A heuristic framework for the bi-objective enhanced index tracking problem

The index tracking problem is the problem of determining a portfolio of assets whose performance replicates, as closely as possible, that of a financial market index chosen as benchmark. In the enhanced index tracking problem the portfolio is expected to outperform the benchmark with minimal additional risk. In this paper, we study the bi-objective enhanced index tracking problem where two competing objectives, i.e., the expected excess return of the portfolio over the benchmark and the tracking error, are taken into consideration. A bi-objective Mixed Integer Linear Programming formulation for the problem is proposed. Computational results on a set of benchmark instances are given, along with a detailed out-of-sample analysis of the performance of the optimal portfolios selected by the proposed model. Then, a heuristic procedure is designed to build an approximation of the set of Pareto optimal solutions. We test the proposed procedure on a reference set of Pareto optimal solutions. Computational results show that the procedure is significantly faster than the exact computation and provides an extremely accurate approximation

A branch-and-cut algorithm for the Orienteering Arc Routing Problem

[EN] In arc routing problems, customers are located on arcs, and routes of minimum cost have to be identified. In the Orienteering Arc Routing Problem (OARP),in addition to a set of regular customers that have to be serviced, a set of potential customers is available. From this latter set, customers have to be chosen on the basis of an associated profit. The objective is to find a route servicing the customers which maximize the total profit collected while satisfying a given time limit on the route.In this paper, we describe large families of facet-inducing inequalities for the OARP and present a branch-and-cut algorithm for its solution. The exact algorithm embeds a procedure which builds a heuristic solution to the OARP on the basis of the information provided by the solution of the linear relaxation. Extensive computational experiments over different sets of OARP instances show that the exact algorithm is capable of solving to optimality large instances, with up to 2000 vertices and 14,000 arcs, within 1 h and often within a few minutes.Authors want to thank two anonymous referees for their careful reading of the original paper and their many valuable comments and suggestions that have helped to improve the paper. Angel Corberan, Isaac Plana and Jose M. Sanchis wish to thank the Ministerio de Economia y Competitividad of Spain (MTM2012-36163-006-02) and the Generalitat Valenciana (project GVPR-OMETE02013-049) for its support.Archetti, C.; Corberán, A.; Plana, I.; Sanchís Llopis, JM.; Speranza, M. (2016). A branch-and-cut algorithm for the Orienteering Arc Routing Problem. Computers & Operations Research. 66:95-104. https://doi.org/10.1016/j.cor.2015.08.003S951046

Nota corta. Especies de ácaros fitoseidos (Acari: Phytoseiidae) en manzanos de Río Negro, Argentina

The presence of phytoseiid mites was determined in two unsprayed apple orchards at Cinco Saltos and Cipolletti, Río Negro Province, Argentina. Twenty apple trees were chosen in each orchard and a sample of 10 leaves per tree was taken at seven different sampling dates. Neoseiulus californicus (McGregor), Euseius fructicolus (Gonzalez &Schuster) and Paraseiulus talbii Athias-Henriot were found at Cinco Saltos, and Proprioseiopsis messor (Wainstein), N. californicus and Metaseiulus camelliae (Chant & Yoshida-Shaul) at Cipolletti. Of these species, only N. californicus has previously been reported from the Alto Valle del Río Negro region. Proprioseiopsis messor and Paraseiulus talbii are reported for the first time in South America and on the American Continent respectively.Se llevó a cabo un estudio para determinar la presencia de ácaros fitoseidos en dos plantaciones de manzanos no tratadas con plaguicidas, localizadas en Cinco Saltos y Cipolletti, Provincia de Río Negro, Argentina. Se seleccionaron 20 árboles en cada huerto y se tomó una muestra de 10 hojas por árbol en siete diferentes fechas de muestreo. Neoseiulus. californicus (McGregor), Euseius fructicolus (Gonzalez & Schuster) y Paraseiulus talbii Athias-Henriot fueron las especies identificadas en Cinco Saltos. Proprioseiopsis messor (Wainstein), N. californicus y Metaseiulus camelliae (Chant & Yoshida-Shaul) fueron identificadas en Cipolletti. De las especies recolectadas solamente había sido mencionada previamente N. californicus en la región del Alto Valle del Río Negro. P. messor y P. talbii constituyen nuevas citas para América del Sur y el continente americano, respectivamente

The split delivery capacitated team orienteering problem

In this article, we study the capacitated team orienteering problem where split deliveries are allowed. A set of potential customers is given, each associated with a demand and a profit. The set of customers to be served by a fleet of capacitated vehicles has to be identified in such a way that the profit collected is maximized, while satisfying constraints on the maximum time duration of each route and the vehicle capacity constraints. When split deliveries are allowed, each customer may be served by more than one vehicle. We show that the profit collected by allowing split deliveries may be as large as twice the profit collected under the constraint that each customer has to be served by one vehicle at most. We then present a branch-and-price exact algorithm and a hybrid heuristic. We show the effectiveness of the proposed approaches on benchmark instances and on a new set of instances that allow us to computationally evaluate the impact of split deliveries

Comparison of policies in dynamic routing problems

We consider a company that has to satisfy customers' pick-up requests arriving over time every day. The overall objective of the company is to serve as many requests as possible at a minimum operational cost. When organizing its business the company has to fix some features of the service that may affect both service quality and operational costs. Some of these features concern the time a request is taken into account to plan its service, the associated deadline and the way requests are managed when the system is overloaded. In this paper we analyse several policies that can be implemented by the management of a carrier company in a multi-period context. For example, a company might reject all the requests that cannot be feasibly scheduled or accept all the requests and rely on a backup service in order to serve requests that are difficult to handle. Another interesting issue considered in this paper is the impact of collaborative service where two or more carrier companies, with their own customers, decide to share customers in order to optimize the overall costs. We set up a general framework to allow comparison of alternative service policies. Extensive computational results evaluating the number of lost requests and the distance travelled provide interesting insights

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury

Effects of sleep disturbance on dyspnoea and impaired lung function following hospital admission due to COVID-19 in the UK: a prospective multicentre cohort study

Background: Sleep disturbance is common following hospital admission both for COVID-19 and other causes. The clinical associations of this for recovery after hospital admission are poorly understood despite sleep disturbance contributing to morbidity in other scenarios. We aimed to investigate the prevalence and nature of sleep disturbance after discharge following hospital admission for COVID-19 and to assess whether this was associated with dyspnoea. Methods: CircCOVID was a prospective multicentre cohort substudy designed to investigate the effects of circadian disruption and sleep disturbance on recovery after COVID-19 in a cohort of participants aged 18 years or older, admitted to hospital for COVID-19 in the UK, and discharged between March, 2020, and October, 2021. Participants were recruited from the Post-hospitalisation COVID-19 study (PHOSP-COVID). Follow-up data were collected at two timepoints: an early time point 2–7 months after hospital discharge and a later time point 10–14 months after hospital discharge. Sleep quality was assessed subjectively using the Pittsburgh Sleep Quality Index questionnaire and a numerical rating scale. Sleep quality was also assessed with an accelerometer worn on the wrist (actigraphy) for 14 days. Participants were also clinically phenotyped, including assessment of symptoms (ie, anxiety [Generalised Anxiety Disorder 7-item scale questionnaire], muscle function [SARC-F questionnaire], dyspnoea [Dyspnoea-12 questionnaire] and measurement of lung function), at the early timepoint after discharge. Actigraphy results were also compared to a matched UK Biobank cohort (non-hospitalised individuals and recently hospitalised individuals). Multivariable linear regression was used to define associations of sleep disturbance with the primary outcome of breathlessness and the other clinical symptoms. PHOSP-COVID is registered on the ISRCTN Registry (ISRCTN10980107). Findings: 2320 of 2468 participants in the PHOSP-COVID study attended an early timepoint research visit a median of 5 months (IQR 4–6) following discharge from 83 hospitals in the UK. Data for sleep quality were assessed by subjective measures (the Pittsburgh Sleep Quality Index questionnaire and the numerical rating scale) for 638 participants at the early time point. Sleep quality was also assessed using device-based measures (actigraphy) a median of 7 months (IQR 5–8 months) after discharge from hospital for 729 participants. After discharge from hospital, the majority (396 [62%] of 638) of participants who had been admitted to hospital for COVID-19 reported poor sleep quality in response to the Pittsburgh Sleep Quality Index questionnaire. A comparable proportion (338 [53%] of 638) of participants felt their sleep quality had deteriorated following discharge after COVID-19 admission, as assessed by the numerical rating scale. Device-based measurements were compared to an age-matched, sex-matched, BMI-matched, and time from discharge-matched UK Biobank cohort who had recently been admitted to hospital. Compared to the recently hospitalised matched UK Biobank cohort, participants in our study slept on average 65 min (95% CI 59 to 71) longer, had a lower sleep regularity index (–19%; 95% CI –20 to –16), and a lower sleep efficiency (3·83 percentage points; 95% CI 3·40 to 4·26). Similar results were obtained when comparisons were made with the non-hospitalised UK Biobank cohort. Overall sleep quality (unadjusted effect estimate 3·94; 95% CI 2·78 to 5·10), deterioration in sleep quality following hospital admission (3·00; 1·82 to 4·28), and sleep regularity (4·38; 2·10 to 6·65) were associated with higher dyspnoea scores. Poor sleep quality, deterioration in sleep quality, and sleep regularity were also associated with impaired lung function, as assessed by forced vital capacity. Depending on the sleep metric, anxiety mediated 18–39% of the effect of sleep disturbance on dyspnoea, while muscle weakness mediated 27–41% of this effect. Interpretation: Sleep disturbance following hospital admission for COVID-19 is associated with dyspnoea, anxiety, and muscle weakness. Due to the association with multiple symptoms, targeting sleep disturbance might be beneficial in treating the post-COVID-19 condition. Funding: UK Research and Innovation, National Institute for Health Research, and Engineering and Physical Sciences Research Council

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Accelarated immune ageing is associated with COVID-19 disease severity

Background The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. Results We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ( = 0.174, p = 0.043), with a major influence being disease severity ( = 0.188, p = 0.01). Conclusions Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease