Telerehabilitation improves cardiorespiratory and muscular fitness and body composition in older people with post-COVID-19 syndrome.

BACKGROUND: The effects of post-coronavirus disease 2019 (COVID-19) syndrome on the cardiorespiratory and muscular fitness in older people are of utmost relevance. This study aimed to evaluate the effects of a 12-week telerehabilitation programme on cardiorespiratory and muscular fitness and body composition in older patients with post-COVID-19 syndrome. METHODS: One hundred twenty older patients with post-COVID-19 syndrome were randomly assigned to one of two groups: patients who carried out the telerehabilitation programme (n = 60; age: 65.0 ± 5.2; female: 14.2%) and a control group (n = 60; age: 64.3 ± 5.0; female: 24.5%). An incremental cardiopulmonary exercise testing, isokinetic strength test, and bioelectrical impedance analysis were performed to compare cardiorespiratory and muscle strength responses and body composition between telerehabilitation and control groups. RESULTS: A significant increase in the cardiopulmonary exercise testing duration was found in the telerehabilitation group compared to the control group (mean difference = 88.9 s, P = 0.001). Peak oxygen uptake increased in the telerehabilitation group (mean difference = 3.0 mL·kg-1·min-1, P < 0.001) and control group (mean difference = 1.9 mL·kg-1·min-1, P < 0.001). Power output in cycle ergometer (mean difference = 25.9 watts, P < 0.001), fat free mass (mean difference = 2.1 kg, P = 0.004), soft lean mass (mean difference = 2.1 kg, P = 0.003), and skeletal muscle mass (mean difference = 1.4 kg, P = 0.003) only increased in the telerehabilitation group. A significant increase in the power output was observed in the telerehabilitation group compared with the control group in both lower limbs after isokinetic strength test of the leg extension at a speed of 60° (right: mean difference = 18.7 watts, P = 0.012; left: mean difference = 15.3 watts, P = 0.010). The peak torque of right leg extension increased only in the telerehabilitation group after isokinetic strength test at a speed of 60° (mean difference = 13.1 N·m, P < 0.001). A significant increase in the power output was observed in the telerehabilitation group compared with the control group in the left leg extension after isokinetic strength test at a speed of 180° (mean difference = 30.2 watts, P = 0.003). CONCLUSIONS: The telerehabilitation programme improved cardiorespiratory and muscular fitness, and body composition in older patients with post-COVID-19 syndrome to a greater extent than a control group. The telerehabilitation programmes may be an alternative to improve the sequelae of post-COVID-19 syndrome in older patients.

Glucose metabolism outcomes after pituitary surgery in patients with acromegaly.

AIM: To investigate the impact of pituitary surgery on glucose metabolism and to identify predictors of remission of diabetes after pituitary surgery in patients with acromegaly. METHODS: A national multicenter retrospective study of patients with acromegaly undergoing transsphenoidal surgery for the first time at 33 tertiary Spanish hospitals (ACRO-SPAIN study) was performed. Surgical remission of acromegaly was evaluated according to the 2000 and 2010 criteria. RESULTS: A total of 604 acromegaly patients were included in the study with a total median follow up of 91 months (interquartile range [IQR] 45-163). At the acromegaly diagnosis, 23.8% of the patients had diabetes mellitus (DM) with a median glycated hemoglobin (HbA1c) of 6.9% (IQR 6.4-7.9) [51.9 mmol/mol (IQR 46.4-62.8)]. In the multivariate analysis, older age (odds ratio [OR] 1.02, 95% CI 1.00-1.05), dyslipidemia (OR 5.25, 95% CI 2.81 to 9.79), arthropathy (OR 1.39, 95% CI 2.82 to 9.79), and higher IGF-I levels (OR 1.30, 95% CI 1.05 to 1.60) were associated with a greater prevalence of DM. At the last follow-up visit after surgery, 21.1% of the DM patients (56.7% of them with surgical remission of acromegaly) experienced diabetes remission. The cure rate of DM was more common in older patients (hazard ratio [HR] 1.77, 95% CI 1.31 to 2.43), when surgical cure was achieved (HR 2.10, 95% CI 1.01 to 4.37) and when anterior pituitary function was not affected after surgery (HR 3.38, 95% CI 1.17 to 9.75). CONCLUSION: Glucose metabolism improved in patients with acromegaly after surgery and 21% of the diabetic patients experienced diabetes remission; being more frequent in patients of older age, and those who experienced surgical cure and those with preserved anterior pituitary function after surgery.

