Genetics Consultation Rates Following a Diagnosis of High-Grade Serous Ovarian Carcinoma in the Canadian Province of Ontario.

OBJECTIVE: In 2001, the province of Ontario expanded cancer genetic testing eligibility to include all women with high-grade serous ovarian carcinoma (HGSC) of the ovary, fallopian tube, and peritoneum. The aim of this study was to determine the proportion of women who attended genetics counseling for consideration of BRCA1/2 gene analysis. We also sought to examine if regional differences in consultation rate exist across administrative health regions in the province of Ontario. METHODS: We identified all women with a pathological diagnosis of HGSC in the province of Ontario between 1997 until 2011. Our primary outcome was the 2-year rate of genetics consultation following a diagnosis of HGSC. We compared consultation rates over time and geographical regions and applied multiple logistic regression to identify predictors of genetics consultation. RESULTS: Of the 5412 women with a diagnosis of HGSC over the study period, 6.6% were seen for genetics consultation within 2 years of diagnosis. Factors predictive of genetics consultation included history of breast cancer (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.87-6.78), era of diagnosis (2009-2011 vs 1997-2000; OR, 10.59; 95% CI, 5.02-22.33), and younger age at diagnosis (OR, 0.95; 95% CI, 0.94-0.97 for each additional year). No regional differences in consultation rate were seen. CONCLUSIONS: Despite an increasing rate across eras, a small proportion of women with HGSC undergo genetics consultation. Efforts are required to increase cancer genetics consultation in patients with HGSC in the province of Ontario.

Disparities in surgery among patients with intractable epilepsy in a universal health system.

OBJECTIVE: To assess the use of epilepsy surgery in patients with medically intractable epilepsy in a publicly funded universal health care system. METHODS: We performed a population-based retrospective cohort study using linked health care databases for Ontario, Canada, between 2001 and 2010. We identified all patients with medically intractable epilepsy, defined as those with seizures that did not respond to at least 2 adequate trials of seizure medications. We assessed the proportion of patients who had epilepsy surgery within the following 2 years. We further identified the characteristics associated with epilepsy surgery. RESULTS: A total of 10,661 patients were identified with medically intractable epilepsy (mean age 47 years, 51% male); most (74%) did not have other comorbidities. Within 2 years of being defined as medically intractable, only 124 patients (1.2%) underwent epilepsy surgery. Death occurred in 12% of those with medically intractable epilepsy. Those who underwent the procedure were younger and had fewer comorbidities compared to those who did not. CONCLUSION: In our setting of publicly funded universal health care, more than 10% of patients died within 2 years of developing medically intractable epilepsy. Epilepsy surgery may be an effective treatment for some patients; however, fewer than 2% of patients who may have benefited from epilepsy surgery received it.

Trends in Psychotropic Dispensing Among Older Adults with Dementia Living in Long-Term Care Facilities: 2004-2013.

OBJECTIVE: Guidelines worldwide have cautioned against the use of antipsychotics as first-line agents to treat neuropsychiatric symptoms of dementia. We aimed to investigate the changes over time in the dispensing of antipsychotics and other psychotropics among older adults with dementia living in long-term care facilities. METHODS: We used drug claims data from Ontario, Canada, to calculate quarterly rates of prescription dispensing of six psychotropic drug classes among all elderly (≥65 years of age) long-term care residents with dementia from January 1, 2004, to March 31, 2013. Psychotropic drugs were classified into the following categories: atypical and conventional antipsychotics, non-sedative and sedative antidepressants, anti-epileptics, and benzodiazepines. We used time-series analysis to assess trends over time. RESULTS: The study sample increased by 21% over the 10-year study period, from 49,251 patients to 59,785 patients. The majority of patients (within the range of 75%-79%) were dispensed at least one psychotropic medication. At the beginning of the study period atypical antipsychotics (38%) were the most frequently dispensed psychotropic, followed by benzodiazepines (28%), non-sedative antidepressants (27%), sedative antidepressants (17%), anti-epileptics (7%), and conventional antipsychotics (3%). Dispensing of anti-epileptics (2% increase) and conventional antipsychotics (1% decrease) displayed modest changes over time, but we observed more pronounced changes in dispensing of benzodiazepines (11% decrease) and atypical antipsychotics (4% decrease). Concurrently, we observed a substantial growth in the dispensing of both sedative (15% increase) and non-sedative (9% increase) antidepressants. The proportion of patients dispensed two or more psychotropic drug classes increased from 42% in 2004 to 50% in 2013. CONCLUSIONS: Utilization patterns of psychotropic drugs in institutionalized patients with dementia have changed over the past decade. Although their use declined slightly over the study period, atypical antipsychotics continue to be used at a high rate. A decline in the use of benzodiazepines along with an increased use of sedative and non-sedative antidepressants suggests that the latter class of drugs is being substituted for the former in the management of neuropsychiatric symptoms. Psychotropic polypharmacy continues to be highly prevalent in these patient samples.

