Monetary costs and hospital burden associated with the management of invasive fungal infections in Mexico: a multicenter study

Background: Invasive fungal infections (IFIs) affect >1.5 million people per year. Nevertheless, IFIs are usually neglected and underdiagnosed. IFIs should be considered as a public-health problem and major actions should be taken to tackle them and their associated costs. Aim To report the incidence of IFIs in four Mexican hospitals, to describe the economic cost associated with IFIs therapy and the impact of adverse events such as acute kidney injury (AKI), liver damage (LD), and ICU stay. Methods: This was a retrospective, transversal study carried-out in four Mexican hospitals. All IFIs occurring during 2016 were included. Incidence rates and estimation of antifungal therapy's expenditure for one year were calculated. Adjustments for costs of AKI were done. An analysis of factors associated with death, AKI, and LD was performed. Results: Two-hundred thirty-eight cases were included. Among all cases, AKI was diagnosed in 16%, LD in 25%, 35% required ICU stay, with a 23% overall mortality rate. AKI and LD showed higher mortality rates (39% vs 9% and 44% vs 18%, respectively, p < 0.0001). The overall incidence of IFIs was 4.8 cases (95% CI = 0.72–8.92) per 1000 discharges and 0.7 cases (95% CI = 0.03–1.16) per 1000 patients-days. Invasive candidiasis showed the highest incidence rate (1.93 per 1000 discharges, 95% CI = −1.01 to 2.84), followed by endemic IFIs (1.53 per 1000 discharges 95% CI = −3.36 to 6.4) and IA (1.25 per 1000 discharges, 95% CI = −0.90 to 3.45). AKI increased the cost of antifungal therapy 4.3-fold. The total expenditure in antifungal therapy for all IFIs, adjusting for AKI, was $233,435,536 USD (95$6,224,993 to $773,810,330). Conclusions: IFIs are as frequent as HIV asymptomatic infection and tuberculosis. Costs estimations allow to assess cost-avoidance strategies to increase targeted driven therapy and decrease adverse events and their costs

A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.Acknowledgments: This work was supported by MINECO (SAF2017-89643-R, SAF2014-57243-R, SAF2015-62547-ERC) (M.V.), Fundacion FERO (IX FERO Grant for Research in Oncology) (M.V.), Fundacio La Marato de TV3 (141) (M.V.), Melanoma Research Alliance (Bristol-Myers Squibb-Melanoma Research Alliance Young Investigator Award 2017 (https://doi.org/10.48050/pc.gr.75716)) (M.V.), Beug Foundation (Prize for Metastasis Research 2017) (M.V.), Fundacion Ramon Areces (CIVP19S8163) (M.V.) and CIVP20S10662 (E.O.P.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Cancer Research Institute (Clinic and Laboratory Integration Program CRI Award 2018 (54545)) (M.V.), AECC (Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002-VALI) (M.V.), ERC CoG (864759) (M.V.), Sophien-Stiftung zur Förderung der klinischen Krebsforschung (T.W.), Promedica Stiftung (T.W.), Stiftung f€ur angewandte Krebsforschung (T.W.), Forschungskredit of the University of Zurich (FK-18-054) (T.W.), Betty and David Koetser Foundation for Brain Research (T.W.), Foundation for Applied Cancer Research in Zurich (T.W., M.W.), Comunidad de Madrid (S2017/BMD-3867 RENIM-CM and Y2018/NMT-4949 NanoLiver-CM) and European structural and investment funds (M.D.), ISCIII (PT20/00044) co-funded by FEDER “A way of making Europe” (M.D.), Ministero dell’Istruzione, dell’Universita e della Ricerca-MIUR, “Dipartimenti di Eccellenza 2018-2022”, (D15D18000410001) (L.B. and P.C.), Science Foundation Ireland Frontiers for the Future Award (19/FFP/6443) (L.Y.), Science Foundation Ireland Strategic Partnership Programme, Precision Oncology Ireland (18/SPP/3522) (L.Y.), Breast Cancer Now Fellowship Award/ with the generous support of Walk the Walk (2019AugSF1310) (D.V.), La Caixa-Severo Ochoa International PhD Program Fellowship (LCF/BQ/SO16/52270014) (L.Z.), La Caixa International PhD Program Fellowship-Marie Sklodowska-Curie (LCF/BQ/DI17/11620028) (P.G-G), MINECO-Severo Ochoa PhD Fellowship (BES-2017-081995) (L.A-E.), AECC Postdoctoral Fellowship (POSTD19016PRIE) (N.P.), Boehringer Ingelheim Fonds MD fellowship (L.M.). The contribution of the Experimental Therapeutics Programme was supported by core funding from the Spanish National Cancer Research Center (CNIO). CNIO is supported by the ISCIII, the Ministerio de Ciencia e Innovacion, and is a Severo Ochoa Center of Excellence (SEV-2015-0510). The CNIC is supported by the ISCIII, the Ministerio de Ciencia e Innovacion and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). M.V. was named Ramon y Cajal Investigator (RYC-2013-13365) and is member of EMBO YIP (4053)

Tumors defective in homologous recombination rely on oxidative metabolism: relevance to treatments with PARP inhibitors

Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors

A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis

We report a medium‐throughput drug‐screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood–brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug‐screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Monetary costs and hospital burden associated with the management of invasive fungal infections in Mexico: a multicenter study

