Epicardial and liver fat implications in albuminuria: a retrospective study.

BACKGROUND: Albuminuria is considered an early and sensitive marker of kidney dysfunction, but also an independent cardiovascular risk factor. Considering the possible relationship among metabolic liver disease, cardiovascular disease and chronic kidney disease, we aimed to evaluate the risk of developing albuminuria regarding the presence of epicardial adipose tissue and the steatotic liver disease status. METHODS: A retrospective long-term longitudinal study including 181 patients was carried out. Epicardial adipose tissue and steatotic liver disease were assessed by computed tomography. The presence of albuminuria at follow-up was defined as the outcome. RESULTS: After a median follow up of 11.2 years, steatotic liver disease (HR 3.15; 95% CI, 1.20-8.26; p = 0.02) and excess amount of epicardial adipose tissue (HR 6.12; 95% CI, 1.69-22.19; p = 0.006) were associated with an increased risk of albuminuria after adjustment for visceral adipose tissue, sex, age, weight status, type 2 diabetes, prediabetes, hypertriglyceridemia, hypercholesterolemia, arterial hypertension, and cardiovascular prevention treatment at baseline. The presence of both conditions was associated with a higher risk of developing albuminuria compared to having steatotic liver disease alone (HR 5.91; 95% CI 1.15-30.41, p = 0.033). Compared with the first tertile of visceral adipose tissue, the proportion of subjects with liver steatosis and abnormal epicardial adipose tissue was significantly higher in the second and third tertile. We found a significant correlation between epicardial fat and steatotic liver disease (rho = 0.43 [p < 0.001]). CONCLUSIONS: Identification and management/decrease of excess adiposity must be a target in the primary and secondary prevention of chronic kidney disease development and progression. Visceral adiposity assessment may be an adequate target in the daily clinical setting. Moreover, epicardial adipose tissue and steatotic liver disease assessment may aid in the primary prevention of renal dysfunction.

Patient-reported outcome measures in severe asthma: an expert consensus.

OBJECTIVE: The study aimed to reach a consensus on the most relevant patient-reported outcomes (PROs), the corresponding measures (PROMs), and measurement frequency during severe asthma patient follow-up. METHODS: Two Delphi rounds were conducted. The questionnaire was developed based on a systematic literature review, a focus group with patients, and a nominal group with experts. It assessed PROs' relevance and the appropriateness (A) and feasibility (F) of PROMs using a Likert scale (1=totally agree; 9=totally disagree). The consensus was established when ≥75% of participants agreed (1-3) or disagreed (7-9). RESULTS: Sixty-three professionals (25 hospital pharmacists, 14 allergists, 13 pulmonologists, and 11 nurses) and 5 patients answered the Delphi questionnaire. A consensus was reached on all PROs regarding their relevance. Experts agreed on the use of ACT (A:95.24%; F:95.24%), mini AQLQ (A:93.65; F:79.37%), mMRC dyspnea scale (A:85.71%; F:85.71%), TAI (A:92.06%; F:85.71%), MMAS (A:75.40%; F:82%), and the dispensing register (A:96.83%; F:92.06%). Also considered suitable were: SNOT-22 (A:90.48%; F:73.80%), PSQI (A:82.54; F:63.90%), HADS (A:82.54; F:64%), WPAI (A:77.78%; F:49.20%), TSQM-9 (A:79.37; F:70.50%) and knowledge of asthma questionnaire (A:77%; F:68.80%); however, their use in clinical practice was considered unfeasible. Panelists also agreed on the appropriateness of EQ-5D, which was finally included despite being considered unfeasible (A: 84.13%; F:67.20%) in clinical practice. Agreement was reached on using ACT, TAI, mMRC, and a dispensing register every three months; mini-AQLQ and MMAS every six months; and EQ-5D every twelve months. CONCLUSION: This consensus paves the way toward patient-centered care, promoting the development of strategies supporting routine assessment of PROs in severe asthma management.

GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing.

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression Models (LRMs), we present a catalogue of 35 431 441 variants, including 89 178 SVs (≥50 bp), 30 325 064 SNVs and 5 017 199 indels, across 785 Illumina high coverage (30x) whole-genomes from the Iberian GCAT Cohort, containing a median of 3.52M SNVs, 606 336 indels and 6393 SVs per individual. The haplotype panel is able to impute up to 14 360 728 SNVs/indels and 23 179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with Mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.

