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Summary: Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, −0.03 to 0.12], −0.02 [95% CI, −0.09 to 0.06], and −0.03 [95% CI, −0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).

Summary: Background: Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers. Methods: We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540. Findings: From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52–1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53–1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57–1·04]). Interpretation: In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting. Funding: COALITION COVID-19 Brazil and EMS.

Introduction: The current methods of preserving donor kidneys in nonoxygenated cold conditions minimally protect the kidney against ischemia-reperfusion injury (IRI), a major source of complications in clinical transplantation. However, preserving kidneys with oxygenated perfusion is not currently feasible due to the lack of an ideal perfusion mechanism that facilitates perfusion with blood at warm temperature. Here, we have designed an innovative renal pump circuit system that can perfuse blood or acellular oxygen carrier under flexible temperatures, pressures, and oxygenation. We have tested this apparatus to study optimal conditions of storage of our porcine model of donation after cardiac death (DCD) kidneys. Methods: Porcine kidneys were retrieved after 30 minutes of cross-clamping renal pedicles in situ. Cessation of blood mimics postcardiac death in humans and simulates DCD warm ischemic injury. Procured kidneys were flushed and subjected to static cold storage (SCS) for 4 hours. For warm perfusion, kidneys were cannulated for pulsatile oxygenated perfusion with blood:PlasmaLyte for 4 hours at 15 °C, 22 °C, and 37 °C. To mimic posttransplant scenario, all kidneys were reperfused with blood for an additional 4 hours at 37 °C. Results: Compared with all other groups, 22 °C perfusion resulted in significant reduction of acute tubular necrosis (ATN), apoptosis, kidney damage markers, Toll-like receptor signaling, and cytokine production. It was associated with maximal renal blood flow and urine output. Kidneys stored at 15 °C thrombosed within 2 hours under this condition. Martius Scarlet Blue staining confirmed that 22 °C was the optimal temperature to minimize hemorrhage and blood clots. Conclusion: Our novel study shows that oxygenated perfusion at near-room-temperature provides optimal donor kidney storage conditions. Keywords: donation after cardiac death, ischemia-reperfusion injury, kidney transplantation, oxygenated perfusion, prolonged storage, subnormothermia

Argentina is one of the main producers and exporters of grains and oilseeds, ranking third in soybean exports and fourth in barley ones. The 90% of this production occurs within the Argentine Pampas region (APR) under rainfed conditions, but its water consumption and pollution has not been studied in depth. Likewise, the link between soil moisture (SM) and Water Footprint (WF) generation is poorly studied at the global level. And yet, SM is a critical factor for the development of rainfed crops. This study aims to evaluate, at plot scale, the role of SM in the generation of the green (WFgreen) and grey (WFgrey) (WF). Additionally, it estimates the WF for rainfed barley and soybean crops in the Southeast of APR, where there are no reference values. Yields, water consumption and nitrogen (N) pollution load were estimated for different campaigns. Field data (weather, crop and production management) recorded in the study plots were used. Results indicated an average WFgreen of 1236 m3/t for soybeans and a WFgreen of 349 m3/t and WFgrey of 547 m3/t for barley. The study highlights the critical role of SM in both WF sub-indicators. Soil water availability, based on the evaporative fraction during critical growth stages, influenced yields and final WFgreen volumes. In addition, there was an effect on N uptake by crops. In the driest barley campaign, WFgrey increased by 234%. Insufficient SM restricted nutrient uptake, reducing yields and increasing N with the potential to leach or runoff. Consequently, it is suggested to adjust the WFgrey methodology incorporating SM fluctuations and unaccounted N losses. The study contributes to understand the WF drivers and highlights the need to assess them accurately. In particular, it aims to reduce the gaps surrounding the water consumption of rainfed crops, thereby supporting resource conservation and grain provisioning efforts.

The levels of polycyclic aromatic hydrocarbons, PAHs, were determined in the liver and salt gland of 19 loggerhead turtles (Caretta caretta Linnaeus, Cheloniidae) stranded along the coasts of the south Tyrrhenian Sea, Italy, from 2019 to 2021. The 16 EPA’s priority PAHs were determined by gas chromatography coupled with mass spectrometry (GC-MS). The average values of ΣPAHs in liver, 139 ± 55.0, were exceptionally high and up to one hundred times those of literature and appeared even more worrying in salt gland, 320 ± 97.6 ng/g, w.w. Naphthalene was the predominant contributor to PAHs richness and accounted for 90.0% and 93.7% of ΣPAHs in the two matrices, highlighting the petrogenic source of exposure. An overall higher bioaccumulation of NAP, more than two-fold, was detected in salt gland and especially in female and adults. Data of PAHs richness highlighted a potential risk of neoplastic disease development and that anthropogenic activities may seriously impair healthy state conditions of C. caretta. populations in south Tyrrhenian Sea.

Summary: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) is recommended in revascularization guidelines for intermediate lesions. However, recent studies comparing FFR-guided PCI with non-physiology-guided revascularization have reported conflicting results. PubMed and Embase were searched for studies comparing FFR-guided PCI with non-physiology-guided revascularization strategies (angiography-guided, intracoronary imaging-guided, coronary artery bypass grafting). Data were pooled by meta-analysis using random-effects model. 26 studies enrolling 78,897 patients were included. FFR-guided PCI as compared to non-physiology-guided coronary revascularization had lower risk of all-cause mortality (odds ratio [OR] 0.79 95% confidence interval [CI] 0.64–0.99, I2 = 53%) and myocardial infarction (MI) (OR 0.74 95% CI 0.59–0.93, I2 = 44.7%). However, no differences between groups were found in terms of major adverse cardiac events (MACEs) (OR 0.86 95% CI 0.72–1.03, I2 = 72.3%) and repeat revascularization (OR 1 95% CI 0.82–1.20, I2 = 43.2%). Among patients with coronary artery disease (CAD), FFR-guided PCI as compared to non-physiology-guided revascularization was associated with a lower risk of all-cause mortality and MI.

Background: the different lockdown phases due to COVID-19 may have negatively impacted pregnant women's mental health. Concerning antenatal stress, most studies focused more on the effect of pandemic onset than on the impact of the following phases and restrictions. Aim: the present study aimed to assess levels of anxiety and depression in a group of Italian pregnant women during the second COVID-19 phase and possible risk factors. Method: We recruited 156 pregnant women through our Perinatal Psychology Outpatient Clinic. We divided the sample into women recruited before the pandemic (N = 88) through a face-to-face antenatal class and pregnant women recruited during the second lockdown (Covid-19 study group) (November 2020–April 2021) through the same antenatal class via Skype (N = 68). To investigate depressive and anxiety symptoms, we administered the Edinburgh Postnatal Depression Scale (EPDS) and the State and Trait Anxiety Inventory (STAI-Y) scales; women's medical history and obstetric data were collected. Findings: women belonging to the Covid-19 study group reported higher depressive and anxious levels than the pre-pandemic group. Moreover, during the second lockdown previous psychopathology and being close to childbirth were related to increased depression; a history of abortion was related to higher levels of trait anxiety instead. Conclusion: recurrent restrictive measures due to COVID-19 negatively affected the antenatal mental well-being of pregnant women, particularly worsening depressive and anxious feelings. Pregnant women during the pandemic represented a vulnerable population to be monitored more closely and timely to prevent psychological problems in the postpartum period and their consequences on the child. Keywords: anxiety, depression, pregnancy, COVID-19, mental health, lockdown.

