A Direct in vivo RNAi screen identifies MKK4 as a key regulator of liver regeneration.

The liver harbors a distinct capacity for endogenous regeneration; however, liver regeneration is often impaired in disease and therefore insufficient to compensate for the loss of hepatocytes and organ function. Here we describe a functional genetic approach for the identification of gene targets that can be exploited to increase the regenerative capacity of hepatocytes. Pools of small hairpin RNAs (shRNAs) were directly and stably delivered into mouse livers to screen for genes modulating liver regeneration. Our studies identify the dual-specific kinase MKK4 as a master regulator of liver regeneration. MKK4 silencing robustly increased the regenerative capacity of hepatocytes in mouse models of liver regeneration and acute and chronic liver failure. Mechanistically, induction of MKK7 and a JNK1-dependent activation of the AP1 transcription factor ATF2 and the Ets factor ELK1 are crucial for increased regeneration of hepatocytes with MKK4 silencing.

Adeno-associated virus serotype 2 capsid variants for improved liver-directed gene therapy.

BACKGROUND AND AIMS: Current liver-directed gene therapies look for adeno-associated virus (AAV) vectors with improved efficacy. With this background, capsid engineering is explored. Whereas shuffled capsid library screenings have resulted in potent liver targeting variants with one first vector in human clinical trials, modifying natural serotypes by peptide insertion has so far been less successful. Here, we now report on two capsid variants, MLIV.K and MLIV.A, both derived from a high-throughput in vivo AAV peptide display selection screen in mice. APPROACH AND RESULTS: The variants transduce primary murine and human hepatocytes at comparable efficiencies, a valuable feature in clinical development, and show significantly improved liver transduction efficacy, thereby allowing a dose reduction, and outperform parental AAV2 and AAV8 in targeting human hepatocytes in humanized mice. The natural heparan sulfate proteoglycan binding ability is markedly reduced, a feature that correlates with improved hepatocyte transduction. A further property that might contribute to the improved transduction efficacy is the lower capsid melting temperature. Peptide insertion also caused a moderate change in sensitivity to human sera containing anti-AAV2 neutralizing antibodies, revealing the impact of epitopes located at the basis of the AAV capsid protrusions. CONCLUSIONS: In conclusion, MLIV.K and MLIV.A are AAV peptide display variants selected in immunocompetent mice with improved hepatocyte tropism and transduction efficiency. Because these features are maintained across species, MLIV variants provide remarkable potential for translation of therapeutic approaches from mice to men.

Correction: Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B.

[This corrects the article DOI: 10.1371/journal.pgen.1008690.].

The world apheresis association registry, 2023 update.

The WAA apheresis registry contains data on more than 140,000 apheresis procedures conducted in 12 different countries. The aim is to give an update of indications, type and number of procedures and adverse events (AEs). MATERIAL AND METHODS: The WAA-registry is used for registration of apheresis procedures and is free of charge. The responsible person for a center can apply at the site www.waa-registry.org RESULTS: Data includes reported AEs from 2012 and various procedures and diagnoses during the years 2018-2022; the latter in total from 27 centers registered a total of 9500 patients (41% women) that began therapeutic apheresis (TA) during the period. A total of 58,355 apheresis procedures were performed. The mean age was 50 years (range 0-94). The most common apheresis procedure was stem cell collection for which multiple myeloma was the most frequent diagnosis (51%). Donor cell collection was done in 14% and plasma exchange (PEX) in 28% of patients; In relation to all performed procedures PEX, using a centrifuge (35%) and LDL-apheresis (20%) were the most common. The main indication for PEX was TTP (17%). Peripheral veins were used in 56% as the vascular access. The preferred anticoagulant was ACD. AEs occurred in 2.7% of all procedures and were mostly mild (1%) and moderate 1.5% (needed supportive medication) and, only rarely, severe (0.15%). CONCLUSION: The data showed a wide range of indications and variability in apheresis procedures with low AE frequency.

Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B.

