Comparing population and incident data for optimal air ambulance base locations in Norway

Background: Helicopter emergency medical services are important in many health care systems. Norway has a nationwide physician manned air ambulance service servicing a country with large geographical variations in population density and incident frequencies. The aim of the study was to compare optimal air ambulance base locations using both population and incident data. Methods: We used municipality population and incident data for Norway from 2015. The 428 municipalities had a median (5-95 percentile) of 4675 (940-36,264) inhabitants and 10 (2-38) incidents. Optimal helicopter base locations were estimated using the Maximal Covering Location Problem (MCLP) optimization model, exploring the number and location of bases needed to cover various fractions of the population for time thresholds 30 and 45 min, in green field scenarios and conditioned on the existing base structure. Results: The existing bases covered 96.90% of the population and 91.86% of the incidents for time threshold 45 min. Correlation between municipality population and incident frequencies was -0.0027, and optimal base locations varied markedly between the two data types, particularly when lowering the target time. The optimal solution using population density data put focus on the greater Oslo area, where one third of Norwegians live, while using incident data put focus on low population high incident areas, such as northern Norway and winter sport resorts. Conclusion: Using population density data as a proxy for incident frequency is not recommended, as the two data types lead to different optimal base locations. Lowering the target time increases the sensitivity to choice of data

Market split and basis reduction: towards a solution of the Cornuejols-Dawande instances

Previously, G. Cornuejols and M. Dawande (1998) proposed a set of 0-1 linear programming instances that proved to be very hard to solve by traditional methods, and in particular by linear programming based branch-and-bound. They offered these market split instances as a challenge to the integer programming community. The market split problem can be formulated as a system of linear diophantine equations in 0-1 variables. We use the algorithm of K. Aardal et al. (1998) based on lattice basis reduction. This algorithm is not restricted to deal with market split instances only but is a general method for solving systems of linear diophantine equations with bounds on the variables. We show computational results from solving both feasibility and optimization versions of the market split instances with up to 7 equations and 60 variables and discuss various branching strategies and their effect on the number of enumerated nodes. To our knowledge, the largest feasibility and optimization instances solved before had 6 equations and 50 variables, and 4 equations and 30 variables, respectively. We also present a probabilistic analysis describing how to compute the probability of generating infeasible market split instances. By generating instances in the way prescribed by Cornuejols and Dawande, one obtains relatively many feasible instances for sizes larger than 5 equations and 40 variable

Cortisol reactivity and suicidal behavior: investigating the role of hypothalamic-pituitary-adrenal axis responses to stress in suicide attempters and ideators

Every 40 seconds a person dies by suicide somewhere in the world. The causes of suicidal behavior are not fully understood. Dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, is one potential risk factor. The current study aimed to investigate whether cortisol reactivity to a laboratory stress task differentiated individuals who had previously made a suicide attempt from those who had thought about suicide (suicide ideators) and control participants. One hundred and sixty participants were recruited to a previous attempt, a suicidal ideation or a control group. Participants completed background questionnaires before completing the Maastricht Acute Stress Test (MAST). Cortisol levels were assessed throughout the stress task. Measures of suicide behavior were measured at baseline, 1 month and 6 month follow-up. Participants who had made a previous suicide attempt exhibited significantly lower aggregate cortisol levels during the MAST compared to participants in the control group; suicide ideators were intermediate to both groups. This effect, however, was driven by participants who made an attempt within the past year, and to some degree by those with a family history of attempt. Participants who had made a suicide attempt and had a family history of suicide exhibited the lowest levels of cortisol in response to stress. Finally, lower levels of cortisol in response to the MAST were associated with higher levels of suicidal ideation at 1-month follow-up in the suicide attempter group. These results are consistent with other findings indicating that blunted HPA axis activity is associated with some forms of suicidal behavior. The challenge for researchers is to elucidate the precise causal mechanisms linking stress, cortisol and suicide risk

Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene

In approximately 20% of cases of severe congenital neutropenia (SCN), mutations are found in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R). These mutations introduce premature stop codons, which result in truncation of 82-98 COOH-terminal amino acids of the receptor. SCN patients who develop secondary myelodysplastic syndrome and acute myeloid leukemia almost invariably acquired a GCSFR mutation, suggesting that this genetic alteration represents a key step in leukemogenesis. Here we show that an equivalent mutation targeted in mice (gcsfr-Delta715) results in the selective expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the bone marrow. In addition, in vivo treatment of gcsfr-Delta715 mice with G-CSF results in increased production of neutrophils leading to a sustained neutrophilia. This hyperproliferative response to G-CSF is accompanied by prolonged activation of signal transducer and activator of transcription (STAT) complexes and extended cell surface expression of mutant receptors due to defective internalization. In view of the continuous G-CSF treatment of SCN patients, these data provide insight into why progenitor cells expressing truncated receptors clonally expand in vivo, and why these cells may be targets for additional genetic events leading to leukemia

The CIRCORT database: Reference ranges and seasonal changes in diurnal salivary cortisol derived from a meta-dataset comprised of 15 field studies

Diurnal salivary cortisol profiles are valuable indicators of adrenocortical functioning in epidemiological research and clinical practice. However, normative reference values derived from a large number of participants and across a wide age range are still missing. To fill this gap, data were compiled from 15 independently conducted field studies with a total of 104,623 salivary cortisol samples obtained from 18,698 unselected individuals (mean age: 48.3 years, age range: 0.5–98.5 years, 39% females). Besides providing a descriptive analysis of the complete dataset, we also performed mixed-effects growth curve modeling of diurnal salivary cortisol (i.e., 1–16 h after awakening). Cortisol decreased significantly across the day and was influenced by both, age and sex. Intriguingly, we also found a pronounced impact of sampling season with elevated diurnal cortisol in spring and decreased levels in autumn. However, the majority of variance was accounted for by between-participant and between-study variance components. Based on these analyses, reference ranges (LC/MS–MS calibrated) for cortisol concentrations in saliva were derived for different times across the day, with more specific reference ranges generated for males and females in different age categories. This integrative summary provides important reference values on salivary cortisol to aid basic scientists and clinicians in interpreting deviations from the normal diurnal cycle

On a Clique-Based Integer Programming Formulation of Vertex Colouring with Applications in Course Timetabling

Vertex colouring is a well-known problem in combinatorial optimisation, whose alternative integer programming formulations have recently attracted considerable attention. This paper briefly surveys seven known formulations of vertex colouring and introduces a formulation of vertex colouring using a suitable clique partition of the graph. This formulation is applicable in timetabling applications, where such a clique partition of the conflict graph is given implicitly. In contrast with some alternatives, the presented formulation can also be easily extended to accommodate complex performance indicators (``soft constraints'') imposed in a number of real-life course timetabling applications. Its performance depends on the quality of the clique partition, but encouraging empirical results for the Udine Course Timetabling problem are reported

Catecholamine Storage Vesicles: Role of Core Protein Genetic Polymorphisms in Hypertension

Hypertension is a complex trait with deranged autonomic control of the circulation. The sympathoadrenal system exerts minute-to-minute control over cardiac output and vascular tone. Catecholamine storage vesicles (or chromaffin granules) of the adrenal medulla contain remarkably high concentrations of chromogranins/secretogranins (or “granins”), catecholamines, neuropeptide Y, adenosine triphosphate (ATP), and Ca2+. Within secretory granules, granins are co-stored with catecholamine neurotransmitters and co-released upon stimulation of the regulated secretory pathway. The principal granin family members, chromogranin A (CHGA), chromogranin B (CHGB), and secretogranin II (SCG2), may have evolved from shared ancestral exons by gene duplication. This article reviews human genetic variation at loci encoding the major granins and probes the effects of such polymorphisms on blood pressure, using twin pairs to probe heritability and individuals with the most extreme blood pressure values in the population to study hypertension

Two Chromogranin A-Derived Peptides Induce Calcium Entry in Human Neutrophils by Calmodulin-Regulated Calcium Independent Phospholipase A2

Background: Antimicrobial peptides derived from the natural processing of chromogranin A (CgA) are co-secreted with catecholamines upon stimulation of chromaffin cells. Since PMNs play a central role in innate immunity, we examine responses by PMNs following stimulation by two antimicrobial CgA-derived peptides. Methodology/Principal Findings: PMNs were treated with different concentrations of CgA-derived peptides in presence of several drugs. Calcium mobilization was observed by using flow cytometry and calcium imaging experiments. Immunocytochemistry and confocal microscopy have shown the intracellular localization of the peptides. The calmodulin-binding and iPLA2 activating properties of the peptides were shown by Surface Plasmon Resonance and iPLA2 activity assays. Finally, a proteomic analysis of the material released after PMNs treatment with CgA-derived peptides was performed by using HPLC and Nano-LC MS-MS. By using flow cytometry we first observed that after 15 s, in presence of extracellular calcium, Chromofungin (CHR) or Catestatin (CAT) induce a concentration-dependent transient increase of intracellular calcium. In contrast, in absence of extra cellular calcium the peptides are unable to induce calcium depletion from the stores after 10 minutes exposure. Treatment with 2-APB (2-aminoethoxydiphenyl borate), a store operated channels (SOCs) blocker, inhibits completely the calcium entry, as shown by calcium imaging. We also showed that they activate iPLA2 as the two CaM-binding factors (W7 and CMZ) and that the two sequences can be aligned with the two CaMbinding domains reported for iPLA2. We finally analyzed by HPLC and Nano-LC MS-MS the material released by PMNs following stimulation by CHR and CAT. We characterized several factors important for inflammation and innate immunity. Conclusions/Significance: For the first time, we demonstrate that CHR and CAT, penetrate into PMNs, inducing extracellular calcium entry by a CaM-regulated iPLA2 pathway. Our study highlights the role of two CgA-derived peptides in the active communication between neuroendocrine and immune systems