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Alcohol-associated liver fibrosis accumulates over decades, driven by hepatic inflammation and cell death. We investigated the diagnostic accuracy of keratin-18 degradation, measured using serum M30 and M65 levels, and the ActiTest for hepatic inflammatory activity in patients with compensated alcohol-associated liver disease (ALD). Furthermore, we evaluated the prognostic accuracy of markers for liver-related events and all-cause mortality. All findings were compared with routine liver function tests: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase. Our prospective, biopsy-controlled, single-center study included 265 patients with ongoing or prior excessive alcohol intake, representing the full spectrum of compensated ALD. We defined hepatic inflammatory activity as a combined score of lobular inflammation and ballooning. For severe hepatic inflammatory activity (n = 40), we found excellent diagnostic accuracy for M30 (area under the receiver operating characteristics curve [AUROC] = 0.90), M65 (AUROC = 0.86), and AST (AUROC = 0.86). Elevated M30 (M30 240 U/L) had the highest positive predictive value (PPV) and specificity, significantly higher than M65, ActiTest and ALT, but not AST (M30: sensitivity = 83%, specificity = 82%, positive predictive value = 45%, negative predictive value = 95%). Patients were followed up for 1445 patient-years. All markers, except for ALT, significantly predicted liver-related events and all-cause mortality. After adjusting for advanced fibrosis, drinking behavior and body mass index, M30 and M65 remained significant predictors of liver-related events, whereas M30 and AST were significant predictors of all-cause mortality. Conclusion: M30 and AST accurately detect severe hepatic inflammatory activity in patients with compensated ALD. M30 was the only significant predictor of both liver-related events and all-cause mortality after adjusting for advanced fibrosis, body mass index, and drinking behavior at inclusion.

Context Glucose-dependent insulinotropic polypeptide (GIP) has been proposed to exert insulin-independent effects on lipid and bone metabolism. Objective We investigated the effects of a 6-day subcutaneous GIP infusion on circulating lipids, white adipose tissue (WAT), brown adipose tissue (BAT), hepatic fat content, inflammatory markers, respiratory exchange ratio (RER), and bone homeostasis in patients with type 1 diabetes. Methods In a randomized, placebo-controlled, double-blind, crossover study, 20 men with type 1 diabetes underwent a 6-day continuous subcutaneous infusion with GIP (6 pmol/kg/min) and placebo (saline), with an interposed 7-day washout period. Results During GIP infusion, participants (26 ± 8 years [mean ± SD]; BMI 23.8 ± 1.8 kg/m2; glycated hemoglobin A1c 51 ± 10 mmol/mol [6.8 ± 3.1%]) experienced transiently increased circulating concentrations of nonesterified fatty acid (NEFA) (P = 0.0005), decreased RER (P = 0.009), indication of increased fatty acid β-oxidation, and decreased levels of the bone resorption marker C-terminal telopeptide (P = 0.000072) compared with placebo. After 6 days of GIP infusion, hepatic fat content was increased by 12.6% (P = 0.007) and supraclavicular skin temperature, a surrogate indicator of BAT activity, was increased by 0.29 °C (P < 0.000001) compared with placebo infusion. WAT transcriptomic profile as well as circulating lipid species, proteome, markers of inflammation, and bone homeostasis were unaffected. Conclusion Six days of subcutaneous GIP infusion in men with type 1 diabetes transiently decreased bone resorption and increased NEFA and β-oxidation. Further, hepatic fat content, and supraclavicular skin temperature were increased without affecting WAT transcriptomics, the circulating proteome, lipids, or inflammatory markers.

Background and Aims: Reliable noninvasive biomarkers are an unmet clinical need for the diagnosis of NASH. This study investigates the diagnostic accuracy of the circulating triggering receptor expressed on myeloid cells 2 (plasma TREM2) as a biomarker for NASH in patients with NAFLD and elevated liver stiffness. Approach and Results: We collected cross-sectional, clinical data including liver biopsies from a derivation (n = 48) and a validation cohort (n = 170) of patients with elevated liver stiffness measurement (LSM ≥ 8.0 kPa). Patients with NAFLD activity scores (NAS) ≥4 were defined as having NASH. Plasma TREM2 levels were significantly elevated in patients with NASH of the derivation cohort, with an area under the receiver operating characteristics curve (AUROC) of 0.92 (95% confidence interval [CI], 0.84–0.99). In the validation cohort, plasma TREM2 level increased approximately two-fold in patients with NASH, and a strong diagnostic accuracy was confirmed (AUROC, 0.83; 95% CI, 0.77–0.89; p < 0.0001). Plasma TREM2 levels were associated with the individual histologic features of NAS: steatosis, lobular inflammation, and ballooning (p < 0.0001), but only weakly with fibrosis stages. Dual cutoffs for rule-in and rule-out were explored: a plasma TREM2 level of ≤38 ng/ml was found to be an optimal NASH rule-out cutoff (sensitivity 90%; specificity 52%), whereas a plasma TREM2 level of ≥65 ng/ml was an optimal NASH rule-in cutoff (specificity 89%; sensitivity 54%). Conclusions: Plasma TREM2 is a plausible individual biomarker that can rule-in or rule-out the presence of NASH with high accuracy and thus has the potential to reduce the need for liver biopsies and to identify patients who are eligible for clinical trials in NASH.

Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease—fibrosis, inflammation and steatosis—remains incomplete. Here, we present a paired liver–plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic–area under the curve (ROC–AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC–AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong’s test, P C-index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver disease testing.

We describe the case of a 24-year-old male patient with multiple sclerosis (MS) who was treated with Teriflunomide for eight months. However, due to MS progression, treatment was switched to Ocrelizumab. After 15 months of therapy with Ocrelizumab the patient developed edema and nephrotic-range albuminuria. Kidney biopsy showed focal segmental glomerulosclerosis (FSGS) and Ocrelizumab treatment was stopped. Teriflunomide is less likely to have caused FSGS due to a three week wash-out period and a timespan of 15 months between the last Teriflunomide dose and development of albuminuria. Treatment with Ocrelizumab has been associated with organ-specific inflammation in MS-patients, thus an association between the development of FSGS and Ocrelizumab therapy is possible, and this case suggests considering this potential association.

