Lithium related thyroid and parathyroid disease: Updated clinical practice guidelines are needed.

OBJECTIVE: This study aims to estimate the prevalence of and determine physician approaches to the screening and management of lithium-associated thyroid and parathyroid disorders in British Columbia, Canada. METHODS: Serum lithium and thyroid/parathyroid laboratory data were collected retrospectively for patients with lithium levels measured at seven BC hospitals between 2012 and 2021. A mail-out survey about screening and management of thyroid/parathyroid disorders in patients on lithium was sent to the ordering physicians of patients with abnormal results. Three months after, a follow-up questionnaire was sent to respondents, and the original survey was re-sent to non-responders. RESULTS: Of 4917 patients, 1.9 % had PTH (mean 22.33 ± 23.00 pmol/L) and 77.1 % had TSH (mean 3.61 ± 6.69 pmol/L) measured. Of 222 hypercalcemic patients (defined as any serum calcium or ionized calcium above the laboratory reference), 17.6 % had a PTH level measured. From 294 surveys sent to 214 physicians, the overall response rate was 31.6 % (n = 93) with twelve fully completed surveys. All twelve respondents monitored TSH levels every 6-12 months, and eight physicians monitored PTH and/or calcium at variable intervals. Two physicians routinely ordered both thyroid and parathyroid screening laboratory tests. Of the 80 non-respondents, limited patient contact was the most common reason for opting out (n = 27). CONCLUSIONS: Our results suggest biochemical screening for lithium-associated parathyroid disorders is less common than for thyroid disorders. There is insufficient data to determine the true prevalence of lithium-associated thyroid and parathyroid disorders. This highlights the need for updated clinical guidelines for management of lithium-associated thyroid and parathyroid disorders.

From clinic to community: A randomized controlled trial of a peer support model for adults with type 2 diabetes from specialty care settings in British Columbia.

AIMS: To examine the impact of a 12-month peer-led diabetes self-management support intervention delivered via telephone amongst adults with type 2 diabetes (T2D) from specialty care settings in British Columbia (BC). METHODS: One-hundred ninety-six adults with T2D were randomly assigned to either a 12-month Peer-Led, Empowerment-based, Approach, to Self-management Efforts in Diabetes (PLEASED) intervention or a usual care condition. PLEASED involved weekly telephone contacts from a peer leader (PL) in the first 3 months followed by bi-weekly telephone contacts in the last 9 months. Assessments were conducted at baseline, 3 and 12 months. The primary outcome was HbA1c ; secondary outcomes included diabetes distress (DD), ApoB, systolic and diastolic blood pressure (BP), body mass index, waist circumference and depressive symptoms. RESULTS: No within or between group changes were observed for HbA1c at 3 or 12 months. However, amongst participants with HbA1c  ≥ 69 mmol/mol (8.5%), the PLEASED group significantly lowered their HbA1c at 12 months [-11.7 mmol/mol (-1.07%); 95% CI: -20.7, -2.5 (-1.89, -0.23); p = 0.016] compared to usual care. Amongst secondary outcomes, within-group improvements in overall DD were found at 3 months (-0.21; 95% CI: -0.35, -0.08; p = 0.002) for the PLEASED group and at 12 months for both groups (PLEASED: -0.35; 95% CI: -0.49, -0.21; p < 0.001 and control: -0.33; 95% CI: -0.47, -0.19; p < 0.001), however, no between-group differences were observed. The PLEASED group improved systolic BP at 12 months (-5.4 mm Hg; 95% CI: -10.0, -0.8; p = 0.023) compared to usual care. CONCLUSIONS: Participation in a peer support intervention in diabetes delivered via telephone leads to long-term improvements in HbA1c amongst high-risk adults with T2D living in BC. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NT02804620).