Hospital and intensive care unit stay associated with body mass index affect cardiorespiratory fitness in patients with COVID-19.

BACKGROUND: The effects of coronavirus disease 2019 (COVID-19) on the cardiorespiratory fitness of hospitalized and obese patients are of utmost relevance. This study aimed to analyze how hospital and intensive care unit (ICU) stay together with body mass index affect cardiorespiratory fitness in patients with COVID-19. METHODS: 251 participants (males, n = 118; females, n = 133) were assigned to four groups: non-hospitalized COVID-19 patients (n = 65, age: 45.3 years), hospitalized COVID-19 patients (n = 63, age: 57.6 years), COVID-19 patients admitted to the ICU (n = 61, age: 56.9 years), and control group (n = 62, age: 49.8 years). An incremental cardiopulmonary exercise test was performed between 3 and 6 weeks after medical discharge from hospital. RESULTS: Higher peak oxygen uptake (VO2peak), ventilatory efficiency and power output were found in ICU patients with normal weight (NW) than in overweight (OW) (Mean difference: 0.1 L·min-1, -5.5, 29.0 W, respectively) and obese (OB) ICU patients (Mean difference: 0.1 L·min-1, -5.0, 26.2 W, respectively) (p < .05). In NW, OW and OB participants, higher VO2peak and power output were observed in control group compared with non-hospitalized (Mean difference: NW: 0.2 L·min-1, 83.3 W; OW: 0.2 L·min-1, 60.0 W; OB: 0.2 L·min-1, 70.9 W, respectively), hospitalized (Mean difference: NW: 0.2 L·min-1, 72.9 W; OW: 0.1 L·min-1, 58.3 W; OB: 0.2 L•min-1, 91.1 W, respectively) and ICU patients (Mean difference: NW: 0.1 L·min-1, 70.9 W; OW: 0.2 L·min-1, 91.1 W; OB: 0.3 L·min-1; 65.0 W, respectively) (p < .05). CONCLUSIONS: The degree of severity of COVID-19, especially identified by hospitalization and ICU stay, together with obesity and overweight were key factors in reducing cardiorespiratory fitness in patients with COVID-19.

Effectiveness of combined first-line medical treatment in acromegaly with prolactin cosecretion.

OBJECTIVE: The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA). DESIGN: This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment. METHODS: Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality. RESULTS: Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline. CONCLUSION: In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.

Differences between GH and PRL co-secreting and GH-secreting pituitary adenomas. A series of 604 cases.

PURPOSE: To evaluate differences in clinical presentation and in surgical outcomes between growth hormone-secreting pituitary adenomas (GH-PAs) and GH and prolactin co-secreting pituitary adenomas (GH&PRL-PAs). METHODS: Multicenter retrospective study of 604 patients with acromegaly submitted to pituitary surgery. Patients were classified into two groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal and IHC for GH and PRL was positive or PRL levels were >100ng/and PRL IHC was not available (n=130) and b) GH-PAs who did not meet the previously mentioned criteria (n=474). RESULTS: GH&PRL-PAs represented 21.5% (n=130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P<0.001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs. 77.4%, P=0.001) and tended to be more invasive (33.6% vs. 24.7%, P=0.057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (OR 2.8, 95% CI 1.83-4.38). IGF-1 upper limit of normality (ULN) levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [IQR 1.73-3.29] vs. 2.7 [IQR 1.91-3.67], P=0.023). There were no differences in the immediate (41.1% vs 43.3%, P=0.659) or long-term post-surgical acromegaly biochemical cure rate (53.5% vs. 53.1%, P=0.936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs. 2.4%, P=0.011) in GH&PRL-PAs patients. CONCLUSIONS: GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.