Semen sEV tRF-Based Models Increase Non-Invasive Prediction Accuracy of Clinically Significant Prostate Cancer among Patients with Moderately Altered PSA Levels.

PSA screening has led to an over-diagnosis of prostate cancer (PCa) and unnecessary biopsies of benign conditions due to its low cancer specificity. Consequently, more accurate, preferentially non-invasive, tests are needed. We aim to evaluate the potential of semen sEV (small extracellular vesicles) tsRNAs (tRNA-derived small RNAs) as PCa indicators. Initially, following a literature review in the OncotRF database and high-throughput small RNA-sequencing studies in PCa tissue together with the sncRNA profile in semen sEVs, we selected four candidate 5'tRF tsRNAs for validation as PCa biomarkers. RT-qPCR analysis in semen sEVs from men with moderately elevated serum PSA levels successfully shows that the differential expression of the four tRFs between PCa and healthy control groups can be detected in a non-invasive manner. The combined model incorporating PSA and specific tRFs (5'-tRNA-Glu-TTC-9-1_L30 and 5'-tRNA-Val-CAC-3-1_L30) achieved high predictive accuracy in identifying samples with a Gleason score ≥ 7 and staging disease beyond IIA, supporting that the 5'tRF fingerprint in semen sEV can improve the PSA predictive value to discriminate between malignant and indolent prostate conditions. The in silico study allowed us to map target genes for the four 5'tRFs possibly involved in PCa. Our findings highlight the synergistic use of multiple biomarkers as an efficient approach to improve PCa screening and prognosis.

Assessing the Reliability, Dimensions, and Variance of Young's Internet Addiction Test by Applying it to Adolescents at the National Psychiatric Hospital in Costa Rica.

BACKGROUND: The Internet Addiction Test (IAT) was the first instrument created specifically to assess Internet addiction (IA). Although it was not validated during its creation, its validity has since been confirmed thanks to subsequent studies. The IAT is the first global psychometric measure tested worldwide that has been used in several studies as a research tool. Regarding the dimensions of the IAT, they were not reported by the creator of the test, during the performed factor analysis. Nonetheless, different studies have defined the test as being one-dimensional and others as having three, four, five, and six dimensions. METHODS: In the present study, seven dimensions were identified; however, there is still a lack of consensus about the number of dimensions that accurately define this test. RESULTS: Hence, Young's Internet Addiction Test presents a shortcoming that may be explained by the influence of several factors such as how it was applied, the place where it was applied, and the population to which it was applied. All of these are factors that could be linked to the sociocultural aspects of the adaptations that have been made to the test. CONCLUSIONS: Moreover, the first dimension of the IAT found, the loss of self-control, is extremely important because it explains 34% of the variance of the data. However, 74% of the variance is explained by applying the 7 dimensions identified in this research. Also, the reliability analysis showed that the IAT is 89% reliable, which indicates that the elements comprising the test used in this research are suitable for measuring the construct of Internet addiction.

Improved Speech Hearing in Noise with Invasive Electrical Brain Stimulation.

Speech perception in noise is a challenging everyday task with which many listeners have difficulty. Here, we report a case in which electrical brain stimulation of implanted intracranial electrodes in the left planum temporale (PT) of a neurosurgical patient significantly and reliably improved subjective quality (up to 50%) and objective intelligibility (up to 97%) of speech in noise perception. Stimulation resulted in a selective enhancement of speech sounds compared with the background noises. The receptive fields of the PT sites whose stimulation improved speech perception were tuned to spectrally broad and rapidly changing sounds. Corticocortical evoked potential analysis revealed that the PT sites were located between the sites in Heschl's gyrus and the superior temporal gyrus. Moreover, the discriminability of speech from nonspeech sounds increased in population neural responses from Heschl's gyrus to the PT to the superior temporal gyrus sites. These findings causally implicate the PT in background noise suppression and may point to a novel potential neuroprosthetic solution to assist in the challenging task of speech perception in noise.SIGNIFICANCE STATEMENT Speech perception in noise remains a challenging task for many individuals. Here, we present a case in which the electrical brain stimulation of intracranially implanted electrodes in the planum temporale of a neurosurgical patient significantly improved both the subjective quality (up to 50%) and objective intelligibility (up to 97%) of speech perception in noise. Stimulation resulted in a selective enhancement of speech sounds compared with the background noises. Our local and network-level functional analyses placed the planum temporale sites in between the sites in the primary auditory areas in Heschl's gyrus and nonprimary auditory areas in the superior temporal gyrus. These findings causally implicate planum temporale in acoustic scene analysis and suggest potential neuroprosthetic applications to assist hearing in noise.

3'IsomiR Species Composition Affects Reliable Quantification of miRNA/isomiR Variants by Poly(A) RT-qPCR: Impact on Small RNA-Seq Profiling Validation.

Small RNA-sequencing (small RNA-seq) has revealed the presence of small RNA-naturally occurring variants such as microRNA (miRNA) isoforms or isomiRs. Due to their small size and the sequence similarity among miRNA isoforms, their validation by RT-qPCR is challenging. We previously identified two miR-31-5p isomiRs-the canonical and a 3'isomiR variant (3' G addition)-which were differentially expressed between individuals with azoospermia of different origin. Here, we sought to determine the discriminatory capacity between these two closely-related miRNA isoforms of three alternative poly(A) based-RT-qPCR strategies in both synthetic and real biological context. We found that these poly(A) RT-qPCR strategies exhibit a significant cross-reactivity between these miR-31-5p isomiRs which differ by a single nucleotide, compromising the reliable quantification of individual miRNA isoforms. Fortunately, in the biological context, given that the two miRNA variants show changes in the same direction, RT-qPCR results were consistent with the findings of small RNA-seq study. We suggest that miRNA selection for RT-qPCR validation should be performed with care, prioritizing those canonical miRNAs that, in small RNA-seq, show parallel/homogeneous expression behavior with their most prevalent isomiRs, to avoid confounding RT-qPCR-based results. This is suggested as the current best strategy for robust biomarker selection to develop clinically useful tests.

Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.

Potential negative pharmacodynamic interaction of spironolactone and abiraterone in two prostate cancer patients.

INTRODUCTION: Spironolactone when combined with abiraterone in metastatic castration-resistant prostate cancer (mCRPC) may theoretically exert androgenic properties, thereby compromising the therapeutic effectiveness of abiraterone. CASE REPORT: Two patients with a medical history of cardiovascular disease and mCRPC combined spironolactone within the course of abiraterone regimen. The abiraterone-spironolactone interaction was identified using the Lexicomp® interaction tool (classified as risk C). MANAGEMENT & OUTCOME: Spironolactone treatment was maintained as it was considered beneficial due to the cardiac condition. The prostate-specific antigen (PSA) levels started to rise when these two drugs were used together. Eventually, tumour progression was observed. DISCUSSION: There is increasing evidence that spironolactone behaves as a selective androgen receptor modulator. Strategies to overcome abiraterone-spironolactone interaction could involve the use of eplerenone, although this drug is also controversial. The best strategy should imply a multidisciplinary evaluation by cardiologists and oncologists.

Evaluation of the quality of multiple-choice questions according to the students' academic level.

BACKGROUND: One of the most important challenges in medical education is the preparation of multiple-choice questions able to discriminate between students with different academic level. Average questions may be very easy for students with good performance, reducing their discriminant power in this group of students. The aim of this study was to analyze if the discriminative power of multiple-choice questions is different according to the students' academic performance. METHODS: We retrospectively analyzed the difficulty and discrimination indices of 257 multiple-choice questions used for the end of course examination of pathophysiology and analyzed whether the discrimination indices were lower in students with good academic performance (group 1) than in students with moderate/poor academic performance (group 2). We also evaluated whether case-based questions maintained their discriminant power better than factual questions in both groups of students or not. Comparison of the difficulty and discrimination indices between both groups was based on the Wilcoxon test. RESULTS: Difficulty index was significantly higher in group 1 (median: 0.78 versus 0.56; P <  0.001) and discrimination index was significantly higher in group 2 (median: 0.21 versus 0.28; P <  0.001). Factual questions had higher discriminative indices in group 2 than in group 1 (median: 0.28 versus 0.20; P <  0.001), but discriminative indices of case-based questions did not differ significantly between groups (median: 0.30 versus 0.24; P = 0.296). CONCLUSIONS: Multiple-choice question exams have lower discriminative power in the group of students with high scores. The use of clinical vignettes may allow to maintain the discriminative power of multiple-choice questions.