Summary: Background: COVID-19 progression is associated with an increased risk of arterial and venous thrombosis. Randomised trials have demonstrated that anticoagulants reduce the risk of thromboembolism in hospitalised patients with COVID-19, but a benefit of routine anticoagulation has not been demonstrated in the outpatient setting. Methods: We conducted a randomised, open-label, controlled, multicentre study, evaluating the use of rivaroxaban in mild or moderate COVID-19 patients. Adults ≥18 years old, with probable or confirmed SARS-CoV-2 infection, presenting within ≤7 days from symptom onset with no clear indication for hospitalization, plus at least 2 risk factors for complication, were randomised 1:1 either to rivaroxaban 10 mg OD for 14 days or to routine care. The primary efficacy endpoint was the composite of venous thromboembolic events, need of mechanical ventilation, acute myocardial infarction, stroke, acute limb ischemia, or death due to COVID-19 during the first 30 days. ClinicalTrials.gov: NCT04757857. Findings: Enrollment was prematurely stopped due to sustained reduction in new COVID-19 cases. From September 29th, 2020, through May 23rd, 2022, 660 patients were randomised (median age 61 [Q1-Q3 47–69], 55.7% women). There was no significant difference between rivaroxaban and control in the primary efficacy endpoint (4.3% [14/327] vs 5.8% [19/330], RR 0.74; 95% CI: 0.38–1.46). There was no major bleeding in the control group and 1 in the rivaroxaban group. Interpretation: On light of these findings no decision can be made about the utility of rivaroxaban to improve outcomes in outpatients with COVID-19. Metanalyses data provide no evidence of a benefit of anticoagulant prophylaxis in outpatients with COVID-19. These findings were the result of an underpowered study, therefore should be interpreted with caution. Funding: COALITION COVID-19 Brazil and Bayer S.A.

Background: Bulk milk samples from 69 dairy buffalo farms of the Campania Region, Italy were drawn for the determination of 20 selected elements by ICP-MS. The main goal was to ascertain how the agricultural soil geo-chemistry could influence the milk pattern with respect to feeding practices. Methods: Local forages (N = 207) and groundwater (N = 486) were analyzed too to recover the feeding-to-milk carry-over rates (COR) of selected elements and identify the main contributors to milk contamination. Left censored data >10% limited to 11 elements (Mn, As, Se, Sr, Zn, Cr, Fe, Co, Ni, Cu, and V) the multivariate system approach based on cluster and factor analysis. Results: We identified 8/11 elements - Sr, Mn, Zn, Co, Se, Cr, Fe, and V - explaining the main quote of variation observed among farms milk pattern. In particular, Co resulted as discriminant for specific villages of the Salerno Province. On median values, cereals (34%) and feed supplement (31%) represented the main contributors to Cr intake; for V, hay (46%) and water (42%); for Fe, water (46%); for Se, Co and Zn, mineral supplements (67; 73; 82%); for Sr, hay (71%), for Mn, mineral supplements (36%) and water (30%). Median CORs rates (%) were the following: Se and Cr: 40; V: 13; Mn: 5.2; Sr: 4.7; Zn: 3.7; Co: 3.4; Fe: 1.6; respectively. Conclusion: The factor analysis could trace the geographical origin of buffalo milk at farm level, according to similar management practices, partially irrespective of the municipality/province level.

Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007.

Background: The evaluation of environmental exposure risk requires a global analysis of pollution phenomena, including biological effects and potentially correlated clinical outcomes in susceptible populations. Although human biomonitoring plays a fundamental role in assessing the degree of contamination, it is not effective alone in identifying a direct link between exposure, biomolecular effects and outcomes on target organisms. While toxicogenomics and epidemiology are mainly focused on the investigation of molecular reactions and clinical outcomes, the monitoring of environmental matrices works independently to characterize the territorial distribution of toxic compounds, without proving any correlated health risk for residents. Objectives: We propose a new biomonitoring model based on a whole systemic analytical evaluation of environmental context. The paradigm of the method consists of identifying the sources of pollution, the migration pathways of those pollutants and their effects on target organisms. By means of this innovative, holistic epidemiological approach, we included healthy human subjects in a cohort to identify potential risks of exposure and predict possible correlated clinical outcomes. 4205 residents of the Campania region were enrolled in the “SPES” biomonitoring study, which especially focused on the areas dubbed “Land of Fires” in the recent decades. Discussion: The analysis of environmental exposure risk suffers the lack of data integration from various science fields, and this comes down to a limited point of view and a limited knowledge of phenomena.In implementing our model, we first constructed an analytical picture of the Real-world situation. We next conducted a comparative risk assessment, in order to identify possible correlations between pollution and health within a holistic view. Conclusion: This type of research activities aims to support the implementation of public health interventions and to become a reference model in the evaluation of the risk of exposure to environmental pollutants.

A 62-year-old woman was admitted with chest pain of two hours’ duration, ECG changes in the precordial leads and left ventricular ejection fraction of 30% on the echocardiogram. Emergent catheterization demonstrated severe flow disturbance in the left coronary artery. An intra-aortic balloon pump and a drug-eluting stent were implanted. However, the flow disturbance persisted. Optical coherence tomography followed by intravascular ultrasound provided crucial data on the mechanism and helped to optimize treatment in this critical patient. Resumo: Uma mulher de 62 anos foi internada devido a dor torácica com duas horas de duração, associada a alterações eletrocardiográficas nas derivações precordiais e FEVE: 30% determinada por ecocardiografia. Um cateterismo emergente revelou alterações graves no fluxo da coronária esquerda. Foram implantados um balão intra-aórtico e um stent revestido. Contudo, o fluxo continuou com alterações. A tomografia de coerência ótica e a ultrassonografia intravascular proporcionaram os dados únicos acerca do mecanismo envolvido e contribuíram para otimizar o tratamento numa doente crítica. Keywords: Acute coronary syndrome, Coronary dissection, Optical coherence tomography, Three-dimensional optical coherence tomography, Intravascular ultrasound, Palavras-chave: Síndrome coronária aguda, Disseção coronária, Tomografia de coerência ótica, Tomografia de coerência ótica 3-D, Ultrassonografia intravascular

Dentre as afecções pulmonares exógenas, a pneumonia lipóide (PL), causada pela broncoaspiração de lipídeos, é uma doença pouco diagnosticada. Ela resulta da reacção tipo corpo estranho que se segue à presença de material lipídico dentro do parênquima pulmonar. Em geral, o agente etiológico é o óleo mineral utilizado como agente laxativo. Doentes com histórico de constipação intestinal e uso crónico de óleo mineral, com tosse e dispneia, devem ser pesquisados quanto a esta doença. Apresentamos um caso de pneumonia lipóide associada ao uso de óleo mineral como agente laxativo, acentuamos as dificuldades relacionadas com a definição diagnóstica e revemos a literatura pertinente ao tema.Lipoid pneumonia (LP) is a pneumonitis resulting from the aspiration of lipids, and is commonly associated with the use of mineral oil as a laxative. LP is relatively unfamiliar to clinicians and is probably underdiagnosed. Making a diagnosis of LP requires a high degree of clinical suspicion. The aim of this publi cation are to present a case of a patient with LP and to increase physician awareness of LP, its diagnosis and prevention.

Resumo: Dentre as afecções pulmonares exógenas, a pneumonia lipóide (PL), causada pela broncoaspiração de lipídeos, é uma doença pouco diagnosticada. Ela resulta da reacção tipo corpo estranho que se segue à presença de material lipídico dentro do parênquima pulmonar. Em geral, o agente etiológico é o óleo mineral utilizado como agente laxativo. Doentes com histórico de constipação intestinal e uso crónico de óleo mineral, com tosse e dispneia, devem ser pesquisados quanto a esta doença. Apresentamos um caso de pneumonia lipóide associada ao uso de óleo mineral como agente laxativo, acentuamos as dificuldades relacionadas com a definição diagnóstica e revemos a literatura pertinente ao tema.Rev Port Pneumol 2008; XIV (4): 545-549 Abstract: Lipoid pneumonia (LP) is a pneumonitis resulting from the aspiration of lipids, and is commonly associated with the use of mineral oil as a laxative. LP is relatively unfamiliar to clinicians and is probably underdiagnosed. Making a diagnosis of LP requires a high degree of clinical suspicion. The aim of this publication are to present a case of a patient with LP and to increase physician awareness of LP, its diagnosis and prevention.Rev Port Pneumol 2008; XIV (4): 545-549 Palavras-chave: Pneumonia lipóide, óleo mineral, doenças pulmonares intersticiais, idoso, Key-words: Lipid pneumonia, mineral oil, interstitial lung diseases, aged

Background & Aims: Assessment of recurrence risk after liver resection (LR) is critical in hepatocellular carcinoma (HCC), particularly with the advent of effective adjuvant therapy. The aim of this study was to analyze the clinical and pathological factors associated with recurrence, aggressive recurrence, and survival after LR., Method: We performed a retrospective study in which all single HCC (BCLC-0/A) patients treated with LR between February 2000 and November 2020 were included. The main clinical variables were recorded. Histological features were blindly evaluated by two independent pathologists. Aggressive recurrence was defined as those that exceeded the Milan criteria at 1 st recurrence., Results: A total of 218 patients were included (30% BCLC 0 and 70% BCLC A), median (IQR) tumor size of 28 (19-42 mm). The prevalence of microvascular invasion and/or satellitosis (mVI/S) was 39%, with a kappa-index between both pathologists of 0.8. After a median follow-up of 49 (23-85) months, 61/218 (28%) patients died, 32/218 (15%) underwent liver transplantation, 127 (58%) developed HCC recurrence. The prevalence of aggressive recurrence was 35% (44/127 Milan-out, with 20 cases at advanced stage), and the 5-year survival rate was 81%. The presence of mVI/S was the only independent predictor of recurrence (hazard ratio [HR] 1.83, 95% CI 1.28-2.61, p <0.001), aggressive recurrence (HR 3.31, 95% CI 1.74-6.29, p <0.001) and mortality (HR 2.23, 95% CI 1.27-3.91, p = 0.005). The macrotrabecular-massive subtype was significantly associated with a higher prevalence of mVI/S, Edmonson Steiner grade III-IV, AFP values and vessels that encapsulate tumor clusters, but not with recurrence, aggressive recurrence, or overall survival., Conclusion: The presence of mVI/S was the only independent risk factor for aggressive recurrence and mortality. This has important implications for early-stage patient management, especially in the setting of adjuvant immunotherapy or ab initio LT., Impact and Implications: Assessment of recurrence risk after liver resection is crucial in patients with hepatocellular carcinoma. Patients with a high risk of recurrence are candidates for liver transplantation as an ab initio indication or for the potential use of adjuvant therapy. Aggressive recurrences, defined as those exceeding the Milan criteria at first recurrence, have a significant impact on overall survival (OS). Fifty-eight percent of patients experienced hepatocellular carcinoma recurrence, with a prevalence of aggressive recurrence at the first occurrence standing at 35%. After a median follow-up of 49 (23-85) months, 61 (28%) patients died, and 32 (15%) underwent liver transplantation, resulting in a 5-year OS rate of 81%. Microvascular invasion and/or satellitosis was present in 39% of our cohort and was the only independent predictor of recurrence, aggressive recurrence, and OS on multivariate analysis. This is important as it could be used to guide therapeutic management., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: Analyze the usefulness, efficacy, and safety of transoperative magnetic resonance imaging (tMRI) in glioma surgery in awake patients., Methods: Retrospective, single-center, analytical study of a cohort of patients who underwent awake surgery for gliomas by the same surgeon in a third-level Argentine center, in the period between 2012 and 2022. Only patients with pathology-confirmed gliomas, with 6-month follow-up, who had preoperative and postoperative volumetric magnetic resonance imaging, were included in this sample. Subsequently, we analyzed which patients received surgery with the tMRI protocol and the results using multivariate regression analysis., Results: A total of 71 patients were included. A tMRI study was performed on 22 (31%) of these patients. The use of tMRI increased the percentage of resection by 20% (P = 0.03), thereby increasing the possibility of gross total resection. However, using tMRI significantly extended surgical time by 84 minutes (P < 0.001). In 55% of the patients in whom tMRI was performed, the resection was continued after it. The use of tMRI did not increase the rate of infections or the development of surgically associated neurological deficits in the long term, despite the fact that 47% of the patients showed the development of a new deficit or worsening of a previous one during the intraoperative period., Conclusions: The use of tMRI in awake glioma surgery proved to be a safe tool that contributes to increasing the degree of tumor resection, compared to the use of neurophysiological mapping and neuronavigation, at the expense of increased surgical times and costs. We consider tMRI in awake glioma surgery should be used in properly selected cases., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The medical body composition analyzer (mBCA) incorporates advances in multifrequency technology and has been validated using a 4-compartment (4C) model in adults but not in youths aged <18 y., Objectives: This study aimed to formulate a 4C model based on 3 reference methods and develop and validate a body composition prediction equation for the mBCA in youths aged 10‒17 y., Methods: The body density of 60 female and male youths was measured by air displacement plethysmography, total body water by deuterium oxide dilution, and BMC by DXA. Data from the equation group (n = 30) were used to formulate a 4C model. The all-possible-regressions method was used to select variables. The model was validated in a second cohort (n = 30) in a random split design. The accuracy, precision, and potential bias were evaluated by the Bland and Altman procedure., Results: Mean age, weight (W), height (H), waist circumference, and z-score of BMI were 13.6 ± 2.3 y, 54.5 ± 15.5 kg, 156 ± 11.9 cm, 75.5 ± 10.9 cm, and 0.70 ± 1.32 z, respectively. The prediction equation was as follows: FFM in kg (FFM kg ) = ([0.2081] ∗ [W] + [0.8814] ∗ [H 2 cm /R Ω ] + [0.2055 ∗ Xc Ω ])-15.343; R 2 = 0.96; standardized root-mean-square error (SRMSE) = 2.18 kg. FFM did not differ between the 4C method (38.9 ± 12.0 kg) and the mBCA (38.4 ± 11.4 kg) (P > 0.05). The relationship between these 2 variables did not deviate from the identity line, was not significantly different from 0, and the slope was not significantly different from 1.0. In the precision prediction model of mBCA, the R 2 value was 0.98 and SRMSE was 2.1. No significant bias was found when regressing differences between methods and their means (P = 0.08)., Conclusions: The equation for the mBCA was accurate, precise, had no significant bias, had substantial strength of agreement and could be used in this age group when subjects were preferentially within the constraints of a specified body size., (Copyright © 2022 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Non-invasive tests (NITs) for clinically significant portal hypertension (CSPH; hepatic venous pressure gradient [HVPG] ≥10 mmHg) have predominantly been studied in patients with active HCV infection. Investigations after HCV cure are limited and have yielded conflicting results. We conducted a pooled analysis to determine the diagnostic/prognostic utility of liver stiffness measurement (LSM)/platelet count (PLT) in this setting., Methods: A total of 418 patients with pre-treatment HVPG ≥6 mmHg who achieved sustained virological response (SVR) and underwent post-treatment HVPG measurement were assessed, of whom 324 (HVPG/NIT-cohort) also had paired data on pre-/post-treatment LSM/PLT. The derived LSM/PLT criteria were then validated against the direct endpoint decompensation in 755 patients with compensated advanced chronic liver disease (cACLD) with SVR (cACLD-validation-cohort)., Results: HVPG/NIT-cohort: Among patients with cACLD, the pre-/post-treatment prevalence of CSPH was 80%/54%. The correlation between LSM/HVPG increased from pre- to post-treatment (r = 0.45 vs. 0.60), while that of PLT/HVPG remained unchanged. For given LSM/PLT values, HVPG tended to be lower post- vs. pre-treatment, indicating the need for dedicated algorithms. Combining post-treatment LSM/PLT yielded a high diagnostic accuracy for post-treatment CSPH in cACLD (AUC 0.884; 95% CI 0.843-0.926). Post-treatment LSM <12 kPa & PLT >150 G/L excluded CSPH (sensitivity: 99.2%), while LSM ≥25 kPa was highly specific for CSPH (93.6%). cACLD-validation-cohort: the 3-year decompensation risk was 0% in the 42.5% of patients who met the LSM <12 kPa & PLT >150 G/L criteria. In patients with post-treatment LSM ≥25 kPa (prevalence: 16.8%), the 3-year decompensation risk was 9.6%, while it was 1.3% in those meeting none of the above criteria (prevalence: 40.7%)., Conclusions: NITs can estimate the probability of CSPH after HCV cure and predict clinical outcomes. Patients with cACLD but LSM <12 kPa & PLT>150 G/L may be discharged from portal hypertension surveillance if no co-factors are present, while patients with LSM ≥25 kPa require surveillance/treatment., Lay Summary: Measurement of liver stiffness by a specific ultrasound device and platelet count (a simple blood test) are broadly used for the non-invasive diagnosis of increased blood pressure in the veins leading to the liver, which drives the development of complications in patients with advanced liver disease. The results of our pooled analysis refute previous concerns that these tests are less accurate after the cure of hepatitis C virus (HCV) infection. We have developed diagnostic criteria that facilitate personalized management after HCV cure and allow for a de-escalation of care in a high proportion of patients, thereby decreasing disease burden., Competing Interests: Conflict of interest G.S. received travel support from Gilead. S.L. received grant support from Gilead and served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and MSD. E.L.M. received grant support from Novartis. A.B. has nothing to disclose. E.A. has nothing to disclose. E.L. has nothing to disclose. L.T. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, Bayern, Janssen, and W. L. Gore & Associates, and received travel support from AbbVie, MSD, and Gilead. P.S. served as a consultant for PharmaIN. E.M. has nothing to disclose. L.E. has nothing to disclose. C.D. has nothing to disclose. L.I.-M. has nothing to disclose. A.P. has nothing to disclose. J.I.F. has nothing to disclose. M.A. has nothing to disclose. A.Z. has nothing to disclose. A.C. has nothing to disclose. H.H.-E. has nothing to disclose. I.S.L.S. has nothing to disclose. J.J. has nothing to disclose. H.Y. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, Otuka, Asuka, and MSD. S.M.F. has nothing to disclose. E.A.T. served as a speaker and/or consultant and/or advisory board member for Intercept, Gilead, Pfizer, NovoNordisk and Orphalan. F.P.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Biotest, Gilead, and MSD, and received travel support from AbbVie, Biotest, and Gilead. G.C. has nothing to disclose. X.F. served as a speaker and/or consultant for AbbVie and Gilead. R.B. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and Janssen. C.V. has nothing to disclose. V.H.-G. served as a speaker and/or consultant and/or advisory board member for W. L. Gore & Associates. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, MSD, Philips, and W. L. Gore & Associates as well as travel support from Boehringer Ingelheim and Gilead. J.B. served as a lecturer or consultant for W. L. Gore & Associates, Actelion and Surrozen, and received grants from the ‘Siftung für Leberkrankheiten Bern’. J.C.G.-P. served as a speaker and/or consultant and/or advisory board member for Cook and W. L. Gore & Associates and received grants/research support from Conatus, Exalenz, Novartis, and Theravance. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Collective Acumen, and W. L. Gore & Associates and received travel support from AbbVie, Bristol-Myers Squibb, and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Severe carotid stenosis (CS) is a major risk factor for stroke. Carotid Endarterectomy (CEA) is the gold standard revascularization technique of CS while carotid artery stenting (CAS) is considered an alternative treatment option, especially in high-risk patients or those with relative contraindications to CEA. The aim of this study was to evaluate the results of CEA and CAS with Roadsaver® stent device., Methods: We made a retrospective analysis of 119 patients undergoing treatment of CS. All CS were evaluated with imaging exams. The patients were divided into CEA group and CAS group. As primary endpoints of the study overall and cardiovascular cause - related mortality, freedom from stroke, and restenosis were considered. All patients were followed up and revaluated with duplex scan over a minimum of 6 months and a maximum of 36 months (follow-up mean time 22.3 ± 3.4 months)., Results: In the whole cohort 86 of 119 patients underwent CEA and 33 of 119 CAS. Risk factors were superposable in both groups. During follow-up, we observed 4 deaths, 2 cardiovascular events and 12 restenosis. CEA was associated with lower death probability than CAS (P = 0.036). Probability of Restenosis and cardiovascular events did not vary between CAS and CEA groups., Conclusions: Albeit CEA remains the gold standard for the treatment of severe CS, CAS with new double layer micromesh stent can be considered a useful and safe alternative in some clinical conditions., (Copyright © 2021. Published by Elsevier Inc.)

Background & Aims: The association between sarcopenia and prognosis in patients with cirrhosis remains to be determined. In this study, we aimed to quantify the association between sarcopenia and the risk of mortality in patients with cirrhosis, stratified by sex, underlying liver disease etiology, and severity of hepatic dysfunction., Methods: PubMed, Web of Science, EMBASE, and major scientific conference sessions were searched without language restriction through 13 January 2021 with an additional manual search of bibliographies of relevant articles. Cohort studies of ≥100 patients with cirrhosis and ≥12 months of follow-up that evaluated the association between sarcopenia, muscle mass and the risk of mortality were included., Results: Twenty-two studies involving 6,965 patients with cirrhosis were included. The pooled prevalence of sarcopenia in patients with cirrhosis was 37.5% overall (95% CI 32.4%-42.8%), and was higher in male patients, those with alcohol-associated liver disease, those with Child-Pugh grade C cirrhosis, and when sarcopenia was defined by L3-SMI (third lumbar-skeletal muscle index). Sarcopenia was associated with an increased risk of mortality in patients with cirrhosis (adjusted hazard ratio [aHR] 2.30, 95% CI 2.01-2.63), with similar findings in a sensitivity analysis of patients with cirrhosis without hepatocellular carcinoma (aHR 2.35, 95% CI 1.95-2.83) and in subgroups stratified by sex, liver disease etiology, and severity of hepatic dysfunction. The association between quantitative muscle mass index and mortality further supports the association between sarcopenia and poor prognosis (aHR 0.95, 95% CI 0.93-0.98). There was no significant heterogeneity in any of our analyses., Conclusions: Sarcopenia was highly and independently associated with higher risk of mortality in patients with cirrhosis., Lay Summary: The prevalence of sarcopenia and its association with death in patients with cirrhosis remain unclear. This meta-analysis indicated that sarcopenia affected about one-third of patients with cirrhosis and up to 50% of patients with alcohol-related liver disease or Child-Pugh class C cirrhosis. Sarcopenia was independently associated with an ∼2-fold higher risk of mortality in patients with cirrhosis. The mortality rate increased with greater severity or longer durations of sarcopenia. Increasing awareness about the importance of sarcopenia in patients with cirrhosis among stakeholders must be prioritized., Competing Interests: Conflict of interest MP is funded by BONFOR-Forschungskommission der Medizinischen Fakultät Bonn and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy–EXC2151–390873048 and Ernst-und-Berta Grimmke Foundation. TB: Grants: Abbvie, BMS, Gilead, Humedics, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical; Consulting or advisory board: Abbvie, Alexion, Bayer, BMS, Gilead, Intercept, Janssen, MSD/Merck, Merz, Novartis, Sequana Medical, and Spring Bank; Speaker: Abbvie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, Janssen, MSD/Merck, Merz, Novartis, Sirtex and Sequana Medical in the past 2 years. JT was supported by grants of Deutsche Forschungsgemeinschaft (SFB TRR57 P18, CRC 1382 A09), the European Union’s Horizon 2020 research and innovation program’s GALAXY study (No. 668031), LIVERHOPE (No. 731875), MICROB-PREDICT (No. 825694), DECISION (No. 84794) and the Cellex Foundation (PREDICT). JT: Grants: Gore; Consultant: Martins Pharma, Ironwood, Gore, Alexion, BMS, Grifols, Sequana Medicals, Versantis; Sponsored lectures (National or International): Gilead Sciences, Gore, Alexion, BMS, Grifols, Sequana Medicals, Norgine, Intercept. FJ: Speaker: Gilead Sciences, MSD and Ascletis. Consulting or advisory board: Gilead Sciences and MSD. MHN: Grants: Gilead, Pfizer, Enanta, Vir, Glycotest, National Cancer Institute, B. K. Kee Foundation, Exact Sciences; Helio Health; Consulting or advisory board: Intercept, Gilead, Exact Sciences, Laboratory of Advanced Medicine, Bayer, Eisai, GSK, Novartis. All other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Sustained human pressures on the environment have significantly increased the frequency, extent, and severity of wildfires, globally. This is particularly the case in Mediterranean regions, in which human-caused wildfires represent up to 90% of all recorded wildfire ignitions. In Chile, it has been estimated that nearly 90% of wildfires are related to human activities, and that their frequency and distribution have steadily increased over the last decade. Despite this, the role of socio-economic factors in driving wildfire activity and its spatiotemporal distribution remains unclear. In this study, we assess the association between socio-economic drivers and spatiotemporal patterns of wildfires in the Mediterranean region of south-central Chile over the period 2010-2018. Our results show that 98.5% of wildfires are related to human activities, either accidentally (58.2%) or intentionally (36.6%). Wildfires occurred primarily during the summer months and their density at the commune-level was associated with increased road access, as well as with the percentage of land covered by agriculture, exotic tree plantations, and native forest. Wildfire activity at the commune-level was also related to socio-economic variables such as population density, proportion of indigenous population, and unemployment rate, although such associations varied considerably depending on the region and on whether the wildfire was started accidentally or intentionally. Our study provides a comprehensive and interdisciplinary assessment of the complex ways in which land-cover and socio-economic factors drive the distribution of wildfire activity in south-central Chile. It represents an important guide for policy-making, as well a baseline for research into strategies aimed at predicting and mitigating wildfire activity at both local and national levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Background: Ultra-processed foodstuffs have been replacing traditional beans with tortillas in the Mexican diet in the last decades. Therefore, scientific support is needed to promote a return to good-quality traditional dishes., Objectives: This study aims to evaluate the amino acid digestibility and score of pinto beans (Phaseolus vulgaris) consumed with corn tortillas and guacamole in adults using the dual-tracer method., Methods: The pinto beans were intrinsically labeled using 250 mL of 2H2O (99.8%) per 19 L pot with 3 plants. A paste of cooked beans on toasted corn tortillas and guacamole topping were administered to 3 male and 3 female adults (21-25 years old; BMI, 19-23.5 kg/m2). The protocol was plateau feeding given along with U-[13C]-spirulina protein to evaluate indispensable amino acid (IAA) digestibility using the dual-tracer method. Blood samples were taken in the plateau state. The digestibility of each IAA of the bean protein was calculated by the ratio of its enrichment in the beans to the spirulina in the meal and its appearance in plasma collected in the plateau state, as a percentage corrected by spirulina digestibility. Additionally, the digestible IAA score (DIAAS) was calculated., Results: The 2H enrichment of IAA in the pinto beans was 471 parts per million excess. The isotopic enrichment of 2H and 13C in IAA at 5-8 hours presented plateau states with mean CVs of 12.2% and 13.3%, respectively. The mean digestibility of IAA from pinto beans was 77% ± 1.6%, with the lowest value for threonine. The DIAAS calculated with respect to the pattern requirement for children older than 3 years, adolescents, and adults was 83%, with methionine and cysteine being the limiting amino acids., Conclusions: A Mexican dish of pinto beans, tortillas, and guacamole is a good source of protein as evaluated in adults and could be promoted as a nutritious snack. The assay is registered with the Ethical Committee of the Centro de Investigación en Alimentación y Desarrollo, A.C. as CE/015/2019., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background & Aims: Breast cancer patients (BCP) during treatment often experience an increase in body weight and fat mass, and a decrease in muscle mass known as sarcopenic obesity, affecting their prognosis and quality of life. We aimed to evaluate the effect of a 6-month individualized food-based nutrition intervention program in nonmetastatic BCP body composition during treatment., Methods: This is a pre-post study in recently diagnosed women with invasive ductal/lobular breast carcinoma (clinical stage I-III). The individualized nutrition intervention was based on the dynamic macronutrient meal equivalent menu method (MEM). Dietary plans were developed according to WCRF/AICR guidelines, BCP total energy expenditure, 1.2-1.5 g/kgBW/d of protein intake, 5-9 servings/day of fruits and vegetables, and a caloric restriction (500-1000 kcal/d) when applicable (BMI ≥ 25 kg/m 2 ). Follow-up was every 2-weeks and a different diet menu was provided in each session during 6 months. Baseline and final measurements included the assessment of anthropometry, body composition, and physical activity., Results: Twenty-two participants completed the study and at diagnosis 68% were overweighed or obese. After the 6-month nutrition intervention program, BCP lost 3.1 kg (p < 0.01) of body weight, 2.7 kg (p < 0.01) of fat-mass, 400 g (p < 0.01) of abdominal fat, 118 g (p < 0.05) of visceral fat, 1.2 kg/m 2 of body mass index and 1.1 kg/m 2 of fat mass index (p < 0.01). During the period, no changes were observed in bone mineral density (p = 0.3), fat-free mass (p = 0.1) and appendicular skeletal muscle mass (p = 0.2). Menopausal status in BCP did not modify the effect of the nutrition intervention., Conclusions: The individualized food-based nutrition intervention program empowered BCP to make informed healthy food choices within their personal preferences, socioeconomic and cultural background. With this type of intervention, nonmetastatic BCP reduced body weight, fat-mass, fat mass index, visceral and abdominal fat, while preserving skeletal muscle mass, during antineoplastic treatment. ClinicalTrials.govNCT03625635., Competing Interests: Conflict of interest The authors have declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: To determine if visceral adipose tissue (VAT) area measured through MRI can be used opportunistically to assess the presence of cardiometabolic risk factors and compare its performance to simpler adiposity measures., Methods: A cross-sectional analysis was carried out on a subset of 1683 participants (856 women) from the Adiposity Phenotype Study (mean age=69.2y; range 59.9-77.4). The association of total VAT area (sum of four cross sections, L1-L2, L2-L3, L3-L4, L4-L5) and each location, as well as BMI and body fat % (per SD) with the metabolic syndrome (MetSx) or its components was evaluated through logistic regression analysis., Results: Total VAT can be accurately predicted using all sites evaluated (R 2 range=0.82-0.96). In men, VAT did not show a superior association to MetSx compared to BMI in men. However, in women, VAT was consistently superior to BMI and body fat % in its association to MetSx, independent of ethnicity [odds ratio for BMI, body fat %and total VAT area=2.25 (95% CI: 1.93-2.62); 1.66 (95% CI: 1.36-2.03); 6.20 (95% CI: 4.69-8.21) respectively in all women]. Ethnic-specific odds ratios to MetSx in women ranged from 5.38 to 8.63 for total VAT area and 2.12-4.08 for BMI., Conclusion: Total VAT area can be accurately predicted from individual VAT regions in men and women and offers superior association to BMI for MetSx in women but not in men for five ethnicities. Therefore, opportunistic screening for elevated VAT area in women may be warranted across multiple ethnic groups., (Copyright © 2021 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Aims: Telemedicine between health care providers could be useful for improving the access to hepatology consultations, which is challenging in some regions. The primary objective of this study was to estimate the proportion of consultations that were resolved through a telemedicine program. Additionally, we evaluated patient satisfaction with this strategy., Methods: Consecutive telemedicine consultations made by non-hepatologist health care providers from different regions of Argentina to a specialty hepatology team were included. Participants and hepatologists used e-mail, teleconference systems, WhatsApp, or telephone to interact, depending on their preferences. Consultations were considered to be resolved through telemedicine when a diagnosis and an adequate follow-up were achieved without the need to refer the patient to a hepatologist or other specialist. Patient satisfaction with telemedicine was evaluated using the Patient Satisfaction Questionnaire Short Form and Telemedicine Satisfaction Questionnaire., Results: A total of 200 telemedicine consultations made by 24 physicians from 10 different provinces of Argentina were evaluated, of which 145 (73%; 95% CI: 66%-79%) were resolved through telemedicine. Practitioners specialities were as follows: family physicians, internists, gastroenterologists, infectious diseases, and obstetrics. The most frequent final diagnoses for those patients whose consultation was resolved through telemedicine were non-alcoholic fatty liver disease, viral hepatitis, and benign hepatic lesions. A high degree of patient satisfaction with telemedicine was observed in both questionnaires., Conclusions: Our results show the effectiveness of telemedicine in hepatology, with high resolution rate of consultations and rapid access to experts' assessment. Additionally, a high degree of patient satisfaction was observed using prevalidated questionnaires., Competing Interests: All authors have none to declare., (© 2020 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) infection affects about 70 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases and can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas. Many studies have demonstrated that, after antiviral therapy, MC can disappear along with HCV eradication. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. Several studies on new DAAs have reported remarkable 90% to 100% eradication rates, regardless of HCV genotype. Treatment with DAAs has comparable efficacy on viral eradication in patients with MC, but definite clinical improvements of vasculitis can be observed only in half the patients. On the contrary, the regression of renal disease and lympho-proliferative disorders, induced by HCV, appears to have a lower remission rate after viral eradication with DAAs and most cases need immunosuppressive treatments. In HCV related CV, the main clinical goal must be early eradication of HCV, to avoid organ complication and manifestation of lympho-proliferative diseases. This review focuses on the role of DAAs in treatment of HCV-related cryoglobulinemic vasculitis., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Retinol isotope dilution (RID) and model-based compartmental analysis are recognized techniques for assessing vitamin A (VA) status. Recent studies have shown that RID predictions of VA total body stores (TBS) can be improved by using modeling and that VA kinetics and TBS in children can be effectively studied by applying population modeling ("super-child" approach) to a composite data set., Objectives: The objectives were to model whole-body retinol kinetics and predict VA TBS in a group of Mexican preschoolers using the super-child approach and to use model predictions of RID coefficients to estimate TBS by RID in individuals., Methods: Twenty-four healthy Mexican children (aged 3-6 y) received an oral dose (2.96 μmol) of [13C10]retinyl acetate in corn oil. Blood samples were collected from 8 h to 21 d after dosing, with each child sampled at 4 d and at 1 other time. Composite data for plasma labeled retinol compared with time were analyzed using a 6-component model to obtain group retinol kinetic parameters and pool sizes. Model-predicted TBS was compared with mean RID predictions at 4 d; RID estimates at 4 d were compared with those calculated at 7-21 d., Results: Model-predicted TBS was 1097 μmol, equivalent to ∼2.4 y-worth of VA; using model-derived coefficients, group mean RID-predicted TBS was 1096 μmol (IQR: 836-1492 μmol). TBS at 4 d compared with a later time was similar (P = 0.33). The model predicted that retinol spent 1.5 h in plasma during each transit and recycled to plasma 13 times before utilization., Conclusions: The super-child modeling approach provides information on whole-body VA kinetics and can be used with RID to estimate TBS at any time between 4 and 21 d postdose. The high TBS predicted for these children suggests positive VA balance, likely due to large-dose VA supplements, and warrants further investigation., (Copyright © The Author(s) 2020.)