Extracorporeal Membrane Oxygenation Utilization in Blunt and Penetrating Traumatic Injuries: A Systematic Review.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become an increasingly used treatment modality for severe respiratory insufficiency in trauma patients. Examining ECMO use specifically in blunt and penetrating traumas can aid in directing future protocols. We aim to evaluate the outcomes of ECMO use in both blunt and penetrating trauma patients through a systematic review of current literature. METHODS: An online search of 2 databases (PubMed and Google Scholar) was performed to analyze studies, which evaluated the use of ECMO in blunt and penetrating traumas. Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Grading of Recommendations Assessment, Development and Evaluation guidelines were followed. Data extracted included mechanism of injury, injury severity scores (ISSs), complications, and mortality rates. RESULTS: The search demonstrated 9 studies that met our review inclusion criteria. A total of 207 patients were included, of which 64 (30.9%) were non-survivors and 143 (69.1%) were survivors. There was a total of 201 blunt traumas with 61 (30.3%) deaths, whereas penetrating traumas had 2 deaths (33.3%) out of 6 total patients. Complications reported included acute renal failure, hemorrhage at the cannula site, and transient neurological deficits. Most studies found better survival rates and less complications in younger patients and those with lower ISS. CONCLUSION: Expanding the use of ECMO to include blunt and penetrating trauma patients provides the trauma surgeons with another crucial potentially lifesaving tool with an overall survival rate of 70%. Anticipating increased future use of ECMO in blunt and penetrating trauma patients, distinct protocols ought to be instilled to better address the care needed for these critically ill trauma patients.

Assessment of an Interactive Digital Health-Based Self-management Program to Reduce Hospitalizations Among Patients With Multiple Chronic Diseases: A Randomized Clinical Trial.

Importance: Digital health programs may have the potential to prevent hospitalizations among patients with chronic diseases by supporting patient self-management, symptom monitoring, and coordinated care. Objective: To compare the effect of an internet-based self-management and symptom monitoring program targeted to patients with 2 or more chronic diseases (internet chronic disease management [CDM]) with usual care on hospitalizations over a 2-year period. Design, Setting, and Participants: This single-blinded randomized clinical trial included patients with multiple chronic diseases from 71 primary care clinics in small urban and rural areas throughout British Columbia, Canada. Recruitment occurred between October 1, 2011, and March 23, 2015. A volunteer sample of 456 patients was screened for eligibility. Inclusion criteria included daily internet access, age older than 19 years, fluency in English, and the presence of 2 or more of the following 5 conditions: diabetes, heart failure, ischemic heart disease, chronic kidney disease, or chronic obstructive pulmonary disease. A total of 230 patients consented to participate and were randomized to receive either the internet CDM intervention (n = 117) or usual care (n = 113). One participant in the internet CDM group withdrew from the study after randomization, resulting in 229 participants for whom data on the primary outcome were available. Interventions: Internet-based self-management program using telephone nursing supports and integration within primary care compared with usual care over a 2-year period. Main Outcomes and Measures: The primary outcome was all-cause hospitalizations at 2 years. Secondary outcomes included hospital length of stay, quality of life, self-management, and social support. Additional outcomes included the number of participants with at least 1 hospitalization, the number of participants who experienced a composite outcome of all-cause hospitalization or death, the time to first hospitalization, and the number of in-hospital days. Results: Among 229 participants included in the analysis, the mean (SD) age was 70.5 (9.1) years, and 141 participants (61.6%) were male; data on race and ethnicity were not collected because there was no planned analysis of these variables. The internet CDM group had 25 fewer hospitalizations compared with the usual care group (56 hospitalizations vs 81 hospitalizations, respectively [30.9% reduction]; relative risk [RR], 0.68; 95% CI, 0.43-1.10; P = .12). The intervention group also had 229 fewer in-hospital days compared with the usual care group (282 days vs 511 days, respectively; RR, 0.52; 95% CI, 0.24-1.10; P = .09). Components of self-management and social support improved in the intervention group. Fewer participants in the internet CDM vs usual care group had at least 1 hospitalization (32 of 116 individuals [27.6%] vs 46 of 113 individuals [40.7%]; odds ratio [OR], 0.55; 95% CI, 0.31-0.96; P = .03) or experienced the composite outcome of all-cause hospitalization or death (37 of 116 individuals [31.9%] vs 51 of 113 individuals [45.1%]; OR, 0.57; 95% CI, 0.33-0.98; P = .04). Participants in the internet CDM group had a lower risk of time to first hospitalization (hazard ratio, 0.62; 95% CI, 0.39-0.97; P = .04) than those in the usual care group. Conclusions and Relevance: In this study, an internet-based self-management program did not result in a significant reduction in hospitalization. However, fewer participants in the intervention group were admitted to the hospital or experienced the composite outcome of all-cause hospitalization or death. These findings suggest the internet CDM program has the potential to augment primary care among patients with multiple chronic diseases. Trial Registration: ClinicalTrials.gov Identifier: NCT01342263.