Loss-of-function mutations in the human coagulation factor 9 (F9) gene lead to hemophilia B. Here, we dissected the consequences and the pathomechanism of a non-coding mutation (c.2545A>G) in the F9 3' untranslated region. Using wild type and mutant factor IX (FIX) minigenes we revealed that the mutation leads to reduced F9 mRNA and FIX protein levels and to lower coagulation activity of cell culture supernatants. The phenotype could not be compensated by increased transcription. The pathomechanism comprises the de novo creation of a binding site for the spliceosomal component U1snRNP, which is able to suppress the nearby F9 poly(A) site. This second, splicing-independent function of U1snRNP was discovered previously and blockade of U1snRNP restored mutant F9 mRNA expression. In addition, we explored the vice versa approach and masked the mutation by antisense oligonucleotides resulting in significantly increased F9 mRNA expression and coagulation activity. This treatment may transform the moderate/severe hemophilia B into a mild or subclinical form in the patients. This antisense based strategy is applicable to other mutations in untranslated regions creating deleterious binding sites for cellular proteins.

From Formation to Closure: Aggregate Morbidity and Mortality Associated With Defunctioning Loop Ileostomies.

BACKGROUND: Defunctioning loop ileostomies are used commonly, but there are significant morbidities. OBJECTIVE: This study aimed to describe the morbidity and mortality associated with the formation and closure of defunctioning loop ileostomies. DESIGN: This descriptive study is based on electronic health records and claims data. SETTINGS: This study was conducted at academic and community hospitals in Ontario, Canada. PATIENTS: Adult patients who had a low anterior resection with concurrent defunctioning loop ileostomy from 2002 to 2014 were included. MAIN OUTCOME MEASURES: Outcomes of interest included 30-day major complications, acute kidney injury, transfusion, and deep space infection. The rate of ileostomy reversal and the percentage of permanent ostomies were also collected. RESULTS: The cohort consists of 4658 patients who underwent low anterior resection with concurrent defunctioning loop ileostomy. The 30-day, 90-day, and 1-year mortality rates of these patients were 1.2%, 2.2%, and 5.1%. The rate of reoperation was 5.5%, the rate of hospital readmission was 13.4%, the rate of major complications was 28.5%, the rate of deep organ/space infection requiring percutaneous intervention was 5.2%, and the rate of acute kidney injury requiring hospitalization was 10.4%. Eighty-six percent had their ileostomy reversed, leaving 13.2% with a permanent ostomy. After ileostomy reversal, 30-day and 90-day mortality rates were 0.6% and 0.9%. The rate of major complications was 10.3%, bowel obstruction 7%, ventral hernia 10.5%, deep space infection 1.7%, and repeat operation 2.3%. LIMITATIONS: This study is based on electronic health records and claims data and, thus, the accuracy of results depends on the accuracy of data administration' which can be variable across institutions. CONCLUSIONS: Morbidity and mortality of defunctioning loop ileostomies are significant. One in 8 patients will have a permanent ostomy. See Video Abstract at http://links.lww.com/DCR/B810 . DESDE LA FORMACIN HASTA EL CIERRE AGREGADA MORBILIDAD Y MORTALIDAD ASOCIADA CON LAS ILEOSTOMAS EN ASA DERIVATIVA: ANTECEDENTES:Las ileostomías en asa derivativa se utilizan con frecuencia, pero existen morbilidades importantes.OBJETIVO:Describir la morbilidad y mortalidad asociadas con la formación y cierre de ileostomías en asa derivativa.DISEÑO:Estudio descriptivo basado en historias clínicas electrónicas y datos de reclamaciones.ENTORNO CLINICO:Hospitales académicos y comunitarios en Ontario, Canadá.PACIENTES:Pacientes adultos sometidos a resección anterior baja con concurrente ileostomía en asa derivativa de 2002 a 2014.PRINCIPALES MEDIDAS DE VALORACION:Los resultados de interés incluyeron complicaciones mayores a los 30 días, lesión renal aguda, transfusión e infección del espacio profundo. También se recolectó la tasa de reversión de la ileostomía y el porcentaje de ostomías permanentes.RESULTADOS:La cohorte consistió de 4658 pacientes sometidos a resección anterior baja con concurrente ileostomía en asa derivativa. La mortalidad de estos pacientes, a treinta días, 90 días y un año, fue del 1,2%, 2,2% y 5,1%, respectivamente. La tasa de reintervención fue del 5,5%, el reingreso hospitalario fue del 13,4%, la complicación mayor fue del 28,5%, la infección profunda de órganos / espacios que requirieron intervención percutánea fue del 5,2%, y la lesión renal aguda que requirió hospitalización fue del 10,4%. Ochenta y seis por ciento tuvieron reversión de su ileostomía, dejando al 13.2% con una ostomía permanente. Después de la reversión de la ileostomía, la mortalidad a los 30 días y 90 días fue de 0,6% y 0,9%, respectivamente. La tasa de complicaciones mayores fue del 10,3%, obstrucción intestinal del 7%, hernia ventral del 10,5%, infección del espacio profundo del 1,7% y reintervención del 2,3%.LIMITACIONES:El estudio se basa en registros médicos electrónicos y datos de reclamos y, por lo tanto, la precisión de los resultados depende de la precisión en la administración de datos, que pueden variar entre instituciones.CONCLUSIONES:La morbilidad y la mortalidad de las ileostomías en asa derivativa son significativas. Uno de cada 8 pacientes tendrá una ostomía permanente. Consulte Video Resumen en http://links.lww.com/DCR/B810 . (Traducción-Dr. Fidel Ruiz Healy ).

