Net Efficacy Adjusted for Risk (NEAR): A Simple Procedure for Measuring Risk:Benefit Balance

BACKGROUND: Although several mathematical models have been proposed to assess the risk:benefit of drugs in one measure, their use in practice has been rather limited. Our objective was to design a simple, easily applicable model. In this respect, measuring the proportion of patients who respond favorably to treatment without being affected by adverse drug reactions (ADR) could be a suitable endpoint. However, remarkably few published clinical trials report the data required to calculate this proportion. As an approach to the problem, we calculated the expected proportion of this type of patients. METHODOLOGY/PRINCIPAL FINDINGS: Theoretically, responders without ADR may be obtained by multiplying the total number of responders by the total number of subjects that did not suffer ADR, and dividing the product by the total number of subjects studied. When two drugs are studied, the same calculation may be repeated for the second drug. Then, by constructing a 2 x 2 table with the expected frequencies of responders with and without ADR, and non-responders with and without ADR, the odds ratio and relative risk with their confidence intervals may be easily calculated and graphically represented on a logarithmic scale. Such measures represent "net efficacy adjusted for risk" (NEAR). We assayed the model with results extracted from several published clinical trials or meta-analyses. On comparing our results with those originally reported by the authors, marked differences were found in some cases, with ADR arising as a relevant factor to balance the clinical benefit obtained. The particular features of the adverse reaction that must be weighed against benefit is discussed in the paper. CONCLUSION: NEAR representing overall risk-benefit may contribute to improving knowledge of drug clinical usefulness. As most published clinical trials tend to overestimate benefits and underestimate toxicity, our measure represents an effort to change this trend

Impact of previous tobacco use with or without cannabis on first psychotic experiences in patients with first-episode psychosis

Objective: There is high prevalence of cigarette smoking in individuals with first-episode psychosis (FEP) prior to psychosis onset. The purpose of the study was to determine the impact of previous tobacco use with or without cannabis on first psychotic experiences in FEP and the impact of this use on age of onset of symptoms, including prodromes. Methods: Retrospective analyses from the naturalistic, longitudinal, multicentre, “Phenotype-Genotype and Environmental Interaction. Application of a Predictive Model in First Psychotic Episodes (PEPs)” Study. The authors analysed sociodemographic/clinical data of 284 FEP patients and 231 matched healthy controls, and evaluated first psychotic experiences of patients using the Symptom Onset in Schizophrenia Inventory. Results: FEP patients had significantly higher prevalence of tobacco, cannabis, and cocaine use than controls. The FEP group with tobacco use only prior to onset (N = 56) had more sleep disturbances (42.9% vs 18.8%, P = 0.003) and lower prevalence of negative symptoms, specifically social withdrawal (33.9% vs 58%, P = 0.007) than FEP with no substance use (N = 70), as well as lower prevalence of ideas of reference (80.4% vs 92.4%, P = 0.015), perceptual abnormalities (46.4% vs 67.4%, P = 0.006), hallucinations (55.4% vs 71.5%, P = 0.029), and disorganised thinking (41.1% vs 61.1%, P = 0.010) than FEP group with previous tobacco and cannabis use (N = 144). FEP patients with cannabis and tobacco use had lower age at first prodromal or psychotic symptom (mean = 23.73 years [SD = 5.09]) versus those with tobacco use only (mean = 26.21 [SD = 4.80]) (P = 0.011). Conclusions: The use of tobacco alone was not related to earlier age of onset of a first psychotic experience, but the clinical profile of FEP patients is different depending on previous tobacco use with or without cannabis. © 2021 The Author

Hypoxia Inducible Factor 1-Alpha (HIF-1 Alpha) Is Induced during Reperfusion after Renal Ischemia and Is Critical for Proximal Tubule Cell Survival

Acute tubular necrosis (ATN) caused by ischemia/reperfusion (I/R) during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 α), using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 α is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 α promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 α was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 α induction during reperfusion with a potential critical role in renal transplant

Hotspots of biogeochemical activity linked to aridity and plant traits across global drylands

