Decision-making in end-of-life care in pediatrics: ethical controversies and management of situations in clinical practice

The concept of “Limitation of the therapeutic effort” (LTE) is based on the withdrawal or non-initiation of futile treatments that delay the death of the patient and prolong their agony. Although medical advances have made it possible to reduce infant mortality rates, management of end-of-life decisions at these ages continues to be difficult and includes ethical and controversial issues of complex resolution. This paper reviews the medical literature and various reference guides aiming 1) to describe some of the most frequent ethical controversies described in the literature and 2) to offer guidance on how to deal with situations of uncertainty that can present themselves in the clinic, integrating them into the physician-family-patient relationship. To do this, the body of the review has been divided into several sections: first, we will review the most recent bibliography related to the complexity and types of LTE described, and the ethical controversies that this poses. Next, we will address the role of the doctor in LTE and the interaction between these ethical controversies and the doctor’s own morals, where an attempt will be made to establish a general orientation of the steps that the doctor should take when making decisions. The next step goes beyond the purely care setting and will consist of including the doctor in the decision-making process relating to the family, going through the bibliography that tells us about the most frequent needs and problems that can arise in this context. Finally, we will integrate the pediatric patient in this process, analyzing very briefly the most frequent problems that may occur in the last oments of life. All this makes us consider the importance of clinical practice guidelines in LTE

Type 1 diabetes-related distress: Current implications in care

Type 1 diabetes (T1D) is a complex chronic disease associated with major health and economic consequences, also involving important issues in the psychosocial sphere. In this regard, T1D-related distress, defined as the emotional burden of living with T1D, has emerged as a specific entity related to the disease. Diabetes distress (DD) is an overlooked but prevalent condition in people living with T1D, and has significant implications in both glycemic control and mental health in this population. Although overlapping symptoms may be found between DD and mental health disorders, specific approaches should be performed for the diagnosis of this problem. In recent years, different DD-targeted interventions have been postulated, including behavioral and psychosocial strategies. Moreover, new technologies in this field may be helpful to address DD in people living with T1D. In this article, we summarize the current knowledge on T1D-related distress, and we also discuss the current approaches and future perspectives in its management.Funding for open access charge: Universidad de Málaga / CBUA. J.I.M.M. was supported by a Rio Hortega grant from Instituto de Salud Carlos III, Madrid, Spain (CM22/00217)

Effects of exercise timing on metabolic health

The increasing prevalence of metabolic syndrome is associated with major health and socioeconomic consequences. Currently, physical exercise, together with dietary interventions, is the mainstay of the treatment of obesity and related metabolic complications. Although exercise training includes different modalities, with variable intensity, duration, volume, or frequency, which may have a distinct impact on several characteristics related to metabolic syndrome, the potential effects of exercise timing on metabolic health are yet to be fully elucidated. Remarkably, promising results with regard to this topic have been reported in the last few years. Similar to other time-based interventions, including nutritional therapy or drug administration, time-of-day-based exercise may become a useful approach for the management of metabolic disorders. In this article, we review the role of exercise timing in metabolic health and discuss the potential mechanisms that could drive the metabolic-related benefits of physical exercise performed in a time-dependent manner.Funding for open access charge: Universidad de Málaga/CBUA

Obesity-related glomerulopathy: Current approaches and future perspectives

Obesity-related glomerulopathy (ORG) is a silent comorbidity which is increasing inincidence as the obesity epidemic escalates. ORG is associated with serious healthconsequences including chronic kidney disease, end-stage renal disease (ESRD), andincreased mortality. Although the pathogenic mechanisms involved in the develop-ment of ORG are not fully understood, glomerular hemodynamic changes, renin-angiotensin-aldosterone system (RAAS) overactivation, insulin-resistance, inflamma-tion and ectopic lipid accumulation seem to play a major role. Despite albuminuriabeing commonly used for the non-invasive evaluation of ORG, promising biomarkersof early kidney injury that are emerging, as well as new approaches with proteomicsand metabolomics, might permit an earlier diagnosis of this disease. In addition, theassessment of ectopic kidney fat by renal imaging could be a useful tool to detectand evaluate the progression of ORG. Weight loss interventions appear to be effec-tive in ORG, although large-scale trials are needed. RAAS blockade has a ren-oprotective effect in patients with ORG, but even so, a significant proportion ofpatients with ORG will eventually progress to ESRD despite therapeutic efforts. It isnoteworthy that certain antidiabetic agents such as sodium-glucose cotransporter2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) couldbe useful in the treatment of ORG through different pleiotropic effects. In this article,we review current approaches and future perspectives in the care and treatmentof ORGInstitute of Health“Carlos III”(ISCIII), Grant/Award Numbers: JR 19/00054, CM 17/00169,PI20/01559; Funding for open access charge: Universidad de Málaga / CBU

