Invasive species eradication campaigns often fail due to stochastic arrival events, unpredictable detectability and incorrect resource allocation. Severe uncertainty in model parameter estimates may ...skew the eradication policy results. Using info-gap decision theory, this research aims to provide managers with a method to quantify their confidence in realizing successful eradication of particular invasive species within their specified eradication budgets (i.e. allowed eradication cost) in face of information-gaps. The potential introduction of the Asian house gecko Hemidactylus frenatus to Barrow Island, Australia is used as a case study to illustrate the model. Results of this research demonstrate that, more robustness to uncertainty in the model parameters can be earnt by (1) increasing the allowed eradication cost (2) investment in pre-border quarantine and border inspection (i.e. prevention) or (3) investment in post-border detection surveillance. The combination of a post-border spatial dispersal model and info-gap decision theory demonstrates a novel and spatially efficient method for managers to evaluate the robustness of eradication policies for incursion of invasive species with unexpected behaviour. These methods can be used to provide insight into the success of management goals, in particular the eradication of invasive species on islands or in broader mainland areas. These insights will assist in avoiding eradication failure and wasteful budget allocation and labour investment.
Tirzepatide (TZP) , a novel dual GIP/GLP-1 receptor agonist, led to greater HbA1c, fasting serum glucose and body weight reductions vs. placebo (PBO) in people with early T2D (baseline mean T2D ...duration 4.7 y and 54% no prior diabetes medications) from the 40-wk SURPASS-1 trial. In a Phase 2b trial, TZP also improved β-cell function and insulin sensitivity (IS) vs. PBO and selective GLP-1 receptor agonist, dulaglutide 1.5 mg. Similarly, in SURPASS-1, TZP improved β-cell function, as indicated by a 75-80% increase in HOMA2-B, and insulin resistance, as indicated by a 2-12% decrease in fasting insulin and 8-20% decrease in HOMA2-IR. In this analysis, we aimed to explore changes in additional biomarkers of β-cell function and IS after TZP monotherapy (5, and 15 mg) . At 40 wks, proinsulin/C-peptide ratios, a marker of insulin processing, β-cell stress and β-cell function improved with decrease by 47-49% with TZP vs. -0.1% with PBO (p<0.001, all doses) (Table) . Fasting proinsulin decreased by 49-55% with TZP vs. no change with PBO (p<0.001, all doses) . Decreases in fasting C-peptide by 3-9% with TZP did not differ vs. PBO. TZP vs. PBO improved biomarkers of IS evidenced by increases in adiponectin (16-23% vs. -0.2%; p≤0.028, all doses) and IGFBP-2 (38-70% vs. 4.1%; p<0.001, all doses) . As a monotherapy for early T2D, TZP achieved significant improvement in markers of β-cell function and IS.
Disclosure
C.Lee: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. H.Mao: Employee; Eli Lilly and Company. V.Thieu: None. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.
Funding
Eli Lilly and Company
Diet-induced obesity is a rising health concern which can lead to the development of glucose intolerance and muscle insulin resistance and, ultimately, type II diabetes mellitus. This research ...investigates the associations between glucose intolerance or muscle insulin resistance and tissue specific changes during the progression of diet-induced obesity.
C57BL/6J mice were fed a normal or high-fat diet (HFD; 60% kcal fat) for 3 or 8 weeks. Disease progression was monitored by measurements of body/tissue mass changes, glucose and insulin tolerance tests, and ex vivo glucose uptake in intact muscles. Lipid metabolism was analyzed using metabolic chambers and ex vivo palmitate assays in intact muscles. Skeletal muscle, liver and adipose tissues were analyzed for changes in inflammatory gene expression. Plasma was analyzed for insulin levels and inflammatory proteins. Histological techniques were used on muscle and liver cryosections to assess metabolic and morphological changes.
A rapid shift in whole body metabolism towards lipids was observed with HFD. Following 3 weeks of HFD, elevated total lipid oxidation and an oxidative fiber type shift had occurred in the skeletal muscle, which we propose was responsible for delaying intramyocellular lipid accumulation and maintaining muscle's insulin sensitivity. Glucose intolerance was present after three weeks of HFD and was associated with an enlarged adipose tissue depot, adipose tissue inflammation and excess hepatic lipids, but not hepatic inflammation. Furthermore, HFD did not significantly increase systemic or muscle inflammation after 3 or 8 weeks of HFD suggesting that early diet-induced obesity does not cause inflammation throughout the whole body. Overall these findings indicate skeletal muscle did not contribute to the development of HFD-induced impairments in whole-body glucose tolerance following 3 weeks of HFD.
A major change has occurred in the evaluation of epilepsy with the availability of robotic stereoelectroencephalography (SEEG) for seizure localization. However, the comparative morbidity and ...outcomes of this minimally invasive procedure relative to traditional subdural electrode (SDE) implantation are unknown.
To perform a comparative analysis of the relative efficacy, procedural morbidity, and epilepsy outcomes consequent to SEEG and SDE in similar patient populations and performed by a single surgeon at 1 center.
