The association between offspring birthweight and future risk of maternal diabetes: A population-based study.

AIMS: As an indicator of maternal cardiometabolic health, newborn birthweight may be an important predictor of maternal type 2 diabetes mellitus (diabetes). We evaluated the relation between offspring birthweight and onset of maternal diabetes after pregnancy. METHODS: This retrospective cohort study used linked population-based health databases from Ontario, Canada. We included women aged 16-50 years without pre-pregnancy diabetes, and who had a live birth between 2006 and 2014. We used Cox proportional hazard regression to evaluate the association between age- and sex-standardized offspring birthweight percentile categories and incident maternal diabetes, while adjusting for maternal age, parity, year, ethnicity, gestational diabetes (GDM) and hypertensive disorders of pregnancy (HDP). Results were further stratified by the presence of GDM in the index pregnancy. RESULTS: Of 893,777 eligible participants, 14,329 (1.6%) women were diagnosed with diabetes over a median (IQR) of 4.4 (1.5-7.4) years of follow-up. There was a continuous positive relation between newborn birthweight above the 75th percentile and maternal diabetes. Relative to a birthweight between the 50th and 74.9th percentiles, women whose newborn had a birthweight between the 97th and 100th percentiles had an adjusted hazards ratio (aHR) of diabetes of 2.30 (95% CI 2.16-2.46), including an aHR of 2.01 (95% CI 1.83-2.21) among those with GDM, and 2.59 (2.36-2.84) in those without GDM. CONCLUSIONS: A higher offspring birthweight signals an increased risk of maternal diabetes, offering another potentially useful way to identify women especially predisposed to diabetes.

The association between immigration status and the development of type 2 diabetes in women with a prior diagnosis of gestational diabetes: A population-based study.

AIMS: The aim of this study was to examine the influence of immigration status and region of origin on the risk of type 2 diabetes in women with prior gestational diabetes (GDM). METHODS: This retrospective population-based cohort study included women with gestational diabetes (GDM) aged 16 to 50 years in Ontario, Canada, who gave birth between 2006 and 2014. We compared the incidence of type 2 diabetes after delivery between long-term residents and immigrants-overall, by time since immigration and by region of-using Cox regression adjusted for age, year, neighbourhood income, rurality, infant birth weight and presence of hypertensive disorders of pregnancy (HDP). RESULTS: Among 38,515 women with prior GDM (42% immigrants), immigrants had a significantly higher risk of type 2 diabetes compared with long-term residents (adjusted hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.13-1.26), with no meaningful difference based on time since immigration. The highest adjusted relative risks of type 2 diabetes compared with long-term residents were found for immigrants from Sub-Saharan Africa (HR 1.63, 95% CI 1.40-1.90), Latin America/Caribbean (HR 1.44, 95% CI 1.28-1.62) and South Asia (HR 1.34, 95% CI 1.25-1.44). CONCLUSIONS: Immigration is associated with a significantly higher risk of type 2 diabetes after GDM, particularly for women from certain low- and middle-income countries. Diabetes prevention strategies will need to consider the unique needs of immigrants from these regions.

Periodic screening for breast and cervical cancer in women with diabetes: a population-based cohort study.

PURPOSE: Diabetes is associated with poorer cancer outcomes. Screening for breast and cervical cancer is recommended by clinical guidelines; however, utilization of these tests in people with diabetes has been unclear due to methodological limitations in the evidence base. We used administrative data to determine the association between diabetes and the rates of becoming up-to-date with periodic breast and cervical cancer screening over a 20-year period. METHODS: Healthcare databases from Ontario, Canada, were linked to assemble two population-based cohorts of 50-70 and 21-70 year-olds between 1994 and 2011, eligible for breast and cervical cancer screening, respectively. Using age as the time scale, multivariable recurrent events models were implemented to examine the association between the presence of diabetes and the rates of becoming up-to-date with the recommended cancer screenings. RESULTS: In each of the breast and cervical cancer screening cohorts, there were, respectively, 1,516,302 (16% had diabetes at baseline) and 4,751,220 (9.5% had diabetes at baseline) screen-eligible women. In multivariable models, prevalent diabetes (duration ≥ 2 years) was associated with lower rates of becoming up-to-date with cervical (hazard ratio, HR 0.85, 95% confidence interval, CI 0.84-0.85) and breast (HR 0.94, CI 0.93-0.94) cancer screening, compared to no diabetes. CONCLUSIONS: Having diabetes is associated with decreased rates of becoming up-to-date with two recommended periodic cancer screenings, with a bigger reduction in the rates of becoming up-to-date with cervical cancer screening. Greater attention to cervical cancer preventive services is needed in women with diabetes.

