Absolute hyperglycemia versus stress hyperglycemia ratio for the prognosis of hospitalized patients with COVID-19 in the first months of the pandemic: a retrospective study

Diabetes is a risk factor for the greater severity of coronavirus disease 2019 (COVID-19). The stress hyperglycemia ratio (SHR) is an independent predictor of critical illness, and it is reported to have a stronger association than absolute hyperglycemia. The aim of this study was to assess the relationship between absolute hyperglycemia and SHR with the severity of COVID-19 since there are no studies investigating SHR in patients with COVID-19. We conducted a retrospective observational study on hospitalized patients with COVID-19 in the first months of the pandemic, regarding absolute hyperglycemia, SHR, and severity outcomes. Of the 374 patients, 28.1% had a previous diagnosis of type 2 diabetes. Absolute hyperglycemia (64.8% versus 22.7%; p < 0.01) and SHR [1.1 (IQR 0.9-1.3) versus 1.0 (IQR 0.9-1.2); p < 0.001] showed a statistically significant association with previous diabetes. Absolute hyperglycemia showed a significant association with the clinical severity of COVID-19 (79.0% versus 62.7%; p < 0.001), need for oxygen therapy (74.8% versus 54.4%; p < 0.001), invasive mechanical ventilation (28.6% versus 11.6%; p < 0.001), and intensive care unit (30.3% versus 14.9%; p = 0.002), but not with mortality; by contrast, there was no statistically significant association between SHR and all these parameters. Our results are in agreement with the literature regarding the impact of absolute hyperglycemia on COVID-19 severity outcomes, while SHR was not a significant marker. We, therefore, suggest that SHR should not be evaluated in all patients admitted to the hospital for COVID-19, and we encourage the standard measures at the admission of blood glucose and HbA1c levels.info:eu-repo/semantics/publishedVersio

A Retrospective Study

Publisher Copyright: © 2022, The Author(s).Diabetes is a risk factor for greater severity of coronavirus disease 2019 (COVID-19). The stress hyperglycemia ratio (SHR) is an independent predictor of critical illness, and it is reported to have a stronger association than absolute hyperglycemia. The aim of this study was to assess the relationship of absolute hyperglycemia and SHR with the severity of COVID-19, since there are no studies investigating SHR in patients with COVID-19. We conducted a retrospective observational study on hospitalized patients with COVID-19 in the first months of the pandemic, regarding absolute hyperglycemia, SHR, and severity outcomes. Of the 374 patients, 28.1% had a previous diagnosis of type 2 diabetes. Absolute hyperglycemia (64.8% versus 22.7%; p < 0.01) and SHR [1.1 (IQR 0.9–1.3) versus 1.0 (IQR 0.9–1.2); p < 0.001] showed a statistically significant association with previous diabetes. Absolute hyperglycemia showed a significant association with clinical severity of COVID-19 (79.0% versus 62.7%; p < 0.001), need for oxygen therapy (74.8% versus 54.4%; p < 0.001), invasive mechanical ventilation (28.6% versus 11.6%; p < 0.001), and intensive care unit (30.3% versus 14.9%; p = 0.002), but not with mortality; by contrast, there was no statistically significant association between SHR and all these parameters. Our results are in agreement with the literature regarding the impact of absolute hyperglycemia on COVID-19 severity outcomes, while SHR was not a significant marker. We therefore suggest that SHR should not be evaluated in all patients admitted in the hospital for COVID-19, and we encourage the standard measures at admission of blood glucose and HbA1c levels.publishersversionepub_ahead_of_prin

FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

[EN] Background & Aims: Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well as its downstream transcriptional effectors, in the development and progression of CCA. Methods: FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Followup RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition. Results: An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss. Conclusions: Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies. Lay summary: Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.A.V. was supported by ADA of the University of Navarra, Spain, O.E. by FSE; MINECO; FJCI-2017-34233, Spain, R.E. by a donation from Mauge Burgos de la Iglesia’s family, Spain, and P. Olaizola by the Basque Government (PRE_2016_1_0269), Basque Country, Spain. M.J.P. was funded by ISCIII [FIS PI14; 00399, PI17; 00022] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER), Spain; Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Program RYC-2015-17755), Spain. M.A.A was funded by La Caixa Foundation, HEPACARE project, Spain, ISCIII FIS PI16/01126 cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER), Spain, and “Fundación Científica de la Asociación Española Contra el Cáncer’’ (AECC Scientific Foundation) Rare Cancers 2017, Spain. J.M.B. was funded by the Spanish Carlos III Health Institute (ISCIII) (FIS PI15; 01132, PI18; 01075 and Miguel Servet Program CON14; 00129 and CPII19; 00008), Spain, co-financed by “Fondo Europeo de Desarrollo Regional” (FEDER), Spain; “Euskadi RIS3” (2019222054) and BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15; CA; 016; BD), Basque Country, Spain; “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation) Rare Cancers 2017, Spain. S.V. was supported by FEDER; MINECO (SAF2017-89944-R), Spain, by the Government of Navarra-Health Research Department (58; 2018), Navarra, Spain, by La Caixa and Caja Navarra Foundation-CIMA agreement, Spain. None of the funding sources were involved in the decision to submit the article for publication. This article is based upon work from COST Action CA18122 European Cholangiocarcinoma Network, supported by COST (European Cooperation in Science and Technology). COST (European Cooperation in Science and Technology) is a funding agency for research and innovation networks (www.cost.eu)

