Biomaterial engineering strategies for modeling the Bruch's membrane in age-related macular degeneration

Age-related macular degeneration,a multifactorial inflammatory degenerative retinal disease,ranks as the leading cause of blindness in the elderly.Strikingly,there is a scarcity of curative therapies,especially for the atrophic advanced form of age-related macular degeneration,likely due to the lack of models able to fully recapitulate the native structure of the outer blood retinal barrier,the prime to rget tissue of age-related macular degeneration.Standard in vitro systems rely on 2D monocultures unable to adequately reproduce the structure and function of the outer blood retinal barrier,integrated by the dynamic interaction of the retinal pigment epithelium,the Bruch's membrane,and the underlying choriocapillaris.The Bruch's membrane provides structu ral and mechanical support and regulates the molecular trafficking in the outer blood retinal barrier,and therefo re adequate Bruch's membrane-mimics are key for the development of physiologically relevant models of the outer blood retinal barrie r.In the last years,advances in the field of biomaterial engineering have provided novel approaches to mimic the Bruch's membrane from a variety of materials.This review provides a discussion of the integrated properties and function of outer blood retinal barrier components in healt hy and age-related macular degeneration status to understand the requirements to adequately fabricate Bruch's membrane biomimetic systems.Then,we discuss novel materials and techniques to fabricate Bruch's membrane-like scaffolds for age-related macular degeneration in vitro modeling,discussing their advantages and challenges with a special focus on the potential of Bruch's membrane-like mimics based on decellularized tissue.

Differential response of injured and healthy retinas to syngeneic and allogeneic transplantation of a clonal cell line of immortalized olfactory ensheathing glia:a double-edged sword

Olfactory ensheathing glia promote axonal regeneration in the mammalian central nervous system,including retinal ganglion cell axonal growth through the injured optic nerve.Still,it is unknown whether olfactory ensheathing glia also have neuroprotective properties.Olfactory ensheathing glia express brain-derived neurotrophic factor,one of the best neuroprotectants for axotomized retinal ganglion cells.Therefore,we aimed to investigate the neuroprotective capacity of olfactory ensheating glia after optic nerve crush.Olfactory ensheathing glia cells from an established rat immortalized clonal cell line,TEG3,were intravitreally injected in intact and axotomized retinas in syngeneic and allogeneic mode with or without microglial inhibition or immunosuppressive treatments.Anatomical and gene expression analyses were performed.Olfactory bulb-derived primary olfactory ensheathing glia and TEG3 express major histocompatibility complex classⅡmolecules.Allogeneically and syngenically transplanted TEG3 cells survived in the vitreous for up to 21 days,forming an epimembrane.In axotomized retinas,only the allogeneic TEG3 transplant rescued retinal ganglion cells at 7 days but not at 21 days.In these retinas,microglial anatomical activation was higher than after optic nerve crush alone.In intact retinas,both transplants activated microglial cells and caused retinal ganglion cell death at 21 days,a loss that was higher after allotransplantation,triggered by pyroptosis and partially rescued by microglial inhibition or immunosuppression.However,neuroprotection of axotomized retinal ganglion cells did not improve with these treatments.The different neuroprotective properties,different toxic effects,and different responses to microglial inhibitory treatments of olfactory ensheathing glia in the retina depending on the type of transplant highlight the importance of thorough preclinical studies to explore these variables.

Effects of Institut Georges Lopez-1 and Celsior preservation solutions on liver graft injury

AIM: To compare Institut Georges Lopez(IGL-1) and Celsior preservation solutions for hepatic endothelium relaxation and liver cold ischemia reperfusion injury(IRI).METHODS: Two experimental models were used.In the first one, acetylcholine-induced endotheliumdependent relaxation(EDR) was measured in isolated ring preparations of rat hepatic arteries preserved or not in IGL-1 or Celsior solutions(24 h at 4 ℃).To determine nitric oxide(NO) and cyclooxygenase EDR, hepatic arteries were incubated with L-NG-nitroarginine methyl ester(L-NAME), an inhibitor of endothelium nitric oxide synthase(e NOS), or with L-NAME plus indomethacin, an inhibitor of cyclooxygenase.In the second experiment, rat livers were cold-stored in IGL-1 or Celsior solutions for 24 h at 4 ℃ and then perfused "ex vivo " for 2 h at 37 ℃.Liver injury was assessed by transaminase measurements, liver function by bile production and bromosulfophthalein clearance, oxidative stress by malondialdehyde levels and catalase activity and alterations in cell signaling pathways by pA kt, pA MPK, eN OS and MAPKs proteins level.RESULTS: After cold storage for 24 h with either Celsior or IGL-1, EDR was only slightly altered.Infreshly isolated arteries, EDR was exclusively mediated by NO.However, cold-stored arteries showed NOand COX-dependent relaxation.The decrease in NO-dependent relaxation after cold storage was significantly more marked with Celsior.The second study indicated that IGL-1 solution obtained better liver preservation and protection against IRI than Celsior.Liver injury was reduced, function was improved and there was less oxidative stress.IGL-1 solution activated Akt and AMPK, which was concomitant with increased eN OS expression and nitrite/nitrate levels.Furthermore, MAPKs kinases were regulated in livers preserved with IGL-1 solution since reductions in p-p38, p-ERK and p-JNK protein levels were observed.CONCLUSION: IGL-1 solution preserved NO-dependent relaxation better than Celsior storage solution and enhanced liver graft preservation.

Relevance of proteolysis and proteasome activation in fatty liver graft preservation: An Institut Georges Lopez-1 vs University of Wisconsin appraisal

To compare liver proteolysis and proteasome activation in steatotic liver grafts conserved in University of Wisconsin (UW) and Institut Georges Lopez-1 (IGL-1) solutions.METHODSFatty liver grafts from male obese Zücker rats were conserved in UW and IGL-1 solutions for 24 h at 4 °Cand subjected to “ex vivo” normo-thermic perfusion (2 h; 37 °C). Liver proteolysis in tissue specimens and perfusate was measured by reverse-phase high performance liquid chromatography. Total free amino acid release was correlated with the activation of the ubiquitin proteasome system (UPS: measured as chymotryptic-like activity and 20S and 19S proteasome), the prevention of liver injury (transaminases), mitochondrial injury (confocal microscopy) and inflammation markers (TNF 1 alpha, high mobility group box-1 (HGMB-1) and PPAR gamma), and liver apoptosis (TUNEL assay, cytochrome c and caspase 3).RESULTSProfiles of free AA (alanine, proline, leucine, isoleucine, methionine, lysine, ornithine, and threonine, among others) were similar for tissue and reperfusion effluent. In all cases, the IGL-1 solution showed a significantly higher prevention of proteolysis than UW (P < 0.05) after cold ischemia reperfusion. Livers conserved in IGL-1 presented more effective prevention of ATP-breakdown and more inhibition of UPS activity (measured as chymotryptic-like activity). In addition, the prevention of liver proteolysis and UPS activation correlated with the prevention of liver injury (AST/ALT) and mitochondrial damage (revealed by confocal microscopy findings) as well as with the prevention of inflammatory markers (TNF1alpha and HMGB) after reperfusion. In addition, the liver grafts preserved in IGL-1 showed a significant decrease in liver apoptosis, as shown by TUNEL assay and the reduction of cytochrome c, caspase 3 and P62 levels.CONCLUSIONOur comparison of these two preservation solutions suggests that IGL-1 helps to prevent ATP breakdown more effectively than UW and subsequently achieves a higher UPS inhibition and reduced liver proteolysis.

Analysis of tumor-draining vein secretome: A direct access to tumor-derived extracellular vesicles in surgical lung cancer patients

Tumor-secreted extracellular vesicles(EVs)participate in the metastasis process through different mechanisms,including the preparation of the pre-metastatic niche to grant circulating tumor cells(CTCs)implantation and growth.The study of the metastasis process through the analysis of CTCs and tumor-derived EVs is difficult because of the dilution grade of these elements in peripheral blood.In early-stage lung cancer patients,the tumor-secreted products are even more diluted.An attractive strategy in surgical lung cancer patients is to purify them from a pulmonary tumor-draining vein where they are enriched.The information obtained from the analysis of EVs and CTCs purified from this source could give more accurate information about tumor biology and could be an important source of biomarkers to identify patients at high risk of relapse after curative surgery.