A Mixed-Methods Analysis of Physician Abortion Practice After Residency.

BACKGROUND AND OBJECTIVES: In the United States, 89% of counties have no clinics providing abortion care. Though training residents increases intention to provide abortion care, rates of postresidency abortion provision are low. This study, conducted at one family medicine residency program in the Southwest United States, examines graduates' postresidency practice of abortion care in the context of their intent to provide during residency training. METHODS: We collected cross-sectional data from a survey of graduates of University of New Mexico Family Medicine Residency from 2005 to 2017. We performed a mixed-methods analysis using descriptive statistics and conceptual content analysis, including a new methodology of performing content analysis of four subgroups based on intention to provide abortion care at different time points. RESULTS: The response rate was 46%, with 54 responses to 115 surveys. Only 35% residents who intended to provide abortion care had done so after graduation from residency. Barrier analysis revealed that the three most frequent barriers were structural, with 52% of respondents saying that their workplace would not allow abortion care. The two most frequent themes affecting intention were "competence" and feeling that abortion care was "medically necessary." However, the two most common themes affecting actual practice were "workplace support" and local "patient access." CONCLUSIONS: This study provides information about the themes associated with changing intentions and practice of abortion care, which may help elucidate new strategies for training residents to anticipate and address challenges to postresidency provision. The study also provides some insight into residents with no intention to provide abortion care in residency who develop an intention to provide abortion care after graduation, which is a group of people for whom there is little information.

Venous Thromboembolism Chemoprophylaxis in Trauma and Emergency General Surgery Patients: A Systematic Review.

BACKGROUND: Appropriate venous thromboembolism (VTE) chemoprophylaxis in trauma and emergency general surgery (EGS) patients is crucial. OBJECTIVE: The purpose of this study is to review the recent literature and offer recommendations for VTE chemoprophylaxis in trauma and EGS patients. METHODS: We conducted a literature search from 2000 to 2021 for articles investigating VTE chemoprophylaxis in adult trauma and EGS patients. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: Our search resulted in 34 articles. Most studies showed low-molecular-weight heparin (LMWH) is similar to unfractionated heparin (UFH) for VTE prevention; however, LMWH was more commonly used. Adjusted chemoprophylaxis dosing did not change the VTE rate but the timing did. Direct oral anticoagulants (DOACs) have been shown to be safe and effective in trauma and traumatic brain injury (TBI)/spinal cord injury (SCI). Studies showed VTE prophylaxis in EGS can be inconsistent and improves with guidelines that lower VTE events. CONCLUSIONS: There may be no benefit to receiving LMWH over UFH in trauma patients. In addition, different drugs under the class of LMWH do not change the incidence of VTE. Adjusted dosing of enoxaparin does not seem to affect VTE incidence. The use of DOACs in the trauma TBI and SCI setting has been shown to be safe and effective in reducing VTE. One important consideration with VTE prophylaxis may be the timing of prophylaxis initiation, specifically as it relates to TBI, with a higher likelihood of developing VTE as time progresses. EGS patients are at a high risk of VTE. Improved compliance with clinical guidelines in this population is correlated with decreased thrombotic events.

Natural Disasters Related Traumatic Injuries/Fatalities in the United States and Their Impact on Emergency Preparedness Operations.