Overall, 239 patients with medically intractable epilepsy underwent 260 consecutive intracranial electroencephalographic procedures to localize their epilepsy. Procedures were performed from November 1, 2004, through June 30, 2017, and data were analyzed in June 2017 and August 2018.
Implantation of SDE using standard techniques vs SEEG using a stereotactic robot, followed by resection or laser ablation of the seizure focus.
Length of surgical procedure, surgical complications, opiate use, and seizure outcomes using the Engel Epilepsy Surgery Outcome Scale.
Of the 260 cases included in the study (54.6% female; mean SD age at evaluation, 30.3 13.1 years), the SEEG (n = 121) and SDE (n = 139) groups were similar in age (mean SD, 30.1 12.2 vs 30.6 13.8 years), sex (47.1% vs 43.9% male), numbers of failed anticonvulsants (mean SD, 5.7 2.5 vs 5.6 2.5), and duration of epilepsy (mean SD, 16.4 12.0 vs17.2 12.1 years). A much greater proportion of SDE vs SEEG cases were lesional (99 71.2% vs 53 43.8%; P < .001). Seven symptomatic hemorrhagic sequelae (1 with permanent neurological deficit) and 3 infections occurred in the SDE cohort with no clinically relevant complications in the SEEG cohort, a marked difference in complication rates (P = .003). A greater proportion of SDE cases resulted in resection or ablation compared with SEEG cases (127 91.4% vs 90 74.4%; P < .001). Favorable epilepsy outcomes (Engel class I free of disabling seizures or II rare disabling seizures) were observed in 57 of 75 SEEG cases (76.0%) and 59 of 108 SDE cases (54.6%; P = .003) amongst patients undergoing resection or ablation, at 1 year. An analysis of only nonlesional cases revealed good outcomes in 27 of 39 cases (69.2%) vs 9 of 26 cases (34.6%) at 12 months in SEEG and SDE cohorts, respectively (P = .006). When considering all patients undergoing evaluation, not just those undergoing definitive procedures, favorable outcomes (Engel class I or II) for SEEG compared with SDE were similar (57 of 121 47.1% vs 59 of 139 42.4% at 1 year; P = .45).
This direct comparison of large matched cohorts undergoing SEEG and SDE implantation reveals distinctly better procedural morbidity favoring SEEG. These modalities intrinsically evaluate somewhat different populations, with SEEG being more versatile and applicable to a range of scenarios, including nonlesional and bilateral cases, than SDE. The significantly favorable adverse effect profile of SEEG should factor into decision making when patients with pharmacoresistant epilepsy are considered for intracranial evaluations.
Tirzepatide (TZP) is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). In the SURPASS-1 (S-1) (monotherapy) and SURPASS-2 (S-2) (on metformin) Phase 3 ...trials, TZP substantially reduced HbA1c and body weight (BW) in people with T2D. Exploratory post hoc analyses examined the predictive value of HOMA2-IR (insulin) and HOMA2-B (C-peptide) by quartiles low (lower beta-cell function or insulin resistance) Q1 to high Q4 for achieving HbA1c (<5.7%, ≤6.5%) and BW reduction (≥10%, ≥15%) targets for those adherent to TZP treatment at Week 40. Odds ratios (OR) were calculated from logistic regression models using the overall mean as the reference. The results showed that TZP was equally likely to achieve BW and HbA1c targets in S-1 and S-2 regardless of baseline HOMA2-B and -IR quartiles, with the exception of S-2 where subjects with Q1 HOMA2-B (lowest beta-cell function) were significantly less likely and those with Q4 HOMA2-B (highest beta-cell function) were significantly more likely to reach HbA1c ≤6.5% (Figure). We conclude that baseline HOMA2-B, but not HOMA2-IR, may predict the likelihood of subjects achieving the HbA1c target ≤6.5% for patients enrolled in S-2 not controlled with metformin alone.
Disclosure
S.H.Hsia: Research Support; Eli Lilly and Company. M.K.Thomas: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. C.Mathieu: Advisory Panel; Novo Nordisk A/S, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated, Roche Diabetes Care, Imcyse, Speaker's Bureau; Novo Nordisk A/S, AstraZeneca, Boehringer Ingelheim Inc., Eli Lilly and Company, Medtronic, Vertex Pharmaceuticals Incorporated. H.Wang: None. J.Peleshok: Employee; Eli Lilly and Company.
Funding
Eli Lilly and Company
Abstract
Background
Hypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are ...often observed years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high-fat diet and metabolic disease (e.g., obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex.
Methods
WT and 3xTg-AD male and female mice were fed a control (10% fat) or high-fat (HF 60% fat) diet from ~ 3–7 months of age, then tested for metabolic and hypothalamic disturbances.
Results
On control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-α, IL-1β). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1β, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group.
Conclusions
These findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet.
