Temporal relations between peripheral and central arousals in good and poor sleepers.

Good sleepers and patients with insomnia symptoms (poor sleepers) were tracked with two measures of arousal; conventional polysomnography (PSG) for electroencephalogram (EEG) assessed cortical arousals, and a peripheral arterial tonometry device was used for the detection of peripheral nervous system (PNS) arousals associated with vasoconstrictions. The relationship between central (cortical) and peripheral (autonomic) arousals was examined by evaluating their close temporal dynamics. Cortical arousals almost invariably were preceded and followed by peripheral activations, while large peripheral autonomic arousals were followed by cortical arousals only half of the time. The temporal contiguity of these two types of arousals was altered in poor sleepers, and poor sleepers displayed a higher number of cortical and peripheral arousals compared with good sleepers. Given the difference in the number of peripheral autonomic arousals between good and poor sleepers, an evaluation of such arousals could become a means of physiologically distinguishing poor sleepers.

Psychological Health of Surgeons in a Time of COVID-19: A Global Survey.

OBJECTIVE: To assess the degree of psychological impact among surgical providers during the COVID-19 pandemic. SUMMARY OF BACKGROUND DATA: The COVID-19 pandemic has extensively impacted global healthcare systems. We hypothesized that the degree of psychological impact would be higher for surgical providers deployed for COVID-19 work, certain surgical specialties, and for those who knew of someone diagnosed with, or who died, of COVID-19. METHODS: We conducted a global web-based survey to investigate the psychological impact of COVID-19. The primary outcomes were the depression anxiety stress scale-21 and Impact of Event Scale-Revised scores. RESULTS: A total of 4283 participants from 101 countries responded. 32.8%, 30.8%, 25.9%, and 24.0% screened positive for depression, anxiety, stress, and PTSD respectively. Respondents who knew someone who died of COVID-19 were more likely to screen positive for depression, anxiety, stress, and PTSD (OR 1.3, 1.6, 1.4, 1.7 respectively, all P < 0.05). Respondents who knew of someone diagnosed with COVID-19 were more likely to screen positive for depression, stress, and PTSD (OR 1.2, 1.2, and 1.3 respectively, all P < 0.05). Surgical specialties that operated in the head and neck region had higher psychological distress among its surgeons. Deployment for COVID- 19-related work was not associated with increased psychological distress. CONCLUSIONS: The COVID-19 pandemic may have a mental health legacy outlasting its course. The long-term impact of this ongoing traumatic event underscores the importance of longitudinal mental health care for healthcare personnel, with particular attention to those who know of someone diagnosed with, or who died of COVID-19.

Intraductal papillary mucinous neoplasm: a new entity among biliary tract neoplasms.

Biliary tract intraductal papillary mucinous neoplasms (BT-IPMN) are a rare entity that develop within the bile duct lumen and are recognized as a precursor of invasive carcinoma in up to 40-80 % of cases.

Hepatic epithelioid hemangioendothelioma: a rare vascular tumor with an unpredictable diagnosis.

We present the case of a 58-year-old female with no relevant medical or surgical history, who was referred to our hospital with a solitary hepatic lesion. She presented a slightly abnormal liver function in a routine blood test: ALT 71 U/l (range 0-33), AST 40 U/l (range 0-32) and GGT 71 U/l (range 0-40), with no symptoms. Ultrasound imaging showed a 3-cm-size focal lesion with a peripheral hypoechoic rim in the right hepatic lobe. Abdominal computed tomography (CT) scan after contrast injection revealed a subcapsular hypodense lesion in segment VII with capsular retraction. Other extrahepatic lesions were not seen.

Low-Cost, High-Frequency, Data Acquisition System for Condition Monitoring of Rotating Machinery through Vibration Analysis-Case Study.

Data acquisition is a crucial stage in the execution of condition monitoring (CM) of rotating machinery, by means of vibration analysis. However, the major challenge in the execution of this technique lies in the features of the recording equipment (accuracy, resolution, sampling frequency and number of channels) and the cost they represent. The present work proposes a low-cost data acquisition system, based on Raspberry-Pi, with a high sampling frequency capacity in the recording of up to three channels. To demonstrate the effectiveness of the proposed data acquisition system, a case study is presented in which the vibrations registered in a bearing are analyzed for four degrees of failure.