Effects of a telerehabilitation program and detraining on cardiorespiratory fitness in patients with post-COVID-19 sequelae: A randomized controlled trial.

BACKGROUND: This study aimed to evaluate the effects of a 15-week telerehabilitation program and a detraining period on cardiorespiratory fitness and mechanical efficiency in patients with post-COVID-19 sequelae. METHODS: 131 patients with post-COVID-19 sequelae were randomly assigned to one of two groups: patients who carried out the supervised telerehabilitation program (TRG, n = 66) and a control group (CG, n = 65). An incremental cardiopulmonary exercise testing (CPET) was performed on cycle ergometer to compare cardioventilatory responses between experimental groups. RESULTS: A significant increase in the CPET duration, peak power output, and mechanical efficiency was observed in TRG compared to CG after the telerehabilitation program (p ≤ 0.001). A significant increase in the CPET duration, peak power output, and mechanical efficiency was verified at 3 months compared to the pretest and after detraining in TRG (p < 0.001). A significant increase in peak oxygen uptake (V̇O2peak ) was identified after the intervention and in the detraining period compared to the pretest in both experimental groups (p < 0.001). A higher ventilatory efficiency was observed after the telerehabilitation program (p = 0.021) than in pretest only in TRG. CONCLUSIONS: A 15-week supervised home telerehabilitation program improved exercise capacity, power output, and mechanical efficiency in TRG compared to a CG. The telerehabilitation program was not more effective in improving V̇O2peak than the activities of the CG. However, ventilatory efficiency was improved only after the telerehabilitation program. The reported results after the detraining period highlight the need to maintain the rehabilitation program over time.

Effect of different types of supervised exercise programs on cardiorespiratory and muscular fitness, pain, fatigue, mental health and inflammatory and oxidative stress biomarkers in older patients with post-COVID-19 sequelae "EJerSA-COVID-19": a randomized controlled trial.

BACKGROUND: Many patients with COVID-19 present the so-called post-acute sequelae of COVID-19 such as fatigue, post-stress discomfort, dyspnea, headache, pain mental impairment, incapacity to perform daily physical tasks ant exercise intolerance. This study aims to investigate the effects of different exercise programs on physical and mental fitness, physical condition and biomarkers of the immune system and oxidative stress in older patients with post-COVID-19 sequelae. METHODS: The sample will be made up of 120 eligible participants, over the age of 60 years who have had COVID-19 disease and are survivors and present persistent COVID-19 symptomatology diagnosed by the corresponding physician. The participants will be randomly assigned to the experimental groups: supervised endurance group (SEG, n = 30), supervised strength group (SSG, n = 30), supervised concurrent group (SCG, n = 30), which will perform the corresponding exercise program 3 days a week compared to the control group (CG, n = 30), which will not carry out a supervised exercise program. The design of this project will include measurements of four relevant dimensions; 1) Cardiorespiratory fitness; 2) Muscle fitness; 3) Pain and mental health; and 4) Biomarkers of inflammation and oxidative stress. CONCLUSIONS: The results of this study will provide insights into the effects of different exercise programs on physical and mental fitness, physical condition and biomarkers of the immune system and oxidative stress in older patients with post-COVID-19 sequelae. These findings may be the basis for the formulation of health plans and rehabilitation programs that allow healthy aging and a reduction in the associated morbidity in patients with post-COVID-19 sequelae. TRIAL REGISTRATION: NCT05848518. Registered on May 8, 2023.

Maternal-fetal outcomes of pregnancies in women treated at an inborn errors of metabolism unit.

