Abstract Objective Weight regain is associated with the promotion of insulin resistance. The newly discovered myokine irisin, which was proposed to be involved in the management of insulin ...sensitivity, could play a role in this process. This study aimed to investigate the association between irisin and reduced insulin sensitivity induced by weight regain. Materials/Methods Insulin sensitivity was evaluated according to the homeostasis model assessment of insulin resistance (HOMA-IR) in 136 obese patients who followed an eight-week hypocaloric diet (30% reduced energy expenditure) to lose weight and was re-evaluated four or six months after treatment. Irisin plasma levels, as well as the levels of leptin, adiponectin, ghrelin and TNF-α, were quantified in a sub-cohort (n = 73) from the initially studied patients at baseline (T0), at the diet endpoint (T1) and after the follow-up period (T2). Results After a successful dietary intervention to lose weight, 50% of the patients who regained the lost weight during the follow-up period were categorized as insulin resistant (HOMA-IR ≥ 2.5) compared with only 25% of patients who maintained the weight loss (p = 0.018). Importantly, in addition to the well-studied hormones leptin and adiponectin, irisin plasma levels were statistically associated with several risk factors for insulin resistance. Indeed, the increased risk of insulin resistance during the follow-up period was related to high irisin levels at baseline (odds ratio = 4.2; p = 0.039). Conclusions Circulating irisin predicts the insulin resistance onset in association with weight regain. Therefore, irisin could be secreted as an adaptive response to counteract the deleterious effect of excess adiposity on glucose homeostasis.
There is no reliable microbiological marker to guide the indication and the response to antiviral treatment in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the dynamics of ...subgenomic RNA (sgRNA) in patients with COVID-19 before and after receiving treatment with remdesivir.
We included consecutive patients admitted for COVID-19 who received remdesivir according to our institutional protocol and accepted to participate in the study. A nasopharyngeal swab for quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was collected at baseline and after 3 and 5 days of treatment with remdesivir. Genomic and sgRNA were analyzed in those samples and main comorbidities and evolution were collected for the analyses. The main outcomes were early discharge (≤10 days) and 30-day mortality.
A total of 117 patients were included in the study, of whom 24 had a negative sgRNA at baseline, with 62.5% (15/24) receiving early discharge (≤10 days) and no deaths in this group. From the 93 remaining patients, 62 had a negative sgRNA at day 5 with 37/62 (59.6%) with early discharge and a mortality rate of 4.8% (3/62). In the subgroup of 31 patients with positive sgRNA after 5 days of remdesivir, the early discharge rate was 29% (9/31) and the mortality rate was 16.1% (5/31). In multivariable analyses, the variables associated with early discharge were negative sgRNA at day 3 and not needing treatment with corticosteroids or intensive care unit admission.
Qualitative sgRNA could help in monitoring the virological response in patients who receive remdesivir. Further studies are needed to confirm these findings.
It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after ...treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10
Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated
unmutated OS: 85.7% alive at 7.2 years
79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies. This trial is registered with EudraCT n. 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714.
Non-coding RNAs (i.e., miRNAs) play a role in the development of obesity and related comorbidities and the regulation of body weight.
To identify candidate miRNA biomarkers throughout omics ...approaches in order to predict the response to specific weight-loss dietary treatments.
Genomic DNA and cDNA isolated from white blood cells of a subset from the RESMENA nutritional intervention study (Low-responders (LR) vs High-responders (HR)) was hybridized in Infinium Human Methylation450 BeadChip and in Illumina Human HT-12 v4 gene expression BeadChips arrays respectively. A bioinformatic prediction of putative target sites of selected miRNAs was performed by applying miRBase algorithms. HEK-293T cells were co-transfected with expression vectors containing the 3'-UTR of candidate genes to validate the binding of miRNAs to its target sites.
134 miRNAs were differentially methylated between HR and LR in the methylation array, whereas 44 miRNAs were differentially expressed between both groups in the expression array. Specifically, miR-1237, miR-1976, miR-642, miR-636, miR-612 and miR-193B were simultaneously hypomethylated and overexpressed in HR. miR-612 and miR-1976 showed greatest differences in methylation and expression levels, respectively. The bioinformatic prediction revealed that TP53 was a putative target gene of miR-612 and CD40 of miR-1976. Moreover, TP53 was downregulated in the expression array when comparing HR vs LR expression levels adjusted by sex, diet, age and baseline weight, and CD40 showed a statistical trend. Furthermore, gene expression levels of TP53 and CD40 in white blood cells, when measured by qPCR, were also downregulated in HR. Finally, miR-612 and miR-1976 potently repressed TP53 and CD40 respectively by targeting its 3'-UTR regions.
miR-612 and miR-1976 levels could be prospective biomarkers of response to specific weight-loss diets and might regulate the gene expression of TP53 and CD40.
Is the automatic embryo grading function of specific time-lapse systems clinically useful as a decision support tool for IVF laboratories?
Blastocyst grading according to the automatic scoring system ...is directly associated with the likelihood of implantation and live birth, at least in treatments without preimplantation genetic testing for aneuploidy (PGT-A).
