake of fecal testing.

Epidemiologic approaches to evaluating the potential for human papillomavirus type replacement postvaccination.

Currently, 2 vaccines exist that prevent infection by the genotypes of human papillomavirus (HPV) responsible for approximately 70% of cervical cancer cases worldwide. Although vaccination is expected to reduce the prevalence of these HPV types, there is concern about the effect this could have on the distribution of other oncogenic types. According to basic ecological principles, if competition exists between ≥2 different HPV types for niche occupation during natural infection, elimination of 1 type may lead to an increase in other type(s). Here, we discuss this issue of "type replacement" and present different epidemiologic approaches for evaluation of HPV type competition. Briefly, these approaches involve: 1) calculation of the expected frequency of coinfection under independence between HPV types for comparison with observed frequency; 2) construction of hierarchical logistic regression models for each vaccine-targeted type; and 3) construction of Kaplan-Meier curves and Cox models to evaluate sequential acquisition and clearance of HPV types according to baseline HPV status. We also discuss a related issue concerning diagnostic artifacts arising when multiple HPV types are present in specific samples (due to the inability of broad-spectrum assays to detect certain types present in lower concentrations). This may result in an apparent increase in previously undetected types postvaccination.

Endoscopist specialty is associated with colonoscopy quality.

BACKGROUND: Some studies have shown that endoscopist specialty is associated with colorectal cancers missed by colonoscopy. We sought to examine the relationship between endoscopist specialty and polypectomy rate, a colonoscopy quality indicator. Polypectomy rate is defined as the proportion of colonoscopies that result in the removal of one or more polyps. METHODS: A cross-sectional study was conducted of endoscopists and their patients from 7 Montreal and 2 Calgary endoscopy clinics. Eligible patients were aged 50-75 and covered by provincial health insurance. A patient questionnaire assessed family history of colorectal cancer, history of large bowel conditions and symptoms, and previous colonoscopy. The outcome, polypectomy status, was obtained from provincial health administrative databases. For each city, Bayesian hierarchical logistic regression was used to estimate the odds ratio for polypectomy comparing surgeons to gastroenterologists. Model covariates included patient age, sex, family history of colorectal cancer, colonoscopy indication, and previous colonoscopy. RESULTS: In total, 2,113 and 538 colonoscopies were included from Montreal and Calgary, respectively. Colonoscopies were performed by 38 gastroenterologists and 6 surgeons in Montreal, and by 31 gastroenterologists and 5 surgeons in Calgary. The adjusted odds ratios comparing surgeons to gastroenterologists were 0.48 (95% CI: 0.32-0.71) in Montreal and 0.73 (95% CI: 0.43-1.21) in Calgary. CONCLUSIONS: An association between endoscopist specialty and polypectomy was observed in both cities after adjusting for patient-level covariates. Results from Montreal suggest that surgeons are half as likely as gastroenterologists to remove polyps, while those from Calgary were associated with a wide, non-significant Bayesian credible interval. However, residual confounding from patient-level variables is possible, and further investigation is required.

Developing model-based algorithms to identify screening colonoscopies using administrative health databases.

BACKGROUND: Algorithms to identify screening colonoscopies in administrative databases would be useful for monitoring colorectal cancer (CRC) screening uptake, tracking health resource utilization, and quality assurance. Previously developed algorithms based on expert opinion were insufficiently accurate. The purpose of this study was to develop and evaluate the accuracy of model-based algorithms to identify screening colonoscopies in health administrative databases. METHODS: Patients aged 50-75 were recruited from endoscopy units in Montreal, Quebec, and Calgary, Alberta. Physician billing records and hospitalization data were obtained for each patient from the provincial administrative health databases. Indication for colonoscopy was derived using Bayesian latent class analysis informed by endoscopist and patient questionnaire responses. Two modeling methods were used to fit the data, multivariate logistic regression and recursive partitioning. The accuracies of these models were assessed. RESULTS: 689 patients from Montreal and 541 from Calgary participated (January to March 2007). The latent class model identified 554 screening exams. Multivariate logistic regression predictions yielded an area under the curve of 0.786. Recursive partitioning using the latent outcome had sensitivity and specificity of 84.5% (95% CI: 81.5-87.5) and 63.3% (95% CI: 59.7-67.0), respectively. CONCLUSIONS: Model-based algorithms using administrative data failed to identify screening colonoscopies with sufficient accuracy. Nevertheless, the approach of constructing a latent reference standard against which model-based algorithms were evaluated may be useful for validating administrative data in other contexts where there lacks a gold standard.