To report trends and characteristics of post-prostate biopsy (PBx) infections, with regard to aetiology and resistance patterns, in a large unique cohort from a single-centre using the same antibiotic prophylactic regimens during a 15-year period.An observational cross-sectional cohort study, including all patients who underwent transrectal ultrasonography-guided PBx (TRUS PBx) for the suspicion of prostate cancer at the Department of Urology, Skåne University Hospital between 1 May 2003 and 31 December 2017. Positive blood and urinary cultures were considered markers of bloodstream infection (BSI) and urinary tract infection (UTI), respectively. For all patients, details regarding blood or urine cultures from the date of the TRUS PBx and 14 days onwards were retrieved.In total, 8973 TRUS PBx procedures were performed in 6597 men during the study period. Over time, there was a trend towards a changing case-mix, with PBx procedures increasingly being performed in older patients, patients with lower prostate-specific antigen values, and higher prostate volumes. During the study period, the number of PBx procedures performed increased for each time period and we found an increasing rate of infectious complications in the last period. Overall, the rates of BSI and UTI with at least one relevant pathogen were 1% (88/8973) and 1.8% (159/8973), respectively. In total, 16 of 90 strains (18%) were extended spectrum beta-lactamases producing, with an increasing proportion over time. The proportion of ciprofloxacin-resistant pathogens did not increase over time.During the 15 years of this study, BSI and UTI after TRUS PBx increased. The rise of infectious complications after TRUS PBx in this population is unlikely to be explained by quinolone-resistance, as ciprofloxacin-resistance did not increase in the blood and urinary samples obtained during the study period. Future longitudinal studies are warranted to investigate why infectious complications after TRUS PBx are increasing.

Background. Living kidney donors (LKDs) are at increased risk of chronic kidney disease, whereas transplant recipients experience progressive reduction of graft function. We examined the predictive value of quantitative stereology on renal function in LKDs and recipients of living donor kidneys, based on perioperative biopsies from the donated kidney. Methods. Cortex volume of both donor kidneys was determined by contrast-enhanced computed tomography and single-kidney glomerular filtration rate (GFR) by 51chrome-EDTA clearance together with renography. Glomerular density was used to estimate total glomeruli number in addition to glomerular volume, glomerular sclerosis, kidney fibrosis, and arteriole dimensions. GFR measurements were repeated 1 y after transplantation in both LKDs and recipients. Associations between GFR at follow-up and cortex volume and histomorphometric parameters after adjustment of age, gender, body mass index, smoking status, 24-h blood pressure, and single-kidney GFR were examined. Results. We included 49 LKDs (age, 51 ± 12 y) and 51 recipients (age, 44 ± 13 y). At follow-up, GFR was 71 ± 16 mL/min in LKDs and 61 ± 18 mL/min in recipients with hyperfiltration being more prominent in LKDs (30.4%) as compared to recipients (16.4%; P < 0.05). One-year GFR in donors correlated to cortex volume (P < 0.001) but not to any histological parameters, whereas GFR in recipients correlated to the amount of interstitial fibrosis (P < 0.01) but not to other histological parameters or cortex volume. Conclusions. Kidney cortex volume, but not renal histology parameters, predicts 1-y renal outcome in LKDs. In contrast, the amount of interstitial fibrosis, but not cortex volume, predicts 1-y graft function in recipients.

Population screening; Liver fibrosis; Early diagnosis Cribratge de població; Fibrosi hepàtica; Diagnòstic precoç Cribado de población; Fibrosis hepática; Diagnóstico precoz Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non-alcoholic fatty liver disease and alcohol-related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at-risk populations. Thus far, a limited number of population-based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate −18% to 27%-in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression. LiverScreen Consortium and the European Commission under the H20/20 program (847989); AGAUR (2017SGR-01281); Centro de Investigacion Biomedica en Enfermedades Hepaticas y Digestivas; Fundación de Investigación Sanitaria, cofunded by Instituto Carlos III–Subdirección General de Evaluación and the European Regional Development Fund (PI18/01330, PI18/00662, and PI18/00862); and Gilead’s Investigator–sponsored research program (IN-ES-989-5309)

McArdle disease; Glycogen phosphorylase; Research models Enfermedad de McArdle; Glucógeno fosforilasa; Modelos de investigación Malaltia de McArdle; Glicogen fosforilasa; Models de recerca McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients. The present manuscript was funded by grants received from the Fondo de Investigaciones Sanitarias (FIS, grant PI19/01313 and PI17/2052) and co-funded by “Fondos FEDER”.

Background & Aims: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. Methods: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. Results: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p

Purpose: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival for selected patients with peritoneal metastases from colorectal cancer. Previous studies report conflicting rates of postoperative bleeding and venous thromboembolism (VTE) after CRS + HIPEC. The aim of the present study was to systematically review the literature and to estimate the overall 30-day incidence of postoperative bleeding and the overall 90-day incidence of VTE after CRS + HIPEC. Methods: Studies were identified in PubMed, Embase, and Web of Science on 29 April 2021. Data were extracted for a qualitative synthesis and to estimate an overall mean incidence in the meta-analysis. Results: Fourteen studies with a total of 3268 patients were included in the systematic review. Postoperative bleeding incidence rates within 30 days ranged from 1.7 to 8.3% with an overall 30-day postoperative bleeding incidence with [95% CI] at 4.2 [2.6;6.2]%. VTE incidence rates within 90 days ranged from 0.2 to 13.6% with an overall 90-day VTE incidence with [95% CI] at 2.7 [1;5.2]% after CRS + HIPEC. Conclusion: This systematic review and meta-analysis indicate a low risk for postoperative bleeding within 30 days and VTE within 90 days after CRS + HIPEC for peritoneal metastases from colorectal cancer.

Cirrhosis is widely prevalent worldwide and can be a consequence of different causes, such as obesity, non-alcoholic fatty liver disease, high alcohol consumption, hepatitis B or C infection, autoimmune diseases, cholestatic diseases, and iron or copper overload. Cirrhosis develops after a long period of inflammation that results in replacement of the healthy liver parenchyma with fibrotic tissue and regenerative nodules, leading to portal hypertension. The disease evolves from an asymptomatic phase (compensated cirrhosis) to a symptomatic phase (decompensated cirrhosis), the complications of which often result in hospitalisation, impaired quality of life, and high mortality. Progressive portal hypertension, systemic inflammation, and liver failure drive disease outcomes. The management of liver cirrhosis is centred on the treatment of the causes and complications, and liver transplantation can be required in some cases. In this Seminar, we discuss the disease burden, pathophysiology, and recommendations for the diagnosis and management of cirrhosis and its complications. Future challenges include better screening for early fibrosis or cirrhosis, early identification and reversal of causative factors, and prevention of complications.