Contemporary Trends in Breast Reconstruction Use and Impact on Survival Among Women with Inflammatory Breast Cancer.

BACKGROUND: Breast reconstruction is generally discouraged in women with inflammatory breast cancer (IBC). Nevertheless, reconstruction rates are increasing in this population. OBJECTIVE: We aimed to determine contemporary trends and predictors of breast reconstruction use and its impact on mortality among IBC patients. METHODS: Demographic, clinicopathologic, and follow-up data for women with non-metastatic IBC having mastectomy between 2004 and 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Rates and predictors of immediate breast reconstruction, along with survival outcomes between the breast reconstruction and no reconstruction groups were calculated. To account for selection bias, a propensity score analysis matching one reconstruction patient to three no reconstruction patients was performed. RESULTS: A total of 4076 women with non-metastatic IBC who underwent mastectomy (388 [9.5%] with breast reconstruction and 3688 [90.5%] without) were included. The proportion of women undergoing breast reconstruction and contralateral prophylactic mastectomy increased from 6.2 to 15.3% and 12.9 to 29.6%, respectively, between 2004 and 2015. Younger age, higher annual income, metropolitan residence, and bilateral mastectomy predicted breast reconstruction use. The 10-year breast cancer-specific survival was 62.9% for women having breast reconstruction and 47.6% for women not having breast reconstruction. After propensity-matched analysis, 10-year cancer-specific survival was similar between the reconstruction (56.6%) and no reconstruction (62.2%) groups (adjusted hazard ratio 0.96, 95% confidence interval 0.79-1.16; p = 0.65). CONCLUSIONS: Breast reconstruction rates continue to rise among IBC patients, particularly young women and women with access to reconstruction. Breast reconstruction is not associated with inferior breast cancer-specific survival and can be an option for select patients.

The risk of contralateral breast cancer: a SEER-based analysis.

BACKGROUND: We sought to estimate the annual risk and 25-year cumulative risk of contralateral breast cancer among women with stage 0-III unilateral breast cancer. METHODS: We identified 812,851 women with unilateral breast cancer diagnosed between 1990 and 2015 in the SEER database and followed them for contralateral breast cancer for up to 25 years. Women with a known bilateral mastectomy were excluded. We calculated the annual risk of contralateral breast cancer by age at diagnosis, by time since diagnosis and by current age. We compared risks by ductal carcinoma in situ (DCIS) versus invasive disease, by race and by oestrogen receptor (ER) status of the first cancer. RESULTS: There were 25,958 cases of contralateral invasive breast cancer diagnosed (3.2% of all patients). The annual risk of contralateral breast cancer over the 25-year follow-up period was 0.37% and the 25-year actuarial risk of contralateral invasive breast cancer was 9.9%. The annual risk varied to a small degree by age of diagnosis, by time elapsed since diagnosis and by current age. The 25-year actuarial risk was similar for DCIS and invasive breast cancer patients (10.1 versus 9.9%). The 25-year actuarial risk was higher for black women (12.7%) than for white women (9.7%) and was lower for women with ER-positive breast cancer (9.5%) than for women with ER-negative breast cancer (11.2%). CONCLUSIONS: Women with unilateral breast cancer experience an annual risk of contralateral breast cancer ~0.4% per year, which persists over the 25-year follow-up period.

The relationship between the predicted risk of death and psychosocial functioning among women with early-stage breast cancer.

PURPOSE: Many women with early-onset breast cancer experience adverse psychological sequelae which impact on their quality of life. We sought to correlate levels of anxiety and cancer-related distress in women with breast cancer shortly after surgery and one year after treatment with the estimated risk of death. METHODS: We studied 596 women with Stage I to III breast cancer. For each woman we estimated the five-year risk of death based on SEER data from 2010 to 2019. For each woman we measured anxiety and cancer-related distress levels shortly after surgery and one year later. RESULTS: The mean estimated five-year survival was 95%. At one week post-surgery, 59% of women had a clinically significant level of anxiety and 74% had a clinically significant level of cancer-related distress. There was no correlation between the objective risk of death and the level of anxiety or distress, at one week or at one year. CONCLUSIONS: Many women diagnosed with early-stage breast cancers experience significant levels of anxiety and distress. The emotional response to a breast cancer diagnosis is not related to the risk of death per se and other factors should be explored.

