Cytochrome P450-soluble epoxide hydrolase derived linoleic acid oxylipins and cognitive performance in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) increases the risk of cognitive decline and dementia. Disruptions in the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway have been reported in T2DM, obesity and cognitive impairment. We examine linoleic acid (LA)-derived CYP450-sEH oxylipins and cognition in T2DM and explore potential differences between obese and nonobese individuals. The study included 51 obese and 57 nonobese participants (mean age 63.0 ± 9.9, 49% women) with T2DM. Executive function was assessed using the Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B. Verbal memory was assessed using the California Verbal Learning Test, second Edition. Four LA-derived oxylipins were analyzed by ultra-high-pressure-LC/MS, and the 12,13-dihydroxyoctadecamonoenoic acid (12,13-DiHOME) considered the main species of interest. Models controlled for age, sex, BMI, glycosylated hemoglobin A1c, diabetes duration, depression, hypertension, and education. The sEH-derived 12,13-DiHOME was associated with poorer executive function scores (F1,98 = 7.513, P = 0.007). The CYP450-derived 12(13)-epoxyoctadecamonoenoic acid (12(13)-EpOME) was associated with poorer executive function and verbal memory scores (F1,98 = 7.222, P = 0.008 and F1,98 = 4.621, P = 0.034, respectively). There were interactions between obesity and the 12,13-DiHOME/12(13)-EpOME ratio (F1,97 = 5.498, P = 0.021) and between obesity and 9(10)-epoxyoctadecamonoenoic acid (9(10)-EpOME) concentrations (F1,97 = 4.126, P = 0.045), predicting executive function such that relationships were stronger in obese individuals. These findings suggest that the CYP450-sEH pathway as a potential therapeutic target for cognitive decline in T2DM. For some markers, relationships may be obesity dependent.

Second primary cancers and survival among neuroendocrine tumor patients.

There is an increased risk of second primary cancers (SPCs) after neuroendocrine tumor (NET) diagnosis. The clinical significance of SPCs in this population is unknown. The purpose of this study was to evaluate the association between SPCs after NET diagnosis and survival. We performed a population-based, retrospective cohort study of NET patients (gastrointestinal, pancreatic, or lung primary) from 2000 to 2016 using the Surveillance, Epidemiology, and End Results database. Cox regression models assessed the association between SPCs and NET-specific (NET-SS), cancer-specific (CSS), and overall survival (OS). Of 58,553 NET patients, 7.9% experienced an SPC. SPCs were associated with worse OS (hazard ratio (HR) 2.14, 95% CI 1.94-2.36) and CSS (HR 2.31, 95% CI 2.06-2.59) with no difference in NET-SS (HR 1.04, 95% CI 0.87-1.23). Stratified analyses by histologic grade showed similar results for well and moderately differentiated NETs, but no difference in OS or CSS for poorly differentiated NETs (P > 0.05). In stratified analyses by NET site, SPCs were associated with worse OS (HR 3.41, 95% CI 3.01-3.87) and CSS (HR 4.96, 95% CI 4.28-5.74) in gastrointestinal NETs and worse OS (HR 1.25, 95% CI 1.03-1.52) with no difference in CSS (HR 1.08, 95% CI 0.85-1.36) in lung NETs. SPCs were not associated with a difference in OS or CSS in pancreatic NETs (P > 0.05). In conclusion, SPCs after NETs were associated with inferior OS and CSS compared to no SPC but were not associated with NET-SS. These data highlight the need for long-term follow-up in NETs to include the detection of SPCs to ensure early diagnosis and timely management.

Parathyroid hormone-driven algorithms after thyroid surgery: Not one-size-fits-all.

BACKGROUND: Underreported variation in parathyroid hormone (PTH) assays exists. Using quality improvement methods, we aimed to develop an institution-specific PTH-based protocol to predict hypocalcemia after thyroidectomy. METHODS: We retrospectively reviewed patients who underwent total/completion thyroidectomy. A receiver operating curve (ROC) determined postoperative PTH cut-offs predictive of hypocalcemia. The stakeholders developed PTH-driven calcium management guidelines. Post-implementation outcomes were prospectively measured. RESULTS: Pre-implementation, 95 patients were assessed. PTH ≤1.5 pmol/L (14.1 pg/ml) predicted hypocalcemia (96%sensitivity), and ≥2.8 pmol/L (26.4 pg/ml) predicted normocalcemia (99%specificity) (area under curve = 0.97, SEM = 0.018). PTH on the day of and morning after surgery were identically predictive. Post-implementation, 64 patients were assessed. Hypocalcemia occurred with PTH >2.8 pmol/L in 2 cases (3.1%). Calcium over-prescribing decreased from 13.7% to 3.1% (p = 0.06). Length of stay (LOS) > 2 nights decreased from 13% to 3.1% (p = 0.05). CONCLUSION: A PTH-driven calcium management protocol post-thyroidectomy effectively reduces unnecessary calcium replacement and LOS. Given the variability in PTH assays, each institution may need to use individual cut-offs.

