Current Therapeutic Approaches to Subglottic Stenosis in Patients With GPA: A Systematic Review

Background: The management of subglottic stenosis (SGS) in granulomatosis patients with polyangiitis (GPA) has no clear guidelines. This systematic review aimed to identify different surgical techniques and evaluate the outcomes of applied procedures. Methods: An electronic search was performed using 3 major databases, CINAHL, PubMed, and Clinical key, to include relevant studies published from the databases from inception through January 2017. All primary studies reporting treatment of SGS in cases with GPA were included. Articles were excluded if not relevant to the research topic or if they were duplicates, review articles, editorials, short comments, unpublished data, conference abstracts, case reports, animal studies, or non-English studies. Results: Thirteen papers were included in our systematic review with a total of 267 cases for the qualitative review Endoscopic approaches showed favorable outcomes with the need to use multiple procedures to achieve remission. The open transcervical approach showed excellent results mainly after failure of other endoscopic techniques. Tracheostomy was necessary for severe respiratory obstruction symptoms. Medical treatment was essential for stabilizing the active disease and therefore may enhance the success rate postoperatively. Conclusion: Subglottic stenosis in patients with GPA requires a multidisciplinary approach to provide optimal management regarding disease activity, grade of stenosis, and severity of symptoms.

Albumin platelet product as a novel score for liver fibrosis stage and prognosis

Fibrosis-4 index, a conventional biomarker for liver fibrosis stage, is confounded by age and hepatitis activity grade. The current retrospective multicenter study aimed to formulate the novel indices of liver fibrosis by mathematically combining items of peripheral blood examination and to evaluate ability of prognosis prediction. After a novel index was established in a training cohort, the index was tested in a validation cohort. Briefly, a total of 426 patients were enrolled in a training cohort. Albumin and platelet most strongly correlated to fibrosis stage among blood examination. Albumin platelet product (APP) = Albumin × platelet/1000 could differentiate the four stages of liver fibrosis (p < 0.05). APP indicated fibrosis stage independent from hepatitis activity grade. A cut-off value = 4.349 diagnosed cirrhosis with area under ROC more than 0.8. Multivariate analysis revealed that smaller APP independently contributed to HCC prevalence and overall mortality. The results were validated in another 707 patients with HCV infection. In conclusion, APP was not confounded by age or hepatitis activity grade contrary to Fibrosis-4 index. APP is as simple as physicians can calculate it by pen calculation. The product serves physicians in managing patients with chronic liver disease.

Assessment of Liver Fibrosis by Transient Elastography in Children with Chronic Hepatitis B Virus Infection

Background: This study aimed to investigate the effectiveness of transient elastography (TE) by comparing liver biopsies to assess liver fibrosis in children with chronic hepatitis B (CHB). Methods: A total of 157 CHB children aged 0 - 6 years in China were enrolled in this single-center prospective study. All patients underwent liver stiffness measurement (LSM) by TE and liver biopsy at an interval of less than a week. Results: LSM, aspartate aminotransferase (AST)-platelet ratio index (APRI), and fibrosis-4 score (FIB-4) positively correlated with activity grade and fibrosis stage in children with CHB. The area under receiver operating characteristic curves (AUCs) of LSM for identifying significant (F ≥ 2) and advanced fibrosis (F ≥ 3) were 0.732 and 0.94, the cut-off values were 5.6 kPa and 6.9 kPa, specificity of 75.7% and 91.5%, and sensitivity of 67.4% and 81.3%, respectively. Compared to LSM, the overall diagnostic performance of APRI and FIB-4 for significant and advanced fibrosis was suboptimal with low AUCs and sensitivity. Since LSM, platelet, and Log10HBsAg were independent factors with the fibrosis stages (F < 2 and F ≥ 2) on the liver biopsy, the LPS index was formulated to predict F ≥ 2 by combining LSM, platelet, and Log10HBsAg. The AUC of LPS for F ≥ 2 was increased to 0.792, which was higher than that of LSM (0.732, p < 0.05), with an improved sensitivity (76.6% vs 67.4%).Conclusions: TE represents a promising technology for the diagnosis of advanced fibrosis in CHB children aged 0 - 6 years.

