Evaluación de la significación estadística y cálculo del intervalo de confianza de la razón de mortalidad estandarizada

ResumenLa razón de mortalidad estandarizada (RME) es la razón entre el número de muertes observadas (D) y el número de muertes esperadas (E), tomando como base las tasas de mortalidad de una población de referencia. En el análisis de la RME han sido propuestos varios tests para la evaluación de su significación estadística y para el cálculo de sus intervalos de confianza.En el presente estudio, donde se han calculado las RME de dos causas de muerte en 27 distritos sanitarios de Castilla-La Mancha, la significación estadística de las diferentes RME se ha valorado mediante un test que utiliza la probabilidad exacta de Poisson y mediante cuatro tests que usan aproximaciones normales a Poisson: 1) cálculo de un estadístico Z basado en la asunción de que una variable de Poisson con media E tiene un error estándar √E; 2) estadístico Z con corrección de continuidad; 3) estadístico Z basado en la transformación de la variable en su raíz cuadrada; y 4) estadístico Z creado por Byar como aproximación al test exacto. Se han obtenido, igualmente, los intervalos de confianza mediante el método exacto y mediante tres métodos aproximados; 1) el de Byar; 2) el basado en el estadístico Z no corregido; y 3) el que se basa en la raíz cuadrada de una variable de Poisson.Los resultados obtenidos con los métodos exactos y con el método Byar son muy similares, por lo que se recomienda la utilización de este último como práctica rutinaria, tanto para la evaluación estadística de una RME, como para el cálculo de sus intervalos de confianzaSummaryThe standardized mortality ratio (SMR) is the ratio of the number of deaths observed (D) to the number expected (E), on the basis of the mortality rates of some reference population. Several procedures have been proposed inorder to test its significance and to estimate its confidence intervals.In this study, the SMR of two causes of death in 27 healths areas of Castilla-La Mancha have been calculated. The significance has been evaluated by exact Poisson test and by four methods approximating the Poisson distribution by the normal: 1) a Z statistic based on the assumption that a Poisson variate with expectation E has a standard deviation equal to √E; 2) the Z statistic with a continuity correction; 3) a Z statistic based on the square root transformation of a Poisson variable and 4) an approximation of the exact test by Byar. Also, theconfidence intervals have been estimated by exact method and by three approximate procedures: 1) by Byar; 2) by Z statistic uncorrected and 3) by the square root transformation of the Poisson distribution.With the exact methods and Byar procedure the results were very similar; therefore, using the last to testing significance and estimate the confidence intervals of SMR, is suggested

A new Merluccius polli reference genome to investigate the effects of global change in West African waters

Genome resources have become crucial to assess genome-wide level of variation as well as to detect adaptive variation. This is particularly important for studying diversity in marine species inhabiting regions highly affected by accelerated climate warming and pollution, also known as global change. A greater awareness of the impacts of global change is urgently needed to ensure sustainable marine fisheries. Despite recent efforts, there are still many gaps in fish reference genomes, both geographical and taxonomic. Here, we sequence, assemble and annotate the genome of Merluccius polli. The total length of this new assembly (~582 Kb, N50 = 168Kb) is approximately 40% longer and much less fragmented than a previous version. Even though it might not be intrinsic of this species, low level of heterozygosity (1.16 SNPs/Kb) and low proportion of repeat content (9.21%) was found in this genome. This hake species has a wide latitudinal distribution; therefore, it is exposed to a changing temperature gradient and to a variety of contaminants in part of its distribution along West African coast. Special emphasis was laid on the identification and characterization of candidate genes known to respond to different stressors (depth, temperature, hypoxia, and heavy metals) happening along its geographical distribution. A total of 68 of the selected candidate genes known to be associated with responses to these stressors were found in the current assembly of the genome, and their predicted sequence can be considered as full-length. Therefore, it is expected that this genome would serve as a tool to further investigations of global change in one of the most stressed marine regions in the planet

Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study

[EN] Sepsis management remains one of the most important challenges in modern clinical practice. Rapid progression from sepsis to septic shock is practically unpredictable, hence the critical need for sepsis biomarkers that can help clinicians in the management of patients to reduce the proba-bility of a fatal outcome. Circulating nucleoproteins released during the inflammatory response to infection, including neutrophil extracellular traps, nucleosomes, and histones, and nuclear pro-teins like HMGB1, have been proposed as markers of disease progression since they are related to inflammation, oxidative stress, endothelial damage, and impairment of the coagulation response, among other pathological features. The aim of this work was to evaluate the actual potential for decision making/outcome prediction of the most commonly proposed chromatin-related bi-omarkers (i.e., nucleosomes, citrullinated H3, and HMGB1). To do this, we compared different ELISA measuring methods for quantifying plasma nucleoproteins in a cohort of critically ill pa-tients diagnosed with sepsis or septic shock compared to nonseptic patients admitted to the inten-sive care unit (ICU), as well as to healthy subjects. Our results show that all studied biomarkers can be used to monitor sepsis progression, although they vary in their effectiveness to separate sepsis and septic shock patients. Our data suggest that HMGB1/citrullinated H3 determination in plasma is potentially the most promising clinical tool for the monitoring and stratification of septic patients.This activity received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union's Horizon 2020 research and innovation program. C.R-M. thanks GVA for starting grant (GV/2018/127) and Spanish Ministry of Science and Innovation for research project (PID2020-119127RA-I00); J.B-G thanks ISCIII, AES2018 for iPFIS fellowship (IFI18/00015) and GVA for APOTI fellowship (APOTIP/2017/012); CG thanks Spanish Ministry of Universities for fellowship FPU18/03969; J.L.G-G and F.V.P thank INCLIVA, GVA and AES2016 and AES2019 (ISCIII) for starting grant (GV/2014/132), project PI16/01036 and PI19/00994 and project DTS17/00132 (co-financed by the ERDF). The project leading to these results has received funding from "la Caixa" Foundation (ID 100010434), under agreement CI18-0009. C.R-M., F.V.P. and A.M. thank Grand Challenges Canada. : We want to particularly acknowledge the patients and the INCLIVA Biobank (PT17/0015/0049; B.000768 ISCIII) integrated in the Valencian Biobanking Network and the Spanish National Biobanks Network for their collaboration.Beltrán-García, J.; Manclus Ciscar, JJ.; García-López, EM.; Carbonell, N.; Ferreres, J.; Rodríguez-Gimillo, M.; Garcés, C.... (2021). Comparative Analysis of Chromatin-Delivered Biomarkers in the Monitoring of Sepsis and Septic Shock: A Pilot Study. International Journal of Molecular Sciences. 22(18):1-15. https://doi.org/10.3390/ijms22189935115221

Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal

The gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.Welcome Trust grants: (WT095908, WT098051), FEBS Long-Term Fellowship, Medical Research Council Grant-in-Aid (U117570528)

No association of CDK5 genetic variants with Alzheimer's disease risk

<p>Abstract</p> <p>Background</p> <p>As cyclin-dependent kinase 5 (CDK5) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD.</p> <p>Methods</p> <p>We examined genetic variations of CDK5 by genotyping haplotype tagging SNPs (htSNPs) (rs9278, rs2069459, rs891507, rs2069454, rs1549759 and rs2069442) in a group of 408 Spanish AD cases and 444 controls.</p> <p>Results</p> <p>There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE ε4 allele.</p> <p>Conclusion</p> <p>Our negative findings in the Spanish population argue against the hypothesis that CDK5 genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between CDK5 gene and AD risk in the Dutch population exists.</p

Loss of NFIX transcription factor biases postnatal stem/progenitor cells towards oligodendrogenesis

Murine postnatal neural stem cells (NSCs) give rise to neurons, astrocytes, or oligodendrocytes (OLs); however, our knowledge of the genes that control this lineage specification is incomplete. In this study, we show that nuclear factor I X (NFIX), a transcription factor known to regulate NSC quiescence, also suppresses oligodendrogenesis (ODG) from NSCs. Immunostaining reveals little or no expression of NFIX in OL lineage cells both in vivo and in vitro. Loss of NFIX from subventricular zone (SVZ) NSCs results in enhanced ODG both in vivo and in vitro, while forced expression of NFIX blocks NSC differentiation into OLs in vitro. RNA-seq analysis shows that genes previously shown to be differentially expressed in OL progenitors are significantly enriched in RNA from Nfix(-/-) versus wild-type NSCs. These data indicate that NFIX influences the lineage specification of postnatal SVZ NSCs, specifically suppressing ODG

Expert consensus on the use of systemic glucocorticoids for managing eosinophil-related diseases

Eosinophil-related diseases represent a group of pathologic conditions with highly heterogeneous clinical presentation and symptoms ranging from mild to critical. Both systemic and localized forms of disease are typically treated with glucocorticoids. The approval of novel biologic therapies targeting the interleukin-5 pathway can help reduce the use of systemic glucocorticoids (SGC) in eosinophilic diseases and reduce the risk of SGC-related adverse effects (AEs). In this article, a panel of experts from different medical specialties reviewed current evidence on the use of SGC in two systemic eosinophilic diseases: Eosinophilic Granulomatosis with PolyAngiitis (EGPA) and HyperEosinophilic Syndrome (HES); and in two single-organ (respiratory) eosinophilic diseases: Chronic RhinoSinusitis with Nasal Polyps (CRSwNP) and Severe Asthma with Eosinophil Phenotype (SA-EP), and contrasted it with their experience in clinical practice. Using nominal group technique, they reached consensus on key aspects related to the dose and tapering of SGC as well as on the initiation of biologics as SGC-sparing agents. Early treatment with biologics could help prevent AEs associated with medium and long-term use of SGC.Funding: The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The author(s) declare that GSK funded the medical writing support for this manuscript. Acknowledgments: We would like to thank Mónica Hoyos (medical writer) on behalf of Springer Healthcare Communications. This medical writing assistance was funded by GSK and facilitated by Springer Healthcare

Detection of early Alzheimer's disease in MCI patients by the combination of MMSE and an episodic memory test

BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous clinical entity that comprises the prodromal phase of Alzheimer's disease (Pr-AD). New biomarkers are useful in detecting Pr-AD, but they are not universally available. We aimed to investigate baseline clinical and neuropsychological variables that might predict progression from MCI to AD dementia. METHODS: All patients underwent a complete clinical and neuropsychological evaluation at baseline and every 6 months during a two-year follow-up period, with 54 out of 109 MCI patients progressing to dementia (50 of them progressed to AD dementia), and 55 remaining as stable MCI (S-MCI). RESULTS: A combination of MMSE and California Verbal Learning Test Long Delayed Total Recall (CVLT-LDTR) constituted the best predictive model: subjects scoring above 26/30 on MMSE and 4/16 on CVLT-LDTR had a negative predictive value of 93.93% at 2 years, whereas those subjects scoring below both of these cut-off scores had a positive predictive value of 80.95%. CONCLUSIONS: Pr-AD might be distinguished from S-MCI at baseline using the combination of MMSE and CVLT-LDTR. These two neuropsychological predictors are relatively brief and may be readily completed in non-specialist clinical settings