Efficacy of Levothyroxine Sodium Soft Gelatin Capsules in Thyroidectomized Patients Taking Proton Pump Inhibitors: An Open-Label Study.

Background: Treatment with proton pump inhibitors (PPIs) and antacids affects the gastrointestinal absorption of levothyroxine sodium (LT4) tablets. Patients with hypothyroidism taking LT4 and PPIs or antacids, thus, require appropriate monitoring. The objective of this study was to determine whether a soft gelatin capsule of LT4 (Tirosint®) would obviate the effect of PPIs on LT4 absorption. The objective was achieved by assessing the effects of a switch from a conventional LT4 tablet form to the same dose as soft capsules in thyroidectomized patients on treatment with LT4 and PPIs. Methods: Patients with history of hypothyroidism due to total thyroidectomy on stable treatment with LT4 tablets, and with gastrointestinal disease treated with PPIs, were switched to a 12-week treatment with Tirosint at the same dose of the LT4 tablets, while maintaining treatment with PPIs. Serum thyrotropin (TSH) levels were the primary endpoint of the study. Secondary efficacy endpoints were: serum levels of free thyroxine (fT4), total thyroxine (TT4), free triiodothyronine (fT3), total triiodothyronine (TT3), creatine-phosphokinase (CPK), sex-hormone binding globulin, ferritin, angiotensin converting enzyme, and a lipid panel. Results: Forty-seven patients (36 females and 11 males, mean age 55.4 years) were enrolled and 45 of them completed the study (2 patients withdrew consent). During treatment with Tirosint, mean TSH levels demonstrated a statistically significant decrease (mean changes from baseline: -0.32 mIU/L at week 6 and -0.68 mIU/L at week 12) and concomitant increases in thyroid hormone (TH) levels from baseline to week 12, which were statistically significant for fT3 and TT3 (mean changes from baseline: 0.26 pmol/L and 0.10 nmol/L, respectively). Significant decreases of serum low-density lipoprotein, total cholesterol, and CPK levels were observed at week 12. No signs/symptoms arose during the study that could be specifically correlated to either hypo- or hyperthyroidism. Conclusions: In thyroidectomized patients taking PPIs and replacement LT4, a switch from conventional LT4 tablets to LT4 soft capsules at the same dose was associated with a significant decrease in TSH and increase in TH, indicating that LT4 absorption may be less affected by PPIs when given in the form of soft capsules. Clinical Trial Registration: NCT03094416.

Inpatient and Outpatient Technologies to Assist in the Management of Insulin Dosing.

Several new technologies use computer algorithms to analyze a person's blood glucose response to insulin treatment, calculate the person's next recommended insulin dose, advise the person regarding when to check blood glucose next, and provide alerts regarding glucose control for the individual patient or across a hospital system. This article reviews U.S. Food and Drug Administration (FDA)-approved products designed to help manage insulin dosing for inpatients, as well as those available to provide people with insulin-requiring diabetes support in making adjustments to their basal and/or mealtime insulin doses. Many of these products have a provider interface that allows for remote monitoring of patients' glucose readings and insulin doses. By alleviating some of the burdens of insulin initiation and dose adjustment, these products may facilitate improved glycemic management and patient outcomes.

Redesigning ambulatory care management for uncontrolled type 2 diabetes: a prospective cohort study of the impact of a Boot Camp model on outcomes.