INTRODUCTION: From 2015 to 2019, the United States experienced a 17% increase in weather-related disasters. OBJECTIVES: We aimed to study the patterns of natural disaster-related traumatic injuries and fatalities across the United States from 2014 to 2019 and to provide recommendations that can serve to mitigate the impact these natural disasters have on trauma patient morbidity and mortality. METHODS: A retrospective analysis of the National Safety Council (2014-2019) of natural disaster-related injuries and fatalities was conducted. Descriptive statistics and independent-samples t tests were performed, with significance defined as p < .05. RESULTS: Floods produced significantly more mean fatalities per year than tornadoes (118 vs. 33; 95% CI [32.0, 139.0]), wildfires (118 vs. 43, 95% CI [24.8, 155.6]), hurricanes (118 vs. 13, 95% CI [51.5, 159.2]), and tropical storms (118 vs. 15, 95% CI [48.8, 158.2]). Tornadoes produced significantly more mean injuries per year than floods (528 vs. 43, 95% CI [255.9, 715.8]), wildfires (528 vs. 69, 95% CI [227.1, 691.2]), hurricanes (528 vs. 26, 95% CI [270.1, 734.2]), and tropical storms (528 vs. 4, 95% CI [295.9, 753.5]). Southern states experienced greater disaster-related morbidity and mortality over the 6-year study period than other regions with 2,752 injuries and 771 fatalities. CONCLUSIONS: The incidence of traumatic injuries and fatalities related to certain natural disasters in the United States has significantly increased from 2014 to 2019. Hospital leaders, public health, emergency preparedness personnel, and policy makers must collaborate to implement protocols and guidelines that ensure adequate training, supplies, and personnel to maintain trauma surge capacity, improve emergency preparedness response, and reduce associated morbidity and mortality.

Post-traumatic Splenic Injury Outcomes for Nonoperative and Operative Management: A Systematic Review.

BACKGROUND: Splenectomies are widely performed, but there exists controversy regarding care for splenic injury patients. The purpose of this study is to provide a comprehensive review of the literature over the last 20 years for operative management (OM) versus nonoperative management (NOM) versus splenic artery embolization (SAE) for traumatic splenic injuries and associated outcomes. METHODS: A review of literature was performed following the PRISMA guidelines through a search of PubMed, EMBASE, Cochrane Library, JAMA Network, and SAGE journals from 2000 to 2020 regarding splenic injury in trauma patients and their management. Articles were then selected based on inclusion/exclusion criteria with GRADE criteria used on the included articles to assess quality. RESULTS: Twenty retrospective cohorts and one prospective cohort assessed patients who received OM versus NOM or SAE. Multiple studies indicated that NOM, in properly selected patients, provided better outcomes than its operative counterpart. CONCLUSION: This review provides additional evidence to support the NOM of splenic injuries for hemodynamically stable patients with benign abdomens as it accounts for consistently shorter hospital length of stay, fewer complications, and lower mortality than OM. For hemodynamically unstable patients, management continues to be intervention with surgery. More studies are needed to further investigate outcomes of post-splenectomy patients based on grade of injury, hemodynamic status, type of procedure (i.e., SAE), and failure of NOM in order to provide additional evidence and improve outcomes for this patient population.

Gender distribution among surgical journals' editorial boards: Empowering women surgeon scientists.

BACKGROUND: Gender disparities still exist in the field of academic surgery. Women face additional obstacles obtaining high-ranking, surgical academia positions compared to men, and this may extend to the appointment of editorial board members. We aim to evaluate the gender distribution of editorial board members, associate editors, and editors-in-chief of top US surgical journals and to recommend interventions, which can promote equitable gender representation among editorial boards. METHODS: The study is a cross-sectional analysis using publicly available data regarding the number and proportion of female editorial board members, associate editors, and editors-in-chief from 42 US surgical journals. Descriptive statistics and linear regression were performed with significance defined as P < .05. RESULTS: Of 2,836 editorial board members from 42 US surgical journals, 420 (14.8%) were women. Of 881 associate editors, 118 (13.3%) were women. Only 2/42 (4.8%) of editors-in-chief were women. The mean proportions of female editorial board members and associate editors were 14.5% and 19.5%, respectively. No significant associations were found between the 2019 Scimago Journal & Country Rank indicator nor the 2019 impact factor and the proportion of female editorial board members and female associate editors after adjusting for author H-index. CONCLUSION: Gender disparities are evident in academic surgery, and women comprise a minority of US surgical editorial board members, associate editors, and editors-in-chief. The implementation of women mentorship from senior faculty on behalf of senior residents and junior faculty, as well as journal-facilitated pipeline programs, can diversify editorial board members by increasing women representation and reduce disparities in surgical journal editorial boards.