Gestational modification of murine spiral arteries does not reduce their drug-induced vasoconstrictive responses in vivo.

Dynamic control of maternal blood flow to the placenta is critical for healthy pregnancy. In many tissues, microvasculature arteries control the flow. The uterine/endometrial vascular bed changes during pregnancy include physiological remodeling of spiral arteries from constricted artery-like structures to dilated vein-like structures between Gestation Day 8 (gd8) and gd12 in mice and wk 12-16 in humans. These changes occur, in part, due to local environmental changes such as decidualization, recruitment of maternal uterine natural killer cells, and invasion of conceptus-derived trophoblasts. No current preparations permit in vivo testing of decidual microvascular reactivity. We report an in vivo intravital fluorescence microscopy model that permits functional study of the entire uterine microvascular bed (uterine, arcuate, radial, basal, and spiral arteries) in gravid C57BL/6 mice. Vascular reactivities were measured at gd8 prespiral arterial remodeling and gd12 (postremodeling) to a range of concentrations of adenosine (10(-8)-10(-6) M), acetylcholine (10(-7)-10(-5) M), phenylephrine (10(-7)-10(-5) M), and angiotensin II (10(-8)-10(-6) M). At baseline, each arterial branch order was significantly more dilated on gd12 than gd8. Each microvascular level responded to each agonist on gd8 and gd12. At gd12, vasodilation to adenosine was attenuated in uterine, arcuate, and basal arteries, while constrictor activity to angiotensin II was enhanced in uterine and arcuate arteries. The tendency for increasing vasoconstriction between gd8 to gd12 and the constrictor responses of modified spiral arteries were unexpected findings that may reflect influences of the intact in vivo environment rather than inherent properties of the vessels and may be relevant to ongoing human pregnancies.

Francisella DnaK inhibits tissue-nonspecific alkaline phosphatase.

Following pulmonary infection with Francisella tularensis, we observed an unexpected but significant reduction of alkaline phosphatase, an enzyme normally up-regulated following inflammation. However, no reduction was observed in mice infected with a closely related gram-negative pneumonic organism (Klebsiella pneumoniae) suggesting the inhibition may be Francisella-specific. In similar fashion to in vivo observations, addition of Francisella lysate to exogenous alkaline phosphatase (tissue-nonspecific isozyme) was inhibitory. Partial purification and subsequent proteomic analysis indicated the inhibitory factor to be the heat shock protein DnaK. Incubation with increasing amounts of anti-DnaK antibody reduced the inhibitory effect in a dose-dependent manner. Furthermore, DnaK contains an adenosine triphosphate binding domain at its N terminus, and addition of adenosine triphosphate enhances dissociation of DnaK with its target protein, e.g. alkaline phosphatase. Addition of adenosine triphosphate resulted in decreased DnaK co-immunoprecipitated with alkaline phosphatase as well as reduction of Francisella-mediated alkaline phosphatase inhibition further supporting the binding of Francisella DnaK to alkaline phosphatase. Release of DnaK via secretion and/or bacterial cell lysis into the extracellular milieu and inhibition of plasma alkaline phosphatase could promote an orchestrated, inflammatory response advantageous to Francisella.

Arteriolar reactivity in lymphocyte-deficient mice.

Mounting evidence suggests that lymphocytes have the capacity to contribute to the regulation of systemic circulatory control. We postulated that T and natural killer (NK) cells could modify basal microvascular activity under physiologically normal conditions. In situ intravital microscopy of mouse cremaster vasculature was used to evaluate arteriolar reactivities to the vasoconstrictors angiotensin II (ANG II) and phenylephrine (Phe) and the vasodilators acetylcholine (ACh) and adenosine (Ado) in normal [+/+; wild type (WT)] and genetically immunodeficient (T(-)B(-)NK(+) or T(-)B(-)\NK(-)) C57BL/6 and BALB/c mice, strain backgrounds with differentially polarized T cell cytokine production. Immunodeficient mice tended to have smaller baseline and maximal diameters of third-order cremaster arterioles than their congenic WT partners. In C57BL/6, baseline diameters were similar in T-B(-) mice without or with NK cells; in BALB/c, baseline diameters were larger in T-B-NK(-) mice than in T(-)B(-)NK(+) mice. Thus, at baseline, lymphocytes tended to promote vasodilation, except BALB/c NK cells, which mediated mild vasoconstriction. The presence of NK cells suppressed dilations to Ado in both strains, to ACh in the C57BL/6 strain, and dilatory responses to ANG II in C57BL/6 and to Phe in BALB/c. In the BALB/c strain, the presence of T and B cells promoted vasodilatory responses to Ado, attenuated dilations to low ACh concentrations, and exaggerated dilation and constriction responses to ANG II. Thus, under agonist challenge, NK cells generally promote constriction, whereas influences of T and B cells depend upon the stimulus. Therefore, lymphocytes or their products have physiological influences on microvascular arteriolar reactivity.