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Background: Severe flares (ALT ≥ 10×ULN) are a well-recognised adverse outcome after nucleos(t)ide analogue (NA) cessation and may lead to liver failure. Thus, identification of patients at risk for these flares is of major importance., Methods: Data were used from two prospective studies on NA cessation conducted in the Netherlands and Canada. Patients were eligible based on EASL criteria. HBcrAg and anti-HBc levels were measured at end of treatment (EOT) and week 6 (FUW6). Logistic regression was used to study the association with severe flares., Results: Seventy-eight patients were analysed with a mean age of 49 years, 16 (21%) Caucasian and a majority (65%) were treated with Tenofovir. Overall, 22 patients (28%) developed a severe flare, and 29 (37%) patients were retreated. At EOT, higher HBcrAg levels (aOR: 1.97, p = 0.05; ≥ 4log: 47% severe flare vs. < 3log: 19%, p = 0.036), lower anti-HBc (aOR: 0.29, p = 0.036; < 2log: 50% vs. ≥ 3log: 11%, p = 0.029) and higher HBcrAg/anti-HBc-ratio (aOR: 3.17, p = 0.015; ≥ 2: 58% vs. < 1.5: 14%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBsAg. At FUW6, higher HBcrAg (aOR: 2.91, p = 0.035; ≥ 5log: 83%, < 3log: 4%, p < 0.001), lower anti-HBc (aOR: 0.46, p = 0.29; < 2log: 50% vs. ≥ 3log: 0%, p = 0.003) and higher HBcrAg/anti-HBc-ratio (aOR: 2.19, p = 0.048; ≥ 1.75: 52% vs. < 1.75: 8%, p < 0.001) were associated with an increased risk of severe flares, adjusted for HBV DNA and ALT., Conclusion: Higher HBcrAg, lower anti-HBc and higher HBcrAg/anti-HBc ratio at EOT and during the first weeks of post-treatment follow-up are associated with an increased risk of hepatic flares after NA withdrawal and could therefore potentially be used to select patients eligible for therapy cessation and to identify patients requiring retreatment., Trial Registration: This study was a post hoc and follow-up study of two previously registered clinical trials (NCT01911156 & NTR7001). No new patients were prospectively included., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Stable slipped capital femoral epiphysis (SCFE) is a pediatric hip disorder managed with in situ fixation of the proximal femoral epiphysis, otherwise known as 'pinning the hip'. The objective of this study was to characterize how the choice of implant for in situ fixation of stable SCFE has changed over time. A systematic review of publications concerning in situ fixation of stable SCFE from January 1993 to November 2021 was conducted. The change in the type, diameter, and number of implants used in publications over time and the age of their respective patient cohorts was evaluated. A total of 207 articles met inclusion criteria. There was an increase in publications using cannulated screws over time ( P  = 0.0113). As the yearly percentage of publications using threadless non-cannulated implants decreased ( P  = 0.0309), the percentage using cannulated screws increased ( P  = 0.0047). Single-implant fixation also increased ( P  = 0.0409). While there was no difference in the rate of increase of implants < 7 mm or ≥ 7 mm in diameter ( P  = 0.299), patients with larger-diameter implants were, on average, older than patients with smaller-diameter implants ( P  = 0.0462). In general, the age of patients undergoing in situ fixation of stable SCFE has not changed ( P  = 0.595). Irrespective of patient-specific considerations, single cannulated screws have become the implant of choice for in situ fixation of stable SCFE. There has not been a consensus on the optimal implant diameter; instead, patient-specific considerations are of paramount importance in this decision., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Despite the success rate of the Pavlik method in the treatment of developmental dislocation of the hip, there is a subset of hips that do not reduce with harness use. The purpose of this study was to determine the outcomes after closed reduction (CR), open reduction (OR) and combined open reduction and pelvic osteotomy (OR+PO) in patients with infantile hip dislocations who initially failed the Pavlik method., Methods: This was a retrospective cohort study of patients with infantile hip dislocations who failed the Pavlik method and subsequently underwent a secondary procedure for persistent hip dislocation. The primary outcome measure was the Severin classification of the involved hip 3 years after the secondary procedure. Other outcomes assessed included rates of redislocation, residual acetabular dysplasia and proximal femoral growth disturbance., Results: Twenty-three patients were included; seven subsequently underwent CR, three underwent isolated OR and 13 proceeded directly to OR+PO. The overall successful outcome rate at final follow-up (as determined by radiographic Severin class I or II) was 11/23 (48%). However, patients undergoing OR+PO had significantly higher rates of successful outcomes (77%) compared with CR (15%) and OR (0%), P  < 0.05. The rate of residual acetabular dysplasia and proximal femoral growth disturbance was significantly lower in patients treated with OR+PO compared with CR and isolated OR, P  < 0.05., Conclusion: Patients with dislocated hips who failed Pavlik harness treatment had better radiographic outcomes 3 years after OR+PO in comparison to patients undergoing CR or isolated OR., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Short-chain enoyl-coA hydratase (SCEH) deficiency due to biallelic pathogenic ECHS1 variants was first reported in 2014 in association with Leigh syndrome (LS) and increased S-(2-carboxypropyl)cysteine excretion. It is potentially treatable with a valine-restricted, high-energy diet and emergency regimen. Recently, Simon et al. described four Samoan children harbouring a hypomorphic allele (c.489G > A, p.Pro163=) associated with reduced levels of normally-spliced mRNA. This synonymous variant, missed on standard genomic testing, is prevalent in the Samoan population (allele frequency 0.17). Patients with LS and one ECHS1 variant were identified in NZ and Australian genomic and clinical databases. ECHS1 sequence data were interrogated for the c.489G > A variant and clinical data were reviewed. Thirteen patients from 10 families were identified; all had Pacific ancestry including Samoan, Māori, Cook Island Māori, and Tokelauan. All developed bilateral globus pallidi lesions, excluding one pre-symptomatic infant. Symptom onset was in early childhood, and was triggered by illness or starvation in 9/13. Four of 13 had exercise-induced dyskinesia, 9/13 optic atrophy and 6/13 nystagmus. Urine S-(2-carboxypropyl)cysteine-carnitine and other SCEH-related metabolites were normal or mildly increased. Functional studies demonstrated skipping of exon four and markedly reduced ECHS1 protein. These data provide further support for the pathogenicity of this ECHS1 variant which is also prevalent in Māori, Cook Island Māori, and Tongan populations (allele frequency 0.14-0.24). It highlights the need to search for a second variant in apparent heterozygotes with an appropriate phenotype, and has implications for genetic counselling in family members who are heterozygous for the more severe ECHS1 alleles. SYNOPSIS: Short-chain enoyl-CoA hydratase deficiency is a frequent cause of Leigh-like disease in Māori and wider-Pacific populations, due to the high carrier frequency of a hypomorphic ECHS1 variant c.489G > A, p.[Pro163=, Phe139Valfs*65] that may be overlooked by standard genomic testing., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Vision and hearing impairments are highly prevalent and have a significant impact on physical, psychological and social wellbeing. There is a need for accurate, contemporary national data on the prevalence, risk factors and impacts of vision and hearing loss in Australian adults., Objectives: The Australian Eye and Ear Health Survey (AEEHS) aims to determine the prevalence, risk factors and impacts of vision and hearing loss in both Aboriginal and Torres Strait Islander and non-Indigenous older adults., Methods and Analysis: The AEEHS is a population-based cross-sectional survey which will include 5,000 participants (3250 non-Indigenous aged 50 years or older and 1750 Aboriginal and Torres Strait Islander people aged 40 years or older) from 30 sites covering urban and rural/regional geographic areas, selected using a multi-stage, random cluster sampling strategy. Questionnaires will be administered to collect data on socio-demographic, medical, ocular and ontological history. The testing battery includes assessment of blood pressure, blood sugar, anthropometry, visual acuity (presenting, unaided, pinhole and best-corrected), refraction, tonometry, slit lamp and dilated eye examination, ocular imaging including optical coherence tomography (OCT), OCT-angiography and retinal photography, and automated visual fields. Audiometry, tympanometry and video otoscopy will also be performed. The primary outcomes are age-standardised prevalence of cause-specific vision and hearing impairment. Secondary outcomes are prevalence of non-blinding eye diseases (including dry eye disease), patterns in health service utilisation, universal health coverage metrics, risk factors for vision and hearing impairment, and impact on quality of life., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the last decades there is a growing interest in the evaluation of human body composition for being an important part of the integral assessment of individuals. Its use has been extended to different disciplines associated with health care (medicine, nutrition, physiotherapy), and to sports and population fields. Specifically, fat percentage can be related to innumerable diseases. However, there are discrepancies in the results of fat percentage measurement measured by different methods., Objective: To evaluate the concordance between two low-cost and easily accessible double indirect methods, which have been used indistinctly in different studies where access to more accurate methods is not available, and to determine fat percentage and its relationship with age, sex, body mass index (BMI), waist circumference, level of physical activity and sedentary hours., Materials and Method: Twenty-four persons between 18 and 38 years and 28 between 39 and 59 years from a university community were evaluated. Calculations were made: BMI, fat % was estimated by anthropometry with a digital adipometer (Skyndex System I USA) and by Electrical Bioimpedance Analysis - BIA (Biody Expert ZM II FRA), physical activity level and sedentary hours were determined with the short IPAQ questionnaire. Pearson's correlation coefficient, Bland & Altman's graphical method and Lin's concordance correlation index were calculated. The significance level p<0.05 was estimated., Results: The fat percentage by anthropometry was: 30.5% ±8.5 (18-38 years) 35.0% ±6.7 (39-59 years); by BIA 27.0% ±7.3 (18-38 years) and 29.2% ±7.0 (39-59 years). Both techniques showed good correlation, but low degree of concordance (Lin index less than 0.9) except for the group of young persons with moderate level of physical activity (0.95)., Conclusions: The doubly indirect methods used in the study showed strong correlation, but low concordance, so their use is not recommended indistinctly for the follow-up of a particular case. According to the study data for this specific population in young people with moderate physical activity, follow-up could be performed with either of the two methods., Competing Interests: Conflict of Interest The authors declare that there is no conflict of interest., (© 2024 Hurtado B. et al., published by Sciendo.)

Background: Migrants from hepatitis B virus (HBV) endemic regions are at high risk of having chronic infection. Despite this, HBV knowledge and awareness programming, and low-barrier screening methods such as point of care (POC) testing, among this group have yet to become routine., Methods: We conducted a mass HBV POC screening and knowledge and awareness campaign for individuals of Chinese descent in Toronto, Canada. POC screening was administered, then participants completed a knowledge questionnaire. Logistic regression identified associations between demographic factors and participants' level of HBV knowledge., Results: From 2015 to 2018, 33 outreach events resulted in 891 individuals completing testing and the knowledge questionnaire. Individuals averaged 64.4 years old. Most, 62% ( N = 552), were female, and 73.6% ( N = 656) have been in Canada for <30 years. The average questionnaire score was 70.7% correct, with 65.2% ( N = 581) demonstrating a high level of HBV knowledge. Post-secondary education (OR: 2.19, 95% CI: 1.41, 3.39), income of $50,000 to <$75,000 (OR: 2.74, 95% CI: 1.39, 5.43), and having familial history of HBV (OR: 1.72, 95% CI: 1.06, 2.78) were associated with high knowledge. The observed prevalence of HBV was 1.5%, with 13 individuals testing positive on the POC test and confirmatory laboratory testing., Conclusions: Improving knowledge and awareness of HBV is critical to empowering people, especially migrants who experience barriers to care, to pursue vaccination, testing, and treatment. Combining knowledge outreach and POC test campaigns, enabled discussion and screening for HBV with large numbers of people, and can be tailored for optimal effectiveness for specific groups., Competing Interests: JJF has received consulting support from AbbVie, Enanta, Gilead, Janssen, and Roche, and research funding from AbbVie, Abbott, Gilead, and Enanta. BEH has received consulting support from Intercept, Cymabay, Mirum, Albireo, Chemomab, and Caliditas, and research support from Intercept, Cymabay, Mirum, and Albireo. HLAJ has received research support from AbbVie, Arbutus, Bristol Myers, Squibb, Gilead Sciences, Janssen, Merck, and Roche, and consulting support from Aligos, Arbutus, Arena, Eiger, Enyo, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Regulus, Roche, VBI Vaccines (Variation Biotechnologies), Vir Biotechnology, Inc, and Viroclinics. DW reports research support from Gilead, BMS, Vertex, and Boehringer. MJB has received research support from AbbVie, Gilead Sciences and Cepheid. CY has received consulting fees from Abbvie, and patient education grant from Gilead., (© Canadian Association for the Study of the Liver, 2024.)

Objectives: The persistence in therapy of rheumatoid arthritis drugs and particularly bDMARD is a limiting factor for their long-term use. The randomized controlled trials (RCTs) may not reflect real-world contexts due to strict inclusion and exclusion criteria. Baricitinib, which targets both JAK1 and JAK2, has been used in Italy for several years. The aim of this multi-center study is to assess the real world persistence on therapy of baricitinib in RA patients and to identify predictive factors of baricitinib's survival rate., Methods: This is a retrospective, multicentric, Italian, longitudinal study. All patients were enrolled according to the following criteria: a) age ≥ 18 years old; b) diagnosed with RA according 2010 ACR/EULAR classification criteria; c) treated with baricitinib. In order to describe baricitinib clinical efficacy, the survival rate was evaluated by The Kaplan-Meier curve. Then, predictive factors of drug retention rate were assessed by performing the Cox analysis, identifying which risk factors influenced treatment persistence., Results: Overall, we included 478 patients treated with baricitinib. Among them, 380 (79.5%) were females. Baricitinib's survival rate was 94.6% at 6 months, 87.9% at 12 months, 81.7% at 24 months and 53.4% at 48 months. The Cox analysis regression showed that a higher bDMARDs/tsDMARD line of therapy seems to be a negative prognostic factor for the drug retention rate (HR 1.26 CI 95% 1.07-1.49, p = 0.006., Conclusion: Real-life study confirms baricitinib effectiveness up to 4 years, but previous treatment with bDMARDs was a negative prognostic factor for its survival rate., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Aims: Perthes' disease (PD) is a relatively rare syndrome of idiopathic osteonecrosis of the proximal femoral epiphysis. Treatment for Perthes' disease is controversial due to the many options available, with no clear superiority of one treatment over another. Despite having few evidence-based approaches, many patients with Perthes' disease are managed surgically. Positive outcome reporting, defined as reporting a study variable producing statistically significant positive (beneficial) results, is a phenomenon that can be considered a proxy for the strength of science. This study aims to conduct a systematic literature review with the hypothesis that positive outcome reporting is frequent in studies on the treatment of Perthes' disease., Methods: We conducted a systematic review of all available abstracts associated with manuscripts in English or with English translation between January 2000 and December 2021, dealing with the treatment of Perthes' disease. Data collection included various study characteristics, surgical versus non-surgical management, treatment modality, mean follow-up time, analysis methods, and clinical recommendations., Results: Our study included 130 manuscripts. Overall, 110 (85%) reported positive (beneficial) results, three (2%) reported negative results, and 17 (13%) reported no significant difference. Despite only 10/130 studies (8%) having a testable hypothesis, 71 (55%) recommended the use of their studied treatment methods for the patients, five (4%) made recommendations against the use of the studied treatment modality, and 54 (42%) did not make any recommendations., Conclusion: The overall rate for positive outcomes among included manuscripts regarding different treatment methods for Perthes' disease (85%) is higher than the 74% positive outcome rate found among studies for other surgically treated disorders and significantly higher than most scientific literature. Despite the lack of testable hypotheses, most manuscripts recommended their studied treatment method as a successful option for managing patients solely based on the reporting of retrospective data., Competing Interests: None declared., (© 2024 The British Editorial Society of Bone & Joint Surgery.)

Group A Rotavirus, Human Astrovirus, and Norovirus (RVA, HAstV, and NoV) are recognized as the major causative agents of acute gastroenteritis in children and adults worldwide. The aim of this study was to determine the prevalence and molecular epidemiology of RVA, HAstV, and NoV in wastewater from three cities in Uruguay. Thirty-six samples from Bella Unión, Salto, and Fray Bentos cities were analyzed using quantitative and qualitative PCR. RVA was the most frequently detected virus (50%), followed by HAstV (39%), NoV GII (36%), and NoV GI (25%). RVA strains were characterized as P[8] and G3 based on the VP4 and VP7 genes, respectively. Among NoV-positive samples, genotypes GI.2, GI.3, GI.5, GI.6, GI.7, GII.2, GII.6, and GII.4 were detected, and only one HAstV genotype (MLB1) was found. Our wastewater-based epidemiological approach provides a snapshot of the overall genetic diversity of these viruses in three cities of the Uruguay River basin during 2017-2018. These findings reinforce the importance of this environmental surveillance tool for monitoring epidemiological trends of enteric viruses circulating in the population, which can be used to guide public health intervention., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Evaluate patient-reported liver symptoms during treatment for chronic hepatitis B viral (HBV) infection and associations between changes in symptoms and levels of alanine aminotransferase (ALT) and viral markers., Methods: Data from 200 participants in the Hepatitis B Research Network Immune Active Trial who completed symptom assessments were analyzed. Patients were treated with tenofovir, with or without peginterferon (TDF + PegIFN vs. TDF alone) for 192 weeks. Participants completed a Symptom Checklist at baseline and every 4-12 weeks. A total symptom score was created, ranging from 0 (none) to 40 (severe). The SF-36 was completed every 48 weeks. Associations of symptom scores with ALT and viral markers were evaluated at baseline and end of treatment., Results: Participants were 65% male, 83% Asian, with a mean age of 42. Baseline symptoms were mild (median = 2, range 0-25) and associated with baseline ALT, HBV DNA levels and HBeAg + status. Patients on TDF alone experienced a more rapid and greater improvement in symptoms, but by week 192, symptom improvement was similar in both groups (54% vs 36%). Symptom improvements correlated with ALT and HBV DNA, most markedly among those with symptoms at baseline. Most patients (4 out of 6) who achieved HBsAg loss experienced symptom improvements. Overall, SF-36 scores did not change with treatment., Conclusions: Reduction in ALT and HBV DNA levels with therapy are associated with significant improvement in liver symptoms such as fatigue and pain over the liver, especially among those with higher ALT, HBV DNA, symptoms and HBeAg + status prior to treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: To estimate the risk of human rotavirus (RV) and astrovirus (HAstV) infections for swimmers and fishers at Las Cañas beach, Uruguay., Methods and Results: Surface water samples were collected monthly for 1 year. The dose-response models used were β-Poisson and 1 F 1 hypergeometric for RV and HAstV, respectively. The probabilities of infection were calculated using a kernel density estimate to fitting the data and then sampling from this distribution (Monte Carlo simulation). The probability of RV infection for fishers was between 0 and 65% and for swimmers was between 0 and 50% (<18 years old) and between 0 and 38% (>18 years old). For HAstV, the probability of infection for fishers was between 0% and 45% and for swimmers was between 0 and 38% (<18 years old) and between 0 and 18% (>18 years old)., Conclusions: This study suggests that fishers are at higher risk of infection for both viruses compared with swimmers mainly due to higher viral frequency and concentration at the site for fishing activities., (© 2022 Society for Applied Microbiology.)

Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to disease-causing PUF60 SNVs have been reported in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported individual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients (n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants., (© 2022 Wiley Periodicals LLC.)

When patients with chronic hepatitis B (CHB) stop nucleos(t)ide analogue (NA) therapy before achieving HBsAg loss, flares often ensue which are challenging to predict early. We determined the incidence, severity, outcome and predictors of flares after NA withdrawal. Forty-five patients enrolled in an RCT were included; 107 patients from an external, prospective cohort were used for validation. Retreatment criteria were pre-defined. Pre- and post-treatment predictors of alanine aminotransferase (ALT) flare (>5× ULN) were evaluated by Cox proportional-hazards regression. Seventy-two weeks after NA withdrawal, 23/45 (51%) patients had developed >5× ULN and 14 (31%) >20× ULN. Median time to develop ALT >5× ULN was 12 weeks after NA withdrawal. Independent predictors of ALT >5× ULN were male sex (HR [95% CI] 3.2 [1.2-8.9]; p = 0.03) and serum HBV DNA (1.2 [1.0-1.8]; p = 0.03) at Week 6 off-therapy. Specifically, week 6 HBV DNA >10,000 IU/ml predicted ALT >5× ULN (3.4 [1.4-8.4]; p = 0.01), which was externally validated. In conclusion, this study on post-treatment flares revealed a high cumulative incidence in CHB. Week 6 HBV DNA >10,000 IU/ml independently predicted flares. The proposed threshold enables prediction of imminent flares in patients who may benefit from closer monitoring and earlier retreatment., (© 2022 John Wiley & Sons Ltd.)

Developmental dysplasia of the hip (DDH) is the most common congenital abnormality in newborns. Untreated DDH can cause significant impairments, including chronic hip pain, osteoarthritis, limb length discrepancy, altered gait, and joint contractures. Treatment outcomes are significantly worse with increasing delay in presentation, making early screening and detection critical. The purpose of this review is to provide a comprehensive guide for the pediatric primary care provider on the cause, diagnosis, and management of DDH. Screening practices, physical examination, imaging modalities, and treatment will be discussed. A missed hip dislocation in a walking-age child is a devastating but preventable event; pediatric primary care providers should have a high index of suspicion for DDH and promptly refer any patient with concerning findings to a pediatric orthopedic surgeon. [ Pediatr Ann . 2022;51(9):e346-e352.] .

Background: Symptoms of chronic hepatitis B (CHB) are not well characterized., Aims: To evaluate CHB symptoms and associations with disease activity and clinical outcomes., Methods: Longitudinal data from 1,576 participants in the Hepatitis B Research Network Cohort Study who completed symptom assessments were analyzed. A composite symptom score was calculated using a Symptom Checklist (0=none to 40=extreme). Multivariable mixed models assessed variables associated with symptom change over time. Latent class symptom trajectories were evaluated. The cumulative probability of long-term clinical outcomes (new onset cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, death) was examined by baseline symptom groups., Results: Participants median age was 42 (range:18-80), 51% were male, 75% Asian, (68% of whom were born outside North America) with a median follow-up of 4.2 years. On average, symptoms did not significantly change over time. The multivariable model identified several variables associated with higher symptoms during follow-up: being female, non-Asian, born in the US/Canada, lower education, higher AST, lower platelets, and more comorbidities. Two patient subgroups were identified based on longitudinal symptom trajectories: a low symptom group (92%, n=1,451) with symptom scores averaging 2.4 over time and a moderate symptom group (8%, n=125) with symptom scores averaging 11.5. During follow-up, 7.3% in the moderate symptom group, but only 3.2% of the low symptom group, developed adverse outcomes (p=0.02)., Conclusions: In this large cohort of CHB patients, symptoms were generally mild and stable over time. However, in some patients with moderate symptoms at baseline, deleterious clinical outcomes were more frequent in follow-up., Competing Interests: Statement of Interests: Donna Evon receives research grant funding (to UNC) from Gilead Sciences Inc and Merck Sharp and Dohme. Mandana Khalili received research grant funding (to her institution) from Gilead Sciences Inc and Intercept Pharmaceutical and has served as a scientific consultant for Gilead Science. Robert Fontana has received research support from Gilead, BMS, and Abbvie and provides consulting to Alynam. Colina Yim has received speakers honorarium from Abbvie Canada, and consulting fees from Abbvie Canada and Lupin Pharma Canada. Hsing-Hua S. Lin, Abdus S. Wahed, and Jay H. Hoofnagle have no conflict of interests to disclose.

The use of Rectangular Hollow Sections (RHS) as columns in steel construction includes important advantages like higher mechanical strength and fire resistance. However, the practical demountable bolted joints between beams and columns are not easy to execute, due to impossibility of access to the inner part of the tube. The use of threaded studs welded to the face of the tube and bolted to the beam by means of angle cleats is one of the cheaper and most efficient solutions to obtain beam-column joints with a semi-rigid behavior, as is usually sought in building structures. Nevertheless, it is important to point out that the stud-diameter and the stud-class selection may affect the mechanical properties of the welded parts of the joint. In this paper, 8MnSi7 (with a commercial designation K800) and 4.8 threaded studs were welded to RHS steel tubes and mechanical properties on the weld, the Heat Affected Zones (HAZ), and the base metal were obtained in two different ways: through a correlation with the Vickers hardness and by means of the Small Punch Test (SPT). A study of the microstructure and tensile tests on the threaded studs and in the columns was also carried out. The research involved different types of stud qualities, tube wall thicknesses, and stud diameters. The work presented in this paper proved that in most cases, the welded joint between these studs and the RHS steel tubes present a reasonable static behavior that fulfils the requirements for the beam-column joints under static loading.

Background: A greater understanding of the determinants of health behavior among those with and at-risk of chronic hepatitis B virus (HBV) infection is needed for effective design and implementation of public health initiatives., Aims: To determine factors associated with (1) willingness to accept HBV antiviral treatment and (2) satisfaction with provider communication regarding HBV care in a diverse cohort of HBV-infected patients., Methods: Using a multifaceted model of health behavior, the Health Behavior Framework, we conducted a comprehensive assessment of knowledge, attitudes, beliefs, and barriers to HBV care., Results: We enrolled 510 patients, with mean age 46 years; 53.1% men; and 71.6% Asian or Hawaiian/Pacific Islander. Patients were knowledgeable about HBV infection, but one-fifth did not think that HBV was a treatable disease; over a quarter felt it was so common among family and friends that it did not concern them, and less than half of patients believed they were likely to have liver problems or transmit HBV to others during their lifetime. Perceived susceptibility to disease risk was the only independent predictor of willingness to accept HBV treatment (β = 0.23, p = 0.0005), and contrary to expectations, having a doctor that speaks the same language was predictive of lower patient satisfaction with provider communication about their HBV care (β = - 0.65, p < 0.0001)., Conclusions: Patients with greater perceived susceptibility to the health consequences of HBV infection are more likely to accept treatment, and patient-provider language concordance impacts patient satisfaction with communication regarding HBV care in an unexpected direction.

Tenofovir disoproxil fumarate (TDF) effectively suppresses viral replication in chronic hepatitis B (CHB), but occasionally leads to renal impairment. We evaluated the prevalence of viral and biochemical breakthrough and renal function kinetics in renally impaired patients with CHB on reduced and on full-dose TDF. This clinic-based longitudinal cohort study included patients receiving full and reduced dose TDF (due to eGFR [Cockcroft-Gault] <60 mL/min/1.73 m 2 ). Viral and biochemical breakthroughs were assessed 1 month after starting full and reduced TDF dose until the end-of-follow-up. Breakthroughs were studied in full and reduced dose TDF, and renal function (MDRD) longitudinally before and after dose reduction within patients starting on full-dose TDF. Of 750 patients on TDF, 78 (10%) had reduced dose and 672 (90%) full dose. At the time of dose reduction, 36 (46%) patients had chronic kidney disease stage G3B. A viral breakthrough occurred in one cirrhotic dialysis-dependent patient (dosed 300 mg weekly) which resolved without signs of decompensation, and in one patient on full dose which resolved spontaneously. One biochemical breakthrough occurred during dose reduction and resolved naturally without viral breakthrough. The MDRD improved within the first year of dose reduction (+3.0 [2.5] mL/min per year; P < .005) and remained stable thereafter. Fifty-three (79%) patients reached an MDRD >50 mL/min during dose reduction. Low dose TDF maintains renal function and viral suppression in most renally impaired patients with CHB, even in those with advanced liver disease. This useful, yet simple strategy could be particularly viable in resource-constrained settings., (© 2020 John Wiley & Sons Ltd.)

Background: The ambulatory specialized palliative care (SAPV) was implemented to enable patients with the need for end-of-life intensive care to die with accompanied professionality and in familiar surroundings. Studies on changes of patient characteristics as well as the contents of care within time are scarce. The aim of this study was the evaluation of care parameters and variations in time as well as a qualitative assessment of the dying process and the stress on the dependents., Methods: Anonymized routine patient data sets from 2012 to 2016 were retrospectively analyzed and compared to assess the efforts, characteristics of care as well as development of work within time. On the basis of the palliative care problem severity score (PCPSS), we developed the instrument "score of concern" to describe the quality of the dying process and the burden on the dependents., Results: In the complete time frame, 1806 cases were treated. The median age was 74 years, 82% had cancer, 36% were counselled, 14% had consultation, 50% had partial care. 98% died at their desired place. The patients of 2016 were older in comparison to those from 2012, had more non-oncological diagnoses, were more severely ill, were infrequently hospitalized and more intensely cared for. The dying process was associated with fewer signs of stress., Conclusion: Data relevant for care document the changes in complexity as well as density of the work within time. The instrument "score of concern", developed to describe the dying process, can be a helpful tool to assess the qualitative outcome of patient and dependents' care and may be helpful also for other SAPV teams., Competing Interests: Alle Autoren geben an, dass keine Interessenkonflikte bestehen., (Thieme. All rights reserved.)

The family of Tre2-Bub2-Cdc16 (TBC)-domain containing GTPase activating proteins (RABGAPs) is not only known as key regulatorof RAB GTPase activity but also has GAP-independent functions. Rab GTPases are implicated in membrane trafficking pathways, such as vesicular trafficking. We report biallelic loss-of-function variants in TBC1D2B, encoding a member of the TBC/RABGAP family with yet unknown function, as the underlying cause of cognitive impairment, seizures, and/or gingival overgrowth in three individuals from unrelated families. TBC1D2B messenger RNA amount was drastically reduced, and the protein was absent in fibroblasts of two patients. In immunofluorescence analysis, ectopically expressed TBC1D2B colocalized with vesicles positive for RAB5, a small GTPase orchestrating early endocytic vesicle trafficking. In two independent TBC1D2B CRISPR/Cas9 knockout HeLa cell lines that serve as cellular model of TBC1D2B deficiency, epidermal growth factor internalization was significantly reduced compared with the parental HeLa cell line suggesting a role of TBC1D2B in early endocytosis. Serum deprivation of TBC1D2B-deficient HeLa cell lines caused a decrease in cell viability and an increase in apoptosis. Our data reveal that loss of TBC1D2B causes a neurodevelopmental disorder with gingival overgrowth, possibly by deficits in vesicle trafficking and/or cell survival., (© 2020 Wiley Periodicals LLC.)

Introduction and Objectives: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described., Materials and Methods: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1-2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values., Results: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34-52). Median ALT was 33U/L (IQR: 22-50), 37% had HBV DNA <10 3 IU/mL, 71% were HBeAg negative, and 65% had a FIB-4 <1.45. At baseline, 8% of participants were at-risk alcohol drinkers, 11% were current smokers and 92% drank <3 cups of coffee/day. Current tobacco and 'at-risk' alcohol use, were significantly associated with elevated ALT levels in univariable analyses, however, these associations were not statistically significant when controlling for sociodemographic and HBV characteristics., Conclusions: In this large diverse cohort of untreated CHB participants, at-risk alcohol use, current tobacco use and limited coffee consumption did not have an association with high ALT and FIB-4 values. In contrast, significant associations were found between the frequency of these lifestyle behaviors and sociodemographic factors., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

The residue lysine 28 (K28) is known to form an important salt bridge that stabilizes the Aβ amyloid structure, and acetylation of lysine 28 (K28Ac) slows the Aβ42 fibrillization rate but does not affect fibril morphology. On the other hand, acetylation of lysine 16 (K16Ac) residue greatly diminishes the fibrillization property of Aβ42 peptide and also affects its toxicity. This is due to the fact that lysine 16 acetylated amyloid beta peptide forms amorphous aggregates instead of amyloid fibrils. This is likely a result of increased hydrophobicity of the K16-A21 region due to K16 acetylation, as confirmed by molecular dynamic simulation studies. The calculated results show that the hydrophobic patches of aggregates from acetylated peptides were different when compared to wild-type (WT) peptide. K16Ac and double acetylated (KKAc) peptide aggregates show significantly higher cytotoxicity compared to the WT or K28Ac peptide aggregates alone. However, the heterogeneous mixture of WT and acetylated Aβ42 peptide aggregates exhibited higher free radical formation as well as cytotoxicity, suggesting dynamic interactions between different species could be a critical contributor to Aβ pathology.

Background: Patient-reported outcomes (PROs) such as health-related quality of life (HRQoL) and symptoms associated with chronic hepatitis B viral (HBV) infection have not been well-described in North American cohorts., Aims: To evaluate several PROs and associations with HBV disease activity markers., Methods: Cross-sectional analysis including 876 adults who completed PRO measures during the Hepatitis B Research Network Adult Cohort Study. Participants on HBV treatment were excluded. Outcomes included: HRQoL using the SF-36 mental component summary and physical component summary scores; symptom burden using a 10-item Total Symptom Checklist and fatigue using an instrument from the Patient-Reported Outcomes Measurement Information System®. Covariates included laboratory markers of disease severity, virological status, comorbidities and medications., Results: Median age was 42 (range: 19-79), 51% were female, 73% Asian, 19% HBeAg (+), 2% had AST-platelet ratio index (APRI) ≥1.5 and 74% without comorbidities. Mean mental component summary T-score = 52, physical component summary T-score = 54 and PROMIS Fatigue T-score = 47. On a scale from 0 (none) to 40 (extreme), the mean Symptom Checklist score = 3 and 25% reported no symptoms. The most frequent symptoms were fatigue (60%), irritability (32%) and itching (32%). Most symptoms were 'a little bit' bothersome. In multivariable regressions, APRI ≥1.50 and more comorbidities were associated with worse patient-reported outcomes; virological markers were not. Adding the Total Symptom Checklist score to original regression models increased explanation of variation in the mental component summary score from 4% to 44% and the Physical Component Summary Score from 17% to 34%., Conclusions: Untreated North American HBV patients with mild liver disease report favourable health-related quality of life and minimal symptoms. HBV does not impact health-related quality of life unless advanced liver disease or comorbidities are present. High symptom burden explains substantial variation in health-related quality of life. (CT.gov identifier: NCT01263587)., (© 2020 John Wiley & Sons Ltd.)

Objective: Although most patients with chronic hepatitis B (CHB) reach effective virological suppression with long-term nucleos(t)ide analogues (NA) therapy, some might not need to continue treatment for life. In this randomised, controlled, phase IV trial, we evaluated off-therapy outcomes in patients after discontinuing long-term NA therapy., Design: Patients who had received NA therapy for ≥1 year and achieved virological suppression (hepatitis B e antigen (HBeAg) seroconversion combined with undetectable hepatitis B virus (HBV) DNA ≥12 months in HBeAg-positive patients or undetectable HBV DNA ≥36 months in HBeAg-negative patients) were randomised 2:1 to stop or continue NA therapy for 72 weeks. Sustained disease remission (HBeAg negative, HBV DNA <2000 IU/mL and normal alanine aminotransferase (ALT)) was evaluated at 72 weeks after stopping NA therapy., Results: Among 67 enrolled patients, sustained disease remission was observed in 13/45 (29%) stop versus 18/22 (82%) continue patients. Hepatitis B surface antigen (HBsAg) loss occurred in two patients (one in each group). The median HBsAg decline from randomisation to week 72 was similar in both groups (0.2 (0.0-0.4) vs 0.1 (0.0-0.2) log IU/mL in stop vs continue patients). Among patients who stopped, 15/45 (33%) had virological or biochemical relapse and 17/45 (38%) were retreated according to predefined criteria. A total of 11/18 (61%) pretreatment HBeAg-positive versus 6/27 (22%) HBeAg-negative patients required retreatment (p=0.01). Fourteen (31%) patients developed ALT >10× upper limit of normal (ULN) and another 7 (16%) had ALT >5× ULN. No patients experienced liver decompensation or died., Conclusion: The findings of this prospective study suggest limited benefit of stopping NA therapy in chronic hepatitis B., Trial Registration Number: NCT01911156., Competing Interests: Competing interests: BEH has received grants from and is consultant to Intercept Pharmaceuticals. HLAJ has received grants from and is consultant to Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Novartis, Roche and Janssen. JJF reports receiving support for research or scientific consulting from Abbott, Abbvie, Contavir, Enanta, Gilead Sciences, Janssen and Roche. SF has received research support from Gilead Sciences and speaking and teaching and/or consulting fees from Gilead Sciences, Merck and AbbVie. DKHW has received speaking and teaching fees from AbbVie and Merck., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Exogenous ochronosis is a cutaneous condition characterized by blue-black pigmentation resulting as a complication of long-term application of skin-lightening creams containing hydroquinone and other substances such as quinine, phenol and mercury derivatives. We report a case of a 55-year-old woman who developed exogenous ochronosis as a result of prolonged use of topical hydroquinone for 5 years, characterized by greyish hyperpigmented patches on the nose and cheeks. The diagnosis was confirmed histologically. Treatment with picosecond laser resulted in marked clinical improvement together with improvement in overall texture and quality of the skin., (© 2018 Wiley Periodicals, Inc.)

Background & Aims: The use of complementary and alternative medicine (CAM) in patients with chronic hepatitis B (CHB) can interact with antiviral treatment or influence health-seeking behaviour. We aimed to study the use of individual CAM modalities in CHB and explore determinants of use, particularly migration-related, socio-economic and clinical factors., Methods: A total of 436 CHB outpatients who attended the Toronto Centre for Liver Disease in 2015-2016 were included in this cross-sectional study. Using the comprehensive I-CAM questionnaire and health records, data were collected on socio-demographic and clinical variables and on usage of 16 CAM modalities in the last year., Results: Sixty percent of patients were male, 74% were Asian and 46% were using antiviral treatment. Three-hundred and nine (71%) patients used CAM. Vitamin/mineral preparations (45% of patients) were most commonly used. Overall CAM use and the specific use of potentially injurious CAM, such as green tea extract (9.2%) and St. John's wort (0.2%), were not associated with liver disease severity. Female sex, family history of CHB, lower serum HBV DNA, and higher socio-economic status were independently associated with bio-holistic CAM use, the clinically most-relevant CAM group (P < 0.05); ethnicity, antiviral therapy use and liver disease severity were not., Conclusions: CAM use among CHB patients was extensive, especially use of vitamin and mineral preparations, but without direct influence on liver disease severity. Bio-holistic CAM use appeared to be associated with socio-economic status rather than with ethnicity or liver disease severity. Despite the rare use of hepatotoxins, physicians should actively inquire about it., (© 2019 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Activation of short-chain free fatty acid receptors 3 (FFAR3) has been suggested to promote sympathetic outflow in postganglionic sympathetic neurons or hamper it by a negative coupling to N-type calcium (Ca V 2.2) channels. Heterogeneity of FFAR3 expression in sympathetic neurons, however, renders single neurons studies extremely time-consuming in wild-type mice. Previous studies demonstrated large variability of the degree of Ca V 2.2 channel inhibition by FFAR3 in a global population of rat sympathetic neurons. Therefore, we focused on a small subpopulation of mouse sympathetic neurons using an FFAR3 antibody and an Ffar3 reporter mouse to perform immunofluorescent and electrophysiological studies. Whole-cell patch-clamp recordings of identified FFAR3-expressing neurons from reporter mice revealed a 2.5-fold decrease in the Ca V 2.2-FFAR3 inhibitory coupling variability and 1.5-fold increase in the mean I Ca 2+ inhibition, when compared with unlabeled neurons from wild-type mice. Further, we found that the ablation of Ffar3 gene expression in two knockout mouse models led to a complete loss-of-function. Subpopulations of sympathetic neurons are associated with discrete functional pathways. However, little is known about the neural pathways of the FFAR3-expressing subpopulation. Our data indicate that FFAR3 is expressed primarily in neurons with a vasoconstrictor phenotype. Thus, fine-tuning of chemically-coded neurotransmitters may accomplish an adequate outcome.

