Overcoming the central planner approach - Bilevel optimization of the European energy transition.

The energy transition is a multinational challenge to mitigate climate change, with a joint reduction target for greenhouse gas emissions. Simultaneously, each country is interested in minimizing its own energy supply cost. Still, most energy system models neglect national interests when identifying cost-optimal transition pathways. We design the European energy system transition until 2050, considering competition between countries in a shared electricity and carbon market using bilevel optimization. We find that national objectives substantially impact the transition pathway: Compared to the model solved using the common centralized optimization, the overall installed capacity increases by just 3% when including national interests. However, the distribution of the installed capacity changes dramatically by more than 40% in most countries. Our results underline the risk of miscalculating the need for national capacity expansion when neglecting stakeholder representation in energy system models and demonstrate the need for cooperation for an efficient energy transition.

Prescription opioids are commonly unused after ambulatory head and neck surgeries: Opioids prescription presence and size has no effect on patient satisfaction with pain control.

PURPOSE: To explore the opioid prescribing practices after common ambulatory head and neck surgeries in a large academic institution; and to examine the association between opioid prescription and the patient's satisfaction with pain control. METHODS: This retrospective cohort study conducted in a tertiary academic medical center. Phone interviews of patients who underwent ambulatory head and neck surgeries one month after their procedures were conducted. The interview included, among several questions, the amount of opioid prescribed and consumed, the use of non-opioid pain medications, and the patient's satisfaction with pain control. Logistic regression models were used to investigate the significant factors affecting the patient's satisfaction with pain control. RESULTS: Most patients were prescribed opioids at discharge (84%). Of those, 17% did not use their prescriptions. The median of leftover opioid was 76.50 morphine milligram equivalents (MMEs) with IQR (45-130.95). Patient satisfaction with pain control is not associated with opioid prescription at discharge (OR 0.195 [95% CL, 0.036-1.036], p = 0.059) or the amount of the prescribed opioid (OR 1.001 [95% CL, 0.997-1.004], p = 0.717) after controlling for other patient and procedural factors. CONCLUSION: A significant portion of ambulatory head and neck surgery patients were discharged with opioid prescriptions they may not use. Patient satisfaction with pain control is not associated with the presence or the amount of opioid prescribed.

Quantifying the Vasculogenic Potential of Induced Pluripotent Stem Cell-Derived Endothelial Progenitors in Collagen Hydrogels.

IMPACT STATEMENT: Our work reinforces the role of extracellular matrix (ECM) density and matrix metalloprotease activity on the formation of microvasculature from induced pluripotent stem cell (iPSC)-derived vascular cells. The cell-matrix interactions discussed in this study underscore the importance of understanding the role of mechanoregulation and matrix degradation on vasculogenesis and can potentially drive the development of ECM-mimicking angiogenic biomaterials. Furthermore, our work has broader implications concerning the response of iPSC-derived cells to the mechanics of engineered microenvironments. An understanding of these interactions will be critical to creating physiologically relevant transplantable tissue replacements.

Fucoidan upregulates TLR4/CHOP-mediated caspase-3 and PARP activation to enhance cisplatin-induced cytotoxicity in human lung cancer cells.

Cisplatin-based therapy is a traditional, clinical treatment for cancers, including lung cancer. In this study, we found that sequential therapy, i.e., cisplatin followed by fucoidan, reduced tumor volume in an LLC1-bearing C57BL/6 mouse model. Using a series of combined therapeutic experiments, we found that the inhibition rate of the sequential treatment (cisplatin→fucoidan) was 50-75%. However, the inhibition rate of the sequential treatment, with fucoidan pretreatment, was increased to 75-85%. Moreover, we found that the simultaneous administration of fucoidan and cisplatin synergistically inhibited lung cancer cell viability via inducing apoptotic responses, including upregulating cleaved caspase-3 and poly (ADP ribose) polymerase (PARP) expression. Mechanistically, we demonstrated that the fucoidan-induced, TLR4-mediated endoplasmic reticulum stress molecule CHOP promoted caspase-3 activation, which was further stimulated by the cisplatin-induced DNA damage responses, and CHOP shRNA eliminated fucoidan-induced caspase-3 cleavage but did not affect cisplatin-mediated apoptotic molecules. In addition, we observed an increasing number of clinical results that suggest combined cisplatin and fucoidan exerts a greater anti-tumorigenic effect in patients with lung cancer in Taiwan. Together, our current results support the potential of combined fucoidan and cisplatin treatment as an effective therapeutic strategy in lung cancer.