Paired-end small RNA sequencing reveals a possible overestimation in the isomiR sequence repertoire previously reported from conventional single read data analysis.

BACKGROUND: Next generation sequencing has allowed the discovery of miRNA isoforms, termed isomiRs. Some isomiRs are derived from imprecise processing of pre-miRNA precursors, leading to length variants. Additional variability is introduced by non-templated addition of bases at the ends or editing of internal bases, resulting in base differences relative to the template DNA sequence. We hypothesized that some component of the isomiR variation reported so far could be due to systematic technical noise and not real. RESULTS: We have developed the XICRA pipeline to analyze small RNA sequencing data at the isomiR level. We exploited its ability to use single or merged reads to compare isomiR results derived from paired-end (PE) reads with those from single reads (SR) to address whether detectable sequence differences relative to canonical miRNAs found in isomiRs are true biological variations or the result of errors in sequencing. We have detected non-negligible systematic differences between SR and PE data which primarily affect putative internally edited isomiRs, and at a much smaller frequency terminal length changing isomiRs. This is relevant for the identification of true isomiRs in small RNA sequencing datasets. CONCLUSIONS: We conclude that potential artifacts derived from sequencing errors and/or data processing could result in an overestimation of abundance and diversity of miRNA isoforms. Efforts in annotating the isomiRnome should take this into account.

Functional characterization of human Heschl's gyrus in response to natural speech.

Heschl's gyrus (HG) is a brain area that includes the primary auditory cortex in humans. Due to the limitations in obtaining direct neural measurements from this region during naturalistic speech listening, the functional organization and the role of HG in speech perception remain uncertain. Here, we used intracranial EEG to directly record neural activity in HG in eight neurosurgical patients as they listened to continuous speech stories. We studied the spatial distribution of acoustic tuning and the organization of linguistic feature encoding. We found a main gradient of change from posteromedial to anterolateral parts of HG. We also observed a decrease in frequency and temporal modulation tuning and an increase in phonemic representation, speaker normalization, speech sensitivity, and response latency. We did not observe a difference between the two brain hemispheres. These findings reveal a functional role for HG in processing and transforming simple to complex acoustic features and inform neurophysiological models of speech processing in the human auditory cortex.

Inducing neuroplasticity through intracranial θ-burst stimulation in the human sensorimotor cortex.

The progress of therapeutic neuromodulation greatly depends on improving stimulation parameters to most efficiently induce neuroplasticity effects. Intermittent θ-burst stimulation (iTBS), a form of electrical stimulation that mimics natural brain activity patterns, has proved to efficiently induce such effects in animal studies and rhythmic transcranial magnetic stimulation studies in humans. However, little is known about the potential neuroplasticity effects of iTBS applied through intracranial electrodes in humans. This study characterizes the physiological effects of intracranial iTBS in humans and compare them with α-frequency stimulation, another frequently used neuromodulatory pattern. We applied these two stimulation patterns to well-defined regions in the sensorimotor cortex, which elicited contralateral hand muscle contractions during clinical mapping, in patients with epilepsy implanted with intracranial electrodes. Treatment effects were evaluated using oscillatory coherence across areas connected to the treatment site, as defined with corticocortical-evoked potentials. Our results show that iTBS increases coherence in the ß-frequency band within the sensorimotor network indicating a potential neuroplasticity effect. The effect is specific to the sensorimotor system, the ß band, and the stimulation pattern and outlasted the stimulation period by ∼3 min. The effect occurred in four out of seven subjects depending on the buildup of the effect during iTBS treatment and other patterns of oscillatory activity related to ceiling effects within the ß band and to preexistent coherence within the α band. By characterizing the neurophysiological effects of iTBS within well-defined cortical networks, we hope to provide an electrophysiological framework that allows clinicians/researchers to optimize brain stimulation protocols which may have translational value.NEW & NOTEWORTHY θ-Burst stimulation (TBS) protocols in transcranial magnetic stimulation studies have shown improved treatment efficacy in a variety of neuropsychiatric disorders. The optimal protocol to induce neuroplasticity in invasive direct electrical stimulation approaches is not known. We report that intracranial TBS applied in human sensorimotor cortex increases local coherence of preexistent ß rhythms. The effect is specific to the stimulation frequency and the stimulated network and outlasts the stimulation period by ∼3 min.

