A pragmatic randomized trial of a primary care antimicrobial stewardship intervention in Ontario, Canada.

BACKGROUND: More than 90% of antibiotics are prescribed in primary care, but 50% may be unnecessary. Reducing unnecessary antibiotic overuse is needed to limit antimicrobial resistance. We conducted a pragmatic trial of a primary care provider-focused antimicrobial stewardship intervention to reduce antibiotic prescriptions in primary care. METHODS: Primary care practitioners from six primary care clinics in Toronto, Ontario were assigned to intervention or control groups to evaluate the effectiveness of a multi-faceted intervention for reducing antibiotic prescriptions to adults with respiratory and urinary tract infections. The intervention included provider education, clinical decision aids, and audit and feedback of antibiotic prescribing. The primary outcome was total antibiotic prescriptions for these infections. Secondary outcomes were delayed prescriptions, prescriptions longer than 7 days, recommended antibiotic use, and outcomes for individual infections. Generalized estimating equations were used to estimate treatment effects, adjusting for clustering by clinic and baseline differences. RESULTS: There were 1682 encounters involving 54 primary care providers from January until May 31, 2019. In intervention clinics, the odds of any antibiotic prescription was reduced 22% (adjusted Odds Ratio (OR) = 0.78; 95% Confidence Interval (CI) = 0.64.0.96). The odds that a delay in filling a prescription was recommended was increased (adjusted OR=2.29; 95% CI=1.37, 3.83), while prescription durations greater than 7 days were reduced (adjusted OR=0.24; 95% CI=0.13, 0.43). Recommended antibiotic use was similar in control (85.4%) and intervention clinics (91.8%, p=0.37). CONCLUSIONS: A community-based, primary care provider-focused antimicrobial stewardship intervention was associated with a reduced likelihood of antibiotic prescriptions for respiratory and urinary infections, an increase in delayed prescriptions, and reduced prescription durations. TRIAL REGISTRATION: clinicaltrials.gov ( NCT03517215 ).

Long-Term Psychosocial Functioning in Women with Bilateral Prophylactic Mastectomy: Does Preservation of the Nipple-Areolar Complex Make a Difference?

INTRODUCTION: Nipple-sparing prophylactic mastectomy (PM) is an option for women at high-risk for breast cancer, and may offer better cosmetic results than a skin-sparing PM where the nipple-areolar complex (NAC) is removed. However, there may be residual breast cancer risk due to the maintained NAC. It is unclear if sparing the NAC with PM impacts on psychosocial functioning, including cancer-related distress and body image after PM. METHODS: This was a cross-sectional survey study of women who had undergone bilateral PM (no previous breast cancer) recruited through surgical or cancer genetics clinics. All women completed standardized questionnaires assessing cancer-related distress, anxiety, depression, satisfaction with decision, decision regret, and health-related quality of life related to breast surgery. Outcomes were compared between women with nipple-areola-sparing PM (NAC-PM) and skin-sparing PM (SS-PM). RESULTS: Overall, 137 women completed the study; 53 (39%) had NAC-PM and 84 (61%) had SS-PM. The mean age of the study population was 41.5 years [standard deviation (SD) 8.8] and the mean time between PM and questionnaire completion was 50 months (SD 31). On the BREAST-Q, we found that women with NAC-PM had significantly higher levels of satisfaction with breasts (p = 0.01), satisfaction with outcome (p = 0.02), and sexual well-being (p < 0.001) compared with SS-PM. No statistically significant differences in total cancer-related distress (p = 0.89), anxiety (p = 0.86), or depression (p = 0.93) were observed between the two groups. CONCLUSIONS: Overall, women with NAC-PM had better body image and sexual functioning compared with women with SS-PM, while both groups had comparable levels of cancer-related distress and perception of breast cancer risk.

Homing receptor expression is deviated on CD56+ blood lymphocytes during pregnancy in Type 1 diabetic women.