Impact of diabetes on colorectal cancer stage and mortality risk: a population-based cohort study.

AIMS/HYPOTHESIS: Diabetes is associated with an increased incidence of colorectal cancer (CRC). There exists conflicting evidence regarding the impact of diabetes on CRC-specific mortality (herein also referred to as cancer-specific mortality). The objectives of this study were to determine whether diabetes is associated with a more advanced CRC stage at diagnosis and with higher all-cause and cancer-specific mortality. METHODS: This retrospective cohort study used linked, population-based health databases from Ontario, Canada. Among individuals diagnosed with CRC from 2007 to 2015, we compared the likelihood of presenting with later- (III or IV) vs early- (I or II) stage CRC between patients with and without diabetes adjusting for relevant covariates. We then determined the association between diabetes and all-cause and CRC-specific mortality, after adjusting for CRC stage at diagnosis and other covariates. RESULTS: Of the 44,178 individuals with CRC, 11,822 (26.7%) had diabetes. After adjustment for CRC screening and other covariates, individuals with diabetes were not more likely to present with later-stage CRC (adjusted OR 0.97, 95% CI 0.93, 1.01). Over a median follow-up of 2.63 (interquartile range [IQR] 0.97-5.10) years, diabetes was associated with higher all-cause mortality (adjusted HR 1.08, 95% CI 1.04, 1.12) but similar cancer-specific survival (adjusted HR 1.0, 95% CI 0.95, 1.06). CONCLUSIONS/INTERPRETATION: Individuals with diabetes who develop CRC are not more likely to present with a later stage of CRC and have similar cancer-specific mortality compared with those without diabetes. Diabetes was associated with higher all-cause mortality in CRC patients, indicating that greater attention to non-cancer care is needed for CRC survivors with diabetes.

A generalizable relationship between mortality and time-to-death among breast cancer patients can be explained by tumour dormancy.

BACKGROUND: Women with ER-positive breast cancer may recur as late as 20 years post-diagnosis. The reason for this delayed recurrence is unknown. We studied survival patterns, including time-to-death in 123,705 women with stage I to III invasive breast cancer, enrolled in the SEER database. Among these 76.8% were ER-positive and 23.2% were ER-negative. METHODS: We divided the cohort into ten classes with varying risks of death from breast cancer. The 20-year mortality for women in the highest risk decile 10 was 69% versus 5% for women in the lowest decile 1. The difference in the time-to-death by decile could be explained by a variable α which represents the annual rate of reactivation from tumour dormancy. RESULTS: The duration of tumour dormancy was much longer, on average, for ER-positive breast cancers than for ER-negative breast cancers. Reactivation from tumour dormancy appears to occur at random and may explain the very long time to cancer recurrence in women with small node-negative ER-positive breast cancers. CONCLUSION: The clinical course of women with low-risk ER-positive breast cancer is inherently unpredictable and consequently death is equally as likely to occur at year 3 than at year 20.

The Association Between Insulin Initiation and Adverse Outcomes After Hospital Discharge in Older Adults: a Population-Based Cohort Study.

BACKGROUND: Starting insulin therapy in hospitalized patients may be associated with an increase in serious adverse events after discharge. OBJECTIVE: Determine whether post-discharge risks of death and rehospitalization are higher for older hospitalized patients prescribed new insulin therapy compared with oral hypoglycemic agents (OHAs). DESIGN: Retrospective population-based cohort study including hospital admissions in Ontario, Canada, between April 1, 2004, and Nov 30, 2013. PATIENTS: Persons aged 66 and over discharged after a hospitalization and dispensed a prescription for insulin and/or an OHA within 7 days of discharge. We included 104,525 individuals, subcategorized into four mutually exclusive exposure groups based on anti-hyperglycemic drug use in the 7 days post-discharge and the 365 days prior to the index admission. MAIN MEASURES: Prescriptions at discharge were categorized as new insulin (no insulin before admission), prevalent insulin (prescribed insulin before admission), new OHA(s) (no OHA or insulin before admission), and prevalent OHA (prescribed OHA only before admission) as the referent category. The primary and secondary outcomes were 30-day deaths and emergency department (ED) visits or readmissions respectively. KEY RESULTS: Of 104,525 patients, 9.2% were initiated on insulin, 4.1% died, and 26.2% had an ED visit or readmission within 30 days of discharge. Deaths occurred in 7.14% of new insulin users, 4.86% of prevalent insulin users, 3.25% of new OHA users, and 3.45% of prevalent OHA users. After adjustment for covariates, new insulin users had a significantly higher risk of death (adjusted hazard ratio (aHR) 1.59, 95% confidence interval (CI) 1.46 to 1.74) and ED visit/readmissions (aHR 1.17, 95% CI 1.12 to 1.22) than prevalent OHA users. CONCLUSIONS: Initiation of insulin therapy in older hospitalized patients is associated with a higher risk of death and ED visits/readmissions after discharge, highlighting a need for better transitional care of insulin-treated patients.

Denosumab and breast cancer risk in postmenopausal women: a population-based cohort study.

BACKGROUND: Denosumab inhibits the receptor activator of nuclear factor κB (RANK) pathway and is used to treat osteoporosis. Emerging evidence suggests RANK-blockade may play a role in mammary tumourigenesis. Thus, we undertook a population-based study of denosumab use and breast cancer risk in a large cohort of postmenopausal women. METHODS: We included women 67+ years with prior bisphosphonate use who filled a first prescription for denosumab. They were matched on age, date, cumulative prior use of and time since last use of a bisphosphonate to women with no history of denosumab. Cox proportional hazards was used to estimate the hazard ratio (HR) of breast cancer with denosumab use. RESULTS: A total of 100,368 women were included in the analysis with 1271 incident breast cancer events. Denosumab use was associated with a 13% decreased breast cancer risk (HR = 0.87; 95% CI 0.76-1.00). There was no relationship between increasing number of denosumab doses and breast cancer risk (P-trend = 0.15). CONCLUSION: These findings suggest a potential protective effect of ever denosumab use on breast cancer risk in a cohort of older women previously treated with bisphosphonates.

The expected benefit of preventive mastectomy on breast cancer incidence and mortality in BRCA mutation carriers, by age at mastectomy.

PURPOSE: Preventive breast surgery is offered to unaffected BRCA mutation carriers to prevent breast cancer incidence and mortality. The clinical benefit of preventive mastectomy can be measured in several ways, including extension of life expectancy (mean years of life gained) and by estimating the probability of surviving until age 80. We sought to estimate the expected benefit of a preventive mastectomy at various ages, using these indices of mortality, by simulating hypothetical cohorts of women. METHODS: The age-specific annual risks of developing breast cancer were used to estimate the actuarial risk of developing breast cancer by age 80 for women with a BRCA1 or BRCA2 mutation. The probability of developing breast cancer before age 80 was then modified to include competing causes of death, including from ovarian cancer. The mortality rate from breast cancer after a diagnosis of breast cancer was set at 2% annually for the first 10 years and then 1% annually for years ten to twenty. The incidence rate and mortality rate from ovarian cancer were based on published literature. We assumed that preventive mastectomy was associated with complete protection against subsequent breast cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) until age 80, according to the age at mastectomy. RESULTS: The actuarial risk of developing breast cancer until age 80 was estimated to be 70.8%. The actual risk (incorporating competing risks) was 64.0%. The probability of being alive at age 80 by having a mastectomy at age 25 increased by 8.7% (from 42.7 to 51.3%). The estimated benefit declined with age at mastectomy; for surgery done at age 50 the improvement in survival to age 80 was much more modest (2.8% at age 80, from 42.7 to 45.5%). CONCLUSIONS: Among BRCA mutation carriers, the mortality benefit of preventive mastectomy at age 25 is substantial, but the expected benefit declines rapidly with increasing age at surgery.

Time to death in breast cancer patients as an indicator of treatment response.

PURPOSE: To describe the mortality experience of women who die of breast cancer in the 20-year period post-diagnosis using various metrics, including annual mortality rates, Kaplan-Meier survival curves and time-to-death histograms. METHODS: We generated three visual representations of SEER-based and hospital-based breast cancer patient cohorts using three different metrics of mortality. RESULTS: The greatest impact of most prognostic factors was on the probability of latent metastases present after treatment, but for some factors the primary impact was on the time to death for those women with metastases. CONCLUSIONS: The use of time-to-death statistics to display mortality benefits for treated versus untreated women helps facilitate the distinction between treatments which increase the likelihood of cure and treatments that delay cancer growth.