Switching from subcutaneous to oral semaglutidein type 2 diabetes: A prospective study

Funding for open access charge: Universidad de Málaga / CBU

Effect of Moderate Consumption of Different Phenolic-Content Beers on the Human Gut Microbiota Composition: A Randomized Crossover Trial

The moderate consumption of beer has been associated with positive effects on health, and these benefits are driven, in part, by the antioxidant properties of phenolic compounds found in this beverage. However, the potential impact of beer polyphenols on the human gut microbiome and their consequences are yet to be elucidated. In this study, our aim was to evaluate the effect of three different phenolic-content beers on the gut microbiome and the potential role of the induced shifts in the antioxidant capacity of beer polyphenols. In total, 20 subjects (10 healthy volunteers and 10 individuals with metabolic syndrome) were randomly assigned in a crossover design to consume each of the different beers (alcohol-free, lager or dark beer) during a 2-week intervention. Significant changes in the relative abundance of Streptococcaceae and Streptococcus were found after beer consumption. An increased abundance of Streptococcaceae and Streptococcus was observed after the consumption of dark beer, with no detected differences between baseline and alcohol-free/lager beer intervention. Moreover, some of the detected differences appeared to be related to the metabolic status. Finally, a decrease in porphyrin metabolism and heme biosynthesis was found after the intervention, especially after the consumption of dark beer. These results show that the antioxidant capacity of beer polyphenols may induce positive shifts in gut microbiota composition, and some of the observed changes may also boost the antioxidant capacity of these compoundsM.Q.-M. was supported by a Manuel de Oya Research fellowship from Foro para la Investigación de la Cerveza y Estilos de Vida (FICYE). I.M.-I. and C.G.-R. were supported by the Miguel Servet Type I program and P.R.-L. by the Sara Borrell program both of the Carlos III Health Institute (co-founded by the European Regional Development Fund-ERDF-) (CP16/00163, CP20/00066 and CD19/00216, respectively). In addition, this study was supported by the “Network of Centers for Biomedical Research” (CIBER) of the Carlos III Health Institute (ISCIII) (CB06/03/0018), research grants from the ISCIII (PI18/01160, PI21/01677) and co-financed by the Regional Development Fund (ERDF). Partial funding for open access charge: Universidad de Málag

Hepatic and serum branched-chain fatty acid profile in patients with nonalcoholic fatty liver disease: A case–control study

Objective Alterations in the hepatic lipidome are a crucial factor involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the serum and hepatic profile of branched-chain fatty acids (BCFAs) in patients with different stages of NAFLD. Methods This was a case–control study performed in 27 patients without NAFLD, 49 patients with nonalcoholic fatty liver, and 17 patients with nonalcoholic steatohepatitis, defined by liver biopsies. Serum and hepatic levels of BCFAs were analyzed by gas chromatography–mass spectrometry. The hepatic expression of genes involved in the endogenous synthesis of BCFAs was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Results A significant increase in hepatic BCFAs was found in subjects with NAFLD compared with those without NAFLD; no differences were observed in serum BCFAs between study groups. Trimethyl BCFAs, iso-BCFAs, and anteiso-BCFAs were increased in subjects with NAFLD (either nonalcoholic fatty liver or nonalcoholic steatohepatitis) compared with those without NAFLD. Correlation analysis showed a relationship between hepatic BCFAs and the histopathological diagnosis of NAFLD, as well as other histological and biochemical parameters related to this disease. Gene expression analysis in liver showed that the mRNA levels of BCAT1, BCAT2, and BCKDHA were upregulated in patients with NAFLD. Conclusions These results suggest that the increased production of liver BCFAs might be related to NAFLD development and progression.This work was funded by the Institute of Health “Carlos III” (ISCIII) and cofunded by the Fondo Europeo de Desarrollo Regional-FEDER (grant number PI20/00505). J.C.F-G was supported by an intensification research program (INT21/00078, ISCIII, Spain; cofunded by the Fondo Europeo de Desarrollo Regional-FEDER), M.A.M-S was supported by a PFIS predoctoral fellowship from the ISCIII (FI21/00003, ISCIII, Spain; cofunded by the Fondo Europeo de Desarrollo Regional-FEDER), and B.R-M was supported by the “Miguel Servet Type I” program (CP19/00098, ISCIII, Spain; cofunded by the Fondo Europeo de Desarrollo Regional-FEDER). The funding organizations played no role in the design of the study, review and interpretation of the data, or final approval of the manuscript. Funding for open access charge: Universidad de Málaga / CBU

Evaluation of Adipose Tissue Zinc-Alpha 2-Glycoprotein Gene Expression and Its Relationship with Metabolic Status and Bariatric Surgery Outcomes in Patients with Class III Obesity

Zinc-α2 glycoprotein (ZAG) is an adipokine involved in adipocyte metabolism with potential implications in the pathogenesis of metabolic disorders. Our aim was to evaluate the relationship between visceral (VAT) and subcutaneous adipose tissue (SAT) ZAG expression and metabolic parameters in patients with class III obesity, along with the impact of basal ZAG expression on short- and medium-term outcomes related to bariatric surgery. 41 patients with class III obesity who underwent bariatric surgery were included in this study. ZAG gene expression was quantified in SAT and VAT. Patients were classified into two groups according to SAT and VAT ZAG percentile. Anthropometric and biochemical variables were obtained before and 15 days, 45 days, and 1 year after surgery. The lower basal SAT ZAG expression percentile was associated with higher weight and waist circumference, while the lower basal VAT ZAG expression percentile was associated with higher weight, waist circumference, insulin, insulin resistance, and the presence of metabolic syndrome. Basal SAT ZAG expression was inversely related to weight loss at 45 days after surgery, whereas no associations were found between basal VAT ZAG expression and weight loss after surgery. Additionally, a negative association was observed between basal SAT and VAT ZAG expression and the decrease of gamma-glutamyl transferase after bariatric surgery. Therefore, lower SAT and VAT ZAG expression levels were associated with an adverse metabolic profile. However, this fact did not seem to confer worse bariatric surgery-related outcomes. Further research is needed to assess the clinical significance of the role of ZAG expression levels in the dynamics of hepatic enzymes after bariatric surgeryThis study has been co-funded by FEDER funds (“A way to make Europe”). M.M. and L.G.S. are also supported by UMA18-FEDERJA-285 and UMA20-FEDERJA-144, co-funded by Malaga University, Junta de Andalucía and FEDER funds, CB06/03/0018, PI-0297-2018 and PI-0194-2017, co-funded by FEDER funds and Consejería de Salud y Familias, Junta de Andalucía, and CP17/00133, Instituto de Salud Carlos III (ISCIII), Ministry of Science, Innovation and Universities, Spain Partial funding for open access charge: Universidad de Málag

Allogeneic stem cell transplantation as a curative option in relapse/refractory diffuse large B cell lymphoma: Spanish multicenter GETH/GELTAMO study

Grupo Español de Trasplante Hematopoyético (GETH) and Grupo Español de Linfoma y Trasplante Autólogo (GELTAMO).We performed a retrospective multicenter study including 140 patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) from March 1995 to November 2018. Our objective was to analyze long term outcomes. Seventy-four percent had received a previous auto-SCT (ASCT) and the median number of lines pre-allo-SCT was 3 (range 1–9). Three year-event free survival (EFS) and overall survival (OS) were 38% and 44%, respectively. Non-relapse mortality (NRM) at day 100 was 19%. Cumulative incidence of grade III–IV acute graft versus host disease (GVHD) at day 100 was 16% and moderate/severe chronic GVHD at 3 years 34%. Active disease at allo-SCT (HR 1.95, p = 0.039) (HR 2.19, p = 0.019), HCT-CI ≥ 2 (2.45, p = 0.002) (HR 2.33, p = 0.006) and donor age >37 years (HR 2.75, p = 0.014) (HR 1.98, p = 0.043) were the only independent variables both for PFS and OS, respectively. NRM was significantly modified by HCT-CI ≥ 2 (HR 4.8, p = 0.008), previous ASCT (HR 4.4, p = 0.048) and grade III–IV acute GVHD on day 100 (HR 6.13, p = 0.016). Our data confirmed that allo-SCT is a curative option for patients with R/R DLBCL, displaying adequate results for fit patients with chemosensitive disease receiving an allo-SCT from a young donor

Role of allogeneic hematopoietic cell transplant for relapsed/refractory aggressive B-cell lymphomas in the CART era

Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y Terapia Celular (GETH-TC) registry, we selected patients with the following characteristics: CART or alloHCT performed between 2016 and 2021; ≥18 years old; ABCL diagnosis; ≥2 lines of therapy; and either anti-CD19 CART or alloHCT as therapy at relapse. The analysis included a total of 316 (CART = 215, alloHCT = 101) patients. Median follow-up was 15 and 36 months for the CART and alloHCT cohorts, respectively. In the multivariate analysis, CART was confirmed to be similar to alloHCT for the primary study endpoint (progression-free survival) (hazard ratio [HR] 0.92, CI95%:0.56–1.51, p = 0.75). Furthermore, when the analysis was limited to only patients with chemo-sensitive diseases (complete and partial response) at infusion (CART = 26, alloHCT=93), no differences were reported (progression-free survival at month +18: 65% versus 55%, p = 0.59). However, CART had lower non-relapse mortality (HR 0.34, 95% CI: 0.13–0.85, p = 0.02). Given the lower toxicity and similar survival outcomes, these results suggest the use of CART before alloHCT.We thank CERCA Programme/Generalitat de Catalunya for institutional support.Peer reviewe