Type 1 Diabetes Mellitus (T1DM) is characterized by an augmented pro-inflammatory immune state. This contributes to the increased risk for gestational complications observed in T1DM mothers. In normal pregnancies, critical immunological changes occur, including the massive recruitment of lymphocytes, particularly CD56bright NK cells, into early decidua basalis and a 2nd trimester shift towards Type 2 immunity. Decidual CD56bright NK cells arise at least partly from circulating progenitors expressing adhesion molecules SELL and ITGA4 and the chemokine receptors CXCR3 and CXCR4. In vitro studies show that T1DM reduces interactions between blood CD56+ NK cells and decidual endothelial cells by reducing SELL and ITGA4-based interactions. To address the mechanisms by which specific lymphocyte subsets may be recruited from the circulation during pregnancy and whether these mechanisms are altered in T1DM, flow cytometry was used to examine eight peripheral blood lymphocyte subsets (Type 1 (IL18R1+) and Type 2 (IL1RL1+) CD56bright NK, CD56dim NK, NKT and T cells) from control and T1DM women. Blood was collected serially over pregnancy and postpartum, and lymphocytes were compared for expression of homing receptors SELL, ITGA4, CXCR3, and CXCR4. The decline of Type 1/Type 2 immune cells in normal pregnancy was driven by an increase in Type 2 cells that did not occur in T1DM. CD56bright NK cells from control women had the highest expression of all four receptors with greatest expression in 2nd trimester. At this time, these receptors were expressed at very low levels by CD56bright NK cells from TIDM patients. Type 1/Type 2 NKT cell ratios were not influenced by either pregnancy or TIDM. Our results suggest that T1DM alters immunological balances during pregnancy with its greatest impact on CD56bright NK cells. This implicates CD56bright NK cells in diabetic pregnancy complications.

Blocking of stromal cell-derived factor-1 reduces neoangiogenesis in human endometriosis lesions in a mouse model.

PROBLEM: Endometriosis affects 5-10% of women and is characterized by the growth of endometrial tissue outside of the uterus. Establishing new blood supply is a fundamental requirement for endometriosis lesion growth. Endothelial progenitor cells (EPCs), recruited by stromal cell-derived factor-1 (SDF-1), contribute to neoangiogenesis in endometriotic lesions. We hypothesized that SDF-1 is central to the neoangiogenesis and survival of endometriotic lesions, and blocking of SDF-1 will reduce vascularization of lesions in a mouse model. METHOD OF STUDY: Using immunohistochemistry, we evaluated SDF-1 and CD34(+) EPCs in human endometriotic lesions and normal endometrium samples. EPCs were co-localized using CD34 and VEGFR2. Effects of SDF-1 blocking on endometriotic lesion survival were assessed in BALB/c-Rag2(-/-) /IL2rγ(-/-) mice engrafted with human endometrium and treated with SDF-1-blocking antibody or an isotype control. Weekly blood samples from experimental mice were analyzed for cytokines and EPCs. RESULTS: SDF-1 and CD34(+) EPCs were abundant in human endometriotic lesions compared with eutopic endometrium. In our mouse model, SDF-1-blocking antibody reduced CD31(+) microvessels compared with isotype control. CONCLUSION: Blocking SDF-1 reduces neovascularization and survival of lesions in a mouse model of endometriosis.

Animal models for anti-angiogenic therapy in endometriosis.