A comparison of two models for breast cancer mortality for women with ductal carcinoma in situ: an SEER-based analysis.

BACKGROUND: Approximately 1% of patients with ductal carcinoma in situ (DCIS) will die of breast cancer within 10 years. Women who develop an invasive breast cancer after DCIS have a much greater risk of dying than those who do not and it is often stated that these deaths are a consequence of metastases from the invasive in-breast recurrence. This progression is the result of a two-step process: first local invasive recurrence and then spread beyond the breast. A large proportion of women who die of DCIS have no record of invasive recurrence. We used SEER data and a simulation approach to test whether the actual mortality data are consistent with the two-step model. METHODS: First, we constructed Kaplan-Meier mortality curves for all patients with pure DCIS and with small node-negative invasive breast cancers in the Surveillance, Epidemiology and End Results (SEER) registries database (1998-2014). We then constructed, through simulation, theoretical breast cancer mortality curves. To model the two-step scenario, we applied the annual incidence rates of incident invasive cancer following DCIS and of death from invasive cancer after DCIS to a theoretical cohort of 100,000 women. RESULTS: The observed 15-year breast cancer-specific mortality rate for patients with pure DCIS in the SEER database was 2.0%. The expected mortality for DCIS patients (assuming a two-step process) was only 1.1% at 15 years. Assuming the mortality rates following DCIS were one-half of those observed for patients with small invasive breast cancers, the expected mortality at 15 years post-DCIS was 2.1%. CONCLUSIONS: In the SEER database, we observed far more deaths from DCIS than would be expected under a model where all deaths from breast cancer occur amongst women who experience an invasive local recurrence. This lends support to the hypothesis that DCIS mortality is not restricted to those women who experience an in-breast invasive cancer and that DCIS has properties similar to small invasive breast cancers.

Predictors and Outcomes of Dysphagia Screening After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Guidelines advocate screening all acute stroke patients for dysphagia. However, limited data are available regarding how many and which patients are screened and how failing a swallowing screen affects patient outcomes. We sought to evaluate predictors of receiving dysphagia screening after acute ischemic stroke and outcomes after failing a screening test. METHODS: We used the Ontario Stroke Registry from April 1, 2010, to March 31, 2013, to identify patients hospitalized with acute ischemic stroke and determine predictors of documented dysphagia screening and outcomes after failing the screening test, including pneumonia, disability, and death. RESULTS: Among 7171 patients, 6677 patients were eligible to receive dysphagia screening within 72 hours, yet 1280 (19.2%) patients did not undergo documented screening. Patients with mild strokes were significantly less likely than those with more severe strokes to have documented screening (adjusted odds ratio, 0.51; 95% confidence interval [CI], 0.41-0.64). Failing dysphagia screening was associated with poor outcomes, including pneumonia (adjusted odds ratio, 4.71; 95% CI, 3.43-6.47), severe disability (adjusted odds ratio, 5.19; 95% CI, 4.48-6.02), discharge to long-term care (adjusted odds ratio, 2.79; 95% CI, 2.11-3.79), and 1-year mortality (adjusted hazard ratio, 2.42; 95% CI, 2.09-2.80). Associations were maintained in patients with mild strokes. CONCLUSIONS: One in 5 patients with acute ischemic stroke did not have documented dysphagia screening, and patients with mild strokes were substantially less likely to have documented screening. Failing dysphagia screening was associated with poor outcomes, including in patients with mild strokes, highlighting the importance of dysphagia screening for all patients with acute ischemic stroke.

The impact of nodal micrometastasis on mortality among women with early-stage breast cancer.