Impostorism and anxiety contribute to burnout among resident physicians.

PURPOSE: Physician burnout is an issue that has come to the forefront in the past decade. While many factors contribute to burnout the impact of impostorism and self-doubt has largely been ignored. We investigated the relationship of anxiety and impostorism to burnout in postgraduate medical learners. MATERIALS AND METHODS: Postgraduate learners in four diverse training programs: Family Medicine (FM), Paediatric Medicine (PM), Anesthesiology (AN), and General Surgery (GS) were surveyed to identify the incidence of impostorism (IP), anxiety, and burnout. IP, anxiety, and burnout were evaluated using the Clance Impostor Phenomenon Scale (CIPS), Maslach Burnout Inventory-Human Services Survey (MBI-HSS), and the General Anxiety Disorder-7 (GAD-7) questionnaires, respectively. Burnout was defined as meeting burnout criteria on all three domains. Relationships between IP, anxiety, and burnout were explored. RESULTS: Two hundred and sixty-nine residents responded to the survey (response rate 18.8%). Respondents were distributed evenly between specialties (FM = 24.9%, PM = 33.1%, AN = 20.4%, GS = 21.6%). IP was identified in 62.7% of all participants. The average score on the CIPS was 66.4 (SD = 14.4), corresponding to 'frequent feelings of impostorism.' Female learners were at higher risk for IP (RR = 1.27, 95% CI: 1.03-1.57). Burnout, as defined by meeting burnout criteria on all three subscales, was detected in 23.3% of respondents. Significant differences were seen in burnout between specialties (p = 0.02). GS residents were more likely to experience burnout (31.7%) than PM and AN residents (26.7 and 10.0%, respectively, p = 0.02). IP was an independent risk factor for both anxiety (RR = 3.64, 95% CI:1.96-6.76) and burnout (RR = 1.82, 95% CI: 1.07-3.08). CONCLUSIONS: Impostorism is commonly experienced by resident learners independent of specialty and contributes to learner anxiety and burnout. Supervisors and Program Directors must be aware of the prevalence of IP and the impact on burnout. Initiatives to mitigate IP may improve resident learner wellness and decrease burnout in postgraduate learners.

Gender-based differences in letters of recommendation in applications for general surgery residency programs in Canada.

