Real-World Patient Experience of Long-Term Hybrid Closed-Loop Insulin Pump Use.

OBJECTIVES: Understanding of patient experiences and adaptations to hybrid closed-loop (HCL) pumps beyond the confines of short-term clinical trials is needed to inform best practices surrounding this emerging technology. We investigated long-term, real-world patient experiences with HCL technology. METHODS: In semistructured interviews, 21 adults with type 1 diabetes at a single Canadian tertiary diabetes centre discussed their transition to use of Medtronic MiniMed 670G auto-mode. Interviews were audio-recorded, transcribed and analyzed iteratively to identify emerging themes. RESULTS: Participants' mean age was 50±13 years, 12 of the 21 participants were female, baseline glycated hemoglobin (A1C) was 7.9±1.0% and auto-mode duration was 9.3±4.6 months. Three had discontinued auto-mode. Most participants praised auto-mode for reducing hypoglycemia, stabilizing glucose overnight and improving A1C, while also reporting frustration with frequency of alarms and user input, sensor quality and inadequate response to hyperglycemia. Participants with the highest baseline A1Cs (8.8% to 9.8%) tended to report immense satisfaction and trust in auto-mode, meeting their primary expectations of improved glycemic control. In contrast, participants with controlled diabetes (A1C <7.5%) had hoped to offload active management but experienced significant cognitive and emotional labour associated with relinquishing control during suboptimal auto-mode performance. Participants were commonly aware of workarounds to "trick" the pump, and almost all participants with A1C <7.5% tried at least 1 workaround. CONCLUSIONS: In the real-world setting, patients' goals and satisfaction with auto-mode appeared to vary considerably with their baseline diabetes control. Patients with the most suboptimal glycemic control described the greatest benefits and easiest adaptation process, challenging commonly held assumptions for patient selection for pump therapy.

A De Novo POLD1 Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome.

Background. Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome is a recently recognized genetic disorder comprised of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy. It is caused by an autosomal dominant mutation in the POLD1 gene, with <20 genetically confirmed cases to date. Clinical overlap with other progeroid syndromes including Werner syndrome (WS) can present diagnostic challenges. Case. The proband is a 36-year-old male of Sicilian ancestry who was phenotypically normal at birth. Onset of lipodystrophic and progeroid features began at 18 months, with progressive loss of subcutaneous fat, prominent eyes, and pinched nose. Over the next 2 decades, he developed hearing loss, small fingers, joint contractures, hypogonadism, osteoporosis, and hypertriglyceridemia. Three of his 4 siblings had premature hair graying and loss, severe bilateral cataracts, skin changes, and varying degrees of age-related metabolic conditions, raising suspicion for a genetic progeroid syndrome. Genetic Analysis. A targeted sequencing panel identified a heterozygous WRN mutation in the proband's genomic DNA. Sanger sequencing further revealed his parents and an asymptomatic brother to be carriers of this mutation, and in his 3 brothers affected with classic WS the mutation was identified in the homozygous state. Whole exome sequencing ultimately revealed the proband harbored the causative de novo in-frame deletion in POLD1 (p.Ser605del), which is the most common mutation in MDPL patients. Conclusion. We report the unusual convergence of 2 rare progeroid disorders in the same family: the proband displayed sporadic MDPL syndrome, while 3 brothers had classical autosomal recessive WS. Whole exome sequencing was invaluable in clarifying the molecular diagnoses in this family.

Complex genetic architecture in severe hypobetalipoproteinemia.

BACKGROUND: Abetalipoproteinemia and homozygous hypobetalipoproteinemia are classical Mendelian autosomal recessive and co-dominant conditions, respectively, which are phenotypically similar and are usually caused by bi-allelic mutations in MTTP and APOB genes, respectively. Instances of more complex patterns of genomic variants resulting in this distinct phenotype have not been reported. METHODS: A 43 year-old male had a longstanding severe deficiency of apolipoprotein (apo) B-containing lipoproteins and circulating fat soluble vitamins consistent with either abetalipoproteinemia or homozygous familial hypobetalipoproteinemia (FHBL). He also had acanthocytosis, a long term history of fat malabsorption, and mild retinopathy, but was free from coagulopathy, myopathy and neuropathy. He had taken high dose oral fat soluble vitamins since childhood. RESULTS: Targeted next generation DNA sequencing revealed several rare heterozygous missense variants in both MTTP and APOB genes known or predicted to be deleterious, in addition to a novel heterozygous missense variant in SAR1B, which encodes the gene causing chylomicron retention disease. Evaluation of first degree relatives with mild FHBL clarified the segregation of variants. CONCLUSIONS: The proband's characteristic phenotype likely resulted from an oligogenic interaction involving multiple rare variants in MTTP and APOB, and related genes, each of which individually was associated with a milder or minimal clinical and biochemical phenotype.

Genetics for the Identification of Lipid Targets Beyond PCSK9.

From studies of rare families to genome-wide associations in populations, understanding of human genetics has accelerated the search for new drug targets for the prevention of atherosclerotic cardiovascular disease. DNA sequencing and genome-wide analyses of DNA markers have illuminated rare as well as common variants in genes that regulate lipids and ultimately atherosclerosis risk. A recent innovative approach called Mendelian randomization can endorse specific genes and variants as causative not just for lipid disturbances, but also for clinical cardiovascular end points. This knowledge helps prioritize the candidate genes and proteins in the drug development pipeline. In this review, we focus on dyslipidemia drug targets traceable to human genetic studies, including statins and ezetimibe, as well as promising new classes such as inhibitors of proprotein convertase subtilisin kexin 9, apolipoprotein B, microsomal triglyceride transfer protein, cholesteryl ester transfer protein, angiopoietin-like proteins types 3 and 4 and apolipoprotein C-III. Several of these new agents have attained or are closing in on "prime-time readiness" for clinical use in specific situations.

Invasive fungal disease in systemic lupus erythematosus: a systematic review of disease characteristics, risk factors, and prognosis.

OBJECTIVES: Invasive fungal disease (IFD) is a life-threatening complication of systemic lupus erythematosus (SLE) and/or its treatment. We conducted a systematic review to characterize IFD in SLE and identify risk factors and outcomes. METHODS: MEDLINE, Embase, and Web of Science were searched up to June 2013 using MeSH terms and keywords pertaining to SLE and IFD. Two independent reviewers selected adult cohort studies and case series/reports on IFD in SLE based on the established classification criteria for both diseases. RESULTS: In total, 393 cases from 182 studies met the criteria for inclusion. Cryptococcus spp., Aspergillus spp., and Candida spp. were the most common fungal pathogens. Cohorts described IFD in 0.6-3.2% of SLE inpatients and 0.28% of SLE outpatients. IFD occurred at a median of 2 years of disease duration (IQR: 0.5-7.1), and 39% of cases occurred within the first year of SLE. Disease activity and corticosteroid dose >60mg/day emerged as risk factors for IFD. IFD was associated with a mortality rate of 53% (161/316 cases), and worse in the absence of antifungal therapy (n = 43). Overall, 44 cases of IFD were only diagnosed on autopsy. CONCLUSIONS: Our systematic review confirms the severe sequelae of IFD in SLE. Cases occurred in patients with active SLE, who were on high daily corticosteroids doses and at early stages of disease. This highlights the role of poor disease control and a high "net state of immunosuppression" in risk. IFD in SLE should be prospectively examined in the modern era.