Etiology and emerging treatments for familial chylomicronemia syndrome.

INTRODUCTION: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition. Effective treatment is important as patients are at risk for severe and potentially fatal acute pancreatitis. We review recent developments in pharmacologic treatment for FCS, namely biological inhibitors of apolipoprotein (apo) C-III and angiopoietin-like protein 3 (ANGPTL3). AREAS COVERED: FCS follows a biallelic inheritance pattern in which an individual inherits two pathogenic loss-of-function alleles of one of the five causal genes - LPL (in 60-80% of patients), GPIHBP1, APOA5, APOC2, and LMF1 - leading to the absence of lipolytic activity. Patients present from childhood with severely elevated triglyceride (TG) levels >10 mmol/L. Most patients with severe hypertriglyceridemia do not have FCS. A strict low-fat diet is the current first-line treatment, and existing lipid-lowering therapies are minimally effective in FCS. Apo C-III inhibitors are emerging TG-lowering therapies shown to be efficacious and safe in clinical trials. ANGPTL3 inhibitors, another class of emerging TG-lowering therapies, have been found to require at least partial lipoprotein lipase activity to lower plasma TG in clinical trials. ANGPTL3 inhibitors reduce plasma TG in patients with multifactorial chylomicronemia but not in patients with FCS who completely lack lipoprotein lipase activity. EXPERT OPINION: Apo C-III inhibitors currently in development are promising treatments for FCS.

Recent advances in treating hypertriglyceridemia in patients at high risk of cardiovascular disease with apolipoprotein C-III inhibitors.

INTRODUCTION: Mild-to-moderate hypertriglyceridemia (HTG) is commonly encountered and is associated with atherosclerotic cardiovascular disease (ASCVD).  Elevated plasma triglyceride (TG) levels reflect high levels of triglyceride-rich lipoproteins, against which lipid-lowering therapies that reduce low-density lipoprotein cholesterol are relatively ineffective.  Apolipoprotein (apo) C-III is a new pharmacological target to reduce triglycerides and potentially also cardiovascular disease risk. AREAS COVERED: Here, we evaluate current lipid-lowering therapies and their effect on TG levels; genetic, pre-clinical, cellular, molecular biology, and translational studies that emphasize the importance of apo C-III in the metabolism of TG-rich lipoproteins and ASCVD risk; and clinical trials of pharmacotherapies that reduce TG levels via apo C-III inhibition. The PubMed database was searched using terms: apolipoprotein C-III, ARO-APOC3, atherosclerotic cardiovascular disease, olezarsen, triglycerides, and volanesorsen; study types: clinical trials, systematic reviews, and meta-analyses; and time criterion 2005 to present. EXPERT OPINION: Apo C-III inhibition is a promising treatment approach for adults with mild-to-moderate HTG and either established atherosclerotic cardiovascular disease or its risk factors.  Biologic agents such as volanesorsen, olezarsen, and ARO-APOC3 significantly reduce plasma levels of apo C-III and TG, although data on cardiovascular outcomes are lacking.  Volanesorsen is associated with thrombocytopenia in patients with severe HTG, but other agents appear to be better tolerated.  Clinical trials with long-term follow-up of cardiovascular outcomes will establish the validity of apo C-III inhibition.

Integrating shared decision-making into primary care: lessons learned from a multi-centre feasibility randomized controlled trial.

BACKGROUND: MyDiabetesPlan is a web-based, interactive patient decision aid that facilitates patient-centred, diabetes-specific, goal-setting and shared decision-making (SDM) with interprofessional health care teams. OBJECTIVE: Assess the feasibility of (1) conducting a cluster randomized controlled trial (RCT) and (2) integrating MyDiabetesPlan into interprofessional primary care clinics. METHODS: We conducted a cluster RCT in 10 interprofessional primary care clinics with patients living with diabetes and at least two other comorbidities; half of the clinics were assigned to MyDiabetesPlan and half were assigned to usual care. To assess recruitment, retention, and resource use, we used RCT conduct logs and financial account summaries. To assess intervention fidelity, we used RCT conduct logs and website usage logs. To identify barriers and facilitators to integration of MyDiabetesPlan into clinical care across the IP team, we used audiotapes of clinical encounters in the intervention groups. RESULTS: One thousand five hundred and ninety-seven potentially eligible patients were identified through searches of electronic medical records, of which 1113 patients met the eligibility criteria upon detailed chart review. A total of 425 patients were randomly selected; of these, 213 were able to participate and were allocated (intervention: n = 102; control: n = 111), for a recruitment rate of 50.1%. One hundred and fifty-one patients completed the study, for a retention rate of 70.9%. A total of 5745 personnel-hours and $6104 CAD were attributed to recruitment and retention activities. A total of 179 appointments occurred (out of 204 expected appointments-two per participant over the 12-month study period; 87.7%). Forty (36%), 25 (23%), and 32 (29%) patients completed MyDiabetesPlan at least twice, once, and zero times, respectively. Mean time for completion of MyDiabetesPlan by the clinician and the patient during initial appointments was 37 min. From the clinical encounter transcripts, we identified diverse strategies used by clinicians and patients to integrate MyDiabetesPlan into the appointment, characterized by rapport building and individualization. Barriers to use included clinician-related, patient-related, and technical factors. CONCLUSION: An interprofessional approach to SDM using a decision aid was feasible. Lower than expected numbers of diabetes-specific appointments and use of MyDiabetesPlan were observed. Addressing facilitators and barriers identified in this study will promote more seamless integration into clinical care. Trial registration Clinicaltrials.gov Identifier: NCT02379078. Date of Registration: February 11, 2015. Protocol version: Version 1; February 26, 2015.