BACKGROUND: In Canada, residency programs do not have many objective measures for ranking candidates. Instead, ranking relies on subjective measures such as letters of reference, which can be affected by the genders of the writer and the applicant. Our study assesses letters of recommendation for a general surgery program in Canada to categorize differences in reference letters based on the genders of applicant and letter writer. METHODS: We assessed 215 reference letters from 51 general surgery candidates for systematic differences in the descriptors used for male and female applicants and differences based on male and female authorship. RESULTS: Female applicants were more often described as mature, pleasant and flexible. Male applicants were more often described as having initiative, completing research, earning awards and performing extracurricular activities. Female writers were more likely to highlight an applicant's interest, initiative, response to feedback, knowledge of their limits, flexibility, communication, achievement in research and awards, confidence and ability to be a good assistant. Significantly more female applicants had female letter writers, compared with male applicants. CONCLUSION: These differences may affect the acceptance of applicants based on their gender and the genders of people who recommend them. Future research is required to explore how these differences in how applicants are described may affect residency selection committees' perceptions and rankings of applicants.

MicroRNA-342-3p is a potent tumour suppressor in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a cancer with multiple aetiologies and widespread prevalence. Largely refractory to current treatments, HCC is the fourth leading cause of cancer-related deaths worldwide. MicroRNAs (miRNAs) are important regulators in HCCs. We aimed to identify tumour suppressor miRNAs during tumour regression in a conditional c-MYC-driven mouse model (LT2/MYC) of HCC, and to evaluate their therapeutic potential for HCC treatment. METHODS: We performed miRNA expression profiling of developed and regressing LT2/MYC tumours and in-depth in vitro gain- and loss-of-function analyses. The effect of adeno-associated virus (AAV) vector-mediated miR-342-3p treatment was evaluated in 3 HCC mouse models. RESULTS: We identified miR-342-3p as a tumour suppressor miRNA in HCC, with increased expression in regressing tumours. Forced miR-342-3p expression in hepatoma cells showed significantly decreased cell proliferation, migration, and colony formation. In vivo administration of AAV-miR-342-3p led to significant attenuation of tumour development and increased overall survival. We identified monocarboxylic acid transporter 1 (MCT1) as a bona fide target of miR-342-3p in HCC. We show that the tumour suppressor role of miR-342-3p is executed partly by modulating the lactate transport function of MCT1. Importantly, we find miR-342-3p downregulated in tumours from patients with HCC compared with matched non-tumour tissues, inversely correlating with MCT1 expression. We observed similar findings in TCGA-LIHC data. CONCLUSIONS: In our study, we identified and validated miR-342-3p as a tumour suppressor miRNA in HCC. We demonstrated its therapeutic efficacy in significantly attenuating tumour development, and prolonging survival, in different HCC mouse models. Identification of miR-342-3p as an effective tumour suppressor opens a therapeutic avenue for miRNA-mediated attenuation of HCC development. LAY SUMMARY: Hepatocellular carcinoma (HCC), the most common type of liver cancer, affects diverse populations and has a global impact, being the fourth leading cause of cancer deaths worldwide. There are currently no systemic therapies for HCC that can significantly prolong long-term survival. Thus, novel effective treatment options are urgently required. To understand the molecular basis of tumour regression, we compared tumours and regressing liver tumours in mice. We show that a small non-coding miRNA, miR-342-3p, is a tumour suppressor in HCC. Expression of miR-342-3p is low in tumours and high in regressing tumours. When miR-342-3p is delivered to mouse livers with HCC, it can significantly slow down liver tumour development and improve survival. Our study highlights the promising therapeutic potential of miR-342-3p intervention in HCC.

Therapeutic HNF4A mRNA attenuates liver fibrosis in a preclinical model.

BACKGROUND & AIMS: Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive approach that, until recently, has remained poorly explored. In this study, we examined the therapeutic utility of mRNA delivery for liver fibrosis and cirrhosis. Specifically, we aimed to demonstrate the therapeutic efficacy of human hepatocyte nuclear factor alpha (HNF4A) mRNA in mouse models of fibrosis and cirrhosis. METHODS: We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNPs) encapsulating HNF4A mRNA. To identify potential mechanisms of action, we performed microarray-based gene expression profiling, single-cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for additional functional validation. RESULTS: Expression of HNF4A mRNA led to restoration of the metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of LNP-encapsulated HNF4A mRNA induced a robust inhibition of fibrogenesis in 4 independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. CONCLUSION: Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver. LAY SUMMARY: Liver fibrosis and cirrhosis remain unmet medical needs and contribute to high mortality worldwide. Herein, we take advantage of a promising therapeutic approach to treat liver fibrosis and cirrhosis. We demonstrate that restoration of a key gene, HNF4A, via mRNA encapsulated in lipid nanoparticles decreased injury in multiple mouse models of fibrosis and cirrhosis. Our study provides proof-of-concept that mRNA therapy is a promising strategy for reversing liver fibrosis and cirrhosis.

Adaptations to general surgery resident education in response to COVID-19.

BACKGROUND: The COVID-19 pandemic led to many new provincial public health measures to reallocate resources in response to an impending surge of cases. These necessary decisions had several downstream effects on general surgery training. We surveyed the actions taken by Canadian general surgery training programs in response to the COVID-19 pandemic. METHOD: A mixed-methods survey was sent to all general surgery program directors to assess various domains in surgical education and modifications made because of the pandemic. Responses were quantified as proportions or qualitative narratives describing those changes. RESULTS: Most programs (13/15) recalled residents from planned rotations and redistributed them to rotations considered as core required services, including acute care surgery, trauma surgery and intensive care. Many programs also restructured their acute care surgery models to allow for a group of "reserve" residents to replace trainees who became infected with SARS-CoV-2. In terms of clinical experience, there was a reduction in both clinical and operative exposure among trainees. The reduction in clinical exposure disproportionately affected junior residents, whose involvement in COVID-19 cases was restricted. Formal educational sessions were maintained, but delivered virtually. Many programs instituted a program of increased frequency of communication with trainees. CONCLUSION: Many programs embraced using virtual platforms for teaching. The demonstrated utility of virtual teaching may lead to rethinking how training programs deliver didactic teaching and expand teaching opportunities. However, many programs also perceived a decrease in clinical and procedural exposure, primarily affecting junior residents. More information is needed to quantify the deficit in learning incurred as a result of the pandemic as well as its long-term effects on resident competency.

Growth differentiation factor 11 attenuates liver fibrosis via expansion of liver progenitor cells.

OBJECTIVE: Liver fibrosis and cirrhosis resulting from chronic liver injury represent a major healthcare burden worldwide. Growth differentiation factor (GDF) 11 has been recently investigated for its role in rejuvenation of ageing organs, but its role in chronic liver diseases has remained unknown. Here, we investigated the expression and function of GDF11 in liver fibrosis, a common feature of most chronic liver diseases. DESIGN: We analysed the expression of GDF11 in patients with liver fibrosis, in a mouse model of liver fibrosis and in hepatic stellate cells (HSCs) as well as in other liver cell types. The functional relevance of GDF11 in toxin-induced and cholestasis-induced mouse models of liver fibrosis was examined by in vivo modulation of Gdf11 expression using adeno-associated virus (AAV) vectors. The effect of GDF11 on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5)+ liver progenitor cells was studied in mouse and human liver organoid culture. Furthermore, in vivo depletion of LGR5+ cells was induced by injecting AAV vectors expressing diptheria toxin A under the transcriptional control of Lgr5 promoter. RESULTS: We showed that the expression of GDF11 is upregulated in patients with liver fibrosis and in experimentally induced murine liver fibrosis models. Furthermore, we found that therapeutic application of GDF11 mounts a protective response against fibrosis by increasing the number of LGR5+ progenitor cells in the liver. CONCLUSION: Collectively, our findings uncover a protective role of GDF11 during liver fibrosis and suggest a potential application of GDF11 for the treatment of chronic liver disease.

