Computationally efficient calibration of WATCLASS Hydrologic models using surrogate optimization

International audienceIn this approach, exploration of the cost function space was performed with an inexpensive surrogate function, not the expensive original function. The Design and Analysis of Computer Experiments(DACE) surrogate function, which is one type of approximate models, which takes correlation function for error was employed. The results for Monte Carlo Sampling, Latin Hypercube Sampling and Design and Analysis of Computer Experiments(DACE) approximate model have been compared. The results show that DACE model has a good potential for predicting the trend of simulation results. The case study of this document was WATCLASS hydrologic model calibration on Smokey-River watershed

A phase II study of capecitabine and oxalplatin combination chemotherapy in patients with inoperable adenocarcinoma of the gall bladder or biliary tract

Background: Advanced biliary tract carcinomas are associated with a poor prognosis, and palliative chemotherapy has only modest benefit. This multi-centre phase II study was conducted to determine the efficacy of capecitabine in combination with oxaliplatin in patients with inoperable gall bladder or biliary tract cancer. Methods: This was a Phase II, non-randomised, two-stage Simon design, multi-centre study. Ethics approval was sought and obtained by the North West MREC, and then locally by the West Glasgow Hospitals Research Ethics Com mittee. Eligible patients with inoperable locally advanced or metastatic adenocarcinoma of the gall bladder or biliary tract and with adequate performance status, haematologic, renal, and hepatic function were treated with capecit abine (1000 mg/m2 po, twice daily, days 1–14) and oxaliplatin (130 mg/m2 i.v., day 1) every 3 weeks for up to six cycles. The primary objective of the study was to determine the objective tumour response rates (complete and partial). The secondary objectives included assessment of toxicity, progression-free survival, and overall survival. Results: Forty-three patients were recruited between July 2003 and December 2005. The regimen was well tolerated with no grade 3/4 neutropenia or thrombocytopenia. Grade 3/4 sensory neuropathy was observed in six patients. Two-thirds of patients received their chemotherapy without any dose delays. Overall response rate was 23.8 % (95 % CI 12.05–39.5 %). Stable disease was observed in a further 13 patients (31 %) and progressive disease observed in 12 (28.6 %) of patients. The median progression-free survival was 4.6 months (95 % CI 2.8–6.4 months; Fig. 1) and the median overall survival 7.9 months (95 % CI 5.3–10.4 months; Fig. 2). Conclusion: Capecitabine combined with oxaliplatin has a lower disease control and shorter overall survival than the combination of cisplatin with gemcitabine which has subsequently become the standard of care in this disease. How ever, capecitabine in combination with oxaliplatin does have modest activity in this disease, and can be considered as an alternative treatment option for patients in whom cisplatin and/or gemcitabine are contra-indicated

Influence of Oscillating Flow on LDL Transport and Wall Shear Stress in the Normal Aortic Arch

Lipid accumulation in the aortic wall is an important factor in the development of atherosclerosis. The Low Density Lipoprotein (LDL) at the surface of the endothelium in relation to Wall Shear Stress (WSS) in the normal human aortic arch under unsteady, normal flow and mass conditions was computationally analysed. Concave sides of the aortic arch exhibit, relatively to the convex ones, elevated LDL levels at the surface of the endothelium for all time steps. At the peak systolic velocity, the LDL level reaches a value 23.0% higher than that at entrance in the ascending-descending aorta region. The corresponding LDL levels at the surface of the endothelium for the near minimum entrance velocity instant reaches 26.0%. During the cardiac cycle, the highest area averaged normalized LDL taken up as compared to the lowest one is 0.69%. WSS plays an important role in the lipid accumulation. Low WSS regions are exposed to high LDL levels at the surface of the endothelium. Regions of elevated LDL levels do not necessarily co-locate to the sites of lowest WSS. The near wall paths of the velocities might be the most important factor for the elevated LDL levels at the surface of the endothelium

Perceptions, attitudes and training needs of primary healthcare professionals in identifying and managing frailty: a qualitative study