CANDIED: A Pan-Canadian Cohort of Immune Checkpoint Inhibitor-Induced Insulin-Dependent Diabetes Mellitus.

Immune checkpoint inhibitor (ICI)-induced insulin-dependent diabetes mellitus (IDDM) is a rare but potentially fatal immune-related adverse event (irAE). In this multicentre retrospective cohort study, we describe the characteristics of ICI-induced IDDM in patients treated across five Canadian cancer centres, as well as their tumor response rates and survival. In 34 patients identified, 25 (74%) were male and 19 (56%) had melanoma. All patients received anti-programed death 1 (anti-PD1) or anti-programmed death ligand-1 (anti-PD-L1)-based therapy. From ICI initiation, median time to onset of IDDM was 2.4 months (95% CI 1.1-3.6). Patients treated with anti-PD1/PD-L1 in combination with an anti-cytotoxic T lymphocyte antigen 4 antibody developed IDDM earlier compared with patients on monotherapy (1.4 vs. 3.9 months, p = 0.05). Diabetic ketoacidosis occurred in 21 (62%) patients. Amongst 30 patients evaluable for response, 10 (33%) had a complete response and another 10 (33%) had a partial response. Median overall survival was not reached (95% CI NE; median follow-up 31.7 months). All patients remained insulin-dependent at the end of follow-up. We observed that ICI-induced IDDM is an irreversible irAE and may be associated with a high response rate and prolonged survival.

U.S. alcohol associated traffic injuries and fatalities from 2014 to 2018.

BACKGROUND: Alcohol-impaired motor vehicle collision (MVC) fatalities comprise almost a third of total crash fatalities in the United States (U.S.). They also impose 20% of the total costs of MVCs annually. This study aims to evaluate an association between blood alcohol concentration (BAC) and number of crash injuries and fatalities from 2014 to 2018 in the U.S. Additionally, we aim to recommend solutions to reduce alcohol-impaired driving related injuries and fatalities. METHODS: A retrospective analysis of National Highway Traffic Safety Administration (NHTSA) data of crash injuries, fatalities, and BAC levels (0.00 g/dl, 0.01-0.07 g/dl, and ≥ 0.08 g/dl) from 2014 through 2018. Descriptive statistical analysis and independent sample t-tests were conducted, with significance defined as p < .05. RESULTS: Compared to BAC 0.01-0.07 g/dl,BAC ≥0.08 g/dl resulted in significantly more injuries (6779 vs. 1357, p < .001) and fatalities (10,522 vs. 1894, p < .001). CONCLUSION: BAC level ≥ 0.08 g/dl produced significantly greater injuries and fatalities in comparison to lower BAC levels evaluated. Given the effects of alcohol-impaired driving on MVCs, the legal BAC level should be re-evaluated to protect citizens and reduce incidence of alcohol related traffic injuries and fatalities. Educational programs promoting responsible alcohol consumption need to be in place for individuals at high risk for driving under the influence.

Treatment for Recurrent Differentiated Thyroid Cancer: A Canadian Population Based Experience.

INTRODUCTION: Management of recurrent differentiated thyroid cancer (DTC) may include surgery, radioactive iodine (RAI), and external beam radiotherapy (EBRT). Systemic therapy may also be offered for RAI-refractory DTC. The study objective was to review patterns of practice in British Columbia (BC) for treatment of recurrent DTC, assess rates of RAI-refractory disease, and evaluate outcomes. METHODS: BC Cancer provides cancer care to a population of 4.6 million. A retrospective review of all patients with DTC stage I-IVB disease referred to BC Cancer from 2009 to 2013 was conducted. Patient and DTC characteristics, locoregional and distant recurrence, surgical management, RAI, EBRT, and systemic therapy details were retrospectively collected. Relapse-free survival (RFS), overall survival (OS), and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. RESULTS/DISCUSSION: Some 1062 DTC patients were identified. Median follow-up was 4.1 years. Baseline characteristics: female 74%, median age 50, papillary/follicular/Hurthle cell 92%/6%/2%. Stage at presentation: I 60%, II 8%, III 22%, IVA/IVB 10%. Locoregional and/or distant recurrence occurred in 136 patients (13%). Locoregional recurrence (n=118) was treated with surgery +/- RAI or EBRT 48%, RAI +/- EBRT 40%, EBRT alone 1%, 11% were observed without treatment. Some 27 patients had a second cancer recurrence. Some 37 patients (3%) developed distant metastatic disease and common sites of distant metastases were: lung 76%, bone 30%, and liver 8%. Some 27 cases (2%) were deemed RAI-refractory. Some six patients (0.6%) received systemic therapy with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF TKI). Five-year RFS was calculated to be 82%, OS 95%, and DSS 98% for the study population. CONCLUSIONS: In our population-based study cohort, 87% of patients were rendered disease-free by primary disease management. Multi-modality treatment of locoregional recurrence facilitated disease-free status in the majority of patients (67%). RAI-refractory disease developed in 2% of patients and despite a significant number of metastatic recurrences, only a small number of patients received systemic therapy.