Prophylactic Negative Pressure Wound Therapy for Closed Laparotomy Incisions: A Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The aim of this study was to determine whether negative pressure wound therapy (NPWT) applied to primarily closed incisions decreases surgical site infections (SSIs) following open abdominal surgery. BACKGROUND: SSIs are a common cause of morbidity following open abdominal surgery. Prophylactic NPWT has shown promise for SSI reduction. However, the results of randomized controlled trials (RCTs) conducted among patients undergoing laparotomy have been inconsistent. METHODS: We performed a meta-analysis of English language RCTs comparing the use of prophylactic NPWT to standard dressings on primarily closed laparotomy incisions following open abdominal surgery. Medline, EMBASE, Cochrane Library, and CINAHL databases were searched from inception to December 31, 2018, for relevant studies. A random-effects model was used for statistical analysis. RESULTS: Five RCTs totaling 792 patients were included in our meta-analysis after application of our exclusion and inclusion criteria. There was no significant difference in the risk of SSIs identified among those patients who had NPWT compared to standard dressings; relative risk (RR) 0.56 (95% confidence interval 0.30-1.03, P = 0.064). There was significant statistical heterogeneity across studies (I = 67.4%; P = 0.015). CONCLUSION: The adoption of NPWT for routine SSI prophylaxis following laparotomy is currently not supported and should be used primarily in the context of a clinical trial.

Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice.

During Coxsackievirus B3 (CVB3) infection hepatitis is a potentially life threatening complication, particularly in newborns. Studies with type I interferon (IFN-I) receptor (IFNAR)-deficient mice revealed a key role of the IFN-I axis in the protection against CVB3 infection, whereas the source of IFN-I and cell types that have to be IFNAR triggered in order to promote survival are still unknown. We found that CVB3 infected IFN-ß reporter mice showed effective reporter induction, especially in hepatocytes and only to a minor extent in liver-resident macrophages. Accordingly, upon in vitro CVB3 infection of primary hepatocytes from murine or human origin abundant IFN-ß responses were induced. To identify sites of IFNAR-triggering we performed experiments with Mx reporter mice, which upon CVB3 infection showed massive luciferase induction in the liver. Immunohistological studies revealed that during CVB3 infection MX1 expression of hepatocytes was induced primarily by IFNAR-, and not by IFN-III receptor (IFNLR)-triggering. CVB3 infection studies with primary human hepatocytes, in which either the IFN-I or the IFN-III axis was inhibited, also indicated that primarily IFNAR-, and to a lesser extent IFNLR-triggering was needed for ISG induction. Interestingly, CVB3 infected mice with a hepatocyte-specific IFNAR ablation showed severe liver cell necrosis and ubiquitous viral dissemination that resulted in lethal disease, as similarly detected in classical IFNAR-/- mice. In conclusion, we found that during CVB3 infection hepatocytes are major IFN-I producers and that the liver is also the organ that shows strong IFNAR-triggering. Importantly, hepatocytes need to be IFNAR-triggered in order to prevent virus dissemination and to assure survival. These data are compatible with the hypothesis that during CVB3 infection hepatocytes serve as important IFN-I producers and sensors not only in the murine, but also in the human system.

NT-pro-BNP as marker for cardiac strain that may be caused by high-output arteriovenous shunting in a haemodialysis patient. A case report.

BACKGROUND: An arteriovenous fistula (AVF) is the first choice when considering access for haemodialysis (HD). When a forearm AVF fails an upper arm AVF is a frequent subsequent dialysis access option. The latter may cause cardiac strain. NT-pro-B-type natriuretic peptide (NT-NT-proBNP) is a marker used to estimate volume overload and cardiac strain. This case report shows the benefit of using longitudinal individual follow-up of pre-dialysis NT-proBNP in clinical practice to detect changes in cardiac condition that may be due to high-output AVF. CASE PRESENTATION: An 18 years old patient performed HD via an upper arm AVF before he was admitted to our unit. NT-proBNP was above the upper detection level of 70,000 ng/L. Echocardiography revealed a left-ventricular cardiac insufficiency. Interdialytic weight gain (IDWG) was above 5%. He was instructed to lower fluid intake and IDWG towards 2%. Four months later NT-proBNP surpassed 70,000 ng/L again. Flow in the brachial artery was at 3034 ml/min. Reconstructive surgery of the AVF did not reduce flow and NT-proBNP in the long run. Clinically, he worsened to NYHA class III-IV. It was decided to close the upper arm AVF and to replace it with a lower arm AVF leading to a reduced artery flow of 1344 mL/min. The clinical condition successively recovered and NT-proBNP decreased to 7000 ng/L. CONCLUSIONS: Pre-dialysis NT-proBNP should be considered as a suitable routine marker for cardiac strain such as caused by high-output AVF besides variables such as IDWG. Brachial artery flow besides AVF flow measurement is helpful.