PURPOSE: The clinical significance of nodal micrometastasis is debated. Our primary objective was to determine whether, among women with early-stage breast cancer, regional lymph node micrometastasis is an independent risk factor for mortality. The secondary objective was to identify subgroups of women who have the highest risk of death from early-stage breast cancer with micrometastases. METHODS: 206,625 women diagnosed with early-stage breast cancer (IA, IB, and IIA) from 2004 to 2012 were identified in the Surveillance, epidemiology, and end results database. Nodal status was classified as node-negative, isolated-tumor cells, micrometastases, and macrometastases. Women were classified into eight ethnic groups. Logistic regression was performed to estimate the odds ratio of being diagnosed with micrometastases. The Cox proportional hazard model was used to estimate the hazard ratio (HR) of breast cancer-specific death associated with micrometastases for each ethnic group. RESULTS: The 8-year breast cancer-specific survival was 96.6 % for women with node-negative breast cancers and was 94.6 % for women with micrometastases (adjusted HR 1.49; 95 % CI 1.31-1.69; P < .001). Among women with micrometastases, the 8-year breast cancer-specific survival was 95.1 % for white women and was 90.6 % for black women (HR 1.80; 95 % CI 1.29-2.52; P = .0006). CONCLUSION(S): Nodal micrometastasis is an independent risk factor for breast cancer mortality among women with early-stage breast cancer. Black women are more likely to die from breast cancer with micrometastases than white women.

Risk of breast cancer after a diagnosis of ovarian cancer in BRCA mutation carriers: Is preventive mastectomy warranted?

OBJECTIVE: Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. METHODS: First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality. RESULTS: Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer. CONCLUSIONS: Among BRCA mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer.

Influences on the start, selection and duration of treatment with antibiotics in long-term care facilities.

BACKGROUND: Understanding the extent to which current antibiotic prescribing behaviour is influenced by clinicians' historical patterns of practice will help target interventions to optimize antibiotic use in long-term care. Our objective was to evaluate whether clinicians' historical prescribing behaviours influence the start, prolongation and class selection for treatment with antibiotics in residents of long-term care facilities. METHODS: We conducted a retrospective cohort study of all physicians who prescribed to residents in long-term care facilities in Ontario between Jan. 1 and Dec. 31, 2014. We examined variability in antibiotic prescribing among physicians for 3 measures: start of treatment with antibiotics, use of prolonged durations exceeding 7 days and selection of fluoroquinolones. Funnel plots with control limits were used to determine the extent of variation and characterize physicians as extreme low, low, average, high and extreme high prescribers for each tendency. Multivariable logistic regression was used to assess whether a clinician's prescribing tendency in the previous year predicted current prescribing patterns, after accounting for residents' demographics, comorbidity, functional status and indwelling devices. RESULTS: Among 1695 long-term care physicians, who prescribed for 93 132 residents, there was wide variability in the start of antibiotic treatment (median 45% of patients, interquartile range [IQR] 32%-55%), use of prolonged treatment durations (median 30% of antibiotic prescriptions, IQR 19%-46%) and selection of fluoroquinolones (median 27% of antibiotic prescriptions, IQR 18%-37%). Prescribing tendencies for antibiotics by physicians in 2014 correlated strongly with tendencies in the previous year. After controlling for individual resident characteristics, prior prescribing tendency was a significant predictor of current practice. INTERPRETATION: Physicians prescribing antibiotics exhibited individual, measurable and historical tendencies toward start of antibiotic treatment, use of prolonged treatment duration and class selection. Prescriber audit and feedback may be a promising tool to optimize antibiotic use in long-term care facilities.

A model for ovarian cancer progression based on inherent resistance.

OBJECTIVE: Women with ovarian cancer are treated with debulking surgery and chemotherapy. The bulk of ovarian cancer cells are resistant to chemotherapy prior to the death of the patient. It is not clear if chemoresistance is an acquired property of cells under the selective pressure of chemotherapy or if it is an innate property of a small proportion of cancer cells from the outset. METHODS: We developed a mathematical model to describe ovarian cancer progression based on the assumption that a small proportion of ovarian cancer cells are chemoresistant from the beginning (0.1%) and that there is no acquired resistance. The doubling time was fixed at two months for sensitive cells and four months for resistant cells. RESULTS: The proportion of chemoresistant cells increased over time and at the time of death, 90% of cells were resistant. The typical patient responded to the first three rounds of chemotherapy but was non-responsive thereafter. When we assume that the doubling times of the cancer cells is not fixed, but varies according to a normal distribution, the mean doubling time of the cells diminishes with time from diagnosis and death ensues shortly after chemoresistance is observed. CONCLUSIONS: We show that a model of inherent resistance in ovarian cancer is able to recapitulate the clinical history of a typical patient with ovarian cancer and that it is not necessary to invoke acquired resistance. This observation has potential clinical implications about how to approach new therapies.