In previous SURPASS studies tirzepatide reduced HbA1c and body weight and improved markers of insulin sensitivity (IS) and beta-cell function to a greater extent than comparators.
Explore changes in ...biomarkers of beta-cell function and IS and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide.
Post-hoc analysis of SURPASS-2 Phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks).
Post-hoc analysis of 128 sites in 8 countries.
1879 participants with T2D.
Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg.
Change in HOMA2-B, HOMA2-IR, fasting glucagon, fasting C-peptide, and fasting insulin.
At week 40, greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9 to 120.4%) than with semaglutide 1 mg (84.0%) p<0.05. There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5 to 24.0%) than with semaglutide 1 mg (5.1%) p<0.05. Tirzepatide 10 and 15 mg resulted a significant reduction in both fasting C-peptide (5.2 to 6.0%) and fasting glucagon (53.0 to 55.3%) compared to an increase of C-peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg p<0.05. HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile.
In this post-hoc analysis improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, irrespective of baseline beta cell function and insulin resistance, compared to semaglutide.
Aims/hypotheses
Ceramides and other sphingolipids comprise a family of lipid molecules that accumulate in skeletal muscle and promote insulin resistance. Chronic endurance exercise training decreases ...muscle ceramides and other sphingolipids, but less is known about the effects of a single bout of exercise.
Methods
We measured basal relationships and the effect of acute exercise (1.5 h at 50%
V
.
O
2
max
) and recovery on muscle sphingolipid content in obese volunteers, endurance trained athletes and individuals with type 2 diabetes.
Results
Muscle C18:0 ceramide (
p =
0.029), dihydroceramide (
p =
0.06) and glucosylceramide (
p =
0.03) species were inversely related to insulin sensitivity without differences in total ceramide, dihydroceramide, and glucosylceramide concentration. Muscle C18:0 dihydroceramide correlated with markers of muscle inflammation (
p =
0.04). Transcription of genes encoding sphingolipid synthesis enzymes was higher in athletes, suggesting an increased capacity for sphingolipid synthesis. The total concentration of muscle ceramides and sphingolipids increased during exercise and then decreased after recovery, during which time ceramide levels reduced to significantly below basal levels.
Conclusions/interpretation
These data suggest ceramide and other sphingolipids containing stearate (18:0) are uniquely related to insulin resistance in skeletal muscle. Recovery from an exercise bout decreased muscle ceramide concentration; this may represent a mechanism promoting the insulin-sensitising effects of acute exercise.
Females in a wide range of taxa have been shown to base their choice of mates on pheromone signals. However, little research has focussed specifically on the form and intensity of selection that mate ...choice imposes on the pheromone signal. Using multivariate selection analysis, we characterise directly the form and intensity of sexual selection acting on cuticular hydrocarbons, chemical compounds widely used in the selection of mates in insects. Using the Australian field cricket Teleogryllus oceanicus as a model organism, we use three measures of male attractiveness to estimate fitness; mating success, the duration of courtship required to elicit copulation, and subsequent spermatophore attachment duration.
We found that all three measures of male attractiveness generated sexual selection on male cuticular hydrocarbons, however there were differences in the form and intensity of selection among these three measures. Mating success was the only measure of attractiveness that imposed both univariate linear and quadratic selection on cuticular hydrocarbons. Although we found that all three attractiveness measures generated nonlinear selection, again only mating success was found to exert statistically significant stabilizing selection.
This study shows that sexual selection plays an important role in the evolution of male cuticular hydrocarbon signals.
Tirzepatide (TZP) achieved significantly greater HbA1c and weight reductions with all doses (5, and 15 mg) vs. semaglutide 1 mg (SEMA) in a Phase 3 trial of 1879 people with type 2 diabetes (T2D) on ...background metformin (mean age 56.6 years; T2D duration 8.6 years; baseline HbA1c 8.3% 67 mmol/mol; BMI 34.2 kg/m2) (SURPASS-2) . Changes in fasting markers of islet cell function and insulin sensitivity were assessed by mixed model repeated measures in the modified intent-to-treat population. At 40 weeks, all TZP doses improved HOMA2-B, calculated with C-peptide, as indicated by a significant increase by 97-120% on average with TZP, compared to 84% with SEMA. Fasting glucagon levels, adjusted for fasting serum glucose, significantly decreased by 53-55% on average with TZP and 15 mg doses compared with SEMA (48%) . All TZP doses improved insulin sensitivity as reflected by a significant decrease by 16-24% on average of HOMA2-IR, calculated with insulin, compared to a decrease by 5% with SEMA. Fasting insulin levels were also significantly reduced by 9-21% on average with all TZP doses compared to an increase of 0.6% with SEMA. Dual GIP/GLP-1 receptor agonist TZP significantly improved markers of islet cell function and insulin sensitivity compared to selective GLP-1 RA SEMA in people with T2D.
Disclosure
K. Brown: Employee; Eli Lilly and Company. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. B. Bergman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. B. Liu: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.
Funding
Eli Lilly and Company
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