Serotonin syndrome: a clinical review of current controversies.

Serotonin syndrome is a state of increased central and peripheral serotonin (5-hydroxytryptamine) activity. Unless recognized and treated early, serotonin syndrome can lead to seizures, shock and death. Both substances with direct and indirect serotonergic activity can precipitate the syndrome. Serotonin syndrome can occur not only in psychiatric but also in non-psychiatric settings. Yet, clinicians may not be familiar with the condition. We explore some of the current controversies regarding serotonin syndrome. Specifically, we tested the following assumptions: (i) Despite being rare, serotonin syndrome is still clinically relevant; (ii) The Hunter criteria are the gold standard for diagnosing serotonin syndrome; (iii) Hyperthermia is common in cases of serotonin syndrome; (iv) Serotonin syndrome usually develops fast; (v) Severe serotonin syndrome usually or almost exclusively involves monoamine oxidase inhibitors. We found that (i) despite being rare, serotonin syndrome was clinically relevant, (ii) the Hunter criteria could not be regarded as the gold standard for the diagnosis of serotonin syndrome since they missed more cases than the other two diagnostic criteria systems (Sternbach and Radomski criteria), (iii) Serotonin syndrome could occur in the absence of an elevated temperature, (iv) fast onset could not be regarded as a reliable clinical sign of serotonin syndrome, and (v) absence of monoamine oxidase inhibitors treatment did not exclude a diagnosis of serotonin syndrome. Clinicians should bear in mind that in the context of relevant drug history, serotonin syndrome may still be possible in these circumstances.

Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis.

BACKGROUND & AIMS: Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The crosstalk between hepatocytes and hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis. Although ample efforts have been devoted to elucidate the functions of HSCs during liver fibrosis, the regulatory functions of hepatocytes remain elusive. METHODS: Using an unbiased functional microRNA (miRNA) screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via miRNA modulation. The in vivo functional analyses were performed by inhibiting miRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride- and 3,5-di-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis. RESULTS: Blocking miRNA-221-3p function in hepatocytes during chronic liver injury facilitated recovery of the liver and faster resolution of the deposited extracellular matrix. Furthermore, we demonstrate that reduced secretion of C-C motif chemokine ligand 2, as a result of post-transcriptional regulation of GNAI2 (G protein alpha inhibiting activity polypeptide 2) by miRNA-221-3p, mitigates liver fibrosis. CONCLUSIONS: Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis. LAY SUMMARY: Liver fibrosis majorly contributes to mortality resulting from various liver diseases. We discovered a small RNA known as miRNA-221-3p, whose downregulation in hepatocytes results in reduced liver fibrosis. Thus, inhibition of miRNA-221-3p may serve as one of the therapeutic approaches for treatment of liver fibrosis.

Negative Pressure Wound Therapy Use to Decrease Surgical Nosocomial Events in Colorectal Resections (NEPTUNE): A Randomized Controlled Trial.

OBJECTIVE: Determine if negative pressure wound therapy (NPWT) reduces surgical site infection (SSI) in primarily closed incision after open and laparoscopic-converted colorectal surgery. BACKGROUND: SSIs after colorectal surgery are a common cause of morbidity. The prophylactic effect of NPWT has not been established. We undertook this study to evaluate if, among patients undergoing open colorectal resection, NPWT, as compared with standard postoperative dressings, is associated with a reduction in the rate of postoperative SSI. METHODS: In a randomized, controlled trial, 300 patients undergoing elective open colorectal surgery were assigned to receive prophylactic NPWT or standard gauze dressing. The primary end-point was 30-day SSI, as assessed by wound care experts blinded to treatment arm. Secondary outcomes included length of stay. Statistical analysis was performed on an intention-to-treat basis. A priori subgroup analysis was planned for patients who received a stoma at the time of initial operation. RESULTS: The incidence of SSI at 30-days postoperatively was no different between experimental and control groups (32% vs 34% respectively, P = 0.68). Length of stay was also no different at a median of 7 days (IQR 5) for both groups. Among patients receiving a stoma, there was also no difference in SSI between the experimental and control groups (38% vs 33% respectively, P = 0.66). CONCLUSIONS: Prophylactic use of NPWT on primarily closed incisions after open colorectal surgery was not associated with a decrease in SSI rate when compared with standard gauze dressing. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT02007018).