Liver damage favors the eliminations of HBV integration and clonal hepatocytes in chronic hepatitis B

Background HBV integration is suspected to be an obstinate risk factor for hepatocellular carcinoma (HCC) in the era of antiviral therapy. Integration events start to occur in the immunotolerance phase, but their fates in the immune clearance phase have not yet been clarified. Here, we report the influences of liver damage on HBV integration and clonal hepatocyte expansion in patients with chronic hepatitis B (CHB). Methods HBV integration breakpoints in liver biopsy samples from 54 CHB patients were detected using a modified next-generation sequencing assay. Results A total of 3729 (69 per sample) integration breakpoints were found in the human genome, including some hotspot genes and KEGG pathways, especially in patients with abnormal transaminases. The number of breakpoint types, an integration risk parameter, was negatively correlated with HBV DNA load and transaminase levels. The average, maximum and total frequencies of given breakpoint types, parameters of clonal hepatocyte expansion, were negatively correlated with HBV DNA load, transaminase levels and liver inflammation activity grade score. The HBV DNA load and inflammation activity grade score were further found to be positively correlated with transaminase levels. Moreover, nucleos(t)ide analog (NUC) treatment that normalized transaminases nonsignificantly reduced the types, but significantly increased the average frequency and negated the enrichments of integration breakpoints. Conclusion Liver damage mainly removed the inventories of viral integration and clonal hepatocytes in CHB. NUC treatment may have reduced HBV integration but clearly increased clonal hepatocyte expansion, which may explain why HCC risk cannot be ruled out by NUC treatment.

Albumin Platelet Product: A Novel Score for Liver Fibrosis Stage and Prognosis.

Fibrosis-4 index, a conventional biomarker for liver fibrosis stage, is confounded by age and hepatitis activity grade . The current retrospective multicenter study aimed to formulate the novel indices of liver fibrosis by mathematically combining items of peripheral blood examination and to evaluate ability of prognosis prediction. After a novel index was established in a training cohort, the index was tested in a validation cohort. Briefly, a total of 426 patients were enrolled in a training cohort. Albumin and platelet most strongly correlated to fibrosis stage among blood examination. Albumin platelet product (APP) = Albumin × platelet / 1000 could differentiate the four stages of liver fibrosis (p < 0.05). APP indicated fibrosis stage independent from hepatitis activity grade. A cut-off value = 4.349 diagnosed cirrhosis with area under ROC more than 0.8. Multivariate analysis revealed that smaller APP independently contributed to HCC prevalence and overall mortality. The results were validated in another 707 patients with HCV infection. In conclusion, APP was not confounded by age or hepatitis activity grade contrary to Fibrosis-4 index. APP is as simple as physicians can calculate it by pen calculation. The product serves physicians in managing patients with chronic liver disease.

SUN-506 Hyperthyroidism Induced Hepatic Apoptosis

Background: Graves’ disease is commonly associated with abnormal liver function tests, most frequently ALP, but the exact mechanism is not fully understood. In vitro and in vivo animal studies have shown elevated T3 activity can induce hepatocyte apoptosis via a mitochondrial-mediated pathway. This case demonstrates a patient with elevated aminotransferases and hepatic apoptosis most likely secondary to severe hyperthyroidism. Clinical Case: 50 year old female with a past medical history of migraines was seen by primary care for fatigue and 15 lb weight loss in one month. She was found to be hyperthyroid with TSH &lt; 0.1 uIU/L (n=0.34-5.6), free T4 3.48 ng/dL (n=0.58-1.64) and mildly elevated aminotransferases of AST 77 IU/L (n=15-41), ALT 144 IU/L (n=12-63), which increased within a week to 159 IU/L and 309 IU/L respectively. ALP and bilirubin were within normal range. She was started on methimazole 20 mg twice daily by her PCP. The patient developed vomiting and stopped taking methimazole after 3-4 days. Upon initial presentation to endocrine clinic, found to be clinically hyperthyroid and as LFTs were improved but still elevated, she was re-challenged with methimazole at a lower dose as well as started on a beta blocker and cholestyramine. TT3 checked was elevated at 2.10 ng/mL (n 0.87-1.78). Graves’ disease was confirmed with elevated TSI as well as RAI uptake and scan showing increased homogenous uptake. She had extensive workup for another etiology by hepatology including autoimmune, which were negative. Her fibrosis score was stage F1-F2 (n=F0) and necroinflammatory activity grade A3 indicating severe activity (n=grade A0). Core needle biopsy of the liver showed focal lytic necrosis/apoptosis and abundant pigment-laden Kupffer cells signifying recent hepatocellular injury. Her AST and ALT down trended and normalized with repeat fibrosis score of F1 and necroinflammatory activity grade A0. She eventually had definitive therapy with RAI treatment. Conclusion: In most cases of hyperthyroid induced liver dysfunction, liver histology showed fatty infiltration, cytoplasmic vacuolization, nuclear irregularity and hyperchromatism. This case, without any other known causes that could explain her hepatic injury, indicates the possible role of hyperthyroidism in hepatic apoptosis.