The ovarian steroid hormone progesterone and its nuclear receptor, the Progesterone Receptor (PR), play an essential role in the regulation of cell proliferation and differentiation in the mammary gland. In addition, experimental and clinical evidence demonstrate their critical role in controlling mammary gland tumorigenesis and breast cancer development. When bound to its ligand, the main action of PR is as a transcription factor, which regulates the expression of target genes networks. PR also activates signal transduction pathways through a rapid or non-genomic mechanism in breast cancer cells, an event that is fully integrated with its genomic effects. This review summarizes the molecular mechanisms of the ligand-activated PR actions that drive epithelial cell proliferation and the regulation of the stem cell population in the normal breast and in breast cancer., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The current methods of preserving donor kidneys in nonoxygenated cold conditions minimally protect the kidney against ischemia-reperfusion injury (IRI), a major source of complications in clinical transplantation. However, preserving kidneys with oxygenated perfusion is not currently feasible due to the lack of an ideal perfusion mechanism that facilitates perfusion with blood at warm temperature. Here, we have designed an innovative renal pump circuit system that can perfuse blood or acellular oxygen carrier under flexible temperatures, pressures, and oxygenation. We have tested this apparatus to study optimal conditions of storage of our porcine model of donation after cardiac death (DCD) kidneys., Methods: Porcine kidneys were retrieved after 30 minutes of cross-clamping renal pedicles in situ . Cessation of blood mimics postcardiac death in humans and simulates DCD warm ischemic injury. Procured kidneys were flushed and subjected to static cold storage (SCS) for 4 hours. For warm perfusion, kidneys were cannulated for pulsatile oxygenated perfusion with blood:PlasmaLyte for 4 hours at 15 °C, 22 °C, and 37 °C. To mimic posttransplant scenario, all kidneys were reperfused with blood for an additional 4 hours at 37 °C., Results: Compared with all other groups, 22 °C perfusion resulted in significant reduction of acute tubular necrosis (ATN), apoptosis, kidney damage markers, Toll-like receptor signaling, and cytokine production. It was associated with maximal renal blood flow and urine output. Kidneys stored at 15 °C thrombosed within 2 hours under this condition. Martius Scarlet Blue staining confirmed that 22 °C was the optimal temperature to minimize hemorrhage and blood clots., Conclusion: Our novel study shows that oxygenated perfusion at near-room-temperature provides optimal donor kidney storage conditions.

Background & Aims: The efficacy of direct-acting antivirals (DAAs) has dramatically changed the prognosis of patients with chronic hepatitis C. We aimed to evaluate the impact of DAA therapy on the composition of the liver transplant (LT) waiting list and the early post-transplant survival., Methods: We evaluated all patients admitted to the waiting list for a primary LT between 1st January 2008 and 31st of December 2016 in Catalonia, Spain. Time span was divided into two periods according to the availability of different antiviral therapies: 2008-2013 (interferon-based therapies) and 2014-2016 (DAA). Changes in the indications of LT and the aetiology of liver disease, as well as post-LT patient survival, were evaluated according to the year of inclusion and transplantation, respectively., Results: We included 1,483 patients. Admissions in the waiting list for hepatitis C virus (HCV)-related liver disease decreased significantly, from 47% in 2008-2013 to 35% in 2014-2016 (p <0.001), particularly because of a reduction in patients with decompensated cirrhosis. In contrast, NASH-related inclusions increased from 4% to 7% (p = 0.003). Three-year post-LT patient survival increased significantly in the second period in the whole cohort (82% vs. 91%, p = 0.002), because of better survival in anti-HCV positive patients (76% vs. 91%, p = 0.001), but not in anti-HCV negative patients (88% vs. 91% p = 0.359). Anti-HCV positive serology, the time period of 2008-2013 and higher donor age were independently associated with post-LT mortality in the whole cohort; while time period and donor age were independently associated with post-LT mortality in anti-HCV positive recipients., Conclusions: The high efficacy of DAAs is associated with significant changes in the composition of the LT waiting list and, more importantly, results in improved post-transplant survival., Lay Summary: The efficacy of the new direct-acting antivirals is associated with a significant improvement in survival of patients undergoing liver transplantation because of hepatitis C virus-related liver disease. In addition, it has decreased the number of patients with hepatitis C that need a liver transplant., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Progesterone receptor (PR) is a master regulator in female reproductive tissues that controls developmental processes and proliferation and differentiation during the reproductive cycle and pregnancy. PR also plays a role in progression of endocrine-dependent breast cancer. As a member of the nuclear receptor family of ligand-dependent transcription factors, the main action of PR is to regulate networks of target gene expression in response to binding its cognate steroid hormone, progesterone. Liganded-PR transcriptional activation has been thoroughly studied and associated mechanisms have been described while progesterone-mediated repression has remained less explored. The present work summarizes recent advances in the understanding of how PR-mediated repression is accomplished in breast cancer cells and highlights the significance of fully understanding the determinants of context-dependent PR action., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen-Gill model) was performed in 240 LTs. Four hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]-related, and 38 viral non-CMV-related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04-2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33-4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92-16.4], p = 0.002) compared with recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient versus MBL-sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1-year bacterial infection-related mortality after LT., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background/objectives: to compare the prognostic accuracy for 28 and 90-day transplant-free mortality of a modified CLIF-SOFA score (including a dynamic definition of acute kidney injury) with that of the classic CLIF-SOFA score and KDIGO score for acute kidney injury in patients with acute decompensation of cirrhosis., Methods: A retrospective analysis of all admissions of acutely decompensated patients with cirrhosis was carried out from January 2012 to December 2014. Classic and modified CLIF-SOFA scores were analyzed, as well as acute kidney injury diagnosis using the KDIGO score regarding their accuracy for 28- and 90-day transplant free mortality prediction., Results: 108 admissions were analyzed. Acute kidney injury diagnosis was met in 37 (34%) patients. Acute-on-chronic liver failure was diagnosed in 59 (55%) patients using the classic CLIF-SOFA score; and in 64 (59%) patients using the modified CLIF-SOFA score. Both CLIF-SOFA scores were highly effective in predicting 28-day transplant-free mortality (AUCROC 0.93 and 0.92, p  = 0.34) as well as 90-day transplant-free mortality (AUCROC 0.79 and 0.78, p  = 0.78). Acute kidney injury diagnosis had significantly lower accuracy in mortality assessment (28 and 90-day transplant free mortality AUCROC 0.67 [ p  = 0.002] and 0.63 [ p  = 0.02])., Conclusions: To our knowledge, this is the first evidence of the limited impact of modifying the fixed kidney injury definition currently used for acute-on-chronic liver failure.

Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a "real-life" cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatment is ill-defined., Aims: To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the efficacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine, was explored., Methods: In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45-70) were enrolled., Results: The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy (29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobulinemias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1-14), rheumatoid factor was 200U/L (range 20-5850), C4 was 12mg/dl (range 2-31), ALT 71U/L (range 36-114). All patients were HBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight), Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no disease progression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regression of purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidney failure and two of liver cirrhosis., Conclusion: NUC therapy appeared to be safe and effective in CV-related HBV., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Aims: It is well-known that unaccustomed exercise, especially eccentric exercise, is associated to delayed onset muscle soreness (DOMS). Whether DOMS is associated with reactive oxygen species (ROS) and the transient receptor potential vanilloid 1 (TRPV1) is still an open question. Thus, the aim of this study was to investigate the association between TRPV1 and xanthine oxidase-related ROS production in muscle and DOMS after a bout of eccentric exercise., Main Methods: Male Wistar rats performed a downhill running exercise on a treadmill at a -16° tilt and a constant speed for 90min (5min/bout separated by 2min of rest). Mechanical allodynia and grip force tests were performed before and 1, 3, 6, 9, 12, 24, 48 and 72h after the downhill running. Biochemical assays probing oxidative stress, purine degradation, xanthine oxidase activity, Ca(2+) ATPase activity and TRPV1 protein content were performed in gastrocnemius muscle at 12, 24, and 48h after the downhill running., Key Findings: Our statistical analysis showed an increase in mechanical allodynia and a loss of strength after the downhill running. Similarly, an increase in carbonyl, xanthine oxidase activity, uric acid levels and TRPV1 immunoreactivity were found 12h post-exercise. On the other hand, Ca(2+) ATPase activity decreased in all analyzed times., Significance: Our results suggest that a possible relationship between xanthine oxidase-related ROS and TRPV1 may exist during the events preceding eccentric exercise-related DOMS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The most frequent form of renal involvement in patients with hepatitis C infection is cryoglobulinemic membrano-proliferative glomerulonephritis. Nonetheless, some reports indicate that the eradication of the hepatitis C virus may also lead to the remission of this renal disease., Methods: The virological, immunological and nephrological response to pegylated interferon α plus ribavirin (48 weeks in patients infected with genotype 1, and 24 weeks for patients infected with genotypes 2 and 3) was evaluated retrospectively in 10 patients with cryoglobulinemic glomerulonephritis., Results: 6 patients obtained end of treatment virological response (60%); during follow-up, 2 relapsed, and 4 patients maintained a sustained virological response (40%). At the end of follow-up, three patients obtained a significant nephrological response and decrease in cryoglobulin levels (p<0.05). No significant changes in clinical and biological parameters were observed in non-responders/relapsers., Conclusions: Eradication of hepatitis C may be associated with the regression of cryoglobulinemic glomerulonephritis., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Allergic asthma can vanish over time either spontaneously or induced by allergen-specific immunotherapy. In mice with established airway allergic inflammation, chronic intranasal (IN) allergen challenges decreases progressively airway allergic inflammation. Here we compared the contribution of different regulatory pathways that could be associated with this phenomenon, known as local inhalational tolerance. We found that inhalational tolerance was not associated with increased number of regulatory T cells or suppressive cytokines. Instead, it was associated with increased apoptosis of airway inflammatory leukocytes revealed by annexin-V staining and the expression of apical caspase 8 and effector caspase 3. Also, the transition from acute to chronic phase was associated with a shift in the expression of pro-allergic to pro-apoptotic molecules. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was found to be a key molecule in mediating resolution of allergic inflammation because anti-TRAIL treatment blocked apoptosis and increased the infiltration of T helper type 2 (Th2) cells and eosinophils. Notably, repeated IN treatment with recombinant TRAIL in established airway allergic inflammation augmented leukocyte apoptosis and decreased the frequency of interleukin-5-producing Th2 cells and eosinophils to airways. Our data indicate that TRAIL signaling is sufficient for downmodulation of allergic airway disease, suggesting a potential therapeutic use of TRAIL for asthma treatment.

Vitamin A (VA) deficiency (VAD) continues to be a major nutritional problem in developing countries, including Central America. In Mexico, milk is a well-accepted vehicle for the administration of micronutrients, including VA, to preschoolers. Thus, we conducted a randomized, controlled, clinical trial to investigate the efficacy of daily consumption of 250 mL of VA-fortified milk (which provided 196 retinol equivalents/d) for 3 mo on VA stores in mildly to moderately VAD (serum retinol concentration 0.35-0.7 μmol/L) preschoolers who were not enrolled in a food assistance program. Twenty-seven mildly to moderately VAD children were randomly assigned based on screening measurements to either the intervention (n = 14) or control group (n = 13) (children in the control group did not receive placebo). All children in the control group and 79% (n = 11) of the children in the intervention group completed the study. The total body VA (TBVA) pool size was estimated using the deuterated retinol dilution technique before and after the intervention. After 3 mo, median changes in the serum retinol concentration for the intervention and control groups were 0.13 and -0.21 μmol/L, respectively (P = 0.009). Median changes in the TBVA stores were 0.06 and 0.01 mmol, respectively (P = 0.006) and estimated median changes in the liver VA concentration were 0.09 and 0.01 μmol/g, respectively (P = 0.002). The VA-fortified milk was well accepted among preschoolers and significantly increased TBVA stores, liver VA stores, and serum retinol concentration, indicating that it may be an effective means to ameliorate VAD in young Mexican children.