Health and Economic Impact of Intensive Surveillance for Distant Recurrence After Curative Treatment of Colon Cancer: A Mathematical Modeling Study.

BACKGROUND: Intensive surveillance strategies are currently recommended for patients after curative treatment of colon cancer, with the aim of secondary prevention of recurrence. Yet, intensive surveillance has not yielded improvements in overall patient survival compared with minimal follow-up, and more intensive surveillance may be costlier. OBJECTIVE: The purpose of this study was to estimate the quality-adjusted life-years, economic costs, and cost-effectiveness of various surveillance strategies after curative treatment of colon cancer. DESIGN: A Markov model was calibrated to reflect the natural history of colon cancer recurrence and used to estimate surveillance costs and outcomes. SETTINGS: This was a decision-analytic model. PATIENTS: Individuals entered the model at age 60 years after curative treatment for stage I, II, or III colon cancer. Other initial age groups were assessed in secondary analyses. MAIN OUTCOME MEASURES: We estimated the gains in quality-adjusted life-years achieved by early detection and treatment of recurrence, as well as the economic costs of surveillance under various strategies. RESULTS: Cost-effective strategies for patients with stage I colon cancer improved quality-adjusted life-expectancy by 0.02 to 0.06 quality-adjusted life-years at an incremental cost of $1702 to $13,019. For stage II, they improved quality-adjusted life expectancy by 0.03 to 0.09 quality-adjusted life-years at a cost of $2300 to $14,363. For stage III, they improved quality-adjusted life expectancy by 0.03 to 0.17 quality-adjusted life-years for a cost of $1416 to $17,631. At a commonly cited willingness-to-pay threshold of $100,000 per quality-adjusted life-year, the most cost-effective strategy for patients with a history of stage I or II colon cancer was liver ultrasound and chest x-ray annually. For those with a history of stage III colon cancer, the optimal strategy was liver ultrasound and chest x-ray every 6 months with CEA measurement every 6 months. LIMITATIONS: The study was limited by model structure assumptions and uncertainty around the values of the model's parameters. CONCLUSIONS: Given currently available data and within the limitations of a model-based decision-analytic approach, the effectiveness of routine intensive surveillance for patients after treatment of colon cancer appears, on average, to be small. Compared with testing using lower cost imaging, currently recommended strategies are associated with cost-effectiveness ratios that indicate low value according to well-accepted willingness-to-pay thresholds in the United States. See Video Abstract at http://links.lww.com/DCR/A921.

Proceedings of the signature series event of the international society for cellular therapy: "Advancements in cellular therapies and regenerative medicine in digestive diseases," London, United Kingdom, May 3, 2017.

A summary of the First Signature Series Event, "Advancements in Cellular Therapies and Regenerative Medicine for Digestive Diseases," held on May 3, 2017, in London, United Kingdom, is presented. Twelve speakers from three continents covered major topics in the areas of cellular therapy and regenerative medicine applied to liver and gastrointestinal medicine as well as to diabetes mellitus. Highlights from their presentations, together with an overview of the global impact of digestive diseases and a proposal for a shared online collection and data-monitoring platform tool, are included in this proceedings. Although growing evidence demonstrate the feasibility and safety of exploiting cell-based technologies for the treatment of digestive diseases, regulatory and methodological obstacles will need to be overcome before the successful implementation in the clinic of these novel attractive therapeutic strategies.