Heather Lochnan

Thyroid-stimulating hormone stimulates lipolysis in adipocytes in culture and raises serum free fatty acid levels in vivo

Thyroid-stimulating hormone (TSH) stimulates adipocyte lipolysis, but signal transduction pathways activated by TSH for this response have not been directly studied. Using differentiated 3T3-L1 adipocytes as well as primary human adipocytes, we characterized the lipolytic action of TSH with dose-response and time-course studies, and compared it with isoproterenol. Thyroid-stimulating hormone stimulated phosphorylation of perilipin and hormone-sensitive lipase (HSL). Inhibition of protein kinase A with H89 blocked TSH-stimulated lipolysis as well as phosphorylation of perilipin and HSL. Thyroid-stimulating hormone stimulated lipolysis in vivo, as indicated by an elevation in serum free fatty acid (FFA) levels after recombinant human TSH administration to thyroidectomized patients (42% increase, n = 19, P < .05). For patients with a body mass index less than 30 kg/m(2), the TSH-induced increase in serum FFA levels was 53% (n = 11, P < .05), whereas levels in patients with a body mass index of at least 30 kg/m(2) (n = 8) did not change after TSH treatment. In summary, TSH stimulates lipolysis and phosphorylation of perilipin and HSL in a protein kinase A-dependent manner in differentiated adipocytes in culture and raises serum FFA levels in vivo.

Immune Checkpoint Inhibitor Therapy Associated Hypophysitis

Ipilimumab is a monoclonal antibody directed against CTLA4 T-lymphocyte antigen used as cancer therapy. Immune-related adverse events are common side effects and may include hypophysitis-related hypopituitarism. The clinical features of six patients with ipilimumab-induced hypophysitis (IH) are described. The clinical features of IH reported in clinical trials, including the incidence of IH by gender and the likelihood of adrenal axis recovery, are summarized. Following the development of IH, most patients remain on glucocorticoid replacement despite efforts to withdraw therapy. Analysis of gender information in published clinical trials suggests that men are more prone to developing IH than women, and few patients fully recover the pituitary-adrenal axis function. Ipilimumab and other drugs within its class are likely to be used to treat many forms of cancer. Endocrinologists should anticipate a significant increase in the incidence of autoimmune hypophysitis. Strategies for early detection of IH and long-term management should be considered.

Socialization to professionalism in medical schools: a Canadian experience

BackgroundAccrediting bodies now recognize the importance of developing the professionalism competency, by setting standards that require medical schools to identify where professionalism is addressed and how it is evaluated within the formal curriculum.The objective of this study was to compare how professionalism competency is formally addressed in the curricula of Canadian medical schools, and to better understand the Canadian approach to reporting and remediation of lapses.MethodsA literature review was performed and with the input of the AFMC(Association of Faculties of Medicine of Canada) Professionalism group, questionnaires were generated. An electronic survey was circulated to key leaders across the country at all the medical schools. In-depth telephone interviews were used to further explore themes, and a subsequent focus group was held to discuss challenges, particularly related to reporting and remediation.ResultsThe preponderance of formal professionalism teaching remains in the form of lectures and small group sessions in the preclinical years. Formal teaching declines significantly in the clerkship/clinical years. Evaluation is usually performed by a clinical supervisor, but OSCE, portfolio, and concern notes are increasingly used. Role modeling is heavily relied upon in clinical years, suggesting faculty training can help ensure clinical teachers recognize their influence on trainees. Formal remediation strategies are in place at most schools, and often involve essay writing, reflection exercises, or completion of learning modules about professionalism. Lack of clarity on what defines a lapse and fear of reprisal (for both trainees and faculty) limits reporting.ConclusionsThis study provides an overview of how professional identity formation is supported in the Canadian context, guided by the standards set out by CanMEDS. Despite a rich literature that describes the definition, program design and evaluation methods for professionalism, in some areas of the curriculum there is still an opportunity to ensure programs embrace the suggested framework. Examples of teaching and evaluation methods, deficiencies in the clinical years of study (clerkship) and challenges in addressing lapses and organizational structure are identified. The results help identify the gaps that need to be addressed and some solutions that can be modeled at other academic institutions.