Thyrotoxicosis after massive triiodothyronine (LT3) overdose: a coast-to-coast case series and review.

Excessive exogenous thyroid hormone ingestion may lead to severe thyrotoxicosis and cause potential harm. We have reviewed the literature and suggested that thyroid hormone supplementation should not be used to alleviate nonspecific complaints in patients with normal endogenous thyroid function. Failure to do so may cause serious harm, as demonstrated in one of the cases described here. In addition, treatment based on symptom relief only without biochemical measure may lead to overmedication - as reported from academic hospitals both in Canada and the United States. Given the risk of severe thyrotoxicosis from potential compounding errors, pharmacies providing a compounding service should be subject to more rigorous monitoring by the food and drug administration. Clinicians should also use local biochemical markers when titrating thyroid hormone supplements even though the normal thyroid function reference range has its limitation, failure to do so may result in iatrogenic thyrotoxicosis.

Study protocol and baseline sample characteristics: From clinic to community: Using peer support as a transition model for improving long-term diabetes-related health outcomes.

BACKGROUND: The objective of this randomized controlled trial is to examine the effects of a 12-month telephone-based peer-led diabetes self-management support (DSMS) intervention on long-term diabetes-related health outcomes. METHODS: In total, 197 participants with type 2 diabetes were recruited from specialty care settings (diabetes and endocrinology clinics). They were randomly assigned to 1) a 12-month Peer-Led, Empowerment-based Approach to Self-management Efforts in Diabetes (PLEASED) program where they received 12 weekly contacts from their peer supporter (PS) in the first 3 months, followed by 18 biweekly telephone support contacts over the last 9 months, or 2) usual care. The primary clinical and psychosocial outcomes were HbA1c and diabetes distress (DD), respectively. Secondary outcomes were cardiovascular risk factors. Assessments were conducted at baseline, 3 months, and 12 months. RESULT: Of 197 recruited participants, 49.7% were female. The majority of participants were married/partnered, well-educated, employed, and Caucasian, with a mean HbA1c of 8.09 ±â€¯1.7. Forty-two percent of participants reported little or no distress. There was no significant difference between the two groups. DISCUSSION: Despite evidence showing that individuals with poor glycemic control benefit the most from peer support interventions, the majority of such interventions have been designed for and implemented in community and primary care-based settings. The present study investigates a 12-month peer support model to help patients initiate and sustain effective self-management behaviors while transitioning from specialty care to a community setting. The study was completed in November 2018. The outcome data analyses are currently underway. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov (NT02804620). PROTOCOL VERSION: The protocol version is 3.5.

Pathological, Disabled, Transgender: The Ethics, History, Laws, and Contradictions in Models that Best Serve Transgender Rights.

This article addresses the precarious place of transgender and gender non-cis persons in relation to their discrimination-protections in recent legal, medical, and ethical policies in the United States. At present, there exists a contradiction such that trans persons are considered "pathological" enough that they are included in the latest iteration of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-V) as "gender dysphoric," but they are not included in the category of "disabled" under the Americans with Disabilities Act (ADA). As such, trans persons in America are subject to the stigma of pathology (albeit with medical treatment) without the full protections of the ADA. By contrast, transgender and non-cis-gender Americans find their queer cohorts who are HIV-positive to be fully protected by the ADA. We ask whether transgender and non-cis-gender persons should embrace their (already pathologized) personhood as a disability. Sometimes "choosing disability" affords more rights than it deploys stigma.