BACKGROUND The laminin gamma 1 chain (LMγ1) is abundant along the crypt-villus axis in the intestinal basement membrane. AIMS We investigated whether a serological biomarker of laminin degradation was associated with disease activity in patients with Crohn's disease (CD) and in rats with dextran sulfate sodium (DSS)-induced colitis. METHODS Serum samples from CD patients (n = 43), healthy subjects (n = 19), and Sprague Dawley rats receiving 5-6% DSS water for five days and regular drinking water for 11 days were included in this study. The LG1M biomarker, a neo-epitope degradation fragment of the LMγ1 chain generated by matrix metalloproteinases-9 (MMP-9), was measured in serum to estimate the level of laminin degradation. RESULTS Serum LG1M was elevated in CD patients with active and inactive disease compared to healthy subjects (p

In this case report, a 17-year-old female underwent microsurgical exploration and neurorrhaphy after a glass pane accident resulting in traumatic lesion of the right temporal facial nerve branch. Nine months after reconstruction she had regained function of the frontalis muscle. When patients with traumatic facial nerve injuries are admitted to hospital, it is crucial to consult with a microsurgical center to ensure that reconstruction is completed within 24-72 hours from the time of accident to regain mimetic function.

This review summarises the current knowledge of treatment strategies in traumatic extracranial facial nerve injuries. Facial nerve injuries cause significant psychologic and functional morbidity. We present a guideline for the clinical management including physical examination and surgical treatment. To regain mimetic function after facial nerve injuries it is crucial to ensure that microsurgical reconstruction is completed preferably within 24 hours, and no later than 72 hours from the time of accident.

ObjectiveAlpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the ‘Pi*Z’ variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous ‘Pi*Z’ carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common ‘Pi*S’ variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD.DesignBaseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption.ResultsAmong UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8–53.7)) and primary liver cancer (aOR=44.5 (10.8–183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2–2.2)) and cholelithiasis (aOR=1.3 (1.2–1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1–8.2)) and primary liver cancer (aOR=6.6 (1.6–26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis.ConclusionOur study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

BACKGROUND: Alcohol is a main cause of preventable deaths and frequently leads to the development of alcohol-related liver disease. Due to the lack of diagnostics, patients are commonly diagnosed after developing clinical manifestations. Recently, the biomarker PRO-C3 was shown to accurately identify fibrosis due to non-alcoholic fatty liver disease.AIM: To assess the diagnostic accuracy of PRO-C3, the ADAPT score and best-performing non-patented serological test to detect advanced alcohol-related liver fibrosis.METHODS: We enrolled 426 patients with alcohol overuse in a prospective biopsy-controlled study. We evaluated the accuracy of PRO-C3 and the PRO-C3-based algorithm ADAPT to detect advanced liver fibrosis.RESULTS: The accuracy of PRO-C3 was good with an AUROC of 0.85 (95% CI 0.79-0.90). The best-performing non-patented test was the Forns index with an AUROC of 0.83 (95% CI 0.78-0.89). The ADAPT algorithm performed better as compared to both the Forns index and PRO-C3 alone with an AUROC = 0.88 (95% CI 0.83-0.93).CONCLUSION: PRO-C3 is a new marker with high accuracy to detect advanced alcohol-related liver fibrosis. The diagnostic accuracy of PRO-C3 can be further improved by using the ADAPT algorithm in which the test outperforms currently available non-patented serological fibrosis markers. The study is registered in the Odense Patient Data Exploratory Network (OPEN) under study identification numbers OP_040 (https://open.rsyd.dk/OpenProjects/da/openProject.jsp?openNo=40) and OP_239 (https://open.rsyd.dk/OpenProjects/openProject.jsp?openNo=239&lang=da).

T1-weighted, cross-sectional MR images showing shoulder girdle, abdominal, paraspinal, gluteal and thigh muscles almost completely replaced by fat, whereas lower leg muscles are almost unaffected i a patient who is compound heterozygous for pathogenic variants in GOSR2.

Normothermic machine perfusion (NMP) of injured kidneys offers the opportunity for interventions to metabolically active organs prior to transplantation. Mesenchymal stromal cells (MSCs) can exert regenerative and anti-inflammatory effects in ischemia-reperfusion injury. The aims of this study were to evaluate the safety and feasibility of MSC treatment of kidneys during NMP using a porcine autotransplantation model, and examine potential MSC treatment-associated kidney improvements up to 14 days posttransplant. After 75 min of kidney warm ischemia, four experimental groups of n = 7 underwent 14 h of oxygenated hypothermic machine perfusion. In three groups this was followed by 240 min of NMP with infusion of vehicle, 10 million porcine, or 10 million human adipose-derived MSCs. All kidneys were autotransplanted after contralateral nephrectomy. MSC treatment did not affect perfusion hemodynamics during NMP or cause adverse effects at reperfusion, with 100% animal survival. MSCs did not affect plasma creatinine, glomerular filtration rate, neutrophil gelatinase-associated lipocalin concentrations or kidney damage assessed by histology during the 14 days, and MSCs retention was demonstrated in renal cortex. Infusing MSCs during ex vivo NMP of porcine kidneys was safe and feasible. Within the short posttransplant follow-up period, no beneficial effects of ex vivo MSC therapy could be demonstrated.

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling. ispartof: GASTROENTEROLOGY vol:159 issue:2 pages:534-+ ispartof: location:United States status: published

Fatty liver disease is a global health concern, but in the absence of specific guidelines, current referral patterns differ according to the preferences of the general practitioners. Outpatient Gastroenterology clinics spend futile resources on liver-healthy patients while diagnosing decompensated patients delayed. We aimed to describe referral patterns to a regional outpatient Gastroenterology clinic.We reviewed 9684 referrals from primary care for suspected liver disease in the years 2016-2017, during two years. Data were extracted from the patients' hospital records to assess the clinical workup and patient outcomes until a mean of 43 months after the time of referral. Referrals were categorized as unnecessary (no signs of liver disease), timely (significant fibrosis/compensated cirrhosis), or delayed (decompensated cirrhosis).We included 375 patient referrals from primary care. The main reason for referral was elevated transaminases. More than half (54%) of patients had no signs of liver disease, being unnecessarily referred for evaluation, while 17% had decompensated liver disease and were thus referred too late.Only one-third of patients referred on suspicion of liver disease were referred on time, either before presenting with decompensated liver cirrhosis or with some evidence of significant liver disease, e.g., liver fibrosis. There is a huge unmet need for clinical referral pathways in primary care. Strengths and Limitations of this StudyA strength of this study is the complete mapping of all potential referrals to the outpatient clinic in the two-year period. Instead of retrieving the historic data by ICD-10 diagnosis codes, and reflecting only those patients where the GP clearly suspects liver disease, we have a strong reliance on our methods. We screened all potentially relevant referrals, e.g., referrals due to weight loss or fatigue, which may reflect symptoms of cirrhosis. Thereby we are confident that we have not missed any patients that originally were referred with unspecific symptoms, but after evaluation are diagnosed with liver disease.Another strength of our study is the long follow-up period, which allows us to fully evaluate the course for the individual patient, and the potential later coming diagnoses.Finally, it is a strength of the study that we were not exclusive to one liver disease etiology, both ALD and NAFLD etiology were included in the study.A limitation of this study is the use of historic data, and the fact that it is a single-center study, showing only the referral patterns in one outpatient Gastroenterology clinic.

BACKGROUND: Diabetic nephropathy (DN) is a serious complication of diabetes and a common cause of end stage renal failure. Insulin-like growth factor (IGF)-signaling has been implicated in DN, but is mechanistically poorly understood. Here, we assessed the activity of the metalloproteinase PAPP-A, an activator of IGF activity, and its possible interaction with the endogenous PAPP-A inhibitors stanniocalcin (STC)-1 and -2 in the mammalian kidney under normal and hyperglycemic conditions.METHODS AND RESULTS: Immunohistochemistry demonstrated that PAPP-A, its proteolytic substrate IGF binding protein-4, STC1 and STC2 are present in the human kidney. Endogenous inhibited complexes of PAPP-A (PAPP-A:STC1 and PAPP-A:STC2) were demonstrated in media conditioned by human mesangial cells (HMCs), suggesting that PAPP-A activity is regulated by the STCs in kidney tissue. A method for the selective detection of active PAPP-A in tissue was developed and a significant increase in glomerular active PAPP-A in human diabetic kidney relative to normal was observed. In DN patients, the estimated glomerular filtration rate correlated with PAPP-A activity. In diabetic mice, glomerular growth was reduced when PAPP-A activity was antagonized by adeno-associated virus-mediated overexpression of STC2.CONCLUSION: We propose that PAPP-A activity in renal tissue is precisely balanced by STC1 and STC2. An imbalance in this equilibrium causing increased PAPP-A enzymatic activity potentially contributes to the development of DN, and thus, therapeutic targeting of PAPP-A activity may represent a novel strategy for its treatment.

Tumor heterogeneity is a fundamental problem in treating cancer with monotargeting therapy, including chemical, antibody, and T cell therapies. Our goal is to target multiple mutated peptides found in a patient's cancer to increase antibody therapy effectiveness.Tumor samples were derived from patients with neuroblastoma. Whole-exome sequencing was performed of tumor and normal cells. Mutated proteins with missense mutations were selected from the patient tumor. These mutated proteins were further selected for the presence of missense mutations in the outer cell surface. Peptides representing a mutated section of the proteins were used for vaccinating rabbits and generating anti-peptide antibodies. The binding of individual polyclonal antibodies (pAbs) and the mixtures of pAbs were determined against the patient's tumor as cultured neuroblastoma cells and in a murine xenograft model. Antibodies were prepared according to FDA requirements of a phase I clinical protocol.All of the generated rabbit pAbs bound with high affinity to the corresponding peptide used for vaccination. The pAbs also bound to low passage neuroblastoma cells. Mixed as cocktails, the pAbs had substantially increased binding to cells and bound well to the xenograft tissue. No binding was observed to the panel of normal human tissues. Preparation of pAbs by an academic lab to clinical-grade was approved by FDA for phase I clinical trial.We describe a new strategy to make customized antibodies for individual cancer patients and present the data required to meet FDA specifications to begin a phase I clinical trial.

Background In previous studies of predictors of gastrointestinal (GI) bleeding in the intensive care unit (ICU), most patients received pharmacological stress ulcer prophylaxis (SUP). We aimed to assess associations between potential predictors of clinically important GI bleeding (CIB) and overt GI bleeding in adult ICU patients, while considering the effect and potential interaction with use of SUP. Methods We included 3291 acutely admitted adult ICU patients with risk factors for GI bleeding randomized to SUP (pantoprazole) or placebo in the SUP-ICU trial. We used logistic regression models adjusted for allocation to SUP to estimate associations between 23 potential predictors and CIB (primary outcome) and overt GI bleeding (secondary outcome). Furthermore, we assessed associations between potential predictors and both outcomes in each allocation group and assessed potential interaction with allocation to SUP. Results Increasing SAPS II and SOFA scores, use of circulatory support and renal replacement therapy were associated with increased risk of CIB and overt GI bleeding; chronic lung disease was associated with increased risk of overt GI bleeding. Results for the remaining potential predictors were compatible with both no difference or increased and decreased risks. We found no strong evidence for any interaction between treatment allocation and any potential predictors. Conclusion In adult ICU patients at risk of GI bleeding, severity of illness, use of circulatory support and renal replacement therapy were associated with higher odds of CIB, with no strong evidence of interaction with SUP.

The complexity of facial synkinesis will likely benefit from an individualized approach to intervene on discrete synkinetic facial subunits. This overarching treatment algorithm requires understanding each synkinetic mimetic subunit. The depressor anguli oris muscle, because of its antagonistic relationship to the zygomaticus major, is of particular interest. This study aims to provide outcomes of depressor anguli oris muscle myectomies and the predictive value of preoperative lidocaine blocks. Preoperative depressor anguli oris muscle lidocaine blocks were administered to patients with postparetic facial synkinesis, and subsequent isolated depressor anguli oris muscle myectomies were performed on those who showed improvement and elected to proceed. Twenty synkinetic patients underwent isolated depressor anguli oris myectomies after lidocaine blockade, with an average follow-up of 9 months. Facial mimetic parameters and measurements were recorded and analyzed by Massachusetts Eye and Ear Infirmary Emotrics and National Institutes of Health ImageJ software to compare results from both blocks and myectomies. Both lidocaine block and depressor anguli oris myectomy improved dental show by 14.42 mm 2 and 23.012 mm 2 , respectively, and open mouth smile angles above a horizontal plane by 4.66 and 3.32 degrees, respectively. There was no statistical difference between the groups in terms of improvements noted in closed and open mouth smile angles above a horizontal plane, or in dental show ( p = 0.695, p = 0.351, and p = 0.242, respectively). Preoperative lidocaine blockade accurately predicts the improvement in dental show and modiolus smile angle that is provided by isolated depressor anguli oris muscle myectomy. This furthers our understanding of depressor anguli oris muscle abnormality in the overall spectrum of facial synkinesis.Therapeutic, IV.

Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary muscle disease, characterized by the clinical triade of early-onset joint contractures, progressive muscle weakness, and cardiac involvement. Pathogenic variants in FHL1 can cause a rare X-linked recessive form of EDMD, type 6. We report three men with novel variants in FHL1 leading to EDMD6. The onset of muscle symptoms was in late adulthood and muscle weakness was not prominent in either of the patients. All patients had hypertrophic cardiomyopathy and one of them also had cardiac arrhythmias. Western blot performed on muscle biopsies from two of the patients showed no FHL1 protein expression. We predict that the variant in the third patient also leads to the absence of FHL1 protein. Complete loss of all FHL1 isoforms combined with mild muscle involvement supports the hypothesis that loss of all FHL1 isoforms is more benign than the cytotoxic effects of expressed FHL1 protein with pathogenic missense variants.

Dyslipidaemia is a modifiable cause of increased mortality in patients with mental illness. We described prevalence, aetiology and treatment of dyslipidaemia in patients with mental illness. Patients with mental illness have a higher prevalence of dyslipidaemia than the general population due to genetic predisposition, unhealthy lifestyle and/or psychotropic medications. Attention towards early identification of dyslipidaemia, close monitoring, and a low threshold for initiating treatment with lifestyle interventions and lipid-lowering agents are warranted in patients with mental illness.

Background: Atrial fibrillation (AF) is common in intensive care unit (ICU) patients and is associated with poor outcomes. Different management strategies exist, but the evidence is limited and derived from non-ICU patients. This international survey of ICU doctors evaluated the preferred management of acute AF in ICU patients.Method: We conducted an international online survey of ICU doctors with 27 questions about the preferred management of acute AF in the ICU, including antiarrhythmic therapy in hemodynamically stable and unstable patients and use of anticoagulant therapy.Results: A total of 910 respondents from 70 ICUs in 14 countries participated in the survey with 24%–100% of doctors from sites responding. Most ICUs (80%) did not have a local guideline for the management of acute AF. The preferred first-line strategy for the management of hemodynamically stable patients with acute AF was observation (95% of respondents), rhythm control (3%), or rate control (2%). For hemodynamically unstable patients, the preferred strategy was observation (48%), rhythm control (48%), or rate control (4%). Overall, preferred antiarrhythmic interventions included amiodarone, direct current cardioversion, beta-blockers other than sotalol, and magnesium in that order. A total of 67% preferred using anticoagulant therapy in ICU patients with AF, among whom 61% preferred therapeutic dose anticoagulants and 39% prophylactic dose anticoagulants.Conclusion: This international survey indicated considerable practice variation among ICU doctors in the clinical management of acute AF, including the overall management strategies and the use of antiarrhythmic interventions and anticoagulants.

Background and Aims: Hepatic sinusoidal cells are known actors in the fibrogenic response to injury. Activated hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells are responsible for sinusoidal capillarization and perisinusoidal matrix deposition, impairing vascular exchange and heightening the risk of advanced fibrosis. While the overall pathogenesis is well understood, functional relations between cellular transitions during fibrogenesis are only beginning to be resolved. At single-cell resolution, we here explored the heterogeneity of individual cell types and dissected their transitions and crosstalk during fibrogenesis. Approach and Results: We applied single-cell transcriptomics to map the heterogeneity of sinusoid-associated cells in healthy and injured livers and reconstructed the single-lineage HSC trajectory from pericyte to myofibroblast. Stratifying each sinusoidal cell population by activation state, we projected shifts in sinusoidal communication upon injury. Weighted gene correlation network analysis of the HSC trajectory led to the identification of core genes whose expression proved highly predictive of advanced fibrosis in patients with nonalcoholic steatohepatitis (NASH). Among the core members of the injury-repressed gene module, we identified plasmalemma vesicle–associated protein (PLVAP) as a protein amply expressed by mouse and human HSCs. PLVAP expression was suppressed in activated HSCs upon injury and may hence define hitherto unknown roles for HSCs in the regulation of microcirculatory exchange and its breakdown in chronic liver disease. Conclusions: Our study offers a single-cell resolved account of drug-induced injury of the mammalian liver and identifies key genes that may serve important roles in sinusoidal integrity and as markers of advanced fibrosis in human NASH.

STUDY DESIGN A prospective multicenter investigational device exempt trial is underway evaluating a novel conformable mesh interbody fusion device in subjects undergoing single-level fusion for degenerative disc disease. Patients meeting inclusion and exclusion criteria were offered enrollment. There is no comparative group in this study. OBJECTIVE Establish the short and long-term safety and effectiveness of a novel conformable mesh interbody fusion device in subjects undergoing single-level fusion for degenerative disc disease unresponsive to conservative care. SUMMARY OF BACKGROUND DATA Transforaminal lumbar interbody fusion remains a critical procedure for patients with degenerative lumbar disc disease. Increasingly minimally invasive techniques have been proposed to minimize muscle dissection and tissue damage with the goal of minimizing pain and length of stay. METHODS One hundred two subjects were enrolled across 10 sites. Ninety nine subjects remained available for follow-up at 12-months. Physical evaluations/imaging were performed serially through 12-months. Validated assessment tools included 100 mm visual analogue scale (VAS) for pain, Oswestry Disability Index (ODI) for function, and computerized tomography scan for fusion. Independent committees were used to identify adverse events and for assessment of radiographic fusion. RESULTS Reductions in low back pain (LBP)/leg pain and improvements in functional status occur early and are maintained through 12-month follow-up. Mean VAS-LBP change from baseline to 6-weeks post-op (-46 mm) continued to improve through 12 months (-51 mm). Similar trends were observed for leg pain. Mean ODI change from baseline to 6 weeks post-op (-17) was almost doubled by 12 months (-32). Fusion rates at 12-months are high (98%). No device-related serious adverse events have occurred. CONCLUSION 12-month outcomes demonstrated excellent patient compliance and positive outcomes for pain, function, fusion, and device safety. Clinical improvements were observed by 6-weeks post-op and appear durable up to 1 year later. A novel mesh interbody device may provide an alternative means of interbody fusion that reduces connective tissue disruption.Level of Evidence: 3.

Remote ischemic conditioning (RIC) by repetitive brief periods of limb ischemia and reperfusion renders organs more resistant to ischemic injury. The protection is partly through down-regulation of the inflammatory response. Our aim was to investigate the clinical and anti-inflammatory effects of RIC in patients with active ulcerative colitis (UC). We included 22 patients with active UC in this explorative, randomized, sham-controlled clinical trial. The patients were randomly assigned 1:1 to RIC (induced in the arm through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff) or sham (incomplete inflation of the blood-pressure cuff) once daily for 10 days. Outcome variables were measured at baseline and on day 11. When compared with sham, RIC did not affect inflammation in the UC patients measured by fecal calprotectin, plasma C-reactive protein, Mayo Score, Mayo Endoscopic Subscore, Nancy Histological Index or inflammatory cytokines involved in UC and RIC. The mRNA and miRNA expression profiles in the UC patients were measured by RNA sequencing and multiplexed hybridization, respectively, but were not significantly affected by RIC. We used the Langendorff heart model to assess activation of the organ protective mechanism induced by RIC, but could not confirm activation of the organ protective mechanism in the UC patients.