Thyroid-stimulating hormone acutely increases levels of circulating pro-coagulant microparticles.

Thyroid-stimulating hormone (TSH) acts on extra-thyroidal targets. When recombinant human (rh)TSH is administered to patients treated for thyroid cancer (thyroidectomy and radioablation) to screen for recurrence, metabolic and vascular stress occurs. This is indicated by elevations in levels of interleukin (IL)-6, C-reactive protein (CRP), oxidative stress and free fatty acids (FFA), as well as a decrease in endothelium-dependent relaxation. Microparticles (0 1–1 0 lm; or microvesicles) form by outward plasma membrane blebbing followed by shedding from cells. They display pro-coagulant activity by presenting surface phosphatidylserine. Platelet microparticles predominate; other sources include erythrocytes, leucocytes and endothelial cells. Elevations in total, and endothelial, microparticles correlate with indices of inflammation and vascular injury and may independently predict cardiovascular disease. Our objective was to determine whether rhTSH alters microparticle levels and procoagulant activity. Patients (12 women, six men) with a mean ( SD) age of 52 12 years and body mass index (BMI) of 29 5 kg/m, treated by total thyroidectomy and radioablation (14 papillary carcinoma, four follicular carcinoma), and on L-thyroxine therapy, were recruited (Ottawa Health Sciences Network Research Ethics Board, #2006558). Patients were disease free, that is no thyroglobulin response to rhTSH. They received two intramuscular doses of rhTSH (0 9 mg) on days 1 and 2 without discontinuation of L-thyroxine therapy. Blood was drawn on the mornings of days 1 (baseline; before rhTSH), 3 and 5 (serum separator tubes; BD Biosciences, Mississauga, ON, Canada). Samples were centrifuged at 1300 g for 10 min, and supernatants (sera) were used to measure TSH and free thyroxine (reference ranges 0 3–5 6 mU/l and 7–17 pmol/l, respectively) by AutoIA (Abbot DxI) in The Ottawa Hospital. Sera for microparticle and pro-coagulant measurements were frozen; they were thawed once for aliquoting and refrozen at 80 °C until thawed for analysis. For microparticle analysis, thawed samples (150 ll) were centrifuged at 2500 g (15 min, 4 °C). Supernatants were centrifuged at 2500 g (15 min, 4 °C). Supernatants were removed, then centrifuged at 20 000 g (20 min, 4 °C) to pellet the microparticles. Supernatants were aspirated, and microparticle-containing pellets were resuspended in Annexin V-binding buffer (10 mmol/l HEPES, pH 7 4, 140 mmol/l NaCl, 2 5 mmol/l CaCl2). Samples were labelled with 0 5 lg/ml Alexa-647 conjugated Annexin V (Biolegend, San Diego, CA, USA) and FITC-labelled CD144 antibody (1:50 dilution; Santa Cruz Biotechnology, Dallas, TX, USA) for 30 min for optimal labelling. As negative controls, a subpopulation of microparticles was resuspended in Annexin Vbinding buffer lacking calcium, and a subpopulation of microparticles was labelled with FITC-conjugated IgG isotype controls. Microparticles were assessed using a MoFlo Fluorescence Activated Cell Sorter (Dako Canada Inc, Burlington, ON, Canada) as particles of <1 0 and >0 1 lm that exhibited more fluorescence than negative controls. Results were expressed as number of annexinV total microparticles/ll plasma (interassay CV 9 5%) or of annexinV/CD144 endothelial microparticles/ll (interassay CV 11 4%). Phosphatidylserine-positive microparticles were assessed using a Zymuphen MP-activity kit (Aniara). The assay utilizes immobilized annexin V to capture phosphatidylserine (PS)-expressing microparticles. Microparticles are detected by addition of coagulation factor Va, factor Xa, Ca2 + and prothrombin. The rate of thrombin production, as indicated by a chromogenic substrate (405 nm), is proportional to PS availability and thereby, microparticle concentration. Results are expressed in nmol/l of PS equivalents (interassay CV 10%). Differences between means were assessed by ANOVA with Student Newman Keul post hoc tests. Linear regression and Pearson’s correlation were used to compare rhTSH responses where indicated. P < 0 05 was considered significant. Following rhTSH injection, TSH levels (mean SD) increased from 0 5 0 9 to 98 3 7 1 mU/l (day 3) and then decreased to 17 9 4 3 mU/l (day 5). Free thyroxine values (mean SD) were 17 9 4 3 pmol/l. The level of total microparticles was 36 651 microparticles/ll at baseline, increased 1 6-fold to 57 890 microparticles/ll on day 3 and significantly increased 1 9-fold to 70 969 microparticles/ll on day 5 (Fig. 1a). Baseline pro-coagulant activity was 5 5 nmol/l PS equivalent and increased significantly by 1 5-fold to 8 5 nmol/l PS equivalent and by 1 9-fold to 10 1 nmol/l PS equivalent on days 3 and 5, respectively (Fig. 1b). Endothelial microparticles measured 7535 microparticles/ll at baseline (20 6% of total) and did not change in response to rhTSH (Fig. 1c). Increases in total microparticles and pro-coagulant activity (responses at day 5 for each person) were correlated (r = 0 70; P < 0 05). There was a negative correlation of total microparticle response at day 5 with age (r = 0 56; P < 0 05); a similar trend with pro-coagulant activity (r = 0 40, P = 0 10) did not reach significance. There was no correlation with BMI. There were too few men to compare responses by gender. As levels of total microparticles rose with rhTSH, but endothelial particles did not, the response may be due to platelet microparticles, the main subpopulation, although other microparticle populations (e.g. leucocyte) cannot be excluded. rhTSH increases platelet reactivity (soluble P-selectin and soluble CD40 ligand) and endothelial activation (soluble intercellular adhesion molecule-1, soluble E-selectin). These rhTSH-induced

Time-motion studies of internal medicine residents' duty hours: a systematic review and meta-analysis.

Background Since the mid-1980s, medical residents’ long duty hours have been under scrutiny as a factor affecting patient safety and the work environment for the residents. After several mandated changes in duty hours, it is important to understand how residents spend their time before proposing and implementing future changes. Time-motion methodology may provide reliable information on what residents do while on duty. Purpose The purpose of this study is to review all available literature pertaining to time-motion studies of internal medicine residents while on a medicine service and to understand how much of their time is apportioned to various categories of tasks, and also to determine the effects of the Accreditation Council for Graduate Medical Education (ACGME)-mandated duty hour changes on resident workflow in North America. Methods Electronic bibliographic databases were searched for articles in English between 1941 and April 2013 reporting time-motion studies of internal medicine residents rotating through a general medicine service. Results Eight articles were included. Residents spent 41.8% of time in patient care activities, 18.1% communicating, 13.8% in educational activities, 19.7% in personal/other, and 6.6% in transit. North American data showed the following changes after the implementation of the ACGME 2003 duty hours standard: patient care activities from 41.8% to 40.8%, communication activities from 19.0% to 22.3%, educational activities from 17.7% to 11.6%, and personal/other activities from 21.5% to 17.1%. Conclusion There was a paucity of time-motion data. There was great variability in the operational definitions of task categories reported in the studies. Implementation of the ACGME duty hour standards did not have a significant effect on the percentage of time spent in particular tasks. There are conflicting reports on how duty hour changes have affected patient safety. A low proportion of time spent in educational activities deserves further study and may point to a review of the educational models used.

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.

Learning environment: assessing resident experience.

Given their essential role in developing professional identity, academic institutions now require formal assessment of the learning environment (LE). We describe the experience of introducing a novel and practical tool in postgraduate programmes. The Learning Environment for Professionalism (LEP) survey, validated in the undergraduate setting, is relatively short, with 11 questions balanced for positive and negative professionalism behaviours. LEP is anonymous and focused on rotation setting, not an individual, and can be used on an iterative basis. We describe how we implemented the LEP, preliminary results, challenges encountered and suggestions for future application.

Lack of Evidence to Guide Deprescribing of Antihyperglycemics: A Systematic Review

IntroductionIndividualizing glycemic targets to goals of care and time to benefit in persons with type 2 diabetes is good practice, particularly in populations at risk of hypoglycemia and adverse outcomes relating to the use of antihyperglycemics. Guidelines acknowledge the need for relaxed targets in frail older adults, but there is little guidance on how to safely deprescribe (i.e. stop, reduce or substitute) antihyperglycemics.MethodsThe purpose of this study was to synthesize evidence from all studies evaluating the effects of deprescribing versus continuing antihyperglycemics in older adults with type 2 diabetes. To this end, we searched MEDLINE, EMBASE, and Cochrane Library (July 2015) for controlled studies evaluating the effects of deprescribing antihyperglycemics in adults with type 2 diabetes. All such studies were eligible for inclusion in our study, and two independent reviewers screened titles, abstracts and full-text articles, extracted data, and evaluated risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment and a narrative summary were completed.ResultsWe identified two controlled before-and-after studies, both of very low quality. One study found that an educational intervention decreased glyburide use while not compromising glucose control. The other reported that cessation of antihyperglycemics in elderly nursing home patients resulted in a non-significant increase in glycated hemoglobin (HbA1C). No significant change in hypoglycemia rate was found in the only study with this outcome measure.ConclusionsThere is limited evidence available regarding deprescribing antihyperglycemic medications. Adequately powered, high-quality studies, particularly in the elderly and with clinically important outcomes, are required to support evidence-based decision-making.Protocol registration numberCRD42015017748.

A customised board game enhances learning about obesity

covering the main topics of VM. 2 A pre-test: 10 multiple choice questions (MCQs) to evaluate baseline knowledge and trigger interest in common vascular problems. 3 A teaching log (TL): a list of relevant topics in VM, with extra empty lines, displayed in the conference room. TRs were encouraged to mark their preferred topics, and to add other topics they were interested in to the TL, so they could be prioritised. Attending physicians were encouraged to pick topics from the TL for teaching sessions and mark when they were done. 4 Post-test and discussion: 20 MCQs designed to cover the most relevant topics. This was followed by a dedicated session to go over each question, discuss topics not covered during the rotation and answer any final questions. The results of the tests were for internal use; individual results were not shared, except with the TR, in order to focus on teaching and not on evaluating.

Thyroid-Stimulating Hormone-Stimulated Human Adipocytes Express Thymic Stromal Lymphopoietin

When recombinant human (rh) thyroid-stimulating hormone (TSH) is administered to thyroid cancer survivors, an acute extra-thyroidal effect raises pro-inflammatory cytokines and activates platelets. Thymic stromal lymphopoietin (TSLP) is a cytokine recently implicated in platelet activation. Our aim was to measure platelet microparticle levels after rhTSH stimulation in vivo, and to investigate TSLP expression in TSH-stimulated human adipocytes in culture. Blood samples for total and platelet microparticle analysis were obtained from thyroid cancer survivors before (day 1) and after rhTSH administration (day 5). Adipocytes, differentiated from stromal preadipocytes isolated from adipose tissue from surgical patients, were stimulated with TSH. TSLP mRNA expression, protein expression, and protein release into the adipocyte medium were measured. The level of platelet microparticles in thyroid cancer patients rose 5-fold after rhTSH stimulation. TSH upregulated TSLP mRNA expression in adipocytes in culture through a pathway that was inhibited by 66% by H89, a protein kinase A inhibitor. TSLP protein expression rose in response to TSH, and TSH-stimulated TSLP release into the medium was completely blocked by dexamethasone. In conclusion, TSLP is a novel TSH-responsive adipokine. Future studies will be needed to address the potential role of adipocyte-derived TSLP and whether it is linked to TSH-dependent platelet activation.