Chemotherapy planning and multi-appointment scheduling: formulations, heuristics and bounds

The number of new cancer cases is expected to increase by about 50% in the next 20 years, and the need for chemotherapy treatments will increase accordingly. Chemotherapy treatments are usually performed in outpatient cancer centers where patients affected by different types of tumors are treated. The treatment delivery must be carefully planned to optimize the use of limited resources, such as drugs, medical and nursing staff, consultation and exam rooms, and chairs and beds for the drug infusion. Planning and scheduling chemotherapy treatments involve different problems at different decision levels. In this work, we focus on the patient chemotherapy multi-appointment planning and scheduling problem at an operational level, namely the problem of determining the day and starting time of the oncologist visit and drug infusion for a set of patients to be scheduled along a short-term planning horizon. We use a per-pathology paradigm, where the days of the week in which patients can be treated, depending on their pathology, are known. We consider different metrics and formulate the problem as a multi-objective optimization problem tackled by sequentially solving three problems in a lexicographic multi-objective fashion. The ultimate aim is to minimize the patient's discomfort. The problems turn out to be computationally challenging, thus we propose bounds and ad-hoc approaches, exploiting alternative problem formulations, decomposition, and $k$-opt search. The approaches are tested on real data from an Italian outpatient cancer center and outperform state-of-the-art solvers.Comment: 28 pages, 3 figure

Conceptual modelling of the flow of frail elderly through acute-care hospitals: An evidence-based management approach

This is the author accepted manuscript. The final version is available from Emerald via the DOI in this record.The ageing of the world’s population is causing an increase in the number of frail patients admitted to hospitals. In the absence of appropriate management and organisation, these patients risk an excessive length of stay and poor outcomes. To deal with this problem, we propose a conceptual model to facilitate the pathway of frail elderly patients across acute-care hospitals, focused on avoiding improper wait times and treatment during the process. The conceptual model is developed to enrich the standard flowchart of a clinical pathway in the hospital. The modified flowchart encompasses new organisational units and activities carried out by new dedicated professional roles. The proposed variant aims to provide a correct assessment of frailty at the entrance, a better management of the patient’s stay during different clinical stages and an early discharge, sending the patient home or to other facilities, avoiding a delayed discharge. The model is completed by a set of indicators aimed at measuring performance improvements and creating a strong database of evidence on the managing of frail elderly’s pathways, providing proper information that can validate the model when applied in current practice. The paper proposes a design of the clinical path of frail patients in acute-care hospitals, combining elements that, according to an evidence-based management approach, have proved to be effective in terms of outcomes, costs and organisational issues. We can therefore expect an improvement in the treatment of frail patients in hospital, avoiding their functional decline and worsening frailty conditions, as often happens in current practice following the standard path of other patients The framework proposed is a conceptual model to manage frail elderly patients in acute-care wards. Our research approach lacks application to real data and proof of effectiveness. Further work will be devoted to implementing a simulation model for a specific case study and verifying the impact of the conceptual model in real care settings. The framework proposed is a conceptual model to manage frail elderly patients in acute-care wards. Our research approach lacks application to real data and proof of effectiveness. Further work will be devoted to implementing a simulation model for a specific case study and verifying the impact of the conceptual model in real care settings. This paper fulfills an identified need to study and provide solutions for the management of frail elderly patients in acute-care hospitals, and generally to produce value in a patient-centred model

Effects of Fe(III) binding to the nucleotide-independent site of F1-ATPase: enzyme thermostability and response to activating anions

AbstractMitochondrial F1-ATPase was induced in different conformations by binding of specific ligands, such as nucleotides. Then, Fourier transform infrared spectroscopy (FT-IR) and kinetic analyses were run to evaluate the structural and functional effects of Fe(III) binding to the nucleotide-independent site. Binding of one equivalent of Fe(III) induced a localised stabilising effect on the F1-ATPase structure destabilised by a high concentration of NaCl, through rearrangements of the ionic network essential for the maintenance of enzyme tertiary and/or quaternary structure. Concomitantly, a lower response of ATPase activity to activating anions was observed. Both FT-IR and kinetic data were in accordance with the hypothesis of the Fe(III) site location near one of the catalytic sites, i.e. at the α/β subunit interface

Thermal stability and aggregation of sulfolobus solfataricus b-glycosidase are dependent upon the N-e-methylation of specific lysyl residues: critical role of in vivo post-translational modifications.

Methylation in vivo is a post-translational modification observed in several organisms belonging to eucarya, bacteria, and archaea. Although important implications of this modification have been demonstrated in several eucaryotes, its biological role in hyperthermophilic archaea is far from being understood. The aim of this work is to clarify some effects of methylation on the properties of β-glycosidase from Sulfolobus solfataricus, by a structural comparison between the native, methylated protein and its unmethylated counterpart, recombinantly expressed in Escherichia coli. Analysis by Fourier transform infrared spectroscopy indicated similar secondary structure contents for the two forms of the protein. However, the study of temperature perturbation by Fourier transform infrared spectroscopy and turbidimetry evidenced denaturation and aggregation events more pronounced in recombinant than in native β-glycosidase. Red Nile fluorescence analysis revealed significant differences of surface hydrophobicity between the two forms of the protein. Unlike the native enzyme, which dissociated into SDS-resistant dimers upon exposure to the detergent, the recombinant enzyme partially dissociated into monomers. By electrospray mapping, the methylation sites of the native protein were identified. A computational analysis of β-glycosidase three-dimensional structure and comparisons with other proteins from S. solfataricus revealed analogies in the localization of methylation sites in terms of secondary structural elements and overall topology. These observations suggest a role for the methylation of lysyl residues, located in selected domains, in the thermal stabilization of β-glycosidase from S. solfataricu

the allergen mus m 1 0102 cysteine residues and molecular allergology

Abstract Mus m 1.0102 is a member of the mouse Major Urinary Protein family, belonging to the Lipocalins superfamily. Major Urinary Proteins (MUPs) are characterized by highly conserved structural motifs. These include a disulphide bond, involved in protein oxidative folding and protein structure stabilization, and a free cysteine residue, substituted by serine only in the pheromonal protein Darcin (MUP20). The free cysteine is recognized as responsible for the onset of inter- or intramolecular thiol/disulphide exchange, an event that favours protein aggregation. Here we show that the substitution of selected cysteine residues modulates Mus m 1.0102 protein folding, fold stability and unfolding reversibility, while maintaining its allergenic potency. Recombinant allergens used for immunotherapy or employed in allergy diagnostic kits require, as essential features, conformational stability, sample homogeneity and proper immunogenicity. In this perspective, recombinant Mus m 1.0102 might appear reasonably adequate as lead molecule because of its allergenic potential and thermal stability. However, its modest resistance to aggregation renders the protein unsuitable for pharmacological preparations. Point mutation is considered a winning strategy. We report that, among the tested mutants, C138A mutant acquires a structure more resistant to thermal stress and less prone to aggregation, two events that act positively on the protein shelf life. Those features make that MUP variant an attractive lead molecule for the development of a diagnostic kit and/or a vaccine

Modelling Hospital Medical Wards to Address Patient Complexity: A Case-Based Simulation-Optimization Approach

In this paper we focus on patient flows inside Internal Medicine Departments, with the aim of supporting new organizational models taking into account the patient relevant characteristics such as complexity and frailty. The main contribution of this paper is to develop a Discrete Event Simulation model to describe in detail the pathways of complex patients through medical hospital wards. The model has been applied to reproduce a case study of an Italian middle size hospital. The objective is quantifying the impact on resource use and outcome of introducing a new organizational model for medical departments. The re-organization is mainly focused on changing the available beds assignment among the wards to better address the complexity of care of patients with comorbidities. Following a patient-centered approach, patients are segmented considering the clinical characteristics (i.e. the pathology, proxy of Diagnoses Related Groups classification) and sub-grouped considering other characteristics, such as comorbidities and ward of admission. Then, an optimization component embedded into the model chooses the best pooling strategy to reorganize medical wards, determining the corresponding number of beds able to improve process indicators, such as length of stay. The simulation model is presented, and preliminary results are analyzed and discussed

Vaccinating Italian infants with a new multicomponent vaccine (Bexsero®) against meningococcal B disease: A cost-effectiveness analysis

This is the final version of the article. Available from the publisher via the DOI in this record.The European Medicines Agency has approved a multicomponent serogroup B meningococcal vaccine (Bexsero®) for use in individuals of 2 months of age and older. A cost-effectiveness analysis (CEA) from the societal and Italian National Health Service perspectives was performed in order to evaluate the impact of vaccinating Italian infants less than 1 y of age with Bexsero®, as opposed to non-vaccination. The analysis was carried out by means of Excel Version 2011 and the TreeAge Pro® software Version 2012. Two basal scenarios that differed in terms of disease incidence (official and estimated data to correct for underreporting) were considered. In the basal scenarios, we considered a primary vaccination cycle with 4 doses (at 2, 4, 6 and 12 months of age) and 1 booster dose at the age of 11 y, the societal perspective and no cost for death. Sensitivity analyses were carried out in which crucial variables were changed over probable ranges. In Italy, on the basis of official data on disease incidence, vaccination with Bexsero® could prevent 82.97 cases and 5.61 deaths in each birth cohort, while these figures proved to be three times higher on considering the estimated incidence. The results of the CEA showed that the Incremental Cost Effectiveness Ratio (ICER) per QALY was €109,762 in the basal scenario if official data on disease incidence are considered and €26,599 if estimated data are considered. The tornado diagram indicated that the most influential factor on ICER was the incidence of disease. The probability of sequelae, the cost of the vaccine and vaccine effectiveness also had an impact. Our results suggest that vaccinating infants in Italy with Bexsero® has the ability to significantly reduce meningococcal disease and, if the probable underestimation of disease incidence is considered, routine vaccination is advisable.The study was financed by the Italian Ministry of University and Research (MIUR, project PRIN 2009; Grant number: 2009ZPM4×4)

Amino acid transport in thermophiles: characterization of an arginine-binding protein in Thermotoga maritima. 2. Molecular organization and structural stability

ABC transport systems provide selective passage of metabolites across cell membranes and typically require the presence of a soluble binding protein with high specificity to a specific ligand. In addition to their primary role in nutrient gathering, the binding proteins associated with bacterial transport systems have been studied for their potential to serve as design scaffolds for the development of fluorescent protein biosensors. In this work, we used Fourier transform infrared spectroscopy and molecular dynamics simulations to investigate the physicochemical properties of a hyperthermophilic binding protein from Thermotoga maritima. We demonstrated preferential binding for the polar amino acid arginine and experimentally monitored the significant stabilization achieved upon binding of ligand to protein. The effect of temperature, pH, and detergent was also studied to provide a more complete picture of the protein dynamics. A protein structure model was obtained and molecular dynamic experiments were performed to investigate and couple the spectroscope observations with specific secondary structural elements. The data determined the presence of a buried ẞ-sheet providing significant stability to the protein under all conditions investigated. The specific amino acid residues responsible for arginine binding were also identified. Our data on dynamics and stability will contribute to our understanding bacterial binding protein family members and their potential biotechnological applications