Effects of two personalized dietary strategies during a 2-year intervention in subjects with nonalcoholic fatty liver disease: A randomized trial.

BACKGROUND AND OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) management is focused on lifestyle modifications, but long-term maintenance is a challenge for many individuals. This study aimed to evaluate the long-term effects of two personalized energy-restricted dietary strategies on weight loss, metabolic and hepatic outcomes in overweight/obese subjects with NAFLD. METHODS: Ninety-eight subjects from the Fatty Liver in Obesity (FLiO) study (NCT03183193) were randomly assigned to the American Heart Association (AHA) or the FLiO dietary group in a 2-year controlled trial. Anthropometry, body composition (DXA), biochemical parameters and hepatic status (ultrasonography, Magnetic Resonance Imaging, and elastography) were assessed at baseline, 6, 12 and 24 months. RESULTS: Both the AHA and FLiO diets significantly reduced body weight at 6 (-9.7% vs -10.1%), 12 (-6.7% vs -9.6%), and 24 months (-4.8% vs -7.6%) with significant improvements in body composition, biochemical and liver determinations throughout the intervention. At the end of the follow-up, the FLiO group showed a greater decrease in ALT, liver stiffness and Fatty Liver Index, among others, compared to AHA group, although these differences were attenuated when the analyses were adjusted by weight loss percentage. The FLiO group also showed a greater increase in adiponectin compared to AHA group. CONCLUSIONS: The AHA and FLiO diets were able to improve body weight and body composition, as well as metabolic and hepatic status of participants with overweight/obesity and NAFLD within a 2-year follow-up. These findings show that both strategies are suitable alternatives for NAFLD management. However, the FLiO strategy may provide more persistent benefits in metabolic and hepatic parameters.

Fewer COVID-19-associated strokes and reduced severity during the second COVID-19 wave: The Madrid Stroke Network.

BACKGROUND AND PURPOSE: The experience gained during the first COVID-19 wave could have mitigated the negative impact on stroke care in the following waves. Our aims were to analyze the characteristics and outcomes of patients with stroke admitted during the second COVID-19 wave and to evaluate the differences in the stroke care provision compared with the first wave. METHODS: This retrospective multicenter cohort study included consecutive stroke patients admitted to any of the seven hospitals with stroke units (SUs) and endovascular treatment facilities in the Madrid Health Region. The characteristics of the stroke patients with or without a COVID-19 diagnosis were compared and the organizational changes in stroke care between the first wave (25 February to 25 April 2020) and second wave (21 July to 21 November 2020) were analyzed. RESULTS: A total of 550 and 1191 stroke patients were admitted during the first and second COVID-19 waves, respectively, with an average daily admission rate of nine patients in both waves. During the second wave, there was a decrease in stroke severity (median National Institutes of Health Stroke Scale 5 vs. 6; p = 0.000), in-hospital strokes (3% vs. 8.1%) and in-hospital mortality (9.9% vs. 15.9%). Furthermore, fewer patients experienced concurrent COVID-19 (6.8% vs. 19.1%), and they presented milder COVID-19 and less severe strokes. Fewer hospitals reported a reduction in the number of SU beds or deployment of SU personnel to COVID-19 dedicated wards during the second wave. CONCLUSIONS: During the second COVID-19 wave, fewer stroke patients were diagnosed with COVID-19, and they had less stroke severity and milder COVID-19.

Liver transplant recipients have an increased risk of developing colorectal adenomas: Results from a retrospective study.