PURPOSE: Although frailty can be delayed or prevented by appropriate interventions, these are often not available in countries lacking formal education and infrastructure in geriatrics. The aim of this study was to: (a) explore ideas, perceptions and attitudes of primary health care (PHC) professionals towards frailty in a country where geriatrics is not recognised as a specialty; (b) explore PHC professionals' training needs in frailty; and (c) define components of a frailty educational programme in PHC. METHODS: Qualitative design, using two focus groups with PHC professionals conducted in Thessaloniki, Greece. Focus groups were audio recorded and transcribed. Data were analysed with thematic analysis. RESULTS: In total 31 PHC professionals (mean age: 46 years; gender distribution: 27 females, 4 males) participated in the study (physicians n = 17; nurses n = 12; health visitors n = 2). Four main themes were identified: (1) Perceptions and understanding of frailty; (2) Facilitators and barriers to frailty identification and management; (3) Motivation to participate in a frailty training programme; (4) Education and training. The main barriers for the identification and management of frailty were associated with the healthcare system, including duration of appointments, a focus on prescribing, and problems with staffing of allied health professionals, but also a lack of education. Training opportunities were scarce and entirely based on personal incentive. Professionals were receptive to training either face-to-face or online. A focus on learning practical skills was key. CONCLUSION: Education and training of professionals and interdisciplinary collaboration are essential and much needed for the delivery of person-centred care for people with frailty living in the community

Feasibility and impact of a short training course on frailty destined for primary health care professionals

BACKGROUND: There is an unmet need for training primary health care professionals on frailty, especially in countries where geriatrics is still emerging. PURPOSE: We aimed to evaluate the feasibility and efficacy of a training course for primary health care professionals on the detection, assessment, and management of frailty. METHODS: A single-day training course, developed and facilitated by three physicians trained in geriatrics abroad, was organized by the Aristotle University of Thessaloniki Primary Hearth Care Research Network. Primary health care professionals' attitudes, knowledge, and everyday practices regarding frailty were assessed by self-administered anonymous questionnaires (using Likert-type scales) at three time-points (before, upon completion of the training course, and 3 months afterward). RESULTS: Out of 31 participants (17 physicians, 12 nurses, 2 health visitors; 87.1% women; mean age 46.4 years), 31(100%) filled in the first, 30(97%) the second, and 25(81%) the third questionnaire. Improvements were reported in familiarization with the frailty syndrome (p = 0.041) and in self-perception of knowledge and skills to detect (p < 0.001) and manage (p < 0.001) frailty, that were also sustained 3 months afterward (p = 0.001 and p = 0.003 respectively). Improvement was also observed in the attitude that frailty is an inevitable consequence of aging (p = 0.007) and in the frequency of application of screening (but not management) strategies, 3 months following the workshop compared to baseline (p = 0.014). Participants reported less disagreement with the statement that systematic screening for frailty was unfeasible in their daily practice at 3 months compared to baseline (p = 0.006), mainly due to time restrictions. CONCLUSION: A short skill-oriented training course can significantly and sustainably improve primary health care professionals' attitudes and practices regarding frailty

The Relevance and Added Value of Geriatric Medicine (GM): Introducing GM to Non-Geriatricians

Geriatric Medicine (GM) holds a crucial role in promoting health and managing the complex medical, cognitive, social, and psychological issues of older people. However, basic principles of GM, essential for optimizing the care of older people, are commonly unknown or undermined, especially in countries where GM is still under development. This narrative review aims at providing insights into the role of GM to non-geriatrician readers and summarizing the main aspects of the added value of a geriatric approach across the spectrum of healthcare. Health practitioners of all specialties are frequently encountered with clinical conditions, common in older patients (such as cancer, hypertension, delirium, major neurocognitive and mental health disorders, malnutrition, and peri-operative complications), which could be more appropriately managed under the light of the approach of GM. The role of allied health professionals with specialized knowledge and skills in dealing with older people’s issues is essential, and a multidisciplinary team is required for the delivery of optimal care in response to the needs and aspirations of older people. Thus, countries should assure the educational background of all health care providers and the specialized health and social care services required to meet the demands of a rapidly aging society

Energy levels of periodic solutions of the circular 2+2 Sitnikov problem

We study a 2+2 body problem introduced in a previous paper as the circular double Sitnikov problem. Since the secondary bodies are moving on the same perpendicular line where evolve the primaries, almost every solution is a collision orbit. We extend the solutions beyond collisions with a symplectic regularization and study the set of energy surfaces that contain periodic orbits and their foliations .Comment: 20 pages, 5 figures. This is not the final version

Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

<p>Abstract</p> <p>Background</p> <p>To determine association of nine single nucleotide polymorphisms (SNPs) in ADP ribosyltransferase-1 (ADPRT1), aldo-keto reductase family 1 member B1 (AKR1B1), receptor for advanced glycation end-products (RAGE), glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2), and plasminogen activator inhibitor-1 (PAI-1) genes with chronic renal insufficiency (CRI) among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS), and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set).</p> <p>Methods</p> <p>Type 2 diabetes subjects with CRI (serum creatinine ≥3.0 mg/dl) constituted the cases (n = 196), and ethnicity and age matched individuals with diabetes for a duration of ≥ 10 years, normal renal functions and normoalbuminuria recruited as controls (n = 225). Allelic and genotypic constitution of 10 polymorphisms (SNPs) from five genes namely- <it>ADPRT1</it>, <it>AKR1B1, RAGE, GFPT2 </it>and <it>PAI-1 </it>with diabetic CRI was investigated. The genetic associations were evaluated by computation of odds ratio and 95% confidence interval. Multiple logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study epistatic interactions between SNPs in different genes.</p> <p>Results</p> <p>Single nucleotide polymorphisms -429 T>C in <it>RAGE </it>and rs7725 C>T SNP in 3' UTR in <it>GFPT2 </it>gene showed a trend towards association with diabetic CRI. Investigation using miRBase statistical tool revealed that rs7725 in <it>GFPT2 </it>was a perfect target for predicted miRNA (hsa miR-378) suggesting the presence of the variant 'T' allele may result in an upregulation of GFPT2 contributing to diabetic renal complication. Epistatic interaction between SNPs in transforming growth factor <it>TGF-β1 </it>(investigated using the same sample set and reported elsewhere) and <it>GFPT2 </it>genotype was observed.</p> <p>Conclusions</p> <p>Association of SNPs in <it>RAGE </it>and <it>GFPT2 </it>suggest that the genes involved in modulation of oxidative pathway could be major contributor to diabetic chronic renal insufficiency. In addition, GFPT2 mediated overproduction of TGF-β1 leading to endothelial expansion and thereby CRI seems likely, suggested by our observation of a significant interaction between GFPT2 with TGF-β1 genes. Further, identification of predicted miRNA targets spanning the associated SNP in <it>GFPT2 </it>implicates the rs7725 SNP in transcriptional regulation of the gene, and suggests <it>GFPT2 </it>could be a relevant target for pharmacological intervention. Larger replication studies are needed to confirm these observations.</p

An Invertebrate Hyperglycemic Model for the Identification of Anti-Diabetic Drugs

The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal insulin secretion, is increasing worldwide, creating a strong demand for the development of more effective anti-diabetic drugs. However, animal-based screening for anti-diabetic compounds requires sacrifice of a large number of diabetic animals, which presents issues in terms of animal welfare. Here, we established a method for evaluating the anti-diabetic effects of compounds using an invertebrate animal, the silkworm, Bombyx mori. Sugar levels in silkworm hemolymph increased immediately after feeding silkworms a high glucose-containing diet, resulting in impaired growth. Human insulin and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, decreased the hemolymph sugar levels of the hyperglycemic silkworms and restored growth. Treatment of the isolated fat body with human insulin in an in vitro culture system increased total sugar in the fat body and stimulated Akt phosphorylation. These responses were inhibited by wortmannin, an inhibitor of phosphoinositide 3 kinase. Moreover, AICAR stimulated AMPK phosphorylation in the silkworm fat body. Administration of aminoguanidine, a Maillard reaction inhibitor, repressed the accumulation of Maillard reaction products (advanced glycation end-products; AGEs) in the hyperglycemic silkworms and restored growth, suggesting that the growth defect of hyperglycemic silkworms is caused by AGE accumulation in the hemolymph. Furthermore, we identified galactose as a hypoglycemic compound in jiou, an herbal medicine for diabetes, by monitoring its hypoglycemic activity in hyperglycemic silkworms. These results suggest that the hyperglycemic silkworm model is useful for identifying anti-diabetic drugs that show therapeutic effects in mammals