Several embryo selection algorithms have been described since the introduction of time-lapse technology in IVF laboratories, but no one algorithm has yet been sufficiently consolidated for universal use. Multicentric models based on automated grading systems offer promise for standardization of embryo selection.
A retrospective cohort study was performed including 1678 patients who underwent IVF treatments between 2018 and 2020 and whose embryos (n = 12 468) were cultured in time-lapse systems.
After obtaining the required parameters (division time to 2, 3, 4 and 5 cells; time of blastocyst formation; inner cell mass quality; and trophectoderm quality), the automatic embryo score was calculated using the software included in the appropriate workstation. First, embryo score was compared with conventional morphological quality and the subsequent clinical outcomes of 1952 single blastocyst transfers. Second, we quantified the contribution of the automatic embryo score and conventional morphological grade to implantation and live birth outcome with multivariate logistic regression analysis in different patient populations.
A higher embryo score was associated with a better clinical outcome of IVF treatment. The mean of the automatic embryo score varied significantly (P < 0.001) among embryos with different morphological categories, between euploid and aneuploid embryos, between embryos resulting in positive versus negative pregnancy, between implanted and non-implanted embryos, and between embryos resulting in positive and negative live birth. Embryo score was related to the odds of implantation and live birth in the oocyte donation program (odds ratio (OR)=1.29; 95% CI 1.19-1.39; P < 0.001 for implantation and OR = 1.26; 95% CI 1.16-1.36; P < 0.001 for live birth) and in conventional treatments with autologous oocytes (OR = 1.38; 95% CI 1.24-1.54; P < 0.001 for implantation and OR = 1.47; 95% CI 1.30-1.65; P < 0.001 for live birth). There was no significant association of embryo score with implantation or live birth in treatments involving PGT-A.
This study is limited by its retrospective nature. Further prospective randomized trials are required to confirm the clinical impact of these findings. The single-center design should be taken into account when considering the universal application of the model.
Evidence of the clinical efficiency of automated embryo scoring for ranking embryos with different morphological grade and potential in order to achieve higher implantation and live birth rates may make it a decision support tool for embryologists when selecting blastocysts for embryo transfer.
This research has been funded by a grant from the Ministry of Science, Innovation and Universities FIS (PI21/00283) awarded to M.M. There are no competing interests to declare.
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Hoverflies are relevant to pollination, predation, phytophagy and decomposition processes and they are also used as bioindicators. The numerous recent advances in the study of Spanish hoverflies and ...the absence of species lists for the Spanish provinces prompted us to update the national catalogue and fill in the gap at the provincial level. Andorra and Gibraltar are also included in this review. A total of 421 species of 72 genera are included in the present catalogue (417 species in Spain; 86 in Andorra; 43 in Gibraltar). León (182 spp), Salamanca (143 spp), Madrid (134 spp), Ciudad Real (124 spp) and Huesca (121 spp) are the Spanish provinces with the highest numbers of species recorded. The Balearic Islands have 81 species and the Canary Islands 41, with one and 11 endemic species respectively. The richest hoverfly genera in Spain are Cheilosia (56 spp), Merodon (40 spp plus 1 sp from Gibraltar) and Eumerus (38 spp plus 1 sp from Gibraltar), all of them being Eristalinae; within the Syrphinae, Paragus is the richest genus (18 spp). The possibility of elaborating regional (provincial) species lists from the information provided in the present study also contributes to 'Syrph the Net, the database of European Syrphidae' as a tool for assessment of habitat conservation in Spain.
A catalytic enantioselective addition reaction of alkylzirconium species to aromatic aldehydes is reported. The reaction, facilitated by a chiral nonracemic diol ligand complex with Ti(O
Pr)₄, ...proceeds under mild and convenient conditions, and no premade organometallic reagents are required since the alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The methodology is compatible with functionalized nucleophiles and a broad range of aromatic aldehydes.
Objective To estimate the contribution of 9 obesity-related polymorphisms and a genetic predisposition score (GPS) on anthropometric and biochemical variables before and after a weight loss ...intervention program in overweight/obese Spanish adolescents. Study design Overweight/obese adolescents (n = 168; 12-16 years) participating in the EVASYON program were genotyped for 9 obesity-related single nucleotide polymorphisms in the FTO, MC4R, TMEM18, IL6, PPARG, and ADIPQ genes. Results At baseline, the GPS showed a significant association with body mass index-standard deviation score (BMI-SDS) and fat mass. After 3 months of intervention, this GPS also showed a relationship with the variation of both anthropometric measurements. After adjusting for baseline BMI-SDS, subjects with a lower GPS had a greater improvement on metabolic profile, as well as a better response to physical activity, compared with those subjects with a higher GPS. Conclusions The GPS seems to have an important relationship with BMI-SDS and fat mass both at baseline and after a 3-month weight loss lifestyle intervention. Obese and overweight adolescents with a lower GPS have a greater benefit of weight loss after 3 months of a multidisciplinary lifestyle intervention.
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