14 páginas.- 4 figuras.- 67 referencias.- The online version contains supplementary material available at https://doi.org/10.1038/s41477-024-01670-7Perennial plants create productive and biodiverse hotspots, known as fertile islands, beneath their canopies. These hotspots largely determine the structure and functioning of drylands worldwide. Despite their ubiquity, the factors controlling fertile islands under conditions of contrasting grazing by livestock, the most prevalent land use in drylands, remain virtually unknown. Here we evaluated the relative importance of grazing pressure and herbivore type, climate and plant functional traits on 24 soil physical and chemical attributes that represent proxies of key ecosystem services related to decomposition, soil fertility, and soil and water conservation. To do this, we conducted a standardized global survey of 288 plots at 88 sites in 25 countries worldwide. We show that aridity and plant traits are the major factors associated with the magnitude of plant effects on fertile islands in grazed drylands worldwide. Grazing pressure had little influence on the capacity of plants to support fertile islands. Taller and wider shrubs and grasses supported stronger island effects. Stable and functional soils tended to be linked to species-rich sites with taller plants. Together, our findings dispel the notion that grazing pressure or herbivore type are linked to the formation or intensification of fertile islands in drylands. Rather, our study suggests that changes in aridity, and processes that alter island identity and therefore plant traits, will have marked effects on how perennial plants support and maintain the functioning of drylands in a more arid and grazed world.This research was supported by the European Research Council (ERC grant 647038 (BIODESERT) awarded to F.T.M.) and Generalitat Valenciana (CIDEGENT/2018/041). D.J.E. was supported by the Hermon Slade Foundation (HSF21040). J. Ding was supported by the National Natural Science Foundation of China Project (41991232) and the Fundamental Research Funds for the Central Universities of China. M.D.-B. acknowledges support from TED2021-130908B-C41/AEI/10.13039/501100011033/Unión Europea Next Generation EU/PRTR and the Spanish Ministry of Science and Innovation for the I + D + i project PID2020-115813RA-I00 funded by MCIN/AEI/10.13039/501100011033. O.S. was supported by US National Science Foundation (Grants DEB 1754106, 20-25166), and Y.L.B.-P. by a Marie Sklodowska-Curie Actions Individual Fellowship (MSCA-1018 IF) within the European Program Horizon 2020 (DRYFUN Project 656035). K.G. and N.B. acknowledge support from the German Federal Ministry of Education and Research (BMBF) SPACES projects OPTIMASS (FKZ: 01LL1302A) and ORYCS (FKZ: FKZ01LL1804A). B.B. was supported by the Taylor Family-Asia Foundation Endowed Chair in Ecology and Conservation Biology, and M. Bowker by funding from the School of Forestry, Northern Arizona University. C.B. acknowledges funding from the National Natural Science Foundation of China (41971131). D.B. acknowledges support from the Hungarian Research, Development and Innovation Office (NKFI KKP 144096), and A. Fajardo support from ANID PIA/BASAL FB 210006 and the Millennium Science Initiative Program NCN2021-050. M.F. and H.E. received funding from Ferdowsi University of Mashhad (grant 39843). A.N. and M.K. acknowledge support from FCT (CEECIND/02453/2018/CP1534/CT0001, SFRH/BD/130274/2017, PTDC/ASP-SIL/7743/2020, UIDB/00329/2020), EEA (10/CALL#5), AdaptForGrazing (PRR-C05-i03-I-000035) and LTsER Montado platform (LTER_EU_PT_001) grants. O.V. acknowledges support from the Hungarian Research, Development and Innovation Office (NKFI KKP 144096). L.W. was supported by the US National Science Foundation (EAR 1554894). Y.Z. and X.Z. were supported by the National Natural Science Foundation of China (U2003214). H.S. is supported by a María Zambrano fellowship funded by the Ministry of Universities and European Union-Next Generation plan. The use of any trade, firm or product names does not imply endorsement by any agency, institution or government. Finally, we thank the many people who assisted with field work and the landowners, corporations and national bodies that allowed us access to their land.Peer reviewe

Response to retreatment with interferon-α plus ribavirin in chronic hepatitis C patients is independent of the NS5A gene nucleotide sequence

OBJECTIVE Interferon-α plus ribavirin is an effective treatment for chronic hepatitis C patients. We evaluated whether the response to this combined therapy correlated with the presence of mutations in a region of 372 nucleotides within the NS5A gene. METHODS Sixty-two patients, 42 nonresponders and 20 relapsers to a previous course of interferon-α, received 3 million units thrice weekly of interferon-α-2b and 1-1.2 g daily of ribavirin for 12 months. Basal biochemical and virological (HCV RNA and genotype) parameters were determined. Clinical examinations were carried out at 1, 2, 3, 6, and 12 months. In addition, nucleotide sequencing of the NS5A gene was determined for viral samples obtained from 38 of these patients at the baseline of the combined therapy, as well as in 15 of them before initiating the previous course of interferon as monotherapy. RESULTS On finishing the 12 months, 36 patients (58.1%) had normal aminotransferases and 25 (40.3%) cleared viremia. Nucleotide sequencing indicated the same level of genetic variability within the group of responder and nonresponder patients all along the 124 amino acid residues of the NS5A gene studied. Neither the type of amino acid substitution nor the number of them was significantly different in one group relative to the other. CONCLUSIONS Therapy with interferon-α-2b plus ribavirin was well tolerated, achieving an end-of- treatment response in 25 (40.3%) patients. Response did not correlate with the presence of mutations in the NS5A gene analyzed, including the interferon sensitivity determining region (ISDR) and its flanking sequences

Administrative simplification as an instrument for coping with the economic crisis

The papers collected in this chapter address the relationship between administrative simplification and the economic crisis by analysing the experience of several European countries (particularly, France and Spain). Simplification programs implemented in these countries affect two different profiles, one regulatory and the other procedural, in order to reduce bureaucratic fulfilments for citizens and support the creation of new businesses. In conclusion, the authors point out the difficulties of implementing such programs, often hindered by the public administration