IntroductionThe chemical composition of feces plays an important role in human metabolism. Metabolomics and lipidomics are valuable tools for screening the metabolite composition in feces. Here we set out to describe fecal metabolite composition in healthy participants in frozen stools.MethodsFrozen stool samples were collected from 10 healthy volunteers and cryogenically drilled in four areas along the specimen. Polar metabolites were analyzed using derivatization followed by two-dimensional gas chromatography and time of flight mass spectrometry. Lipids were detected using ultra high-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry. The technical variation threshold was set to 30% in pooled quality control samples and metabolite variation was then assessed in four areas per specimen. A data-generated network using metabolites found in all areas was computed for healthy participants.Results2326 metabolic features were detected. Out of a total of 298 metabolites that were annotated we report here 185 that showed a technical variation of x< 30%. These metabolites included amino acids, fatty acid derivatives, carboxylic acids and phenolic compounds. Lipids predominantly belonged to the groups of diacylglycerols, triacylglycerols and ceramides. Metabolites varied between sampling areas (14%-80%). A network using metabolites present in all areas showed two main clusters, DAG lipids and phenyllactic acid.ConclusionsIn feces from healthy participants, the main groups detected were phenolic compounds, ceramides, diacylglycerols and triacylglycerols. Metabolite levels differed considerably depending on the sampling area.

Objective We investigated if Growth and Differentiation Factor 15 (GDF-15) can be used as a biomarker to distinguish patients with mitochondrial myopathy from patients with other myopathies. Methods Serum GDF-15 was measured in 28 patients with mitochondrial disease, 24 with metabolic myopathies, 27 with muscular dystrophy and 21 healthy controls. Results and conclusions Our findings indicate that elevated GDF-15 can distinguish patients with mitochondrial myopathy from other myopathies, including metabolic myopathies. This suggests that increases in GDF-15 is specific to respiratory chain dysfunction rather than general metabolic dysfunction or muscle defect.

For years, hepatologists have been seeking non-invasive methods able to detect significant liver fibrosis. However, no previous algorithm using routine blood markers has proven to be clinically appropriate in primary care. We present a novel approach based on artificial intelligence, able to predict significant liver fibrosis in low-prevalence populations using routinely available patient data. We built six ensemble learning models (LiverAID) with different complexities using a prospective screening cohort of 3352 asymptomatic subjects. 463 patients were at a significant risk that justified performing a liver biopsy. Using an unseen hold-out dataset, we conducted a head-to-head comparison with conventional methods: standard blood-based indices (FIB-4, Forns and APRI) and transient elastography (TE). LiverAID models appropriately identified patients with significant liver stiffness (> 8 kPa) (AUC of 0.86, 0.89, 0.91, 0.92, 0.92 and 0.94, and NPV ≥ 0.98), and had a significantly superior discriminative ability (p

Alcohol is globally the leading risk factor for cirrhosis and is subsumed under the term alcohol-related liver disease (ALD). However, only ca. 10% of people with harmful alcohol consumption (40 gram alcohol per day) develop cirrhosis, while 15% have normal liver histology. Unfortunately, laboratory parameters and ultrasound hold little value to neither rule-in nor rule out alcohol related liver fibrosis. While several indices with combinations of liver associated markers such as FIB4 seem to be promising, non-invasive test strategies are urgently needed with cut-off's that can be applied to guide clinical decision making. The aims of this review article are to highlight novel developments for the diagnosis of ALD and to identify topics of controversy and potential future directions. In the last 15 years, elastography to measure liver stiffness (LS) has significantly improved our screening strategies for cirrhosis. LS values below 6 kPa are considered as normal and exclude ALD. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis. Especially, transient elastography (TE) has been assessed in numerous studies, but similar performance can be obtained with point shear wave elastography, 2 SD shear wave elastography or MR elastography. Important confounders of elevated LS such as inflammation should also be considered and alcohol withdrawal not only improves liver inflammation but also LS. Liver stiffness measurement has signficiantly improved early diagnosis and follow-up of fibrosis in patients with ALD and patients with diagnosed manifest but clinically compensated cirrhosis should undergo further clinical examinations to rule out complications of portal hypertension. In addition, surveillance for the occurrence of hepatocellular carcinoma is recommended in all cirrhotic patients.Alkohol ist weltweit der führende Risikofaktor für eine Leberzirrhose. Subsumiert werden alkoholbedingte Leberschäden unter dem Begriff der alkoholischen Lebererkrankung (ALE). Trotz riskanten Alkoholkonsum (40 g pro Tag) entwickeln nur ca. 10% der alkoholkonsumierenden Personen über Jahre eine Leberzirrhose. Allerdings wird diese Leberzirrhose durch routinemäßige Laborparameter oder den Ultraschall oft übersehen bzw. eignet sich die konventionelle Diagnostik nur eingeschränkt zum Ausschluss einer alkoholischen Leberfibrose. Obwohl verschiedene kombinierte Leberscores wie z.B. FIB4 vielversprechend sind, werden aber daher dringend vor allem nichtinvasive Teststrategien benötigt. Ziel dieses Übersichtsartikels ist es, neue Entwicklungen zur Diagnose der ALE vorzustellen, sowie offene Fragen und zukünftige Entwicklungsstrategien zu diskutieren. In den letzten 15 Jahren ist vor allem durch die Einführung der Leberelastografie zur Messung der Lebersteifigkeit (LS) eine entscheidende Verbesserung beim Zirrhosescreening erreicht worden. LS Werte unter 6 kPa gelten als normal und schließen eine ALE aus. LS Werte von 8 und 12,5 kPa sind allgemein akzeptiere Schwellwerte für die F3 Fibrose bzw. F4 Zirrhose. Besonders die transiente Elastografie (TE) ist bisher in zahlreichen Studien validiert worden, eine ähnliche Performance wird aber auch mit der Scherwellenelastografie und der MR Elastografie erreicht. Wichtige modulierende Faktoren einer erhöhten LS wie eine Leberentzündung (Hepatitis) müssen in der Diagnostik ebenfalls berücksichtigt werden. So führt eine Alkoholentgiftung nicht nur zu einer Verbesserung der Leberentzündung sondern auch zu einem Abfall oder sogar Normalisierung der LS. Zusammengefasst kann man sagen, dass die Einführung der LS die frühe Diagnose und auch die Verlaufsbeurteilung der ALE deutlich verbessert hat. Bei Patienten mit einer manifesten aber klinisch kompensierten Leberzirrhose müssen durch weiterführende Untersuchungen mögliche Komplikationen z.B. einer portalen Hypertension ausgeschlossen werden. Außerdem sollten diese Patienten in ein HCC Screening Programm eingeschlossen werden.

The recurrence rate of colorectal liver metastases (CRLM) patients treated with curative intent is above 50%. Standard of care surveillance includes intensive computed tomographic (CT) imaging as well as carcinoembryonic antigen (CEA) measurements. Nonetheless, relapse detection often happens too late to resume curative treatment. This longitudinal cohort study enrolled 115 patients with plasma samples (N = 439) prospectively collected before surgery, postoperatively at day 30 and every third month for up to 3 years. Droplet digital PCR (ddPCR) was used to monitor serial plasma samples for somatic mutations. Assessment of ctDNA status either immediately after surgery, or serially during surveillance, stratified the patients into groups of high and low recurrence risk (hazard ratio [HR], 7.6; 95% CI, 3.0-19.7; P .0001; and HR, 4.3; 95% CI, 2.3-8.1; P .0001, respectively). The positive predictive value (PPV) of ctDNA was 100% in all postoperative analyses. In multivariable analyses, postoperative ctDNA status was the only consistently significant risk marker associated with relapse (P .0001). Indeterminate CT findings were observed for 30.8% (21/68) of patients. All patients (9/21) that were ctDNA positive at the time of the indeterminate CT scan later relapsed, contrasting 42.6% (5/12) of those ctDNA negative (P = .0046). Recurrence diagnoses in patients with indeterminate CT findings were delayed (median 2.8 months, P .0001). ctDNA status is strongly associated with detection of minimal residual disease and early detection of relapse. Furthermore, ctDNA status can potentially contribute to clinical decision-making in case of indeterminate CT findings, reducing time-to-intervention.

BackgroundLicensed vaccines against SARS-CoV-2 effectively protect against severe disease, but display incomplete protection against virus transmission. Mucosal vaccines providing immune responses in the upper airways are one strategy to protect against transmission.MethodsWe administered Spike HexaPro trimer formulated in a cationic liposomal adjuvant as a parenteral (subcutaneous – s.c.) prime - intranasal boost regimen to elicit airway mucosal immune responses and evaluated this in a Syrian hamster model of virus transmission.FindingsParenteral prime - intranasal boost elicited high-magnitude serum neutralizing antibody responses and IgA responses in the upper respiratory tract. The vaccine strategy protected against virus in the lower airways and lung pathology, but virus could still be detected in the upper airways. Despite this, the parenteral prime - intranasal booster vaccine effectively protected against onward SARS-CoV-2 transmission.InterpretationThis study suggests that parenteral-prime mucosal boost is an effective strategy for protecting against SARS-CoV-2 infection and highlights that protection against virus transmission may be obtained despite incomplete clearance of virus from the upper respiratory tract. It should be noted that protection against onward transmission was not compared to standard parenteral prime-boost, which should be a focus for future studies.FundingThis work was primarily supported by the European Union Horizon 2020 research and innovation program under grant agreement no. 101003653.

BackgroundA pre-emptive transjugular intrahepatic portosystemic shunt (pTIPS) reduces mortality in high-risk patients with cirrhosis (Child-Pugh C/B+active bleeding) with acute variceal bleeding (AVB). Real-life studies point out that Patients and methodsThis is an observational study including 2138 patients from 34 centres between October 2011 and May 2015. Placement of pTIPS was based on individual centre policy. Patients were followed up to 1 year, death or liver transplantation.Results671 of 2138 patients were considered at high risk, 66 received pTIPS and 605 endoscopic+drug treatment. At admission, HE was significantly more frequent in high-risk than in low-risk patients (39.2% vs 10.6%, p56, shock, Model for End-Stage Liver Disease score >15, endoscopic+drug treatment and HE at admission were independent factors of death in high-risk patients.ConclusionpTIPS is associated with better survival than endoscopic treatment in high-risk patients with cirrhosis with variceal bleeding displaying HE at admission.

Background & Aims: Binge drinking is associated with an increased risk of liver disease. Morbidity and mortality of alcohol-related liver disease (ALD) is associated with collagen deposition in the hepatic extracellular matrix (ECM). However, the acute effects of binge drinking on ECM turnover are unknown. We aimed to investigate the effects on hepatic ECM turnover following a binge drinking episode. Methods: We performed a pathophysiological intervention study with 15 non-alcoholic fatty liver disease (NAFLD) patients, 15 ALD patients and 10 healthy controls. We used 40% ethanol in 9 mg/mL NaCl administered through a nasogastric tube to simulate binge drinking. Hepatic vein catheterisation allowed simultaneous hepatic- and systemic vein sampling. Markers of ECM formation and degradation were measured with competitive ELISA. Results: The interstitial matrix formation marker PRO-C3 increased by 1.2 ng/mL (10%, P

Background: Gastrointestinal motility is an important contributor to the effective uptake of water and nutrition. However, it is often impaired in acutely ill hospitalised patients. Amongst other indications, prokinetic agents are used to improve GI motility, but the body of evidence is not well described. Accordingly, we aim to systematically describe and explore the body of evidence on the use of prokinetic agents in hospitalised adults. Methods: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews statement, we plan to conduct a scoping review of studies assessing the use of prokinetic agents, for any indication, in hospitalised adults. We plan to assess study design, population, agents, indications and outcomes across included studies. When applicable, we plan to assess the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: We plan to provide descriptive analyses of the included studies accompanied by tabulated results and characterise knowledge gaps. Conclusion: The outlined scoping review will provide a summary of the body of evidence on the use, indications, effects and side effects of prokinetic agents in hospitalised adults.

Background The development of liver cirrhosis is usually an asymptomatic process until late stages when complications occur. The potential reversibility of the disease is dependent on early diagnosis of liver fibrosis and timely targeted treatment. Recently, the use of non-invasive tools has been suggested for screening of liver fibrosis, especially in subjects with risk factors for chronic liver disease. Nevertheless, large population-based studies with cost-effectiveness analyses are still lacking to support the widespread use of such tools. The aim of this study is to investigate whether non-invasive liver stiffness measurement in the general population is useful to identify subjects with asymptomatic, advanced chronic liver disease. Methods This study aims to include 30,000 subjects from eight European countries. Subjects from the general population aged ≥ 40 years without known liver disease will be invited to participate in the study either through phone calls/letters or through their primary care center. In the first study visit, subjects will undergo bloodwork as well as hepatic fat quantification and liver stiffness measurement (LSM) by vibration-controlled transient elastography. If LSM is ≥ 8 kPa and/or if ALT levels are ≥1.5 x upper limit of normal, subjects will be referred to hospital for further evaluation and consideration of liver biopsy. The primary outcome is the percentage of subjects with LSM ≥ 8kPa. In addition, a health economic evaluation will be performed to assess the cost-effectiveness and budget impact of such an intervention. The project is funded by the European Commission H2020 program. Discussion This study comes at an especially important time, as the burden of chronic liver diseases is expected to increase in the coming years. There is consequently an urgent need to change our current approach, from diagnosing the disease late when the impact of interventions may be limited to diagnosing the disease earlier, when the patient is asymptomatic and free of complications, and the disease potentially reversible. Ultimately, the LiverScreen study will serve as a basis from which diagnostic pathways can be developed and adapted to the specific socio-economic and healthcare conditions in each country. Trial registration This study is registered on Clinicaltrials.gov (NCT03789825).

Background: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations. Methods: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-to-treat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co-interventions with interactions terms. The primary analytical measure of interest will be the analyses’ tests of interaction. A p-value below.05 will be considered statically significant. The stratification variable- and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. Conclusion: This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co-enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.

Aim: To investigate the efficacy and safety of a non-calorie–restricted low-carbohydrate diet (LCD) on glycaemic control, body composition, and cardiovascular risk factors in patients with type 2 diabetes (T2D) instructed to maintain their non-insulin antidiabetic medication and physical activity. Materials and Methods: In an open-label randomized controlled trial, patients with T2D were randomized 2:1 to either a LCD with a maximum of 20 E% (percentage of total energy intake) from carbohydrates (n = 49) or a control diet with 50-60 E% from carbohydrates (n = 22) for 6 months. Examinations at enrolment and after 3 and 6 months included blood sample analyses, anthropometrics, blood pressure, accelerometer-based assessment of physical activity, and food diaries. Total fat mass and lean mass were determined by dual-energy x-ray absorptiometry scan. The mean difference in change between groups from baseline are reported. Results: The LCD group decreased carbohydrate intake to 13.4 E% and increased fat intake to 63.2 E%, which was −30.5 ± 2.2 E% lower for carbohydrates and 30.6 ± 2.2 E% higher for fat, respectively, compared with the control group (all P 2), and waist circumference (−4.9 ± 1.3 cm) compared with the control diet (all P

Purpose: To investigate the risk of steroid-induced ocular hypertension in children treated with systemic glucocorticoid. Methods: Prospective cohort study of children treated with high-dose systemic glucocorticoid (prednisolone-equivalent >0.5 mg/kg/day) for more than 2 weeks. Intraocular pressure (IOP) was measured by an Icare tonometer. An intraocular hypertensive response was defined as a net increase in IOP ≥6 mmHg from baseline or a peak IOP ≥21 mmHg in either eye. Patients with a peak IOP ≥31 mmHg or a net increase in IOP ≥15 mmHg were considered as high responders. Results: Sixteen children with median age 12 years (range 5–17) were included in the study. Nine children (56%) developed a steroid-induced ocular hypertensive response. Two children (12%) were high responders with peak IOP between 32 and 44 mmHg and a net increase in IOP between 15 and 23 mmHg. All children were asymptomatic and IOP was normalized in all after withdrawal of steroid. Steroid responders were significantly younger than nonresponders (p = 0.03). No associations were found between net IOP increase and time to peak pressure, steroid dose at peak pressure or accumulated prednisolone dose at peak IOP. Conclusion: Systemic treatment of children with glucocorticoid can cause a significant increase in IOP which indicates the need for IOP screening of these children. The risk of steroid-induced ocular hypertension may depend on age and ethnicity. In this perspective, further studies on Caucasian children are needed.

Clinical trials; Liver transplant; Quality of life Ensayos clínicos; Trasplante de hígado; Calidad de vida Assaigs clínics; Trasplantament de fetge; Qualitat de vida Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.

Antibodies and other recognition molecules direct cancer cell death by multiple types of immune cells. Therapy directed at only one target typically results in tumor regrowth because of tumor heterogeneity. Our goal is to direct therapy to multiple targets simultaneously. Our previous studies showed that multiple antibodies targeting mutated tumor proteins inhibited tumor growth when injected subcutaneously near the time of cancer cell implantation.A cocktail of rabbit antibodies against B16-F10 cell surface related mutated proteins were generated. Implanted B16-F10 cells were allowed to grow to palpable size before treatment. Antibodies were administered using different routes of exposure. Free antibody was compared to antibody armed on mouse splenic white blood cells (WBCs). Binding of the antibody cocktail was determined for mouse and human WBCs.The antibody cocktail inhibited tumor growth and prolonged survival when administered as free antibody or armed on WBCs. The antibody cocktail armed on WBCs achieved similar tumor inhibition as free antibody but at a dose 1000-fold less. Armed WBCs achieved tumor inhibition by intravenous and subcutaneous administration. The antibody cocktail bound well to human WBCs and saturation dose was defined. Binding was stable under simulated in vivo condition in human plasma at 37 °C.Antibodies targeting multiple tumor mutated proteins inhibited tumor growth and prolonged survival. Effective antibody dose was reduced 1000-fold by arming WBCs. Rabbit antibodies saturated human WBCs using1 mg per billion cells. A phase I trial in cancer patients using this strategy has been approved by the FDA.

Previous studies have reported that magnetic resonance imaging (MRI) and computed tomography (CT) do not predict response to facet blocks. However, single photon emission computed tomography (SPECT) uptake within facet joints has been shown to correlate with pain relief after intervention in the lumbar spine. There is minimal data regarding the predictive value of single photon emission computed tomography/computed tomography (SPECT/CT) for neck pain.The aim of this study was to evaluate the utility of SPECT/CT in patients with axial neck pain for the identification of specific facet joints that would benefit from diagnostic and therapeutic facet joint steroid injections and/or medial branch block/RFA treatments.A retrospective cohort study.One hundred seventy-nine patients at a single institution pain center with neck pain and a SPECT/CT scan between 2009 and 2015. One hundred twelve patients had no prior intervention at the level of interest and met inclusion criteria.Pain reduction at 50% and 80% thresholds within 24 hours of facet intervention. Concordance of facet intervention with the focus of maximal uptake on SPECT/CT scan.All patients were referred to our institution's Center for Pain Medicine and were treated with facet interventions. The site of facet intervention was determined by pain center providers based on their clinical examination and interpretation of images. Groups were formed based on whether the facet intervention included the level of maximal uptake on SPECT/CT scan. A positive response to intervention was defined at both 50% and 80% thresholds for reduction in pain within 24 hours of facet injection with steroid and local anesthetic or medial branch block with local anesthetic only. These were the facet interventions used for our data collection. A Chi-square statistic was used to analyze categorical data and a Student's t-test was used to analyze non-categorical data. SPSS (IBM Corp. IBM SPSS Version 24.0) was used for all analyses.Of our 112 patients, Group 1 consisted of 89 with an intervention occurring at the level with increased uptake on SPECT/CT. Group 2 consisted of 23 patients with an intervention at a level without uptake on SPECT/CT. Demographic data did not significantly differ between cohorts. A Chi-square test of independence demonstrated that intervention at a level concordant with SPECT/CT was significantly correlated with self-reported pain relief thresholds of both 50% and 80% (p=.0002).Facet interventions based on SPECT/CT scan uptake were more successful in pain reduction than those which were not. This suggests a role for SPECT/CT in diagnosing therapeutic targets for neck pain.