Endometriosis is a gynecological disease characterized by the growth of endometrium outside of the uterine cavity. It is often associated with dysmenorrhea, dyspareunia, pelvic pain and infertility. One of the key requirements for endometriotic lesions to survive is development of a blood supply to support their growth. Indeed, dense vascularization is characteristic feature of endometriotic lesions. This has led to the idea that suppression of blood vessel growth (anti-angiogenic therapy) may be a successful therapeutic approach for endometriosis. Potential effectiveness of anti-angiogenic therapies has been assessed in some animal models but there are no reports of human clinical trials. Without understanding the specific mechanism by which endometriosis lesions establish a new blood supply, short-term animal experiments will have limited value for translation into human medicine. Further, it is crucial to use appropriate animal models to assess efficacy of anti-angiogenic compounds. Syngeneic and autologous rodent models, where endometrial fragments are auto-transplanted into the peritoneal cavity are commonly used in anti-angiogenic therapy studies. Another approach is xenograft models where human endometrium is engrafted into immunodeficient mice. Here we review the animal models and experimental techniques used to evaluate anti-angiogenic therapies for endometriosis. We also review our own work on the role of stromal cell derived factor-1 in the recruitment of endothelial progenitor cells in endometriotic lesion angiogenesis, and the effects of the anti-angiogenic peptide ABT-898, a thrombospondin-1 mimetic, on endometriotic lesion growth and vascular development.

Thrombospondin-1 mimetic peptide ABT-898 affects neovascularization and survival of human endometriotic lesions in a mouse model.

Endometriosis is a common cause of pelvic pain and infertility in women, and a common indication for hysterectomy, yet the disease remains poorly diagnosed and ineffectively treated. Because endometriotic lesions require new blood supply for survival, inhibiting angiogenesis could provide a novel therapeutic strategy. ABT-898 mimics the antiangiogenic properties of thrombospondin-1, so we hypothesized that ABT-898 will prevent neovascularization of human endometriotic lesions and that ABT-898 treatment will not affect reproductive outcomes in a mouse model. Endometriosis was induced in BALB/c-Rag2(-/-)Il2rg(-/-) mice by surgical implantation of human endometrial fragments in the peritoneal cavity. Mice received daily injections of ABT-898 for 21 days. Flow cytometry was performed to measure circulating endothelial progenitor cells in peripheral blood. Cytokines were measured in plasma samples. Half of the ABT-898-treated and control mice were euthanized to assess neovascularization of endometriotic lesions, using CD31(+) immunofluorescence. The remaining mice were mated and euthanized at gestation day 12. Endometriotic lesions increased circulating endothelial progenitor cells 13 days after engraftment, relative to baseline. Endometriotic lesions from ABT-898-treated mice exhibited reduced neovascularization, compared with controls, and lesions had fewer CD31(+) microvessels. Chronic treatment with ABT-898 did not lead to any fetal anomalies or affect litter size at gestation day 12, compared with controls. Our results suggest that ABT-898 inhibits neovascularization of human endometriotic lesions without affecting mouse fecundity.

Morbidity and mortality after liver resection: results of the patient safety in surgery study.

BACKGROUND: Liver resection is performed with increasing frequency. Nearly all of the published information on operative mortality and morbidity rates associated with liver resection is derived from studies that rely on retrospective data collection from single centers. The goal of this study is to use audited multiinstitutional data from the private sector of the Patient Safety in Surgery Study to characterize complications after liver resection and to identify variables that are associated with 30-day morbidity and mortality. STUDY DESIGN: Prospectively collected data on liver resection patients from 14 hospitals were collected using National Surgical Quality Improvement Program's methodology. Rates of occurrence of 21 defined postoperative complications were measured. Bivariate analyses and stepwise logistic regression were used to identify factors associated with 30-day morbidity and mortality. RESULTS: At least one complication occurred in 22.6% of patients within 30 days. Stepwise logistic regression identified several preoperative factors associated with morbidity, including serum albumin, SGOT > 40, previous cardiac operation, operative work relative value unit, and history of severe COPD. Mortality within 30 days was observed in 2.6% of patients. Factors associated with mortality were found to be male gender, American Society of Anesthesiologists class 3 or higher, presence of ascites, dyspnea, and severe COPD. Only 0.7% of patients without any complications died, compared with 9.0% of patients with at least 1 complication (p < 0.0001). CONCLUSIONS: Prospective, standardized, audited, multiinstitutional data were analyzed to identify several preoperative and intraoperative factors associated with morbidity and mortality after liver resection. These factors should be considered during patient selection and perioperative management.