A Broad Set of Chromatin Factors Influences Splicing.

Several studies propose an influence of chromatin on pre-mRNA splicing, but it is still unclear how widespread and how direct this phenomenon is. We find here that when assembled in vivo, the U2 snRNP co-purifies with a subset of chromatin-proteins, including histones and remodeling complexes like SWI/SNF. Yet, an unbiased RNAi screen revealed that the outcome of splicing is influenced by a much larger variety of chromatin factors not all associating with the spliceosome. The availability of this broad range of chromatin factors impacting splicing further unveiled their very context specific effect, resulting in either inclusion or skipping, depending on the exon under scrutiny. Finally, a direct assessment of the impact of chromatin on splicing using an in vitro co-transcriptional splicing assay with pre-mRNAs transcribed from a nucleosomal template, demonstrated that chromatin impacts nascent pre-mRNP in their competence for splicing. Altogether, our data show that numerous chromatin factors associated or not with the spliceosome can affect the outcome of splicing, possibly as a function of the local chromatin environment that by default interferes with the efficiency of splicing.

Villous adenoma of the choledocho: an infrequent pathology of the main bile duct.

We present the case of a patient with obstructive jaundice due to a polylobulated lesion at the middle common bile duct that is identified as a villous adenoma of the main bile duct. This entity is infrequent with few references in the bibliography. It is a benign pathology but with risk of malignancy, so the diagnosis and resection is essential for adequate treatment.

Lower gastrointestinal bleeding as a form of presentation in an adult case of Abernethy syndrome.

We report the case of a 29-year-old patient who presented with a short history of lower gastrointestinal bleeding. A diagnosis of Abernethy syndrome was made (congenital extrahepatic portosystemic shunt) after this uncommon clinical presentation. The prevalence of this congenital malformation is very low and usually manifests during the pediatric age, according to previously published reports.

Phenotypic Diversity Using Bimodal and Unimodal Expression of Stress Response Proteins.

Populations of cells need to express proteins to survive the sudden appearance of stressors. However, these mechanisms may be taxing. Populations can introduce diversity, allowing individual cells to stochastically switch between fast-growing and stress-tolerant states. One way to achieve this is to use genetic networks coupled with noise to generate bimodal distributions with two distinct subpopulations, each adapted to a stress condition. Another survival strategy is to rely on random fluctuations in gene expression to produce continuous, unimodal distributions of the stress response protein. To quantify the environmental conditions where bimodal versus unimodal expression is beneficial, we used a differential evolution algorithm to evolve optimal distributions of stress response proteins given environments with sudden fluctuations between low and high stress. We found that bimodality evolved for a large range of environmental conditions. However, we asked whether these findings were an artifact of considering two well-defined stress environments (low and high stress). As noise in the environment increases, or when there is an intermediate environment (medium stress), the benefits of bimodality decrease. Our results indicate that under realistic conditions, a continuum of resistance phenotypes generated through a unimodal distribution is sufficient to ensure survival without a high cost to the population.

Noise and low-level dynamics can coordinate multicomponent bet hedging mechanisms.

To counter future uncertainty, cells can stochastically express stress response mechanisms to diversify their population and hedge against stress. This approach allows a small subset of the population to survive without the prohibitive cost of constantly expressing resistance machinery at the population level. However, expression of multiple genes in concert is often needed to ensure survival, requiring coordination of infrequent events across many downstream targets. This raises the question of how cells orchestrate the timing of multiple rare events without adding cost. To investigate this, we used a stochastic model to study regulation of downstream target genes by a transcription factor. We compared several upstream regulator profiles, including constant expression, pulsatile dynamics, and noisy expression. We found that pulsatile dynamics and noise are sufficient to coordinate expression of multiple downstream genes. Notably, this is true even when fluctuations in the upstream regulator are far below the dissociation constants of the regulated genes, as with infrequently activated genes. As an example, we simulated the dynamics of the multiple antibiotic resistance activator (MarA) and 40 diverse downstream genes it regulates, determining that low-level dynamics in MarA are sufficient to coordinate expression of resistance mechanisms. We also demonstrated that noise can play a similar coordinating role. Importantly, we found that these benefits are present without a corresponding increase in the population-level cost. Therefore, our model suggests that low-level dynamics or noise in a transcription factor can coordinate expression of multiple stress response mechanisms by engaging them simultaneously without adding to the overall cost.

Tunable stochastic pulsing in the Escherichia coli multiple antibiotic resistance network from interlinked positive and negative feedback loops.

Cells live in uncertain, dynamic environments and have many mechanisms for sensing and responding to changes in their surroundings. However, sudden fluctuations in the environment can be catastrophic to a population if it relies solely on sensory responses, which have a delay associated with them. Cells can reconcile these effects by using a tunable stochastic response, where in the absence of a stressor they create phenotypic diversity within an isogenic population, but use a deterministic response when stressors are sensed. Here, we develop a stochastic model of the multiple antibiotic resistance network of Escherichia coli and show that it can produce tunable stochastic pulses in the activator MarA. In particular, we show that a combination of interlinked positive and negative feedback loops plays an important role in setting the dynamics of the stochastic pulses. Negative feedback produces a pulsatile response that is tunable, while positive feedback serves to amplify the effect. Our simulations show that the uninduced native network is in a parameter regime that is of low cost to the cell (taxing resistance mechanisms are expressed infrequently) and also elevated noise strength (phenotypic variability is high). The stochastic pulsing can be tuned by MarA induction such that variability is decreased once stresses are sensed, avoiding the detrimental effects of noise when an optimal MarA concentration is needed. We further show that variability in the expression of MarA can act as a bet hedging mechanism, allowing for survival in time-varying stress environments, however this effect is tunable to allow for a fully induced, deterministic response in the presence of a stressor.

Recommendations from the Galician Oncological Society and the Galician Society of Nuclear Medicine for the use of 177Lu-PSMA-617 radioligand-therapy in prostate cancer.

Theragnostic is a type of precision medicine that uses molecules linked to radioactive isotopes for the diagnosis and treatment of diseases. In recent years, it has gained significant importance to treat neuroendocrine tumors and is currently being used in prostate cancer. Various radiopharmaceuticals have emerged for diagnosing and detecting lesions showing prostate-specific membrane antigen (PSMA) positivity on the Positron emission tomography/computed tomography scan, being the most widely used labeled with [68Ga] and [18F]. Its use as therapy in prostate cancer (PC) has been assessed in the VISION, TheraP, and PSMAfore clinical trials conducted with the radioligand [177Lu]Lu-PSMA-617, demonstrating significant antitumor activity. The aim of this article is to present practical recommendations, based on current available scientific evidence and on a multidisciplinary consensus, for the diagnosis and treatment with [177Lu]Lu-PSMA-617 in patients with PC.

Effective tax rates of multinational corporations: Country-level estimates.

Effective tax rates (ETRs) estimated from the income statement data of multinational corporations (MNCs) are useful for comparing MNCs' corporate income taxation across countries. In this paper, we propose a new methodological approach to estimate ETRs as reliably and for as many countries as possible using Orbis' unconsolidated data for the 2011-2015 period. We focus on countries with at least 50 available companies, which results in a sample of 47, mostly European, countries. We estimate the ETR of a country as the ratio of corporate income tax to gross income for all affiliates of MNCs in that country, weighted by gross income. We propose four ETR estimations, including lower and upper bounds, which differ by gross income calculation. We find that ETRs substantially differ from statutory tax rates for some countries. For example, we show that despite similar statutory rates of 28% and 29%, MNCs in Luxembourg paid as little as 1-8% of gross income in taxes, while those in Norway paid as much as 46-67%. Despite being the best available, existing data is still imperfect. We therefore call for better data in the form of MNCs' unconsolidated, public country-by-country reporting data.