BACKGROUND: Liver transplant recipients have an increased incidence of malignancies, but it is unclear whether they have a higher risk of colorectal cancer. AIM: To investigate whether liver transplant recipients have an increased risk of developing colorectal adenomas (a surrogate marker of colorectal cancer risk). PATIENTS AND METHODS: One hundred thirty-nine liver transplant recipients (excluding primary sclerosing cholangitis) who underwent a colonoscopy and polypectomy before and after transplantation, and 367 nontransplanted patients who underwent a colonoscopy for colorectal cancer screening and a second colonoscopy later were retrospectively studied. The risks of incident colorectal adenomas and high-risk adenomas (advanced or multiple adenomas or carcinomas) were compared between both cohorts. RESULTS: Incident colorectal adenomas were found in 40.3% of the transplanted patients and 30.0% of the nontransplanted patients (15.1% and 5.5%, respectively, had high-risk adenomas). After adjusting for age, sex, presence of adenomas in the baseline endoscopy, and interval between colonoscopies, transplant recipients showed a higher risk of developing colorectal adenomas (OR: 1.61; 95% CI: 1.05-2.47; p = .03) and high-risk adenomas (OR: 2.87; 95% CI: 1.46-5.65; p = .002). CONCLUSIONS: Our results suggest that liver transplant recipients have an increased risk of developing colorectal adenomas and lesions with high risk of colorectal cancer.

Differential response to a 6-month energy-restricted treatment depending on SH2B1 rs7359397 variant in NAFLD subjects: Fatty Liver in Obesity (FLiO) Study.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is worldwide recognized as the most common cause of chronic liver disease. Current NAFLD clinical management relies on lifestyle change, nevertheless, the importance of the genetic make-up on liver damage and the possible interactions with diet are still poorly understood. The aim of the study was to evaluate the influence of the SH2B1 rs7359397 genetic variant on changes in body composition, metabolic status and liver health after 6-month energy-restricted treatment in overweight/obese subjects with NAFLD. In addition, gene-treatment interactions over the course of the intervention were examined. METHODS: The SH2B1 genetic variant was genotyped in 86 overweight/obese subjects with NAFLD from the FLiO study (Fatty Liver in Obesity study). Subjects were metabolically evaluated at baseline and at 6-months. Liver assessment included ultrasonography, Magnetic Resonance Imaging, elastography, a lipidomic test (OWL®-test) and specific blood liver biomarkers. Additionally, body composition, general biochemical markers and dietary intake were determined. RESULTS: Both genotypes significantly improved their body composition, general metabolic status and liver health after following an energy-restricted strategy. Liver imaging techniques showed a greater decrease in liver fat content (- 44.3%, p < 0.001) and in serum ferritin levels (p < 0.001) in the carriers of the T allele after the intervention. Moreover, lipidomic analysis, revealed a higher improvement in liver status when comparing risk vs. no-risk genotype (p = 0.006 vs. p = 0.926, respectively). Gene-treatment interactions showed an increase in fiber intake and omega-3 fatty acid in risk genotype (p interaction = 0.056 and p interaction = 0.053, respectively), while a significant increase in MedDiet score was observed in both genotype groups (p = 0.020). Moreover, no-risk genotype presented a relevant decrease in hepatic iron as well as in MUFA intake (p = 0.047 and p = 0.034, respectively). CONCLUSION: Subjects carrying the T allele of the rs7359397 polymorphism may benefit more in terms of hepatic health and liver status when prescribed an energy-restricted treatment, where a Mediterranean dietary pattern rich in fiber and other components such as omega-3 fatty acids might boost the benefits. TRIAL REGISTRATION: The Fatty Liver in Obesity was approved by the Research Ethics Committee of the University of Navarra and retrospectively registered (NCT03183193; www.clinicaltrials.gov ); June 2017.

Dietary intake of specific amino acids and liver status in subjects with nonalcoholic fatty liver disease: fatty liver in obesity (FLiO) study.