Expansion of the hepatocellular carcinoma Milan criteria in liver transplantation: Future directions

Milan criteria are currently the benchmark related to liver transplantation(LT) for hepatocellular carcinoma. However, several groups have proposed different expanded criteria with acceptable results. In this article, we review the current status of LT beyond the Milan criteria in three different scenarios-expanded criteria with cadaveric LT, downstaging to Milan criteria before LT, and expansion in the context of adult living donor LT. The review focuses on three main questions: what would the impact of the expansion beyond Milan criteria be on the patients on the waiting list; whether the dichotomous criteria(yes/no) currently used are appropriate for LT or continuous survival estimations, such as the one of "Metroticket" and whether it should enter into the clinical practice; and, whether the use of living donor LT in the context of expansion beyond Milan criteria is justified.

Sustained low diffusing capacity in hepatopulmonary syndrome after liver transplantation

AIM： To study the presence of sustained low diffusing capacity （DLco） after liver transplantation （LT） in patients with hepatopulmonary syndrome （HPS）. METHODS： Six patients with mild-to-severe HPS and 24 without HPS who underwent LT were prospectively followed before and after LT at mid-term （median, 15 mo）. HPS patients were also assessed at Iong-tem （median, 86 mo）. RESULTS： Before LT, HPS patients showed lower PaO2 （71 ± 8 mmHg）, higher AaPO2 （43 ± 10 mmHg） and lower DLco （54% ± 9% predicted）, due to a combination of moderate-to-severe ventilation-perfusion （VA/Q） imbalance, mild shunt and diffusion limitation, than non- HPS patients （94 ± 4 mmHg and 19 ± 3 mmHg, and 85% ± 3% predicted, respectively） （P 〈 0.05 each）. Seven non-HPS patients had also reduced DLco （70% ± 4% predicted）. At mid- and long-term after LT, compared to pre- LT, HPS patients normalized PaO2 （91 ± 3 mmHg and 87 ± 5 mmHg）, AaPO2 （14 ± 3 mmHg and 23 ± 5 mmHg） and all VA/Q descriptors （P 〈 0.05 each） without changes in DLco （53% ± 8% and 56% ± 7% predicted, respectively）. Post-LT DLco in non-HPS patients with pre- LT low DLco was unchanged （75% ± 6% predicted）. CONCLUSION： While complete VA/Q resolution in HPS indicates a reversible functional disturbance, sustained low DLco after LT also present in some non-HPS patients, points to persistence of sub-clinical liver-induced pulmonary vascular changes.

Colonic polyps: Is it useful to characterize them with advanced endoscopy?

There have been major developments in endoscopic imaging techniques in recent years.Endoscopes with high definition and magnification can provide high quality images that allow for the histological estimation of lesions in vivo and in situ when combined with ancillary enhancement techniques such as chromoendoscopy(CE)and virtual CE(narrow band imaging fujinon intelligent chromoendoscopy,or i-Scan).Despite the enormous potential for these advanced techniques,their value and feasibility in the clinic are still doubted,particularly in cases of colonic polyps that are slated for removal,where in vivo characterization may be deemed unnecessary.However,there are several advantages offered by such advanced endoscopic imaging.CE with or without magnification demonstrates highly accurate histology and invasion depth prediction,and virtual CE is a feasible and less cumbersome alternative to CE in terms of histological estimation,though not sufficiently accurate for depth invasion prediction.Furthermore,the supplementary information provided by advanced imaging systems can assist the endoscopist in the selection of a strategic approach,such as in deciding whether a colonic lesion should be resected,left in situ,or requires more intensive surgical treatment.Lastly,advanced high-resolution imaging techniques may be more cost effective,such that histopathology of lowrisk lesions following resection can be eliminated.The results of these evaluations and comparisons with traditional CE are presented and discussed.Taken together,the benefits provided by these advanced capabilities justify their development,and advocates their use for the treatment and management of colonic polyps.

Age-related changes in resting-state functional connectivity in older adults

Age-related changes in the brain connectivity of healthy older adults have been widely studied in recent years,with some differences in the obtained results.Most of these studies showed decreases in general functional connectivity,but they also found increases in some particular regions and areas.Frequently,these studies compared young individuals with older subjects,but few studies compared different age groups only in older populations.The purpose of this study is to analyze whole-brain functional connectivity in healthy older adult groups and its network characteristics through functional segregation.A total of 114 individuals,48 to 89 years old,were scanned using resting-state functional magnetic resonance imaging in a resting state paradigm and were divided into six different age groups(<60,60–64,65–69,70–74,75–79,≥80 years old).A partial correlation analysis,a pooled correlation analysis and a study of 3-cycle regions with prominent connectivity were conducted.Our results showed progressive diminution in the functional connectivity among different age groups and this was particularly pronounced between 75 and 79 years old.The oldest group(≥80 years old)showed a slight increase in functional connectivity compared to the other groups.This occurred possibly because of compensatory mechanism in brain functioning.This study provides information on the brain functional characteristics of every age group,with more specific information on the functional progressive decline,and supplies methodological tools to study functional connectivity characteristics.Approval for the study was obtained from the ethics committee of the Comision de Bioetica de la Universidad de Barcelona(approval No.PSI2012-38257)on June 5,2012,and from the ethics committee of the Barcelona’s Hospital Clinic(approval No.2009-5306 and 2011-6604)on October 22,2009 and April 7,2011 respectively.

New determinants of prognosis in bacterial infections in cirrhosis

Despite major advances in the knowledge and management of liver diseases achieved in recent decades,decompensation of cirrhosis still carries a high burden of morbidity and mortality.Bacterial infections are one of the main causes of decompensation.It is very important for clinical management to be aware of the population with the highest risk of poor outcome.This review deals with the new determinants of prognosis in patients with cirrhosis and bacterial infections reported recently.Emergence of multiresistant bacteria has led to an increasing failure rate of the standard empirical antibiotic therapy recommended by international guidelines.Moreover,it has been recently reported that endothelial dysfunction is associated with the degree of liver dysfunction and,in infected patients,with the degree of sepsis.It has also been reported that relative adrenal insufficiency is frequent in the non-critically ill cirrhotic population and it is associated with a higher risk of developing infection,severe sepsis,hepatorenal syndrome and death.We advise a change in the standard empirical antibiotic therapy in patients with high risk for multiresistant infections and also to take into account endothelial and adrenal dysfunction in prognostic models in hospitalized patients with decompensated cirrhosis.

Neuroimaging studies of cognitive remediation in schizophrenia:A systematic and critical review

AIM To examine the effects of cognitive remediation therapies on brain functioning through neuroimaging procedures in patients with schizophrenia.METHODS A systematic, computerised literature search was conducted in the PubM ed/Medline and PsychI nfo databases. The search was performed through February 2016 without any restrictions on language or publication date. The search was performed using the following search terms: [("cogniti*" and "remediation" or "training" or "enhancement") and("fMRI" or "MRI" or "PET" or "SPECT") and(schizophrenia or schiz*)]. The search was accompanied by a manual online search and a review of the references from each of the papers selected, and those papers fulfilling our inclusion criteria were also included.RESULTS A total of 101 studies were found, but only 18 of them fulfilled the inclusion criteria. These studies indicated that cognitive remediation improves brain activation in neuroimaging studies. The most commonly reported changes were those that involved the prefrontal and thalamic regions. Those findings are in agreement with the hypofrontality hypothesis, which proposes that frontal hypoactivation is the underlying mechanism of cognitive impairments in schizophrenia. Nonetheless,great heterogeneity among the studies was found. They presented different hypotheses, different results and different findings. The results of more recent studies interpreted cognitive recovery within broader frameworks, namely, as amelioration of the efficiency of different networks. Furthermore, advances in neuroimaging methodologies, such as the use of wholebrain analysis, tractography, graph analysis, and other sophisticated methodologies of data processing, might be conditioning the interpretation of results and generating new theoretical frameworks. Additionally, structural changes were described in both the grey and white matter, suggesting a neuroprotective effect of cognitive remediation. Cognitive, functional and structural improvements tended to be positively correlated.CONCLUSION Neuroimaging studies of cognitive remediation in patients with schizophrenia suggest a positive effect on brain functioning in terms of the functional reorganisation of neural networks.