Incidence of psychiatric illness in patients with neuroendocrine tumors: a comparative population-based analysis.

PURPOSE: Diversion of tryptophan to tumoral hormonal production has been suggested to result in psychiatric illnesses in neuroendocrine tumors (NET). We measured the occurrence of psychiatric illness after NET diagnosis and compare it to colon cancer (CC). METHODS: We conducted a population-based retrospective cohort study. Adults with NET were matched 1:1 to CC (2000-2019). Psychiatric illness was defined by mental health diagnoses and mental health care use after a cancer diagnosis, categorized as severe, other, and none. Cumulative incidence functions accounted for death as a competing risk. RESULTS: A total of 11,223 NETs were matched to CC controls. Five-year cumulative incidences of severe psychiatric illness for NETs vs. CC was 7.7% (95%CI 7.2-8.2%) vs 7.6% (95%CI 7.2-8.2%) (p = 0.50), and that of other psychiatric illness was 32.9% (95%CI 32.0-33.9%) vs 31.6% (95%CI 30.8-32.6%) (p = 0.005). In small bowel and lung NETs, 5-year cumulative incidences of severe (8.1% [95%CI 7.3-8.9%] vs. 7.0% [95%CI 6.3-7.8%]; p = 0.01) and other psychiatric illness (34.7% [95%CI 33.3-36.1%] vs. 31.1% [95%CI 29.7-32.5%]; p < 0.01) were higher than for matched CC. The same was observed for serotonin-producing NETs for both severe (7.9% [95%CI 6.5-9.4%] vs. 6.8% [95%CI 5.5-8.2%]; p = 0.02) and other psychiatric illness (35.4% [95%CI 32.8-38.1%] vs. 31.9% [95%CI 29.3-34.4%]; p = 0.02). CONCLUSIONS: In all NETs, there was no difference observed in the incidence of psychiatric illness compared to CC. For sub-groups of small bowel and lung NETs and of serotonin-producing NETs, the incidence of psychiatric illness was higher than for CC. These data suggest a signal towards a relationship between those sub-groups of NETs and psychiatric illness.

Patients' preferences for distributing limited government-funded IVF cycles.

OBJECTIVE: On December 21, 2015, Ontario began funding one cycle of IVF for each resident with a uterus under the age of 43, but with a program cap that is insufficient to meet the annual demand. Our objective was to determine how fertility patients believe that the limited number of funded IVF cycles should be distributed. METHODS: A survey was distributed to patients attending a university affiliated hospital-based fertility clinic in downtown Toronto, including its associated peripheral satellite clinics. RESULTS: From August 2016 to March 2017, 271 patients responded to the survey, of whom 90.3% were in favour of public funding for IVF. The majority of participants favoured allocating IVF cycles to maximize patients' access to IVF in Ontario rather than targeting funded IVF cycles so as to maximize live births (62.7% vs. 32.8%). Most participants wanted all clinics to adopt the same approach for distributing funded IVF cycles compared to the current system in which each clinic chooses its own criteria for allocation (84.5% vs. 8.5%). Participants favoured distributing IVF by way of a scoring system that took individual patient factors into account. However, the factors that each respondent considered important varied materially. CONCLUSION: Patients overwhelmingly supported public funding for IVF, desired a consistent policy for distribution of limited funded IVF cycles at all clinics, and preferred a method that took individual patient factors into consideration when determining patient priority for funded IVF but there were heterogenous opinions on which factors should be included.

Risk of Cancer-Specific Death for Patients Diagnosed With Neuroendocrine Tumors: A Population-Based Analysis.

BACKGROUND: Although patients with neuroendocrine tumors (NETs) are known to have prolonged overall survival, the contribution of cancer-specific and noncancer deaths is undefined. This study examined cancer-specific and noncancer death after NET diagnosis. METHODS: We conducted a population-based retrospective cohort study of adult patients with NETs from 2001 through 2015. Using competing risks methods, we estimated the cumulative incidence of cancer-specific and noncancer death and stratified by primary NET site and metastatic status. Subdistribution hazard models examined prognostic factors. RESULTS: Among 8,607 included patients, median follow-up was 42 months (interquartile range, 17-82). Risk of cancer-specific death was higher than that of noncancer death, at 27.3% (95% CI, 26.3%-28.4%) and 5.6% (95% CI, 5.1%-6.1%), respectively, at 5 years. Cancer-specific deaths largely exceeded noncancer deaths in synchronous and metachronous metastatic NETs. Patterns varied by primary tumor site, with highest risks of cancer-specific death in bronchopulmonary and pancreatic NETs. For nonmetastatic gastric, small intestine, colonic, and rectal NETs, the risk of noncancer death exceeded that of cancer-specific deaths. Advancing age, higher material deprivation, and metastases were independently associated with higher hazards, and female sex and high comorbidity burden with lower hazards of cancer-specific death. CONCLUSIONS: Among all NETs, the risk of dying of cancer was higher than that of dying of other causes. Heterogeneity exists by primary NET site. Some patients with nonmetastatic NETs are more likely to die of noncancer causes than of cancer causes. This information is important for counseling, decision-making, and design of future trials. Cancer-specific mortality should be included in outcomes when assessing treatment strategies.

Serum soluble epoxide hydrolase related oxylipins and major depression in patients with type 2 diabetes.

BACKGROUND: People with type 2 diabetes mellitus (T2DM) are at increased risk for depression. Both conditions are associated with disturbances in polyunsaturated fatty acids. Omega-3 and omega-6 fatty acids can be converted into bioactive epoxides by cytochrome P450s (CYP450), which play pro-resolving roles in the inflammatory response; however, soluble epoxide hydrolase (sEH) metabolizes epoxides into diols, which lack pro-resolving functions and can be cytotoxic. Here, we survey serum CYP450- and sEH-derived metabolite concentrations in people with T2DM with and without a major depressive episode. METHODS: Sunnybrook Type 2 Diabetes Study (NCT04455867) participants experiencing a major depressive episode (research version of the Structured Clinical Interview for DSM-5 criteria) were matched 1:1 for gender, glycosylated hemoglobin A1c and body mass index to participants without a current depressive episode. Depression severity was assessed using the Beck Depression Inventory 2nd Edition (BDI-II). From fasting morning blood, unesterified serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass spectrometry following solid phase extraction, and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay. RESULTS: Between 20 depressed and 20 non-depressed participants (mean age 58.9 ± 8.5 years, 65% women) with T2DM, several sEH-derived fatty acid diols, but not IL-6, were higher among those with a depressive episode (effect sizes up to d = 0.796 for 17,18-DiHETE, a metabolite of eicosapentaenoic acid [EPA]; t = 2.516, p = 0.016). Among people with a depressive episode, two epoxides were correlated with lower BDI-II scores: 12(13)-EpOME (ρ = -0.541, p = 0.014) and 10(11)-EpDPE (ρ = -0.444, p = 0.049), metabolites of linoleic acid and docosahexaenoic acid (DHA), respectively, while the ratio of 12,13-DiHOME/12(13)-EpOME was correlated with higher BDI-II scores (ρ = 0.513, p = 0.021). CONCLUSIONS: In people with T2DM, major depressive episodes and depressive symptom severity were associated with an oxylipin profile consistent with elimination of pro-resolving lipid mediators by sEH.

Serum osteocalcin is associated with subjective stress in people with depression and type 2 diabetes.

BACKGROUND: Low serum osteocalcin is a risk factor for type 2 diabetes mellitus (T2DM), and osteocalcin release from bone is associated with an acute stress response in mice. Both diabetes and stress are associated with depression. Here, we assess relationships between serum osteocalcin, depression and subjective stress in people with T2DM. METHODS: Participants with T2DM (HbA1c above 6.4 %, impaired fasting glucose or impaired glucose tolerance) were assessed for a major depressive episode using the research version of the Structured Clinical Interview for DSM-5 depression criteria (SCID-5RV). Subjective stress over the past month was assessed using the Perceived Stress Scale (PSS). Serum carboxylated (cOCN) and fully decarboxylated (dcOCN) osteocalcin were assayed from fasting morning blood by commercial enzyme-linked immunosorbent assay. RESULTS: Among 95 participants (mean age 62.4 ± 9.9, 51 % women), 22 % were experiencing a depressive episode (9 men, 12 women). The presence of a depressive episode was not associated with dcOCN or cOCN concentrations; however, higher concentrations of cOCN were associated with higher PSS scores in participants with depression (r = 0.585, p = 0.005). In an analysis of covariance model controlling for age, sex, body mass index, glycemic control (glycosylated hemoglobin), insulin resistance (homeostatic model), depression, and antidepressant use, cOCN was associated with PSS scores (F=10.302, p = 0.002), and this relationship was stronger in those with depression (depression × cOCN interaction F=4.978, p = 0.028). Although associations between dcOCN concentrations and PSS scores did not reach significance, the same trend seen with cOCN concentrations was observed in participants with depression for dcOCN (r=0.365, p=0.10), and for a depression × dcOCN interaction associated with PSS scores in the whole group (F=2.165, p = 0.15). CONCLUSIONS: Osteocalcin is a neuroendocrine marker associated with perceived chronic stress among people with T2DM experiencing a depressive episode.

Proof of concept for stereotactic body radiation therapy in the treatment of functional neuroendocrine neoplasms.

Dysregulated hormonal production remains a challenge in the management of neuroendocrine neoplasms (NEN). We report 4 cases of patients with functional NEN treated with stereotactic body radiation therapy (SBRT) to either the primary/dominant metastatic site of disease or the end organ of hormonal release. No significant toxicities were observed during or after treatment. Each patient has had biochemical, clinical and radiographic response to therapy, providing proof of concept that SBRT is an effective therapeutic strategy for functional neuroendocrine neoplasms.

The Impact of the Ontario Fertility Program on Duplicate Fertility Consultations.

Objectives: The Ontario Fertility Program (OFP) funds 5,000 annual in vitro fertilization (IVF) cycles. We hypothesized that after introduction of the OFP, there would be an increase in duplicate infertility consultations by patients attempting to increase chances at obtaining publicly funded IVF through enlisting at multiple fertility clinics. Methods: This retrospective observational study included women eligible for healthcare services in Ontario from 2014 to 2016 and compared infertility consultations pre- and post-initiation of the OFP. Results: Post-OFP, the average number of consultations per patient and the proportion of patients with more than one consult increased (1.04 vs. 1.05, p = 0.015 and 3.8% vs. 4.2%, p = 0.027, respectively). Total consultations for infertility increased from 24,565 to 27,714 post-OFP. The OFP had the largest impact in the Greater Toronto Area (GTA). Conclusion: The OFP resulted in a statistically significant increase in duplicate consultations, although unlikely to be of clinical relevance. The disproportionate impact seen in the GTA highlights the inequitable access to fertility care in Ontario.

Patients' perspectives on allocation of publicly funded in vitro fertilization in Ontario: a qualitative study.

BACKGROUND: The aim of this study was to determine consumers' perspectives on fair allocation of publicly funded in vitro fertilization (IVF) in the recently implemented Ontario Fertility Program (OFP). The research questions were as follows: 1) What factors do those who require IVF think are important to consider when distributing funded IVF? and 2) What are the barriers to accessing publicly funded IVF? METHODS: We approached this qualitative study with a social constructivist interpretative framework with grounded theory methodology. Data were obtained via focus group. We recruited participants eligible for the OFP from a tertiary care fertility clinic. Two researchers conducted all interviews, independently reviewed the transcriptions and analyzed the data for open coding, followed by axial coding and then selective coding to determine themes. RESULTS: A total of 13 participants (10 women and 3 men with an average age of 36.4 [range 28-40.7] yr) partook in 4 focus groups. The average duration of infertility was 1.9 (range 0.4-3) years. Three important domains were identified. First, the procedure of distributing funds should be done in a transparent and consistent manner. Second, everyone should have a fair and equal chance to accessing the funds. Participants suggested a combination of first-come, first-served and a scoring system as a method to distribute funds. Lack of communication, associated costs and stress of experiencing infertility were cited as barriers to accessing publicly funded IVF. INTERPRETATION: Ensuring equal and fair access to funds should be prioritized, and information about the process and distribution method to obtain OFP funding should be clearly provided to patients. Transparency, standardization and better communication should be implemented to uphold procedural justice for patients and reduce emotional stress. The findings may be considered by policy-makers to improve the current OFP and when developing similar programs.

Development and Implementation of a Diabetic Ketoacidosis Protocol for Adults With Type 1 and Type 2 Diabetes at a Tertiary Care Multicampus Hospital.

OBJECTIVES: Diabetic ketoacidosis (DKA) is associated with significant morbidity and mortality. Using standardized protocols for DKA management improves outcomes and is recommended in Diabetes Canada's clinical practice guidelines. Audits of DKA care at our institution revealed inconsistent management. We developed, piloted and evaluated a standardized DKA protocol adapted into preprinted order sets for use in the emergency department and the acute monitoring area. METHODS: The protocol was developed by an expert committee on the basis of Diabetes Canada's clinical practice guidelines, a literature review and an environmental survey. A before-and-after analysis was used. Uptake of the DKA protocol and clinical outcomes were monitored through statistical process control. RESULTS: Patients admitted postprotocol (n=55, mean age 37.9 years [SD 17.5 years], 62% male, 85% type 1 diabetes) were compared to those admitted preprotocol (n=55, mean age 43.3 years [SD 17.5 years], 53% male, 67.2% type 1 diabetes). Postimplementation, 87% of patients were managed according to the protocol. Postprotocol ordering of appropriate laboratory investigations increased, appropriate intravenous (IV) fluid resuscitation improved, continuation of IV insulin until anion gap closure increased, mean time to anion gap closure decreased and mean length of stay was reduced. Of those surveyed, 85% of nurses and 74% of physicians felt that the protocol improved patient care, and 75% of patients rated their DKA management as being satisfactory. CONCLUSIONS: Successful implementation of a standardized preprinted protocol for DKA management significantly improved best practices for DKA management and was valued by treating clinicians.

Preconception counselling for women with acromegaly: More questions than answers.

BACKGROUND AND AIMS: Approximately 174 pregnancies in acromegaly have been reported. Our objectives were to identify the key challenges of preconception counselling in this population. METHODS: Case series of three acromegalic women with desire for pregnancy. Issues were identified from chart review and discussion with attending physicians. Literature review of acromegaly and pregnancy was conducted. RESULTS: Important issues identified included: impact of acromegaly on fertility, management of acromegaly in the peripartum period, screening for associated conditions, risk of progression of acromegaly/tumour growth during pregnancy, impact of acromegaly on pregnancy outcomes, surveillance during pregnancy, method of delivery and impact on neonatal outcomes and breastfeeding. CONCLUSIONS: Pregnancy can be safely achieved in patients with acromegaly. There is little evidence to guide recommendations around conception and pregnancy surveillance. Patients can be reassured that in most situations, pregnancy proceeds without complication and that medical treatment can be used during pregnancy if necessary.

Transient elastography, APRI, and ultrasound have minimal utility in chronic low-replicative hepatitis B infection.

BACKGROUND AND AIMS: Chronic hepatitis B (CHB) is a significant cause of morbidity and mortality. E-antigen-negative CHB patients, with low liver enzymes and viremia, generally fare better. We determined the proportion of chronic low-replicative hepatitis B patients not meeting guideline-based antiviral therapy criteria nonetheless requiring treatment and increased hepatocellular carcinoma and varices surveillance based on transient elastography (TE), aspartate aminotransferase-to-platelet ratio index (APRI), and/or ultrasound (US) findings. MATERIALS AND METHODS: The Ottawa Hospital Viral Hepatitis Database was utilized. Included CHB patients were observed from January 2011 to April 2013, who were at least 18 years of age, e-antigen negative, with hepatitis B virus (HBV) DNA levels below 20,000 IU/ml, normal liver enzymes (alanine transaminase <64 U/l), and normal synthetic function. Patients with other liver diseases, HIV, or HBV antiviral use were excluded. TE and US results were recorded and APRI was calculated. RESULTS: A total of 264 patients met the eligibility criteria and 79 underwent TE. The median age was 41 years (quartiles: 37, 49); 53% were male patients and 95% were immigrants. Races included 47% Southeast Asians, 37% Black, and 11% White. Mean alanine transaminase and aspartate aminotransferase were 34 U/l (SD 13) and 21 U/l (SD 7), respectively. The mean HBV DNA level was 2.15×10 IU/ml. The mean TE score was 4.5 kPa (SD 1.1). One patient had F2 fibrosis by TE. All others were F0-F1. The mean APRI was 0.30 (SD 0.20) with no values greater than 1.5. CONCLUSION: No patients were identified with advanced fibrosis by TE, APRI, or US meriting HBV antiviral therapy and/or enhanced screening. TE and US have minimal apparent utility in this specific population.