Diabetic Pharmacotherapy and Endometrial Cancer Risk Within a Publicly Funded Health Care System.

OBJECTIVE: There is conflicting evidence regarding the association between metformin and endometrial cancer risk. The objective of this study was to evaluate the association between type of diabetic pharmacotherapy and endometrial cancer risk within a population-based study. The hypothesis was that metformin was associated with the lowest risk. METHODS: This was a nested case-control study using data from the BC Cancer Registry (2000-2009) and from a province-wide prescription network (PharmaNet) since 1996. Patients were classified by drug exposure (metformin, thiazolidinediones, secretagogues, with or without insulin). The primary analysis was a conditional logistic regression to estimate the odds ratios for endometrial cancer in the drug exposure groups. Sensitivity analysis was carried out to account for uncertainty regarding various parameters. The secondary analysis evaluated the effect of dosage using a principal components analysis. RESULTS: The study cohort comprised 492 cases and 4404 controls. The primary analysis revealed no difference in endometrial cancer risk between those using metformin and those prescribed other classes of medications (OR 1.5, 95% CI 0.9 to 2.4). Women receiving all classes of medications had almost a two-fold increase in risk (OR 1.9, 95% CI 1.1 to 3.3). The secondary analysis revealed an increased risk associated with a greater duration of treatment and number of prescriptions (OR 1.3, 95% CI 1.2 to 1.4). CONCLUSION: In this population-based study, metformin was not associated with a decreased endometrial cancer risk. Women receiving multiple types of medications over a long time had the highest risk, implying that the extent of insulin resistance, rather than the effect of any specific medication, drives endometrial cancer risk.

Relationship between mutant Cu/Zn superoxide dismutase 1 maturation and inclusion formation in cell models.

A common property of Cu/Zn superoxide dismutase 1 (SOD1), harboring mutations associated with amyotrophic lateral sclerosis, is a high propensity to misfold and form abnormal aggregates. The aggregation of mutant SOD1 has been demonstrated in vitro, with purified proteins, in mouse models, in human tissues, and in cultured cell models. In vitro translation studies have determined that SOD1 with amyotrophic lateral sclerosis mutations is slower to mature, and thus perhaps vulnerable to off-pathway folding that could generate aggregates. The aggregation of mutant SOD1 in living cells can be monitored by tagging the protein with fluorescent fluorophores. In this study, we have taken advantage of the Dendra2 fluorophore technology in which excitation can be used to switch the output color from green to red, thereby clearly creating a time stamp that distinguishes pre-existing and newly made proteins. In cells that transiently over-express the Ala 4 to Val variant of SOD1-Dendra2, we observed that newly made mutant SOD1 was rapidly captured by pathologic intracellular inclusions. In cell models of mutant SOD1 aggregation over-expressing untagged A4V-SOD1, we observed that immature forms of the protein, lacking a Cu co-factor and a normal intramolecular disulfide, persist for extended periods. Our findings fit with a model in which immature forms of mutant A4V-SOD1, including newly made protein, are prone to misfolding and aggregation.

Exploring the Functional Complementation between Grp94 and Hsp90.

Grp94 and Hsp90 are the ER and cytoplasmic paralog members, respectively, of the hsp90 family of molecular chaperones. The structural and biochemical differences between Hsp90 and Grp94 that allow each paralog to efficiently chaperone its particular set of clients are poorly understood. The two paralogs exhibit a high degree of sequence similarity, yet also display significant differences in their quaternary conformations and ATPase activity. In order to identify the structural elements that distinguish Grp94 from Hsp90, we characterized the similarities and differences between the two proteins by testing the ability of Hsp90/Grp94 chimeras to functionally substitute for the wild-type chaperones in vivo. We show that the N-terminal domain or the combination of the second lobe of the Middle domain plus the C-terminal domain of Grp94 can functionally substitute for their yeast Hsp90 counterparts but that the equivalent Hsp90 domains cannot functionally replace their counterparts in Grp94. These results also identify the interface between the Middle and C-terminal domains as an important structural unit within the Hsp90 family.