The complexity of life boils down to the definition: "self-sustained chemical system capable of undergoing Darwinian evolution" (Joyce, 1994) [1]. The term "self-sustained" implies a set of chemical reactions capable of harnessing energy from the environment, using it to carry out programmed anabolic and catabolic functions. We briefly present our opinion on the general validity of this definition. Running anabolic and catabolic functions entails complex chemical information whose stability, reproducibility and evolution constitute the core of what is dubbed genetics. Life as-we-know-it is made of the intimate interaction of metabolism and genetics, both built around the chemistry of the most common elements of the Universe (hydrogen, oxygen, nitrogen, carbon). Other elements like phosphorus and sulphur play important but ancillary and potentially replaceable roles. The reproducible interaction of metabolic and genetic cycles results in the hypercycles of organization and de-organization of chemical information that we consider living entities. In order to approach the problem of the origin of life it is therefore reasonable to start from the assumption that both metabolism and genetics had a common origin, shared a common chemical frame, were embedded in physical-chemical conditions favourable for the onset of both. The most abundant three-atoms organic compound in interstellar environment is hydrogen cyanide HCN, the most abundant three-atoms inorganic compound is water H(2)O. The combination of the two results in the formation of formamide H(2)NCOH. We have explored the chemistry of formamide in conditions compatible with the synthesis and the stability of compounds of potential pre-genetic and pre-metabolic interest. We discuss evidence showing (i) that all the compounds necessary for the build-up of nucleic acids are easily obtained abiotically, (ii) that essentially all the steps leading to the spontaneous generation of RNA are abiotically possible, (iii) that the key compounds of extant metabolic cycles are obtained in the same chemical frame, often in the same test tube. How close are these observations to a plausible scenario for the origin of life?, (Copyright © 2011 Elsevier B.V. All rights reserved.)

Insight into the mechanisms by which ambient air particulate matter mediates adverse health effects is needed to provide biological plausibility to epidemiological studies demonstrating an association between PM(10) exposure and increased morbidity and mortality. In vitro studies of the effects of air pollution on human cells help to establish conditions for the analysis of cause-effect relationships. One of the major challenges is to test native atmosphere in its complexity, rather than the various components individually. We have developed an in vitro system in which human monocyte-macrophage U937 cells are directly exposed to filters containing different amounts of PM(10) collected in the city of Rome. Transcriptional profiling obtained after short exposure (1h) of cells to a filter containing 1666μg PM(10) (77.6μg/cm(2)) using a macroarray panel of 1176 genes reveals a significant change in the mRNA level (>2 fold) for 87 genes relative to cells exposed to a control filter. Overall, 9 out of 87 modulated genes were annotated as "lung cancer". qRT-PCR confirmed the induction of relevant genes involved in DNA repair and apoptosis, specifically: ERCC1, TDG, DAD1 and MCL1. In cells exposed for 10min, 1h and 3h to different amounts of PM(10), transcription of TNFα and TRAP1, which code for a key pro-inflammatory cytokine and a mitochondrial protein involved in cell protection from oxidative stress, respectively, was shown to be modulated in a time-dependent, but not a dose-dependent manner. Taken together, these data indicate that it is possible to analyze the effects of untreated particulate matter on human cells by the direct-exposure approach we have developed, possibly providing new clues to traffic-related health hazard., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Intervention studies in youth with obesity that can be translated into primary care are limited. We compared a lifestyle intervention to a brief intervention applied by primary care physicians (control group) for treating pediatric obesity in the primary care setting. Seventy-six youth with obesity (body mass index [BMI] >95th percentile or >90th percentile plus waist circumference >90th percentile, aged 9 to 17 years) participated in a 12-month, randomized, controlled trial, conducted at a primary care unit in Northern México from June 2006 through October 2007. Participants randomized to lifestyle intervention attended a family-centered program consisting of 12 sessions of behavioral curriculum, dietary advice from a registered dietitian (weekly for the first 3 months and monthly thereafter), and monthly consultations with a primary care physician. Control group participants attended monthly consultations with a primary care physician who received a brief training on obesity. Forty-three (57%) participants completed the 12 months of study. After 12 months, mean changes (95% confidence interval) in body weight for the lifestyle group and the control group were -0.8 kg (-3.2, 1.5) vs +5.6 kg (3, 8.2; P<0.001) and mean changes in BMI were -1.8 (-2.6, -0.9) vs +0.4 (-0.5, 1.3; P<0.001), respectively. Intention-to-treat analysis at 12 months confirmed significant differences in primary outcomes (weight -3.5 kg, P=0.02; BMI -1.2, P=0.03) in favor of the lifestyle group. This study provides preliminary evidence that primary care physicians supported by a registered dietitian and a behavioral curriculum can be a successful strategy for treating pediatric obesity in the primary care setting., (Copyright 2010 American Dietetic Association. Published by Elsevier Inc. All rights reserved.)

In pursuing the origin of informational polymers, we followed the assumption that their spontaneous formation could only have occurred: (i) if all the components were present at the same site and in the same reaction, and (ii) if the thermodynamics of the processes involved favored a polymerized over a monomeric state of the precursors. A plausible scenario satisfying both assumptions is provided.

In multiple myeloma (MM), circulating endothelial cells (CECs) represent a vascular marker of angiogenesis and may reflect tumor mass. In this report, we showed that, in 5 MM patients with 13q14 deletion, CECs carried the same chromosome aberration as the neoplastic plasma cells (11%-32% of CECs with 13q14 deletion). Most of the CECs displayed immunophenotypic features of endothelial progenitor cells as they expressed CD133, a marker gradually lost during endothelial differentiation and absent on mature endothelial cells. To the contrary, in 3 patients with monoclonal gammopathy of undetermined significance and 13q14 deletion, CECs were cytogenetically normal and had a mature immunophenotype. In MM CECs, immunoglobulin genes were clonally rearranged. These findings suggest a possible origin of CECs from a common hemangioblast precursor that can give rise to both plasma cells and endothelial cells and point to a direct contribution of MM-derived CECs to tumor vasculogenesis and possibly to the spreading and progression of the disease.

The essential Saccharomyces cerevisiae regulatory protein Rap1 contains two tandem Myb-like DNA binding sub-domains that interact with two defined DNA "hemisites", separated by a trinucleotide linker sequence. We have mapped the thermodynamically defined DNA-binding site of Rap1 by a primer extension method coupled with electrophoretic separation of bound and unbound DNAs. Relative to published consensus sequences, we detect binding interactions that extend 3 bp beyond the 5'-end of the putative DNA-binding site. This new site of interaction is located where the DNA minor groove faces the protein, and may account for the major DNA bending induced by Rap1p that previous studies have mapped to a site immediately upstream of the consensus binding site. In addition, we show that a minimal DNA-binding site made of one single consensus hemisite, preceded or followed by a spacer trinucleotide that interacts with the unstructured protein linker between the two Rap1p DNA binding domains, is able to bind the protein, although at lower affinity. These findings may explain the observed in vivo binding properties of Rap1p at many promoters that lack canonical binding sites.

We have analyzed in detail the structure of RAP1-UAS(RPG) complexes in Saccharomyces cerevisiae cells using multi-hit KMnO(4), UV and micrococcal nuclease high-resolution footprinting. Three copies of the Rap1 protein are bound to the promoter simultaneously in exponentially growing cells, as shown by KMnO(4) multi-hit footprinting analysis, causing extended and diagnostic changes in the DNA structure of the region containing the UAS(RPG). Amino acid starvation does not cause loss of Rap1p from the complex; however, in vivo UV-footprinting reveals the occurrence of structural modifications of the complex. Moreover, low-resolution micrococcal nuclease digestion shows that the chromatin of the entire region is devoid of positioned nucleosomes but is susceptible to changes in accessibility to the nuclease upon amino acid starvation. The implications of these results for the mechanism of Rap1p action are discussed., ((c) 2002 Elsevier Science Ltd.)