Healthy diet,depression and quality of life:A narrative review of biological mechanisms and primary prevention opportunities

Unipolar depressive disorder(UDD)affects more than 264 million people worldwide and was projected well before the severe acute respiratory syndrome coronavirus 2 pandemic to be the leading cause of disability-adjusted life years lost in 2030.It is imperative for leading economies to implement preventive strategies targeted towards UDD,given consistent policies are currently lacking.Recently established similarities between the aetiological hypotheses of depression and cardiometabolic diseases are shifting paradigms within this field.It is believed that dietary practices could potentially reduce the incidence of depression;similar to their effects on metabolism.Thus,the aim of this review was to compile current evidence on healthy dietary patterns as suitable contributors towards primary prevention strategies against UDD.Most of the well-known biological mechanisms behind depression have been positively associated with healthful diets and dietary patterns to varying degrees.Interestingly,a common factor of UDD is the production and overall effects of inflammatory cytokines,such as interleukin-6,tumor necrosis factor-α,and Creactive protein.These compounds have been associated with depressive symptoms,disturbances in neuroendocrine function,leaky gut,monoamine activity and brain function,while also being key factors in the development of cardiometabolic diseases.The Mediterranean diet(MD)in particular,is well supported by first-level evidence regarding its preventive qualities against metabolic and cardiovascular diseases and thus considered a model for healthy eating by various organizations.In one of the few clinical trials investigating these associations,the PREDIMED trial,individuals with diabetes assigned to a MD supplemented with mixed tree nuts experienced a 41%relative risk reduction for developing depression.Lastly,there is a need to include health related quality of life as an indicator of physical and mental well-being,considering its putative associations with depression and suicide risk.Going forward,focusing on clinical trials,using precise nutritional assessments,and identifying nutritional biomarkers which may be related to depression are needed to fully support the implementation of dietary recommendations in the field of psychiatry.

New genes emerging for colorectal cancer predisposition

Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CRC susceptibility involves inherited genetic differences.Mendelian syndromes account for about5%of the total burden of CRC,with Lynch syndrome and familial adenomatous polyposis the most common forms.Excluding hereditary forms,there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause.CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect.So far,30 common,low-penetrance susceptibility variants have been identified for CRC.Recently,new sequencing technologies including exomeand whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition.By using whole-genome sequencing,germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.

Brain-derived neurotrophic factor as a potential biomarker of cognitive recovery in schizophrenia

Brain-derived neurotrophic factor(BDNF) has been proposed as a biomarker of schizophrenia and, more specifically, as a biomarker of cognitive recovery. Evidence collected in this review indicates that BDNF is relevant in the pathophysiology of schizophrenia and could play a role as a marker of clinical response. BDNF has been shown to play a positive role as a marker in antipsychotic treatment, and it has been demonstrated that typical antipsychotics decrease BDNF levels while atypical antipsychotics maintain or increase serum BDNF levels. Furthermore, BDNF levels have been associated with severe cognitive impairments in patients with schizophrenia. Consequently, BDNF has been proposed as a candidate target of strategies to aid the cognitive recovery process. There is some evidence suggesting that BDNF could be mediating neurobiological processes underlying cognitive recovery. Thus, serum BDNF levels seem to be involved in some synaptic plasticity and neurotransmission processes. Additionally, serum BDNF levels significantly increased in schizophrenia subjects after neuroplasticity-based cognitive training. If positive replications of those findings are published in the future then serum BDNF levels could be definitely postulated as a peripheral biomarker for the effects of intensive cognitive training or any sort of cognitive recovery in schizophrenia. All in all, the current consideration of BDNF as a biomarker of cognitive recovery in schizophrenia is promising but still premature.

Circulating immune cell activation and diet: A review on human trials

Protein energy malnutrition is the main cause of immunodeficiency and, secondarily, of several infections. However, immune cell activation is involved in several pathophysiological processes that play a crucial role in the appearance of cardiovascular disease(CVD) or cancer. The aim of this review is to update the knowledge of the modulation of immune cell activation by different dietary patterns and its components focusing on CVD or cancer. While a westernized high-saturated fat highcarbohydrate diet is positively associated with lowgrade inflammation, vegetable- and fruit-based diets rich in monounsaturated fatty acids, polyunsaturated fatty acids and polyphenols, key nutrients of Mediterranean diet, decrease the levels of cellular and circulating inflammatory biomarkers thereby reducing the risk of related chronic diseases.