Reference letters for subspecialty medicine residency positions: are they valuable for decision-making? Results from a Canadian study.

BACKGROUND: The letter of recommendation is currently an integral part of applicant selection for residency programs. Internal medicine residents will spend much time and expense completing sub-specialty away electives to obtain a letter of recommendation. The purpose of this study was 1) to examine a large sample of reference letters in order to define essential components of a high-quality letter, and 2) to elucidate the relationship between quality of reference letter and the letter writer. METHODS: We conducted a two-phase study. In phase one, a large sample of letters of recommendation was examined using an audit tool as a coding framework. A 5-point composite endpoint of high-quality letter components was subsequently developed. In phase two, program director letters were compared to non-program director home institution and non-home institution elective letters based on inclusion of components of the 5-point composite endpoint using Chi square testing. RESULTS: 715 letters were examined (398 non-program director home institution letters, 201 program director letters, and 116 non-home institution elective letters). High-quality letter components were: nature of relationship, duration of relationship, In Training Evaluation Report information, research involvement and comments on areas for improvement. Program director letters had a significantly higher proportion (10.4%) of all 5 high-quality components, compared to 0% in both non-program director home institution letters and elective letters (p < 0.001). A significantly higher proportion of program director letters had 4-5 high-quality components (62.5%) compared to 2% of non-program director home institution letters and 0% of elective letters (p < 0.0001). CONCLUSIONS: Letters of recommendation from elective rotations are of the poorest quality and such rotations should not be pursued for the sole purpose of obtaining a letter. The low quality of elective letters leads to the recommendation that writers should decline to write them, programs should not require them and trainees should not request them. Program directors write the highest quality letters and should be a resource for faculty development. Clinical supervisors can use the 5-point composite endpoint as a guide when writing letters for applicants.

Distance to Specialist Medical Care and Diagnosis of Obstructive Sleep Apnea in Rural Saskatchewan.

Obstructive sleep apnea (OSA) is the most common sleep-disordered breathing condition. Patients with OSA symptoms are often not diagnosed clinically, which is a concern, given the health and safety risks associated with unmanaged OSA. The availability of fewer practicing medical specialists combined with longer travel distances to access health care services results in barriers to diagnosis and treatment in rural communities. This study aimed to (1) determine whether the proportion of adults reporting OSA symptoms in the absence of a sleep apnea diagnosis in rural populations varied by travel distance to specialist medical care and (2) assess whether any distance-related patterns were attributable to differences in the frequency of diagnosis among adults who likely required this specialist medical care. We used a cross-sectional epidemiologic study design, augmented by analysis of follow-up survey data. Our study base included adults who completed a 2010 baseline questionnaire for the Saskatchewan Rural Health Study. Follow-up occurred until 2015. 6525 adults from 3731 households constituted our sample. Statistical models used log-binomial regression. Rural adults who reported the largest travel distances (≥250 km) to specialist medical care were 1.17 (95% CI: 1.07, 1.29) times more likely to report OSA symptoms in the absence of a sleep apnea diagnosis than those who reported the smallest (<100 km; referent) distances. However, the proportion of sleep apnea diagnoses was low and unaffected by reported travel distance among adults who likely required this specialist medical care. Our findings suggest factors other than travel distance may be contributing to the low sleep apnea diagnostic rate. This remains important as undiagnosed and untreated OSA has serious implications on the health of people and populations, but effective treatments are available. Health care access barriers to the diagnosis and treatment of OSA require evaluation to inform health care planning and delivery.