INTRODUCTION: Intermediate Inborn Errors of Metabolism (IEM) are a group of inherited diseases that include phenylketonuria (PKU), tyrosinemia II (TSII), organic acidaemias and ornithine transcarbamylase deficiency (OTCD), among others. They are increasingly more common in adults due to improved management. This has allowed more affected women to consider having children with good prospects. However, pregnancy may worsen metabolic control and/or increase maternal-fetal complications. The objective is to analyse the characteristics and outcomes of pregnancies of our patients with IEM. METHODS: Retrospective descriptive study. Pregnancies of women with IEM attended to at the adult IEM referral unit of the Hospital Universitario Virgen del Rocío were included. The qualitative variables were described as n(%) and the quantitative as P50 (P25-P75). RESULTS: 24 pregnancies were recorded: 12 newborns were healthy, 1 inherited their mother's disease, 2 had maternal phenylketonuria syndrome, 1 was stillborn (gestational week 31 + 5), 5 were spontaneous abortions and 3 were voluntarily terminated. The gestations were divided into metabolically controlled and uncontrolled. CONCLUSIONS: Pregnancy planning and multidisciplinary management through to postpartum is essential to ensure maternal and fetal health. The basis of treatment in PKU and TSII is a strict protein-limited diet. Events that increase protein catabolism in organic acidaemias and DOTC should be avoided. Further investigation of pregnancy outcomes in women with IEM is needed.

Fibroblast-derived EGF ligand neuregulin 1 induces fetal-like reprogramming of the intestinal epithelium without supporting tumorigenic growth.

Growth factors secreted by stromal fibroblasts regulate the intestinal epithelium. Stroma-derived epidermal growth factor (EGF) family ligands are implicated in epithelial regeneration and tumorigenesis, but their specific contributions and associated mechanisms remain unclear. Here, we use primary intestinal organoids modeling homeostatic, injured and tumorigenic epithelia to assess how the fibroblast-derived EGF family ligands neuregulin 1 (NRG1) and epiregulin (EREG) regulate the intestinal epithelium. NRG1 was expressed exclusively in the stroma, robustly increased crypt budding and protected intestinal epithelial organoids from radiation-induced damage. NRG1 also induced regenerative features in the epithelium, including a fetal-like transcriptome, suppression of the Lgr5+ stem cell pool and remodeling of the epithelial actin cytoskeleton. Intriguingly, unlike EGF and EREG, NRG1 failed to support the growth of pre-tumorigenic intestinal organoids lacking the tumor suppressor Apc, commonly mutated in human colorectal cancer (CRC). Interestingly, high expression of stromal NRG1 was associated with improved survival in CRC cohorts, suggesting a tumor-suppressive function. Our results highlight the power of stromal NRG1 in transcriptional reprogramming and protection of the intestinal epithelium from radiation injury without promoting tumorigenesis.

In vivo modulation of endogenous gene expression via CRISPR/Cas9-mediated 3'UTR editing.

The 3' untranslated regions (UTRs) modulate gene expression levels by regulating mRNA stability and translation. We previously showed that the replacement of the negative regulatory elements from the 3'UTR of glial cell line-derived neurotrophic factor (GDNF) resulted in increased endogenous GDNF expression while retaining its normal spatiotemporal expression pattern. Here, we have developed a methodology for the generation of in vivo hyper- and hypomorphic alleles via 3'UTR targeting using the CRISPR/Cas9 system. We demonstrate that CRISPR/Cas9-mediated excision of a long inhibitory sequence from Gdnf native 3'UTR in mouse zygotes increases the levels of endogenous GDNF with similar phenotypic alterations in embryonic kidney development as we described in GDNF constitutive and conditional hypermorphic mice. Furthermore, we show that CRISPR/Cas9-mediated targeting of 3'UTRs in vivo allows the modulation of the expression levels of two other morphogens, Gdf11 and Bdnf. Together, our work demonstrates the power of in vivo 3'UTR editing using the CRISPR/Cas9 system to create hyper- and hypomorphic alleles, suggesting wide applicability in studies on gene function and potentially, in gene therapy.

Tellu - an object-detector algorithm for automatic classification of intestinal organoids.

Intestinal epithelial organoids recapitulate many of the in vivo features of the intestinal epithelium, thus representing excellent research models. Morphology of the organoids based on light-microscopy images is used as a proxy to assess the biological state of the intestinal epithelium. Currently, organoid classification is manual and, therefore, subjective and time consuming, hampering large-scale quantitative analyses. Here, we describe Tellu, an object-detector algorithm trained to classify cultured intestinal organoids. Tellu was trained by manual annotation of >20,000 intestinal organoids to identify cystic non-budding organoids, early organoids, late organoids and spheroids. Tellu can also be used to quantify the relative organoid size, and can classify intestinal organoids into these four subclasses with accuracy comparable to that of trained scientists but is significantly faster and without bias. Tellu is provided as an open, user-friendly online tool to benefit the increasing number of investigations using organoids through fast and unbiased organoid morphology and size analysis.

Cognitive versus emotional modulation within a Stroop paradigm in patients with schizophrenia.

BACKGROUND: Schizophrenia is a complex disorder involving deficits in both cognitive and emotional processes. Specifically, a marked deficit in cognitive control has been found, which seems to increase when dealing with emotional information. AIMS: With the aim of exploring the possible common links behind cognitive and emotional deficits, two versions of the emotional Stroop task were administered. METHOD: In the cognitive-emotional task, participants had to name the ink colour (while ignoring the meaning) of emotional words. In contrast, the emotional-emotional task consisted of emotional words superimposed on emotional faces, and the participants had to indicate the emotional valence of the faces. Fifty-eight participants (29 in-patients diagnosed with schizophrenia and 29 controls) took part in the study. RESULTS: Patients and controls showed similar response times in the cognitive-emotional task; however, patients were significantly slower than controls in the emotional-emotional task. This result supports the idea that patients show a more pronounced impairment in conflict modulation with emotional content. Besides, no significant correlations between the tasks and positive or negative symptoms were found. This would indicate that deficits are relatively independent of the clinical status of patients. However, a significant correlation between the emotional-emotional task and cognitive symptoms was found. CONCLUSIONS: These findings suggest a restricted capacity of patients with schizophrenia to deal with the attentional demands arising from emotional stimuli.

Impaired pulmonary and muscle function during moderate exercise in female patients recovered from SARS-CoV-2.

This study aimed to assess pulmonary and muscle dysfunction by analyzing the slow component of oxygen uptake (VO2SC), and mechanical and ventilatory efficiency in adult women recovered from the severe acute respiratory syndrome coronavirus type II (SARS-CoV-2) during a constant load test. 32 women (N = 17 patients with SARS-CoV-2; N = 15 control group) performed two cardiopulmonary exercise tests (CPX) on a cycle ergometer. In the first test, the participants performed incremental CPX until extenuation. In the second test the participants performed a 10-min CPX at a constant load intensity (watts) corresponding to the first ventilatory threshold. There was a 48-72 h rest period between the two tests. There was a significant increase in the VO2SC in the patients recovered from SARS-CoV-2 (160.4 ± 60 mL min-1) in comparison with the healthy participants (59.6 ± 65 mL min-1) (P < 0.001). Mechanical efficiency significantly decreased in patients recovered from SARS-CoV-2 compared to the control group (P = 0.04). Ventilatory inefficiency significantly increased in the patients recovered from SARS-CoV-2 compared with the control group (P < 0.001). Adult women recovered from SARS-CoV-2 infection have important pulmonary and muscular dysfunction and fatigue which contributes to increasing the VO2SC and reducing mechanical and ventilatory efficiency during mild-moderate exercise at a constant load.

Bayesian reasoning with emotional material in patients with schizophrenia.

Delusions are one of the most classical symptoms described in schizophrenia. However, despite delusions are often emotionally charged, they have been investigated using tasks involving non-affective material, such as the Beads task. In this study we compared 30 patients with schizophrenia experiencing delusions with 32 matched controls in their pattern of responses to two versions of the Beads task within a Bayesian framework. The two versions of the Beads task consisted of one emotional and one neutral, both with ratios of beads of 60:40 and 80:20, considered, respectively, as the "difficult" and "easy" variants of the task. Results indicate that patients showed a greater deviation from the normative model, especially in the 60:40 ratio, suggesting that more inaccurate probability estimations are more likely to occur under uncertainty conditions. Additionally, both patients and controls showed a greater deviation in the emotional version of the task, providing evidence of a reasoning bias modulated by the content of the stimuli. Finally, a positive correlation between patients' deviation and delusional symptomatology was found. Impairments in the 60:40 ratio with emotional content was related to the amount of disruption in life caused by delusions. These results contribute to the understanding of how cognitive mechanisms interact with characteristics of the task (i.e., ambiguity and content) in the context of delusional thinking. These findings might be used to inform improved intervention programs in the domain of inferential reasoning.

Postoperative water and electrolyte disturbances after extended endoscopic endonasal transsphenoidal surgery.

Introduction: Water and electrolyte disturbances are common after pituitary surgery and can generally be classified into transient hypotonic polyuria and transient or permanent diabetes insipidus (DI). The prevalence varies in the literature between 31-51% for transient hypotonic polyuria, 5.1-25.2% for transient DI, and 1-8.8% for permanent DI. Objective: The aim of this study was to identify the prevalence of water and electrolyte disturbances with polyuria and the preoperative and postoperative predictive factors in patients undergoing surgery with an extended endoscopic endonasal approach. Material and methods: This retrospective observational descriptive study included 203 patients with a diagnosis of pituitary adenoma who underwent their first transsphenoidal surgery via the extended endoscopic endonasal approach between April 2013 and February 2020. The diagnosis of water and electrolyte disturbances was based on the criterion for polyuria (>4 ml/kg/h). Postoperative polyuria was defined as those cases diagnosed during the immediate postsurgical period that resolved prior to discharge. Transient DI included all cases with a duration of less than 6 months but still present at hospital discharge, and permanent DI included cases lasting more than 6 months. Results: The overall prevalence of water and electrolyte disorders was 30.5% (62), and the prevalence of postoperative polyuria was 23.6% (48). The median number of desmopressin doses administered to patients with postoperative polyuria was one dose (interquartile range [IQR] 1-2), and thus the median duration of treatment was 0 days. The median initiation of desmopressin was the second day after surgery (IQR 1-2). The overall prevalence of DI was 6.89%. Among the patients with transient DI, the duration was less than 3 months in three patients (1.47%), and between 3 and 6 months in two (0.98%). Nine patients had permanent DI (4.43%). (4.43%). Conclusions: The prevalence of electrolyte disturbances in our study was high, although similar to that found in the literature. Most of the cases were transient hypotonic polyuria that resolved within one day. The prevalence of transient DI in our cohort was lower than that described in the literature, while permanent DI was similar.

Inhibition of polyploidization in Pten-deficient livers reduces steatosis.

The tumour suppressor PTEN is a negative regulator of the PI3K/AKT signalling pathway. Liver-specific deletion of Pten in mice results in the hyper-activation PI3K/AKT signalling accompanied by enhanced genome duplication (polyploidization), marked lipid accumulation (steatosis) and formation of hepatocellular carcinomas. However, it is unknown whether polyploidization in this model has an impact on the development of steatosis and the progression towards liver cancer. Here, we used a liver-specific conditional knockout approach to delete Pten in combination with deletion of E2f7/8, known key inducers of polyploidization. As expected, Pten deletion caused severe steatosis and liver tumours accompanied by enhanced polyploidization. Additional deletion of E2f7/8 inhibited polyploidization, alleviated Pten-induced steatosis without affecting lipid species composition and accelerated liver tumour progression. Global transcriptomic analysis showed that inhibition of polyploidization in Pten-deficient livers resulted in reduced expression of genes involved in energy metabolism, including PPAR-gamma signalling. However, we find no evidence that deregulated genes in Pten-deficient livers are direct transcriptional targets of E2F7/8, supporting that reduction in steatosis and progression towards liver cancer are likely consequences of inhibiting polyploidization. Lastly, flow cytometry and image analysis on isolated primary wildtype mouse hepatocytes provided further support that polyploid cells can accumulate more lipid droplets than diploid hepatocytes. Collectively, we show that polyploidization promotes steatosis and function as an important barrier against liver tumour progression in Pten-deficient livers.

Can you change your mind? An ERP study of cognitive flexibility and new evidence integration.

Cognitive flexibility is an ability that allows individuals to integrate external evidence into previous expectancies. Individual differences in this ability were examined using Event-Related Potentials (ERPs), focusing on the fact that new evidence can either confirm or disprove an initial impression. Written scenarios prompted to make a prediction while either confirmatory or disconfirmatory evidence followed. A final sentence presented participants with a statement congruent with the prediction likely to have been formed based on the first statement or a statement rather congruent with corrective new evidence. A Bias Against Disconfirmatory Evidence (BADE) test rated participants in cognitive flexibility. ERPs revealed that whereas individuals overall typically reacted to unexpected endings (a classical N400 effect) within the confirmatory evidence condition, higher cognitive flexibility scores were associated with smaller N400 effects. Furthermore, individuals showed larger P600s for disconfirmatory than confirmatory evidence conditions, regardless of the final target ending. This result indexes reanalysis processes whenever disconfirmatory evidence was present. Regression analysis of BADE scores and ERP effects are presented and discussed. Late ERP components are sensitive enough to detect new evidence integration capabilities and thus provide a good implicit measure of cognitive flexibility.

Critical Thinking and Motivation in Vocational Training and Baccalaureate: A Comparison Study of Students of Spanish Nationality, Unaccompanied Foreign Minors and Young Care Leavers.

The present study analyzed academic motivation and its relationship with dispositions towards critical thinking in a sample of 131 students of Spanish nationality and 131 students of foreign nationality (unaccompanied foreign minors and foreign adolescents who had previously experienced the Andalusian care system). For this, an ex-post-facto study was conducted which was descriptive, comparative, and cross-sectional in nature. The main analyses carried out are of a descriptive and inferential nature, the latter to analyze the differences and associations between the variables of critical thinking and motivation (ANOVA test and an structural equations models) in both groups. Main outcomes included the lack of significant differences in dispositions towards critical thinking between Spanish and foreign students, alongside the existence of significant differences in academic motivation between both of these groups. In addition to this, significant differences were found within the group of Spanish nationality students in the dimensions of critical thinking as a function of intrinsic motivation, whilst such differences emerged in the foreign nationality group as a function of intrinsic and extrinsic motivation and amotivation. Finally, within the group of Spanish students, a significant and positive relationship was found between motivation and critical thinking, being positive and non-significant in the foreign national group. In conclusion, it is necessary to improve dispositions towards critical thinking and educational motivation from the educational system for the inclusion of minors and youths in today's society.

Characterizing Unaccompanied Foreign Minors: Educational Level and Length of Stay as Individual Difference Factors That Impact Academic Self-Efficacy.

The aim of the present study is to analyze individual differences in academic self-efficacy within a population of Unaccompanied Foreign Minors (UFM) from the European cities of Ceuta and Melilla (Spain). Variables describing educational level and length of stay were considered in a sample of 377 individuals being cared for in different youth centers. Of these, 63.4% belonged to the group who had stayed at the center for less than 9 months and 36.6% reported a length of stay of more than 9 months. The age of participants ranged between 8 and 17 years old (M = 14.87 years). Once the quality parameters of the instrument (academic self-efficacy) were elaborated, reliability and validity was confirmed through Confirmatory Factor Analysis (CFA) using Structural Equation Modeling (SEM) methodology. Data collection was then initiated. The results overall indicate that 87.6% of those who completed the questionnaire reported a higher level of self-efficacy with regards to working with any classmate, whilst at the same time seeing themselves as capable of achieving good marks. ANOVA results indicated significant differences with respect to educational level and length of stay. In this regard, students who had received professional training and had been at the Center for more than 9 months, were the ones who developed greater academic self-efficacy for spending more time working when tasks were judged to be difficult. The results obtained demonstrate that any intervention will be positive as long as it promotes different institutions to develop strategies that cater to a length of stay of more than 9 months and target education, academic self-efficacy, socialization and strengthening the future workforce. Such interventions can be directed through new European, Spanish or local level policies. It is clear that institutions still have a lot of work left to do.

Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease.

CONTEXT: Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse. OBJECTIVES: This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas. METHODS: A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years' follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery. RESULTS: Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001). CONCLUSION: This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.