Objective: Type 2 diabetes care management (DCM) is challenging. Few studies report meaningful improvements in clinical care settings, warranting DCM redesign. We developed a Boot Camp to provide timely, patient-centered, technology-enabled DCM. Impact on hemoglobin A1c (HbA1c), emergency department (ED) visits and hospitalizations among adults with uncontrolled type 2 diabetes were examined. Research design and methods: The intervention was designed using the Practical Robust Implementation and Sustainability Model to embed elements of the chronic care model. Adults with HbA1c>9% (75 mmol/mol) enrolled between November 2014 and November 2017 received diabetes education and medication management by diabetes educators and nurse practitioners via initial clinic and subsequent weekly virtual visits, facilitated by near-real-time blood glucose transmission for 90 days. HbA1c and risk for ED visits and hospitalizations at 90 days, and potential savings from reducing avoidable medical utilizations were examined. Boot Camp completers were compared with concurrent, propensity-matched chart controls receiving usual DCM in primary care practices. Results: A cohort of 366 Boot Camp participants plus 366 controls was analyzed. Participants were 79% African-American, 63% female and 59% Medicare-insured or Medicaid-insured and mean age 56 years. Baseline mean HbA1c for cases and controls was 11.2% (99 mmol/mol) and 11.3% (100 mmol/mol), respectively. At 90 days, HbA1c was 8.1% (65 mmol/mol) and 9.9% (85 mmol/mol), p<0.001, respectively. Risk for 90-day all-cause hospitalizations decreased 77% for participants and increased 58% for controls, p=0.036. Mean potential for monetization of US$3086 annually per participant for averted hospitalizations were calculated. Conclusions: Redesigning diabetes care management using a pragmatic technology-enabled approach supported translation of evidence-based best practices across a mixed-payer regional healthcare system. Diabetes educators successfully participated in medication initiation and titration. Improvement in glycemic control, reduction in hospitalizations and potential for monetization was demonstrated in a high-risk cohort of adults with uncontrolled type 2 diabetes. Trial registration number: NCT02925312.

Future technology-enabled care for diabetes and hyperglycemia in the hospital setting.

Patients with diabetes are increasingly common in hospital settings where optimal glycemic control remains challenging. Inpatient technology-enabled support systems are being designed, adapted and evaluated to meet this challenge. Insulin pump use, increasingly common in outpatients, has been shown to be safe among select inpatients. Dedicated pump protocols and provider training are needed to optimize pump use in the hospital. Continuous glucose monitoring (CGM) has been shown to be comparable to usual care for blood glucose surveillance in intensive care unit (ICU) settings but data on cost effectiveness is lacking. CGM use in non-ICU settings remains investigational and patient use of home CGM in inpatient settings is not recommended due to safety concerns. Compared to unstructured insulin prescription, a continuum of effective electronic medical record-based support for insulin prescription exists from passive order sets to clinical decision support to fully automated electronic Glycemic Management Systems. Relative efficacy and cost among these systems remains unanswered. An array of novel platforms are being evaluated to engage patients in technology-enabled diabetes education in the hospital. These hold tremendous promise in affording universal access to hospitalized patients with diabetes to effective self-management education and its attendant short/long term clinical benefits.

Non-traditional therapies for diabetes: fact or fiction.

The number of medications now available to treat Type 2 Diabetes has been expanding quickly over the past two decades. At the same time, the use of complementary and alternative medicine (CAM) has also been rising. Individuals with diabetes are 1.6 times more likely than those without diabetes to use modalities that are not considered part of conventional medicine. Numerous dietary supplements are available over the counter and are being advertized to treat diabetes and its co morbidities. No conclusive data on their clinical benefit, potential harms, dosing or interaction with other medications is yet available. But for clinicians to maintain a trusting relationship with their patient, a respectful non-confrontational attitude is needed to encourage open dialogue, provide accurate information, and facilitate changes to the medical regimen. It is essential that clinicians stay informed and advise their patient with the available scientific data accordingly. In this review, we focus on current data on six supplements commonly encountered in community practice for treating diabetes, including cinnamon, fenugreek, vinegar, ginseng, bitter melon, gymnema, chromium, and vanadium.

Aspirin Resistance in healthy drug-naive men versus women (from the Heredity and Phenotype Intervention Heart Study).

This study was designed to determine the factors that contribute to interindividual variation in the antiplatelet effects of aspirin. We measured platelet response to aspirin in 745 (400 men and 345 women) drug-naive asymptomatic subjects of the Heredity and Phenotype Intervention (HAPI) Heart Study. Whole blood platelet aggregometry was performed to assess response to arachidonic acid, adenosine diphosphate, and collagen at baseline and after 14 days of aspirin 81 mg/day. There was wide interindividual variation in platelet aggregation in response to aspirin, with no clear biological threshold to define aspirin resistance. Variation in platelet function before and after aspirin was heritable. Women exhibited greater platelet aggregability in response to adenosine diphosphate and collagen at baseline and after aspirin administration. The degree to which aspirin inhibited collagen-induced platelet aggregation was also significantly less in women compared with men (mean +/- SD percent inhibition of collagen-induced [1 microg/ml] platelet aggregation 49.9 +/- 30.9 vs 57.5 +/- 42.5 in women and men, respectively, p = 0.005). Using a cutoff <70% inhibition of collagen-induced platelet aggregation, 21% of the total population demonstrated aspirin resistance, which occurred in 30% of women and 16% of men (p = 0.0002). Aspirin-resistant subjects were older, had significantly higher total cholesterol and low-density lipoprotein cholesterol levels, lower hematocrit, and higher platelet count compared with aspirin-sensitive subjects. In conclusion, in this study group, platelet function is heritable. There is wide interindividual variation in platelet response to aspirin as defined by whole blood platelet aggregometry, with women having lower mean percent inhibition of platelet aggregation and greater prevalence of aspirin resistance than men.

Physical activity and the association of common FTO gene variants with body mass index and obesity.

BACKGROUND: Common FTO (fat mass and obesity associated) gene variants have recently been associated with body mass index (BMI) and obesity in several large studies. The role of lifestyle factors (such as physical activity) in those with an underlying FTO genetic predisposition is unknown. METHODS: To determine if FTO variants are associated with BMI in Old Order Amish (OOA) individuals, and to further determine whether the detrimental associations of FTO gene variants can be lessened by increased physical activity, a total of 704 healthy OOA adults were selected from the Heredity and Phenotype Intervention (HAPI) Heart Study, an investigation of gene x environment interactions in cardiovascular disease, for whom objective quantified physical activity measurements were available and for whom 92 single-nucleotide polymorphisms (SNPs) in FTO were genotyped. RESULTS: Twenty-six FTO SNPs were associated with BMI (P = .04 to <.001), including rs1477196 (P < .001) and rs1861868 (P < .001), 2 SNPs in moderate linkage disequilibrium in the OOA (D' = 0.82; r(2) = 0.36). Stratified analyses of rs1861868 revealed its association with BMI to be restricted entirely to those subjects with low sex- and age-adjusted physical activity scores (P < .001); in contrast, the SNP had no effect on those with above-average physical activity scores (P = .29), with the genotype x physical activity interaction achieving statistical significance (P = .01). Similar evidence for interaction was also obtained for rs1477196. CONCLUSIONS: Our results strongly suggest that the increased risk of obesity owing to genetic susceptibility by FTO variants can be blunted through physical activity. These findings emphasize the important role of physical activity in public health efforts to combat obesity, particularly in genetically susceptible individuals.

Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates.

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of severe juvenile osteoporosis and congenital blindness, due to mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Approximately fifty cases of OPPG have been reported. We report 9 new cases of OPPG, in three related nuclear families of Conservative Mennonites in Pennsylvania. All 9 children with OPPG were blind and had osteoporosis. Four of six parents had low bone mineral density (BMD) or osteoporosis; 2 were normal. Sequence analysis from genomic DNA revealed homozygosity for a nonsense mutation of exon 6 of LRP5 (W425X) in four OPPG cases tested in families A and C. In family B, OPPG cases were compound heterozygotes for the exon 6 W425X LRP5 mutation and a second exon 6 mutation (T409A); bone phenotype was milder than in family A. Neither of these mutations was present in an unrelated normal. The four treated OPPG patients all responded to bisphosphonates (duration 1.5-6.5 years) with improvement in Z-scores. One patient had a negligible response to teriparatide. In summary, we report 9 new cases of OPPG due to two novel LRP5 mutations, note a milder bone phenotype but similar ocular phenotype in LRP5 W425X/T409A compound heterozygotes than in W425X homozygotes and describe positive response to bisphosphonate treatment in four cases.

The genetic response to short-term interventions affecting cardiovascular function: rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study.

BACKGROUND: The etiology of cardiovascular disease (CVD) is multifactorial. Efforts to identify genes influencing CVD risk have met with limited success to date, likely because of the small effect sizes of common CVD risk alleles and the presence of gene by gene and gene by environment interactions. METHODS: The HAPI Heart Study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular risk factors and to identify the genetic and environmental determinants of these responses. The measurements included blood pressure responses to the cold pressor stress test and to a high salt diet, triglyceride excursion in response to a high-fat challenge, and response in platelet aggregation to aspirin therapy. RESULTS: The interventions were carried out in 868 relatively healthy Amish adults from large families. The heritabilities of selected response traits for each intervention ranged from 8% to 38%, suggesting that some of the variation associated with response to each intervention can be attributed to the additive effects of genes. CONCLUSIONS: Identifying these response genes may identify new mechanisms influencing CVD and may lead to individualized preventive strategies and improved early detection of high-risk individuals.

Genetic influences on blood pressure response to the cold pressor test: results from the Heredity and Phenotype Intervention Heart Study.

OBJECTIVES: Blood pressure (BP) response to the cold pressor test (CPT) has been found to predict the development of hypertension and cardiovascular disease in prospective studies. The determinants of BP response to the CPT, including the role of genetic factors, however, are largely unknown. Additionally, to our knowledge, no study has examined the genetics of BP recovery from the CPT, including whether shared genetic factors influence both reactivity and recovery. METHODS: As part of the Heredity and Phenotype Intervention Heart Study, we administered a 2.5 min hand CPT to 835 participants from 18 extended Amish families. We estimated the heritability of BP reactivity and recovery (measured by the incremental area under the curve) and the genetic correlations between baseline, reactivity, and recovery BP phenotypes. RESULTS: After adjusting for relevant covariates, including baseline BP, the heritability estimates for both systolic BP (SBP) and diastolic BP (DBP) reactivity and recovery differed significantly from zero (P < 0.01), with 12-25% of the total variation in BP response attributable to additive genetic effects. The genetic correlations between baseline DBP and response phenotypes were not significantly different from zero, whereas the genetic correlation between DBP reactivity and recovery (0.74) was significantly different from zero and 1 (P < 0.005). The genetic correlation between SBP reactivity and recovery was similar (0.81; P < 0.05). CONCLUSION: We conclude that, independent of baseline BP, BP response to CPT is heritable, and that both shared and unshared genetic factors influence BP reactivity and recovery, thus stressing the importance of identifying genetic variants that influence both traits.

Associations between genetic variants in the NOS1AP (CAPON) gene and cardiac repolarization in the old order Amish.

BACKGROUND: Through a genome-wide association study, we discovered an association of the electrocardiographic QT interval with polymorphisms in the NOS1AP (CAPON) gene. The purpose of the current study was to replicate this association in the Old Order Amish. METHODS: Four NOS1AP SNPs were selected that captured all major haplotypes in the region of interest ( approximately 120 kb segment). Genotyping was completed in 763 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study. Association analyses were performed using a variance components methodology, accounting for relatedness of individuals. RESULTS: Heritability of the QT interval was 0.50 +/- 0.09 (p = 1.9 x 10(-9)). All four SNPs were common with a high degree of correlation between SNPs. Two of the four SNPs (pairwise r(2) = 0.86) were significantly associated with variation in adjusted QT interval (rs1415262, p = 0.02 and rs10494366, p = 0.006, additive models for both). SNP rs10494366 explained 0.9% of QT interval variability, with an average genetic effect of 6.1 ms. Haplotypes that contained the minor allele for rs10494366 were associated with longer QT interval. CONCLUSIONS: This study provides further evidence that NOS1AP variants influence QT interval and further validates the utility of genome-wide association studies, a relatively new approach to gene discovery.

The inpatient consultation approach to osteoporosis treatment in patients with a fracture. Is automatic consultation needed?

BACKGROUND: Osteoporosis has been described as a "silent epidemic." We describe an osteoporosis consultation program to facilitate the evaluation and treatment of inpatients with fragility fractures. METHODS: The inpatient orthopaedic team voluntarily requested an osteoporosis consultation on all patients with a fragility fracture. The osteoporosis consultant evaluated patients for secondary causes and started treatment with calcium, vitamin D, and bisphosphonates unless contraindicated. From November 2001 to December 2003, fifty-three osteoporosis consultations were performed. A retrospective review of the charts of all patients with a hip fracture treated during this twenty-six-month period revealed that only 47% were actually seen by the osteoporosis consultants, creating an unintentional "nonintervention" cohort of thirty-one patients with a hip fracture. Treatment for osteoporosis was assessed by a review of the inpatient charts and by a telephone interview after discharge. RESULTS: The study group consisted of eighty-four patients, which included fifty-three in the intervention cohort (twenty-eight hip and twenty-five other fractures) and thirty-one in the nonintervention cohort (all patients with a hip fracture). In the intervention cohort, most patients were vitamin-D deficient. Calcium and vitamin-D treatment was recommended for all fifty-three patients, and bisphosphonates were recommended for forty-one of the fifty-three patients in the intervention cohort. In the nonintervention cohort, two patients received calcium and vitamin D and one received a bisphosphonate; the difference between the cohorts was significant (p < 0.0001). In the intervention cohort, twenty-seven of the thirty-four patients who were available for a telephone interview after discharge (at a mean of eighteen months) remained on calcium and vitamin D; twenty-two of the thirty-four patients remained on bisphosphonates. In the nonintervention cohort, only one of the twelve patients who were available for follow-up (at a mean of thirty-nine months) was receiving calcium and vitamin D and none were on bisphosphonate treatment. CONCLUSIONS: This consultation program cannot be considered an outright success since only half of all patients with a hip fracture actually received a consultation. However, osteoporosis consultation, when provided, facilitated the recognition of secondary causes and the generic treatment of osteoporosis, and inpatients started on treatment generally continued the medication after discharge. The results of this study strongly support the need for a mechanism of automatic osteoporosis consultation for inpatients with a fragility fracture and suggest that, if consultation is reliably obtained, this approach can be effective in improving patient care. LEVEL OF EVIDENCE: Therapeutic Level III.

The genetics of obesity.

Obesity prevalence has increased markedly over the past few decades. The obesity pandemic has huge implications for public health and our society. Although multiple studies show that the genetic contribution to obesity is significant, our genes have not changed appreciably over this time period. It was hypothesized that natural selection favors genotypes that result in a thrifty metabolism because individuals who carry these genotypes would be more likely to survive times of nutrient scarcity and to pass these genotypes to successive generations. Now that most of the world has adopted an increasingly "obesigenic" lifestyle of excess caloric intake and decreased physical activity, these same genes contribute to obesity and poor health. With the exception of the rare mutations that cause severe morbid obesity, it seems that numerous genes, each with modest effect, contribute to an individual's predisposition toward the more common forms of obesity. Variants in several candidate genes have been identified: association analyses and functional studies show that they contribute to modest obesity and related phenotypes. More recently, insights regarding gene-gene interactions have begun to emerge. Genome-wide scans for obesity phenotypes have led to the identification of several chromosome regions that are likely to harbor obesity susceptibility genes. Because of the increasing number of genome scans, several regions of replication have emerged. Positional cloning of these genes will undoubtedly unveil new insights into the molecular and pathophysiologic mechanisms of energy homeostasis and obesity.