ABSTRACT Background: Invasive fungal infections (IFIs) affect >1.5 million people per year. Nevertheless, IFIs are usually neglected and underdiagnosed. IFIs should be considered as a public-health problem and major actions should be taken to tackle them and their associated costs. Aim To report the incidence of IFIs in four Mexican hospitals, to describe the economic cost associated with IFIs therapy and the impact of adverse events such as acute kidney injury (AKI), liver damage (LD), and ICU stay. Methods: This was a retrospective, transversal study carried-out in four Mexican hospitals. All IFIs occurring during 2016 were included. Incidence rates and estimation of antifungal therapy's expenditure for one year were calculated. Adjustments for costs of AKI were done. An analysis of factors associated with death, AKI, and LD was performed. Results: Two-hundred thirty-eight cases were included. Among all cases, AKI was diagnosed in 16%, LD in 25%, 35% required ICU stay, with a 23% overall mortality rate. AKI and LD showed higher mortality rates (39% vs 9% and 44% vs 18%, respectively, p < 0.0001). The overall incidence of IFIs was 4.8 cases (95% CI = 0.72–8.92) per 1000 discharges and 0.7 cases (95% CI = 0.03–1.16) per 1000 patients-days. Invasive candidiasis showed the highest incidence rate (1.93 per 1000 discharges, 95% CI = −1.01 to 2.84), followed by endemic IFIs (1.53 per 1000 discharges 95% CI = −3.36 to 6.4) and IA (1.25 per 1000 discharges, 95% CI = −0.90 to 3.45). AKI increased the cost of antifungal therapy 4.3-fold. The total expenditure in antifungal therapy for all IFIs, adjusting for AKI, was $233,435,536 USD (95$6,224,993 to $773,810,330). Conclusions: IFIs are as frequent as HIV asymptomatic infection and tuberculosis. Costs estimations allow to assess cost-avoidance strategies to increase targeted driven therapy and decrease adverse events and their costs

Trihexyl(tetradecyl)phosphonium bis-2,4,4-(trimethylpentyl)phosphinate micellar behavior in the extraction of Ag(I) from acidic nitrate media

International audienceThe distribution of Ag(I) between acidic aqueous phase (HNO 3) and organic phases, composed of trihexyl (tetradecyl)phosphonium bis-(2,4,4-trimethylpentyl)phosphinate (Cyphos Ò IL 104) diluted in kerosene or kerosene/1-decanol, has been studied. In order to elucidate the interactions in solution and the chemical equilibria responsible for Ag(I) extraction by Cyphos Ò IL 104, ionic conductivity, dynamic viscosity, and interfacial tension measurements, determination of water and nitric acid extraction were performed, and the organic phases were characterized by infrared spectroscopy (ATR-FTIR). Ag(I) is extracted by Cyphos Ò IL 104 with high affinity, even under slightly acidic conditions (close to 100% at pH 5). The linear relationship between the logarithm of the distribution ratio of Ag(I) (D) and the logarithm of Cyphos Ò IL 104 concentration exhibits a slope greater than the stoichiometry expected (1:1), demonstrating an atypical extraction equilibrium. The change in the physicochemical properties as a function of Cyphos Ò IL 104 concentration permits to deduce the formation of reverse micelles or aggregates in organic phases at the critical micellar concentration CMC = 0.001 mol L-1. The ATR-FTIR characterization showed that Ag(I) was extracted by the phosphinate group of Cyphos Ò IL 104 with the transfer of water and nitric acid. A thorough analysis of these data indicates a similar mechanism to solvation, and the reverse micelles (or agglomerates) are involved in Ag(I) extraction

Violence against Women and Gastroschisis: A Case-Control Study

Background: Gastroschisis, a birth defect characterized by herniated fetal abdominal wall, occurs more commonly in infants born to teenage and young mothers. Ischemia of the vascular vitelline vessels is the likely mechanism of pathogenesis. Given that chronic stress and violence against women are risk factors for cardiovascular disease we explored whether these may represent risk factors for gastroschisis, when they occur during pregnancy. A case-control study was conducted, with 15 incident cases of children born with gastroschisis in the Region of Murcia, Spain, from December 2007 to June 2013. Forty concurrent controls were recruited at gestation weeks 20–24 or post-partum. All mothers of cases and controls completed a comprehensive, in-person, ‘green sheet’ questionnaire on environmental exposures. Results: Mothers of children with gastroschisis were younger, smoked more cigarettes per week relative to controls, were exposed to higher amounts of illegal drugs, and suffered from domestic violence more frequently than the controls. Multivariable logistic regression analysis highlights periconceptional ‘gender-related violence’ (OR: 16.6, 95% CI 2.7 to 101.7) and younger maternal age (OR 1.1, 95% CI 1.0–1.3). Conclusions: Violence against pregnant women is associated with birth defects, and should be studied in more depth as a cause-effect teratogenic. Psychosocial risk factors, including gender-based violence, are important for insuring the health and safety of the pregnant mother and the fetus

Clinical Characteristics and Risk Factors for Mortality in Very Old Patients Hospitalized With COVID-19 in Spain.

Advanced age is a well-known risk factor for poor prognosis in COVID-19. However, few studies have specifically focused on very old inpatients with COVID-19. This study aims to describe the clinical characteristics of very old inpatients with COVID-19 and identify risk factors for in-hospital mortality at admission. We conducted a nationwide, multicenter, retrospective, observational study in patients ≥ 80 years hospitalized with COVID-19 in 150 Spanish hospitals (SEMI-COVID-19) Registry (March 1-May 29, 2020). The primary outcome was in-hospital mortality. A uni- and multivariate logistic regression was performed to assess predictors of mortality at admission. A total of 2772 consecutive patients (49.4% men, median age 86.3 years) were analyzed. Rates of atherosclerotic cardiovascular disease, diabetes mellitus, dementia, and Barthel Index This first large, multicenter cohort of very old inpatients with COVID-19 shows that age, male sex, and poor preadmission functional status-not comorbidities-are independently associated with in-hospital mortality. Severe COVID-19 at admission is related to poor prognosis