Detrimental NFKB1 missense variants affecting the Rel-homology domain of p105/p50

Most of the currently known heterozygous pathogenic NFKB1 (Nuclear factor kappa B subunit 1) variants comprise deleterious defects such as severe truncations, internal deletions, and frameshift variants. Collectively, these represent the most frequent monogenic cause of common variable immunodeficiency (CVID) identified so far. NFKB1 encodes the transcription factor precursor p105 which undergoes limited proteasomal processing of its C-terminal half to generate the mature NF-kappa B subunit p50. Whereas p105/p50 haploinsufficiency due to devastating genetic damages and protein loss is a well-known disease mechanism, the pathogenic significance of numerous NFKB1 missense variants still remains uncertain and/or unexplored, due to the unavailability of accurate test procedures to confirm causality. In this study we functionally characterized 47 distinct missense variants residing within the N-terminal domains, thus affecting both proteins, the p105 precursor and the processed p50. Following transient overexpression of EGFP-fused mutant p105 and p50 in HEK293T cells, we used fluorescence microscopy, Western blotting, electrophoretic mobility shift assays (EMSA), and reporter assays to analyze their effects on subcellular localization, protein stability and precursor processing, DNA binding, and on the RelA-dependent target promoter activation, respectively. We found nine missense variants to cause harmful damage with intensified protein decay, while two variants left protein stability unaffected but caused a loss of the DNA-binding activity. Seven of the analyzed single amino acid changes caused ambiguous protein defects and four variants were associated with only minor adverse effects. For 25 variants, test results were indistinguishable from those of the wildtype controls, hence, their pathogenic impact remained elusive. In summary, we show that pathogenic missense variants affecting the Rel-homology domain may cause protein-decaying defects, thus resembling the disease-mechanisms of p105/p50 haploinsufficiency or may cause DNA-binding deficiency. However, rare variants (with a population frequency of less than 0.01%) with minor abnormalities or with neutral tests should still be considered as potentially pathogenic, until suitable tests have approved them being benign.Peer reviewe

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

New magnetic survey in the Tagus Abyssal Plain (TECTAP Project)

European Geosciences Union General Assembly 2009 (EGU 2009), Vienna, Austria, April 19-24, 200

Clinical, ultrasound and molecular biomarkers for early prediction of large for gestational age infants in nulliparous women: an international prospective cohort study

Objective: To develop a prediction model for term infants born large for gestational age (LGA) by customised birthweight centiles. Methods: International prospective cohort of nulliparous women with singleton pregnancy recruited to the Screening for Pregnancy Endpoints (SCOPE) study. LGA was defined as birthweight above the 90th customised centile, including adjustment for parity, ethnicity, maternal height and weight, fetal gender and gestational age. Clinical risk factors, ultrasound parameters and biomarkers at 14–16 or 19–21 weeks were combined into a prediction model for LGA infants at term using stepwise logistic regression in a training dataset. Prediction performance was assessed in a validation dataset using area under the Receiver Operating Characteristics curve (AUC) and detection rate at fixed false positive rates. Results: The prevalence of LGA at term was 8.8% (n = 491/5628). Clinical and ultrasound factors selected in the prediction model for LGA infants were maternal birthweight, gestational weight gain between 14–16 and 19–21 weeks, and fetal abdominal circumference, head circumference and uterine artery Doppler resistance index at 19–21 weeks (AUC 0.67; 95%CI 0.63–0.71). Sensitivity of this model was 24% and 49% for a fixed false positive rate of 10% and 25%, respectively. The addition of biomarkers resulted in selection of random glucose, LDL-cholesterol, vascular endothelial growth factor receptor-1 (VEGFR1) and neutrophil gelatinase-associated lipocalin (NGAL), but with minimal improvement in model performance (AUC 0.69; 95%CI 0.65–0.73). Sensitivity of the full model was 26% and 50% for a fixed false positive rate of 10% and 25%, respectively. Conclusion: Prediction of LGA infants at term has limited diagnostic performance before 22 weeks but may have a role in contingency screening in later pregnancy

Show your beaks and we tell you what you eat: Different ecology in sympatric Antarctic benthic octopods under a climate change context

Sympatry can lead to higher competition under climate change and other environmental pressures, including in South Georgia, Antarctica, where the two most common octopod species, Adelieledone polymorpha and Pareledone turqueti, occur side by side. Since cephalopods are typically elusive animals, the ecology of both species is poorly known. As beaks of cephalopods are recurrently found in top predator's stomachs, we studied the feeding ecology of both octopods through the evaluation of niche overlapping and specific beak adaptations that both species present. A multidisciplinary approach combining carbon (δ13C) and nitrogen (δ15N) stable isotope signatures, mercury (Hg) analysis and biomaterials' engineering techniques was applied to investigate the beaks. An isotopic niche overlap of 95.6% was recorded for the juvenile stages of both octopod species, dropping to 19.2% for the adult stages. Both A. polymorpha and P. turqueti inhabit benthic ecosystems around South Georgia throughout their lifecycles (δ13C: −19.21 ± 1.87‰, mean ± SD for both species) but explore trophic niches partially different during adult life stages (δ15N: 7.01 ± 0.40‰, in A. polymorpha, and 7.84 ± 0.65‰, in P. turqueti). The beaks of A. polymorpha are less dense and significantly less stiff than in P. turqueti. Beaks showed lower mercury concentration relative to muscle (A. polymorpha - beaks: 0.052 ± 0.009  μg g−1, muscle: 0.322 ± 0.088  μg g−1; P. turqueti - beaks: 0.038 ± 0.009  μg g−1; muscle: 0.434 ± 0.128  μg g−1). Overall, both octopods exhibit similar habitats but different trophic niches, related to morphology/function of beaks. The high Hg concentrations in both octopods can have negative consequences on their top predators and may increase under the present climate change context.British Antarctic Survey for assisting in the collection of the specimens for this work. Many thanks to 3B's Research Group (University of Minho) and MAREFOZ who were responsible for analysing the physical properties of beaks and stable isotope signatures. A special thank you to our colleague José Queirós from MARE-UC (Coimbra, Portugal) for his suggestions and guidance. A debt of gratitude is also owed to Dr. A. Louise Allcock (NUI Galway) for her useful guidelines. This work is an international effort under the Scientific Committee on Antarctic Research (SCAR) associated programs, expert and action groups, namely SCAR AnT-ERA, SCAR EGBAMM and ICED. J.C. Xavier was supported by the Investigator Programme (IF/00616/2013) of the Foundation for Science and Technology (FCT-Portugal) and PROPOLAR, and F.R. Ceia was supported by a postdoctoral fellowship (SFRH/BPD/95372/2013) attributed by FCT-Portugal and the European Social Fund (POPH, EU). This study benefited from the strategic program of MARE, financed by FCT-Portugal (MARE- UID/MAR/04292/2019). We also acknowledge FCT-Portugal through a PhD grant to J. Seco (SRFH/PD/BD/113487

Mongooses (\u3ci\u3eUrva auropunctata\u3c/i\u3e) as reservoir hosts of leptospira species in the United States Virgin Islands, 2019–2020

During 2019–2020, the Virgin Islands Department of Health investigated potential animal reservoirs of Leptospira spp., the bacteria that cause leptospirosis. In this cross-sectional study, we investigated Leptospira spp. exposure and carriage in the small Indian mongoose (Urva auropunctata, syn: Herpestes auropunctatus), an invasive animal species. This study was conducted across the three main islands of the U.S. Virgin Islands (USVI), which are St. Croix, St. Thomas, and St. John. We used the microscopic agglutination test (MAT), fluorescent antibody test (FAT), real-time polymerase chain reaction (lipl32 rt-PCR), and bacterial culture to evaluate serum and kidney specimens and compared the sensitivity, specificity, positive predictive value, and negative predictive value of these laboratory meth-ods. Mongooses (n = 274) were live-trapped at 31 field sites in ten regions across USVI and humanely euthanized for Leptospira spp. testing. Bacterial isolates were sequenced and evaluated for species and phylogenetic analysis using the ppk gene. Anti-Leptospira spp. antibodies were detected in 34% (87/256) of mongooses. Reactions were observed with the following serogroups: Sejroe, Icterohaemorrhagiae, Pyrogenes, Mini, Cynopteri, Australis, Hebdomadis, Autumnalis, Mankarso, Pomona, and Ballum. Of the kidney specimens exam-ined, 5.8% (16/270) were FAT-positive, 10% (27/274) were culture-positive, and 12.4% (34/ 274) were positive by rt-PCR. Of the Leptospira spp. isolated from mongooses, 25 were L. borgpetersenii, one was L. interrogans, and one was L. kirschneri. Positive predictive values of FAT and rt-PCR testing for predicting successful isolation of Leptospira by culture were 88% and 65%, respectively. The isolation and identification of Leptospira spp. in mongooses highlights the potential role of mongooses as a wildlife reservoir of leptospirosis; mongooses could be a source of Leptospira spp. infections for other wildlife, domestic animals, and humans