Brain-derived neurotrophic factor levels in first episode of psychosis:A systematic review

AIM: To systematically review studies measuring peripheric brain-derived neurotrophic factor(BDNF) levels on first-episode psychosis patients and variables related to them.METHODS: A systematic search was made of articles published in the Medline database from 2002 up to June 2014. Included are original studies that report enzyme-linked immunosorbent assay measurement of BDNF levels in serum or plasma in patients with a diagnosis of first episode psychosis(FEP) and age- and gender- matched healthy controls.RESULTS: Of the initially identified 147 articles, only 18 satisfied the inclusion criteria. Of this, 15 found a significant reduction in patients with FEP compared with age- and gender- matched controls. CONCLUSION: Peripheral BDNF levels are generally reduced in FEP patients. There are some factors that may influence BDNF levels that need to be further studied. Furthermore, a future meta-analysis in this topic is needed.

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress.Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances.In this study,we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells.SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1.Consistent with this,SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α.Notably,these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1.Finally,we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter.These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway.Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy,heart failure,and diabetic cardiomyopathy,our results point to SIRT3 as a potential target for treating these diseases.

Gut microbiota metabolites for sweetening type I diabetes

Type 1 diabetes(T1D),also referred to as insulin-dependent diabetes mellitus,is a debilitating disease that follows the destruction of pancreatic insulin-producingβcells by autologous T-cells.T1D primarily affects children and has a strong genetic component,with>50 susceptibility loci identified,including HLA-DQβchains.1 However,the striking differences between European regions with similar genetic backgrounds and a sharp rise in T1D incidence in developed countries over the last several decades suggest that environmental factor(s)also play a relevant etiopathogenic role.2 Given the accumulating evidence linking the gut microbiota to protection against metabolic diseases,3 Mariño et al.4 recently tested the hypothesis that short-chain fatty acids(SCFAs),which are the end products of fermentation of dietary fibers by anaerobic intestinal microbiota,can protect genetically susceptible mice from developing T1D.Interestingly,the authors found that diets enriched in acetate or butyrate(two of the main SCFAs)can protect animals from developing diabetes through different and complementary cellular mechanisms.Such findings significantly enhance our understanding of the role of diet and gut microbiota in the development of autoimmune diseases and indicate that the use of medicinal foods may be a cost-effective treatment against T1D and other autoimmune diseases with a cellular component.Given that current anti-T1D approaches(which focus on prevention or modulation of the adaptive specific immune response against autoantigens)have been generally disappointing,5 such a new and refreshing strategy has attracted a great deal of attention(reviewed in Ref.2).

The lymphocyte scavenger receptor CD5 plays a nonredundant role in fungal infection

Invasive fungal diseases(IFD)impact morbidity,mortality,hospital stay and healthcare costs in critically ill patients,constituting an unmet medical need.1 Pathogenic fungi rarely cause IFD in immunocompetent individuals but become life-threatening in cases of immunodeficiency,young infants,disrupted mucosal barriers or polyantibiotic therapy,highlighting the role of immune surveillance in IFD control.^(2)

The presence and outcome of biliary sphincter disorders in liver-transplant recipients according to the Rome IV classification

Background Biliary sphincter disorders after liver transplantation(LT)are poorly described.We aim to describe the presence and outcome of patients with papillary stenosis(PS)and functional biliary sphincter disorders(FBSDs)after LT according to the updated Rome IV criteria.Methods We reviewed all endoscopic retrograde cholangiopancreatographies(ERCPs)performed in LT recipients between January 2003 and December 2019.Information on clinical and endoscopic findings was obtained from electronic health records and endoscopy databases.Laboratory and clinical findings were collected at the time of ERCP and 1 month after ERCP.Results Among the 1,307 LT recipients,336 underwent 849 ERCPs.Thirteen(1.0%)patients met the updated Rome IV criteria for PS[former sphincter of Oddi dysfunction(SOD)type I]and 14 patients(1.0%)met the Rome IV criteria for FBSD(former SOD type II).Biliary sphincterotomy was performed in 13 PS and 10 FBSD cases.One month after sphincterotomy,bilirubin,gamma-glutamyl transferase and alkaline phosphatase levels decreased in 85%,61%,and 92%of those in the PS group(P¼0.019,0.087,and 0.003,respectively)and in 50%,70%,and 80%of those in the FBSD group(P¼0.721,0.013,and 0.093,respectively).All the 14 patients initially suspected of having a FBSD turned out to have a different diagnosis during the follow-up.Conclusions PS after LT is uncommon and occurs in only 1%of LT recipients.Our data do not support the presence of an FBSD after LT.Sphincterotomy is a safe and effective procedure in LT recipients with PS.