PURPOSE: Identification of dietary factors involved in the development and progression of nonalcoholic fatty liver disease (NAFLD) is relevant to the current epidemics of the disease. Dietary amino acids appear to play a key role in the onset and progression of NAFLD. The aim of this study was to analyze potential associations between specific dietary amino acids and variables related to glucose metabolism and hepatic status in adults with overweight/obesity and NAFLD. METHODS: One hundred and twelve individuals from the Fatty Liver in Obesity (FLiO) study were evaluated. Liver assessment was carried out by ultrasonography, magnetic resonance imaging and analysis of biochemical parameters. Dietary amino acid intake (aromatic amino acids (AAA); branched-chain amino acids (BCAA); sulfur amino acids (SAA)) was estimated by means of a validated 137-item food frequency questionnaire. RESULTS: Higher consumption of these amino acids was associated with worse hepatic health. Multiple adjusted regression models confirmed that dietary AAA, BCAA and SAA were positively associated with liver fat content. AAA and BCAA were positively associated with liver iron concentration. Regarding ferritin levels, a positive association was found with BCAA. Dietary intake of these amino acids was positively correlated with glucose metabolism (glycated hemoglobin, triglyceride and glucose index) although the significance disappeared when potential confounders were included in the model. CONCLUSION: These findings suggest that the consumption of specific dietary amino acids might negatively impact on liver status and, to a lesser extent on glucose metabolism in subjects with overweight/obesity and NAFLD. A control of specific dietary amino acid composition should be considered in the management of NAFLD and associated insulin resistance. NCT03183193; June 2017.

Assessment of diarrhea as side effect of oral targeted antineoplastic agents in clinical practice.

BACKGROUND: Diarrhea is one of the most frequent class adverse events associated with targeted oral antineoplastic agents (OAAs). Our objective was to analyze the incidence, characteristics, and severity of diarrhea in cancer patients in clinical practice. METHODS: An observational, longitudinal, and prospective study of cancer outpatients treated with targeted OAAs was carried out in a tertiary hospital. Targed OAAs analyzed were anaplastic lymphoma kinase inhibitors, BCR-ABL inhibitors, cyclin-dependent kinase inhibitors, epidermal growth factor receptor inhibitors, mTOR inhibitors, poly (ADP-ribose) polymerase inhibitors, and vascular endothelial growth factor receptor inhibitors. Patients were given a data collection form to record daily the number, severity (CTCAE version 5.0), and characteristics of stools during the first 30 days of treatment with OAAs. Multivariate analysis was performed to identify risk factors associated with the incidence of diarrhea. RESULTS: We analyzed 240 patients, of whom 28.7% experienced diarrhea (25.4% grades 1-2 and 3.3% grades 3-4). Patients treated with EGFR and VEGFR inhibitors had a higher incidence of diarrhea. The multivariate analysis revealed that taking the OAA with food was associated with a lower risk of diarrhea (OR = 0.404 [0.205-0.956], p = 0.038). CONCLUSIONS: More than a third of patients in treatment with OAAs presented diarrhea (any grade), and 22.1% of stools were semi-liquid/liquid. In multivariate analysis, taking the OAA on an empty stomach was associated with a statistically significant increase in the incidence of diarrhea.

Tocilizumab as salvage treatment of refractory pulmonary acute graft-versus-host disease.

INTRODUCTION: Acute graft-versus-host disease GVHD (aGVHD) is the main complication during the first months after bone transplantation. Steroid therapy is clearly the upfront established treatment for aGVHD. However, there are patients with partial response to steroid treatment and steroid-refractory cases. For those patients, a vast number of therapeutic options have emerged, although the evidence is scarce. CASE REPORT: We report the use of tocilizumab as salvage treatment in a patient with corticosteroid refractory pulmonary aGVHD that was admitted to the critical care unit for respiratory support measures. MANAGEMENT & OUTCOME: We decided to use tocilizumab as rescue treatment, after failure of corticosteroid treatment, standard treatment with broad-spectrum antibiotics and etanercept. The patient showed a remarkable clinical improvement two days after first infusion and a total resolution of the symptomatology with normalization of the spirometry tests after 4 weeks of the administration of tocilizumab. DISCUSSION: To the authors' knowledge, this is the first case that describes the effective and safe use of tocilizumab as a rescue treatment in a patient with steroid-refractory pulmonary aGVHD. It showed a rapid onset of action and a favorable safety profile, which could make it an interesting option for the treatment of this potentially fatal complication.