Conservative treatment of suprahepatic pseudoaneurysm in a pediatric patient. / Manejo conservador de un pseudoaneurisma suprahepático en un paciente pediátrico.

INTRODUCTION: Suprahepatic and inferior vena cava (IVC) pseudoaneurysms are rare in children. Most cases in adults are treated surgically due to the high risk of rupture. CASE REPORT: Seven-year-old girl referred for a thoracic-abdominal trauma of unknown origin. Hemodynamically stable, with a hemoglobin level of 9.1 g/dl. An emergency CT scan was performed, showing a pseudoaneurysm at the confluence of the IVC with the middle and left suprahepatic veins, with active bleeding contained by the hepatic capsule. Given the hemodynamic stability and surgical risk, conservative treatment was decided upon. CT-scan at 24 hours showed cessation of bleeding. A control CT-scan was performed one month, three months, one year, and one and a half years later, showing the lesion had disappeared. DISCUSSION: Conservative treatment of suprahepatic vein pseudoaneurysm/ICV is feasible in the case of hemodynamic stability provided that strict clinical and radiological surveillance is maintained.

INTRODUCCION: Los pseudoaneurismas suprahepáticos y de la vena cava inferior (VCI) son excepcionales en niños. La mayoría de casos en adultos se manejan quirúrgicamente debido al alto riesgo de rotura. CASO CLINICO: Niña de siete años remitida por traumatismo tóraco-abdominal no presenciado. Hemodinámicamente estable, con hemoglobina de 9,1 g/dL. Se realiza un TC urgente, objetivándose un pseudoaneurisma en la confluencia de la VCI con las suprahepáticas media e izquierda, con sangrado activo contenido por la cápsula hepática. Dada la estabilidad hemodinámica y el riesgo quirúrgico, se optó por un manejo conservador. En el TC a las veinticuatro horas se observó cese del sangrado. Se realizó un TC de control al mes, tres meses, un año y año y medio, con desaparición de la lesión. COMENTARIOS: El manejo conservador del pseudoaneurisma de las venas suprahepáticas/VCI es factible en caso de estabilidad hemodinámica siempre que se mantenga una vigilancia clínica y radiológica estrechas.

Correlation of Prenatal and Postnatal Diagnosis in Umbilical-Portal-Systemic Venous Shunts.

INTRODUCTION: Umbilical-portal-systemic venous shunts (UPSVS) are rare anomalies in the development of the fetal venous system. There are several postnatal and prenatal classifications of hepatic venous anomalies but the link between them is missing. We aimed to review the prenatal to postnatal diagnosis correlation in UPSVS at our center. METHODS: It is a retrospective study of patients diagnosed with UPSVS between 2019 and 2021 at our institution. Demographic, obstetric, genetic, and neonatal data were reviewed with special focus on prenatal and postnatal ultrasounds. RESULTS: A total of seven patients were diagnosed with UPSVS at a median of 24 (20-34) weeks of gestational age. All patients were male and 62% were Caucasian. None of the patients had chromosomopathies or cardiac anomalies. One patient had renal ectopia, another one had a single umbilical artery, and a third one suffered from intrauterine growth retardation. An umbilico-systemic shunt (USS) was found in two patients and a ductus venosus-systemic shunt (DVSS) in the rest. Patients with USS were diagnosed postnatally with intrahepatic portosystemic shunts. One of the DVSS patients was transferred to another hospital and the other four had normal postnatal cardiac ultrasounds, with normal abdominal ultrasounds in two patients and lack of postnatally abdominal control in the other two. All babies were found to be doing well at a median follow-up of 1 month (0-24). CONCLUSION: There is a knowledge gap in the natural history of UPSVS between fetal and neonatal life. Building bridges between prenatal and postnatal research is mandatory in order to understand these rare anomalies.

Usefulness of PIVKA-II for monitoring after liver transplantation in patients with hepatocellular carcinoma.