A 15-year follow-up of transfemoral amputees with bone-anchored transcutaneous prostheses

Aims The aim of this study was to describe implant and patient-reported outcome in patients with a unilateral transfemoral amputation (TFA) treated with a bone-anchored, transcutaneous prosthesis. Methods In this cohort study, all patients with a unilateral TFA treated with the Osseointegrated Prostheses for the Rehabilitation of Amputees (OPRA) implant system in Sahlgrenska University Hospital, Gothenburg, Sweden, between January 1999 and December 2017 were included. The cohort comprised 111 patients (78 male (70%)), with a mean age 45 years (17 to 70). The main reason for amputation was trauma in 75 (68%) and tumours in 23 (21%). Patients answered the Questionnaire for Persons with Transfemoral Amputation (Q-TFA) before treatment and at two, five, seven, ten, and 15 years’ follow-up. A prosthetic activity grade was assigned to each patient at each timepoint. All mechanical complications, defined as fracture, bending, or wear to any part of the implant system resulting in removal or change, were recorded. Results The Q-TFA scores at two, five, seven, and ten years showed significantly more prosthetic use, better mobility, fewer problems, and an improved global situation, compared with baseline. The survival rate of the osseointegrated implant part (the fixture) was 89% and 72% after seven and 15 years, respectively. A total of 61 patients (55%) had mechanical complications (mean 3.3 (SD 5.76)), resulting in exchange of the percutaneous implant parts. There was a positive relationship between a higher activity grade and the number of mechanical complications. Conclusion Compared with before treatment, the patient-reported outcome was significantly better and remained so over time. Although osseointegration and the ability to transfer loads over a 15-year period have been demonstrated, a large number of mechanical failures in the external implant parts were found. Since these were related to higher activity, restrictions in activity and improvements to the mechanical properties of the implant system are required. Cite this article: Bone Joint J 2020;102-B(1):55–63

IL-9 promotes the pathogenesis of ulcerative colitis through STAT3/SOCS3 signaling

Ulcerative colitis (UC) is a chronic condition in which the overreacting immune system may play an important role. It has been confirmed that the interleukin (IL) 9 (IL-9) participates in the pathogenesis of UC but the molecular mechanism is not fully illustrated. Here, we show that levels of peripheral blood cytokines IL-9, IL-8, IL-10, IL-6, IL-1β, IL-12, and tumor necrosis factor (TNF) were higher in patients with UC than normal control, and serum and local IL-9 levels were positively correlated with the disease activity grade. Moreover, IL-9 stimulation inhibited suppressor of cytokine signaling 3 (SOCS3) expression and wound healing ability in colonic epithelial cells and promoted the phosphorylation level of signal transducers and activators of transcription 3 (STAT3). And IL-9 stimulation promoted claudin-2 expression while inhibited claudin-3 and occludin expression. Furthermore, SOCS3 overexpression rescued the IL-9-induced effects. Altogether, IL-9 participates in the pathogenesis of UC through STAT3/SOCS3 signaling pathway and has the potential to serve as a possible therapeutic candidate in patients with UC.

Physical activity on prescription in accordance with the Swedish model increases physical activity: a systematic review

ObjectivesThis study investigates the effects of the core elements of the Swedish model for physical activity on prescription (PAP) by evaluating studies that compared adults who received PAP with adults who did not receive PAP. All participants were adults identified by a healthcare professional as in need of increased physical activity. Primary outcome was level of physical activity.DesignSystematic review.Eligibility criteria(1) Published 1999. (2) Systematic review, randomised controlled trial (RCT), non-RCT or case series (for adverse events). (3) ≥12 weeks’ follow-up. (4) Performed in the Nordic countries. (5) Presented in English, Swedish, Norwegian or Danish.Data sourcesSystematic searches in PubMed, Embase, the Cochrane Library, AMED, CINAHL and SweMed+ in September 2017. Included articles were evaluated using checklists to determine risk of bias.ResultsNine relevant articles were included: seven RCTs, one cohort study and one case series. Primary outcome was reported in seven articles from six studies (five RCTs, one cohort study, 642 participants). Positive results were reported from three of the five RCTs and from the cohort study. No study reported any negative results. Swedish PAP probably results in an increased level of physical activity (GRADE⊕⊕⊕Ο).ConclusionsAlthough the number of the reviewed articles was relatively modest, this systematic review shows that PAP in accordance with the Swedish model probably increases the level of physical activity. As a model for exercise prescription, Swedish PAP may be considered as part of regular healthcare to increase physical activity in patients.