Treatment intensification with stepwise addition of prandial insulin aspart boluses compared with full basal-bolus therapy (FullSTEP Study): a randomised, treat-to-target clinical trial.

BACKGROUND: We compared stepwise addition of bolus insulin with a full basal-bolus regimen in patients with type 2 diabetes inadequately controlled on basal insulin plus oral antidiabetic drugs. METHODS: The FullSTEP study was a phase 4, 32-week, randomised, open-label, two-arm, parallel-group, multinational, treat-to-target, non-inferiority trial done at 150 sites across seven countries to assess the effectiveness of a stepwise dosing approach versus a basal-bolus regimen. In this trial, 401 patients (mean age 59·8 years [SD 9·3]; HbA1c 7·9% [63 mmol/mol]; mean diabetes duration 12·6 years [SD 8·0]) were block randomised (ratio 1:1) to receive either stepwise treatment or full basal-bolus treatment. Patients in the basal-bolus group received insulin aspart before every meal throughout the trial. Patients in the stepwise group received one bolus dose with the largest meal, with additional insulin aspart doses before the next largest meal added to their regimen at 11 weeks and 22 weeks if HbA1c remained at 7% or higher. The primary outcome was non-inferiority of stepwise addition of bolus insulin versus complete basal-bolus therapy, as assessed by change in HbA1c from baseline to 32 weeks (non-inferiority margin of 0·4%). This trial is registered with ClinicalTrials.gov, number NCT01165684. FINDINGS: The study was started on Oct 27, 2010, and completed on April 25, 2012. After 32 weeks, HbA1c change from baseline was -0·98% (95% CI -1·09 to -0·87) for the stepwise group and -1·12% (-1·23 to -1·00) for the basal-bolus group; mean treatment difference 0·14 (95% CI -0·02 to 0·30), non-significant (p=0·0876). Fewer hypoglycaemic episodes occurred in the stepwise group than in the basal-bolus group (rate ratio 0·58 [95% CI 0·45 to 0·75]; p<0·0001). Treatment-emergent adverse events did not differ between the two treatment groups. The most frequently reported treatment-emergent adverse event were nasopharyngitis, influenza, diarrhoea, headache, peripheral oedema, and wrong drug given. Three participants died: two before randomisation and one in the basal-bolus group (due to severe acute myocardial infarction and respiratory tract inflammation). INTERPRETATION: Stepwise prandial insulin intensification provides glycaemic control non-inferior to a full basal-bolus regimen after 32 weeks, with significantly lower hypoglycaemia risk and better patient satisfaction. FUNDING: Novo Nordisk.

Anemia is an independent risk for mortality after acute myocardial infarction in patients with and without diabetes.

INTRODUCTION: Anemia and diabetes are risk factors for short-term mortality following an acute myocardial infarction(AMI). Anemia is more prevalent in patients with diabetes. We performed a retrospective study to assess the impact of the combination of diabetes and anemia on post-myocardial infarction outcomes. METHODS: Data relating to all consecutive patients hospitalized with AMI was obtained from a population-based disease-specific registry. Patients were divided into 4 groups: diabetes and anemia (group A, n = 716), diabetes and no anemia (group B, n = 1894), no diabetes and anemia (group C, n = 869), and no diabetes and no anemia (group D, n = 3987). Mortality at 30 days and 31 days to 36 months were the main outcome measures. RESULTS: 30-day mortality was 32.3% in group A, 16.1% in group B, 21.5% in group C, 6.6% in group D (all p < 0.001). 31-day to 36-month mortality was 47.6% in group A, 20.8% in group B, 34.3% in group C, and 10.4% in group D (all p < 0.001). Diabetes and anemia remained independent risk factors for mortality with odds ratios of 1.61 (1.41-1.85, p < 0.001) and 1.59 (1.38-1.85, p < 0.001) respectively at 36 months. Cardiovascular death from 31-days to 36-months was 43.7% of deaths in group A, 54.1% in group B, 47.0% in group C, 50.8% group D (A vs B, p < 0.05). INTERPRETATION: Patients with both diabetes and anemia have a significantly higher mortality than those with either diabetes or anemia alone. Cardiovascular death remained the most likely cause of mortality in all groups.