The high morbidity and mortality of hepatocellular carcinoma (HCC) has encouraged the search for new biomarkers to be used alongside alpha-foetoprotein (AFP) and imaging tests. The aim of this study was to evaluate the clinical contribution of protein induced by vitamin K absence or antagonist-II (PIVKA-II) for HCC monitoring after liver transplantation (LT) and compare it with AFP, a routinely used tumour marker. A total of 46 HCC patients (Milan criteria) were enrolled in this study. Serum levels of PIVKA-II and AFP were measured before and after transplantation. Clinical features were determined for all the patients that were included. Significant correlations were found between PIVKA-II expression levels and some clinicopathological features, such as tumour size and number of pre-transplant transarterial chemoembolizations (TACEs). Serum levels of PIVKA-II and AFP decreased significantly after LT and increased in patients with tumour recurrence. Serum PIVKA-II levels may play an important role in predicting disease severity. Furthermore, monitoring PIVKA-II levels in HCC transplant recipients reflects the tumor early recurrence after transplantation and could be used, complementing AFP and imaging tests, as a novel biomarker of this pathology.

Immunohistochemical expression of VEGFR1 in non small cell lung carcinomas: Lower VEGFR1 expression is asociated with squamous cell carcinoma subtype and high SUV max values in 18F-FDG PET.

BACKGROUND: To study the possible relation between immunohistochemical expression of vascular endothelial growth factor receptor 1 (VEGFR1) and the maximum standardised uptake value (SUV max) of 18F-FDG PET in patients with non small cell lung cancer (NSCLC). MATERIAL AND METHODS: The study included 39 patients with NSCLC (24 squamous cell carcinomas and 15 adenocarcinomas). According to the clinical stage, the patients were distributed as follows: 8 stage I, 7 stage II, 15 stage III and 9 stage IV. Immunohistochemical expression of VEGFR1 was studied through the technique of tissue-matrix using Tissue Arrayer Device (Beecher Instruments, Sun Prairie, WI), using the polyclonal antibody against VEGFR1 (Santa Cruz Biotechnology, California, USA). RESULTS: Positive VEGFR1 immunohistochemical expression was noted in 23 cases (59%). The number of positive tumours was not related with clinical stage but there was a different statistically significant association (p:0,0009) between VEGFR1 positivity and histological type, corresponding the greater percentages of positive results to adenocarcinomas (93,3%) versus in squamous cell carcinomas (37,5%). Likewise, SUV max values were higher (p: 0,039) in negative VEGFR1 carcinomas than in positive VEGFR1 tumors (r: 4-32,1; 16,4+/-6,4 (median 16,1) vs r: 3-47; 14,5+/-8,6 (12,8)). CONCLUSIONS: Our results led us to consider that in NSCLC, the negative VEGFR1 immunohistochemical expression is associated significantly with squamous cell carcinomas subtype and with higher SUV max values in 18F-FDG-PET.

Tissue-Specific Human Extracellular Matrix Scaffolds Promote Pancreatic Tumour Progression and Chemotherapy Resistance.

Over 80% of patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed at a late stage and are locally advanced or with concurrent metastases. The aggressive phenotype and relative chemo- and radiotherapeutic resistance of PDAC is thought to be mediated largely by its prominent stroma, which is supported by an extracellular matrix (ECM). Therefore, we investigated the impact of tissue-matched human ECM in driving PDAC and the role of the ECM in promoting chemotherapy resistance. Decellularized human pancreata and livers were recellularized with PANC-1 and MIA PaCa-2 (PDAC cell lines), as well as PK-1 cells (liver-derived metastatic PDAC cell line). PANC-1 cells migrated into the pancreatic scaffolds, MIA PaCa-2 cells were able to migrate into both scaffolds, whereas PK-1 cells were able to migrate into the liver scaffolds only. These differences were supported by significant deregulations in gene and protein expression between the pancreas scaffolds, liver scaffolds, and 2D culture. Moreover, these cell lines were significantly more resistant to gemcitabine and doxorubicin chemotherapy treatments in the 3D models compared to 2D cultures, even after confirmed uptake by confocal microscopy. These results suggest that tissue-specific ECM provides the preserved native cues for primary and metastatic PDAC cells necessary for a more reliable in vitro cell culture.

Single-cell atlas of human liver development reveals pathways directing hepatic cell fates.

The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications.