Research Spotlight

Hammoud, R., Pannia, E., Kubant, R., Wasek, B., Bottiglieri, T., Malysheva, O.V., Caudill, M.A. and Anderson, G.H. (2021). “Choline and Folic Acid in Diets Consumed during Pregnancy Interact to Program Food Intake and Metabolic Regulation of Male Wistar Rat Offspring.” J Nutr Feb 9;nxaa419. [Epub ahead of print].

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BACKGROUND: North American women consume high folic acid (FA), but most are not meeting the adequate intakes for choline. High-FA gestational diets induce an obesogenic phenotype in rat offspring. It is unclear if imbalances between FA and other methyl-nutrients (i.e., choline) account for these effects. OBJECTIVE: This study investigated the interaction of choline and FA in gestational diets on food intake, body weight, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring. METHODS: Pregnant Wistar rats were fed an AIN-93G diet with recommended choline and FA [RCRF; 1-fold, control] or high (5-fold) FA with choline at 0.5-fold [low choline and high folic acid (LCHF)], 1-fold [recommended choline and high folic acid (RCHF)], or 2.5-fold [high choline and high folic acid (HCHF)]. Male offspring were weaned to an RCRF diet for 20 wk. Food intake, weight gain, plasma energy-regulatory hormones, brain and plasma one-carbon metabolites, and RNA sequencing (RNA-seq) in pup hypothalamuses were assessed. RESULTS: Adult offspring from LCHF and RCHF, but not HCHF, gestational diets had 10% higher food intake and weight gain than controls (P < 0.01). HCHF newborn pups had lower plasma insulin and leptin compared with LCHF and RCHF pups (P < 0.05), respectively. Pup brain choline (P < 0.05) and betaine (P < 0.01) were 22-33% higher in HCHF pups compared with LCHF pups; methionine was ∼23% lower after all high FA diets compared with RCRF (P < 0.01). LCHF adult offspring had lower brain choline (P < 0.05) than all groups and lower plasma 5-methyltetrahydrofolate (P < 0.05) than RCRF and RCHF groups. HCHF adult offspring had lower plasma cystathionine (P < 0.05) than LCHF adult offspring and lower homocysteine (P < 0.01) than RCHF and RCRF adult offspring. RNA-seq identified 144 differentially expressed genes in the hypothalamus of HCHF newborns compared with controls. CONCLUSIONS: Increased choline in gestational diets modified the programming effects of high FA on long-term food intake regulation, plasma energy-regulatory hormones, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring, emphasizing a need for more attention to the choline and FA balance in maternal diets.

Weiss, E., Saner, F., Asrani, S.K., Biancofiore, G., Blasi, A., Lerut, J., Durand, F., Fernandez, J., Findlay, J.Y., Fondevila, C., Francoz, C., Gustot, T., Jaber, S., Karvellas, C., Kronish, K., Laleman, W., Laterre, P.F., Levesque, E., Mandell, M.S., Mc Phail, M., Muiesan, P., Olson, J.C., Olthoff, K., Daniele Pinna, A., Reiberger, T., Reyntjens, K., Saliba, F., Scatton, O., Simpson, K.J., Soubrane, O., Subramanian, R.M., Tacke, F., Tomescu, D., Xia, V., Wagener, G. and Paugam-Burtz, C. (2021). “When Is a Critically Ill Cirrhotic Patient Too Sick to Transplant? Development of Consensus Criteria by a Multidisciplinary Panel of 35 International Experts.” Transplantation 105(3): 561-568.

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BACKGROUND: Critically ill cirrhotic patients are increasingly transplanted, but there is no consensus about futile liver transplantation (LT). Therefore, the decision to delay or deny LT is often extensively debated. These debates arise from different opinions of futility among transplant team members. This study aims to achieve a multinational and multidisciplinary consensus on the definition of futility in LT and to develop well-articulated criteria for not proceeding with LT due to futility. METHODS: Thirty-five international experts from anesthesiology/intensive care, hepatology, and transplant surgery were surveyed using the Delphi method. More than 70% of similar answers to a question were necessary to define agreement. RESULTS: The panel recommended patient and graft survival at 1 year after LT to define futility. Severe frailty and persistent fever or <72 hours of appropriate antimicrobial therapy in case of ongoing sepsis were considered reasons to delay LT. A simple assessment of the number of organs failing was considered the most appropriate way to decide whether LT should be delayed or denied, with respiratory, circulatory and metabolic failures having the most influence in this decision. The thresholds of severity of organ failures contraindicating LT for which a consensus was achieved were a Pao2/FiO2 ratio<150 mm Hg, a norepinephrine dose >1 μg/kg per minute and a serum lactate level >9 mmol/L. CONCLUSIONS: Our expert panel provides a consensus on the definition of futile LT and on specific criteria for postponing or denying LT. A framework that may facilitate the decision if a patient is too sick for transplant is presented.

Fallahzadeh, M.A., Hansen, D.J., Trotter, J.F., Everson, G.T., Saracino, G., Rahimi, R.S., Helmke, S., Boutte, J. and Asrani, S.K. (2021). “Predicting clinical decompensation in patients with cirrhosis using the Hepquant-SHUNT test.” Aliment Pharmacol Ther Feb 8. [Epub ahead of print].

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BACKGROUND: Early identification of risk for decompensation in clinically stable cirrhotic patients helps specialists target early interventions and supports effective referrals from primary care providers to specialty centres. AIMS: To examine whether the HepQuant-SHUNT test (HepQuant LLC, Greenwood Village, Colorado, USA) predicts decompensation and the need for liver transplantation, hospitalisation or liver-related death. METHODS: Thirty-five compensated and 35 subjects with a previous episode of decompensation underwent the SHUNT Test and were followed for a median of 4.2 years. The disease severity index (DSI) (range 0-50) was examined for association with decompensation in compensated patients; and liver transplantation, liver-related death, and the number and days of liver related hospitalisations in all. DSI prediction of decompensation was also evaluated in 84 subjects with compensated cirrhosis from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C) followed for a median of 5.8 years. RESULTS: At baseline, subjects with prior decompensation had significantly higher DSI than compensated subjects (32.6 vs 20.9, P < 0.001). DSI ≥24 distinguished the decompensated from the compensated patients and independently predicted adverse clinical outcomes (hazard ratio: 4.92, 95% confidence interval: 1.42-17.06). In the HALT-C cohort, 65% with baseline DSI ≥24 vs 19% with DSI <24 experienced adverse clinical outcomes (relative risk 3.45, P < 0.0001). CONCLUSIONS: The SHUNT test is a novel, noninvasive test that predicts risk of decompensation in previously compensated patients. DSI ≥24 is independently associated with risk for clinical decompensation, liver transplantation, death and hospitalisation.

Schinstock, C.A., Askar, M., Bagnasco, S.M., Batal, I., Bow, L., Budde, K., Campbell, P., Carroll, R., Clahsen-van Groningen, M.C., Cooper, M., Cornell, L.D., Cozzi, E., Dadhania, D., Diekmann, F., Hesselink, D.A., Jackson, A.M., Kikic, Z., Lower, F., Naesens, M., Roelofs, J.J., Sapir-Pichhadze, R. and Kraus, E.S. (2021). “A 2020 Banff Antibody-mediatedInjury Working Group examination of international practices for diagnosing antibody-mediated rejection in kidney transplantation – a cohort study.” Transpl Int 34(3): 488-498.

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The Banff antibody-mediated rejection (ABMR) classification is vulnerable to misinterpretation, but the reasons are unclear. To better understand this vulnerability, we evaluated how ABMR is diagnosed in practice. To do this, the Banff Antibody-Mediated Injury Workgroup electronically surveyed an international cohort of nephrologists/surgeons (n = 133) and renal pathologists (n = 99). Most providers (97%) responded that they use the Banff ABMR classification at least sometimes, but DSA information is often not readily available. Only 41.1% (55/133) of nephrologists/surgeons and 19.2% (19/99) of pathologists reported that they always have DSA results when the biopsy is available. Additionally, only 19.6% (26/133) of nephrologists/surgeons responded that non-HLA antibody or molecular transcripts are obtained when ABMR histologic features are present but DSA is undetected. Several respondents agreed that histologic features concerning for ABMR in the absence of DSA and/or C4d are not well accounted for in the current classification [31.3% (31/99) pathologists and 37.6% (50/133) nephrologist/surgeons]. The Banff ABMR classification appears widely accepted, but efforts to improve the accessibility of DSA information for the multidisciplinary care team are needed. Further clarity is also needed in Banff ABMR nomenclature to account for the spectrum of ABMR and for histologic features suspicious for ABMR when DSA is absent.

Zhu, Q., Shao, Y., Wang, Z., Chen, X., Li, C., Liang, Z., Jia, M., Guo, Q., Zhao, H., Kong, L. and Zhang, L. (2021). “DeepS: A web server for image optical sectioning and super resolution microscopy based on a deep learning framework.” Bioinformatics Mar 2;btab144. [Epub ahead of print].

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MOTIVATION: Microscopy technology plays important roles in many biological research fields. Solvent-cleared brain high-resolution (HR) 3 D image reconstruction is an important microscopy application. However, 3 D microscopy image generation is time-consuming and expensive. Therefore, we have developed a deep learning framework (DeepS) for both image optical sectioning and super resolution microscopy. RESULTS: Using DeepS to perform super resolution solvent-cleared mouse brain microscopy 3 D image yields improved performance in comparison with the standard image processing workflow. We have also developed a web server to allow online usage of DeepS. Users can train their own models with only one pair of training images using the transfer learning function of the web server. AVAILABILITY: http://deeps.cibr.ac.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.