Investing in antibiotics to alleviate future catastrophic outcomes: What is the value of having an effective antibiotic to mitigate pandemic influenza?

Over 95% of post‐mortem samples from the 1918 pandemic, which caused 50 to 100 million deaths, showed bacterial infection complications. The introduction of antibiotics in the 1940s has since reduced the risk of bacterial infections, but growing resistance to antibiotics could increase the toll from future influenza pandemics if secondary bacterial infections are as serious as in 1918, or even if they are less severe. We develop a valuation model of the option to withhold wide use of an antibiotic until significant outbreaks such as pandemic influenza or foodborne diseases are identified. Using real options theory, we derive conditions under which withholding wide use is beneficial, and calculate the option value for influenza pandemic scenarios that lead to secondary infections with a resistant Staphylococcus aureus strain. We find that the value of withholding an effective novel oral antibiotic can be positive and significant unless the pandemic is mild and causes few secondary infections with the resistant strain or if most patients can be treated intravenously. Although the option value is sensitive to parameter uncertainty, our results suggest that further analysis on a case‐by‐case basis could guide investment in novel agents as well as strategies on how to use them.     

Dose-response relationship of oral insulin spray in healthy subjects

OBJECTIVE: To evaluate the pharmacodynamic and pharmacokinetic properties and the dose-ranging effects of an oral insulin spray in comparison with subcutaneous regular insulin. RESEARCH DESIGN AND METHODS: In this randomized, five-way, cross-over study, seven healthy volunteers were assessed under euglycemic clamp and received four different doses of oral spray and one dose of subcutaneous regular insulin. RESULTS: The time to maximum insulin concentration was shorter for oral insulin than for subcutaneous insulin (25.9 +/- 9 vs. 145.7 +/- 49.5 min, P < 0.05). Maximum serum insulin levels (C(max)) were comparable between the subcutaneous and 20 puffs of oral insulin (39.1 +/- 19.6 vs. 34.0 +/- 7.4 microU/ml, NS). The Ins-AUC(0-120) (area under the curve from 0 to 120 min for serum insulin) (339.8 +/- 218, 681.3 +/- 407, and 1,586.7 +/- 8 microU/ml, P < 0.05) and C(max) (7.6 +/- 2.8, 16.4 +/- 9.3, and 39.1 +/- 19.6 microU/ml, P < 0.005) proved a dose-response relationship for the three doses of oral insulin (5, 10, and 20 puffs, respectively). Oral insulin had an earlier onset of action (31.7 +/- 12 vs. 77.8 +/- 3 min, P < 0.05), earlier peak (44.2 +/- 10 vs. 159.2 +/- 68 min, P < 0.05), and a shorter duration of action (85.1 +/- 25 vs. 319.2 +/- 45 min, P < 0.05) compared with subcutaneous insulin. The maximum metabolic effect (1.7 +/- 1.0, 3.09 +/- 1.7, and 4.6 +/- 1.5 mg . kg(-1) . min(-1), P < 0.05) and the GIR-AUC(0-120) (amount of glucose infused from 0 to 120 min) (106.7 +/- 74.3, 162.9 +/- 116.1, and 254 +/- 123 mg/kg) increased in a dose-dependent relationship for the three doses. CONCLUSIONS: Oral insulin was absorbed in direct relation to the amount given and had a faster onset and a shorter duration of action compared with subcutaneous regular insulin. A dose-response relationship in the absorption and metabolic effect of the oral insulin was noted.     

Prevention of type 1 diabetes: today and tomorrow

The aim of therapeutic interventions for type 1 diabetes is to suppress pathogenic autoreactivity and to preserve/restore beta-cell mass and function to physiologically sufficient levels to maintain good metabolic control. During the natural history of type 1 diabetes, several strategies have been applied at various stages in the form of primary, secondary or tertiary prevention approaches. Clinical trials using antigen-specific (e.g. DiaPep277, human glutamic acid decarboxylase 65 (GAD65)) or non-specific immune therapies (e.g. anti-CD3 monoclonal antibodies) have shown some benefit in the modulation of the autoimmune process and prevention of the insulin secretion loss in the short term after diagnosis of diabetes. A single long-term effective therapy has not been identified yet, and it is likely that in most cases a rationally designed combinatorial approach using immunotherapeutic methods coupled with islet regeneration or replacement will prove to be most effective.     

Increased power of mixed models facilitates association mapping of 10 loci for metabolic traits in an isolated population

The potential benefits of using population isolates in genetic mapping, such as reduced genetic, phenotypic and environmental heterogeneity, are offset by the challenges posed by the large amounts of direct and cryptic relatedness in these populations confounding basic assumptions of independence. We have evaluated four representative specialized methods for association testing in the presence of relatedness; (i) within-family (ii) within- and between-family and (iii) mixed-models methods, using simulated traits for 2906 subjects with known genome-wide genotype data from an extremely isolated population, the Island of Kosrae, Federated States of Micronesia. We report that mixed models optimally extract association information from such samples, demonstrating 88% power to rank the true variant as among the top 10 genome-wide with 56% achieving genome-wide significance, a >80% improvement over the other methods, and demonstrate that population isolates have similar power to non-isolate populations for observing variants of known effects. We then used the mixed-model method to reanalyze data for 17 published phenotypes relating to metabolic traits and electrocardiographic measures, along with another 8 previously unreported. We replicate nine genome-wide significant associations with known loci of plasma cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, thyroid stimulating hormone, homocysteine, C-reactive protein and uric acid, with only one detected in the previous analysis of the same traits. Further, we leveraged shared identity-by-descent genetic segments in the region of the uric acid locus to fine-map the signal, refining the known locus by a factor of 4. Finally, we report a novel associations for height (rs17629022, P< 2.1 × 10??).     

Predicting the 20-year diabetes incidence rate

BACKGROUND: The long-range prediction from clinical variables of the onset of diabetes is important to patients and clinicians. Our objective was to evaluate the efficacy of various glucose-related clinical measurements in predicting the 20-year risk of developing type 2 diabetes (T2DM) in an elderly population. METHODS: In a prospective study, 672 men and women aged 59-92 years, who were not diabetic in 1980 and were part of a nationwide longitudinal randomized study, were followed-up in 2000-2003. Fasting glucose, 1- and 2-h post-oral glucose tolerance and insulin were measured in 1980 and 2000-2003. RESULTS: A group of 174 (25.9%) survivors had progressed to diabetes during the 20-year follow-up. Fasting glucose values were a good predictor for diabetes. With the 100 mg/dL cut-off of impaired fasting glucose (IFG), a 2-4-times higher predictive sensitivity followed the dramatic increase in IFG prevalence compared to the 110 mg/dL cut-off, but at a cost of reduced specificity and positive predictive value (PPV). By receiver operating curve (ROC) analysis, a 1-h post-load glucose was similar to 2 h and fasting glucose in prediction of the 20-year incidence of diabetes, and classifying correctly the 77, 74 and 73% of the group, respectively. In adjusted logistic regressions, 2.28, 1.78 and 1.69-folds increased the 20-year risk, and were associated with each SD increment of the respective glucose values (p < 0.001). CONCLUSIONS: Although the best population-based strategy for the diagnosis of T2DM would be the combination of fasting glucose followed by post-load glucose, for the purposes of long-term prediction of T2DM risk, fasting glucose is sufficient.     

Brain Activity Dissociates Mentalization from Motivation During an Interpersonal Competitive Game

Studies demonstrating selective brain networks subserving motivation and mentalization (i.e. attributing states of mind to others) during social interactions have not investigated their mutual independence. We report the results of two fMRI studies using a competitive game requiring players to use implicit ‘on-line’ mentalization simultaneously with motivational processes of gains and losses in playing against a human or a computer opponent. We delineate a network, consisting of bilateral temporoparietal junction, temporal pole (TP), medial prefrontal cortex (MPFC) and right fusiform gyrus, which is sensitive to the opponent’s response (challenging>not challenging the player) and opponent type (human>computer). This network is similar to a known explicit ‘off-line’ mentalization circuit, suggesting its additional involvement in implicit ‘on-line’ mentalization, a process more applicable to real-life social interactions. Importantly, only MPFC and TP were selective to mentalization compared to motivation, highlighting their specific operation in attributing states of mind to others during social interactions.