Eurocode 3 establishes the component method to analytically characterize the structural joints between beam and columns. When one of the members involved in the joint is a hollow section (i.e., a tube) there is a lack of information for the specific components present in the joint. There are two different ways to bridge the gap: experimental testing on the actual beam column joints involving tubular sections; or numerical modelization, typically by means of finite element analysis. For this second option, it is necessary to know the actual mechanical properties of the material. As long as the joint implies a welding process, there is a concern related to how the mechanical properties in the heat-affected zone (HAZ) influence the behavior of the joint. In this work, some coupons were extracted from the HAZ of the beam-column joint. The coupons were tested and the results were implemented in the numerical model of the joint, in an attempt to bring it closer to the experimental results of the tested joints., Competing Interests: The authors declare no conflict of interest.

Syndromes caused by copy number variations are described as reciprocal when they result from deletions or duplications of the same chromosomal region. When comparing the phenotypes of these syndromes, various clinical features could be described as reversed, probably due to the opposite effect of these imbalances on the expression of genes located at this locus. The NFIX gene codes for a transcription factor implicated in neurogenesis and chondrocyte differentiation. Microdeletions and loss of function variants of NFIX are responsible for Sotos syndrome-2 (also described as Malan syndrome), a syndromic form of intellectual disability associated with overgrowth and macrocephaly. Here, we report a cohort of nine patients harboring microduplications encompassing NFIX. These patients exhibit variable intellectual disability, short stature and small head circumference, which can be described as a reversed Sotos syndrome-2 phenotype. Strikingly, such a reversed phenotype has already been described in patients harboring microduplications encompassing NSD1, the gene whose deletions and loss-of-function variants are responsible for classical Sotos syndrome. Even though the type/contre-type concept has been criticized, this model seems to give a plausible explanation for the pathogenicity of 19p13 microduplications, and the common phenotype observed in our cohort.

It is well known that the cold-forming process used to manufacture tubes causes an increase in both the yielding stress and the ultimate strength of the corner material in rectangular steel hollow sections. This may have a significant effect on the resistance of any structure built with those profiles. However, the mentioned material hardening can be difficult to take into account in the calculations for member design or to evaluate the connection resistance through the design formulation or when using numerical simulation models. As an attempt to face the above-mentioned problem, the present paper presents a comparison among simplified approaches that consider homogeneous material properties for the whole section. It has been carried out by comparing the results obtained from the finite element modelling of stub column tests in which the material properties based on the flat faces were considered for the whole profile., Competing Interests: The authors declare no conflict of interest.

Background & Aims: Current guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in all patients with cirrhosis, regardless of etiology. However, HCC incidence is not well established for many causes of cirrhosis. We aimed to assess the disease-specific incidence of HCC in a large cohort of patients with cirrhosis and to develop a scoring system to predict HCC risk., Methods: A derivation cohort of patients with cirrhosis diagnosed by biopsy or non-invasive measures was identified through retrospective chart review. The disease-specific incidence of HCC was calculated according to etiology of cirrhosis. Factors associated with HCC were identified through multivariable Cox regression and used to develop a scoring system to predict HCC risk. The scoring system was evaluated in an external cohort for validation., Results: Of 2,079 patients with cirrhosis and ≥6months follow-up, 226 (10.8%) developed HCC. The 10-year cumulative incidence of HCC varied by etiologic category from 22% in patients with viral hepatitis, to 16% in those with steatohepatitis and 5% in those with autoimmune liver disease (p<0.001). By multivariable Cox regression, age, sex, etiology and platelets were associated with HCC. Points were assigned in proportion to each hazard ratio to create the Toronto HCC Risk Index (THRI). The 10-year cumulative HCC incidence was 3%, 10% and 32% in the low-risk (<120points), medium-risk (120-240) and high-risk (>240) groups respectively, values that remained consistent after internal validation. External validation was performed on a cohort of patients with primary biliary cirrhosis, hepatitis B viral and hepatitis C viral cirrhosis (n=1,144), with similar predictive ability (Harrell's c statistic 0.77) in the validation and derivation cohorts., Conclusion: HCC incidence varies markedly by etiology of cirrhosis. The THRI, using readily available clinical and laboratory parameters, has good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis., Lay Summary: HCC incidence varies markedly depending on the underlying cause of cirrhosis. Herein, using readily available clinical and laboratory parameters we describe a risk score, THRI, which has a good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis., (Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

A novel near-infrared fluorescent probe for β-galactosidase has been developed based on a hemicyanine skeleton, which is conjugated with a d-galactose residue via a glycosidic bond. The probe serves as a substrate of β-galactosidase and displays rapid and sensitive turn-on fluorescent responses to β-galactosidase in aqueous solution. A 12.8-fold enhancement of fluorescence intensity at 703 nm was observed after incubation of 10 nM of β-galactosidase with 5 μM probe for 10 min. The probe can sensitively detect as little as 0.1 nM of β-galactosidase and shows linear responses to the enzyme concentration below 1.4 nM. The kinetic study showed that the probe has high binding affinity to β-galactosidase with K m  = 3.6 μM. The probe was used to detect β-galactosidase in living cells by employing the premature cell senescence model. The probe exhibited strong fluorescent signals in senescent cells but not in normal cells, which demonstrates that the probe is able to detect the endogenous senescence-associated β-galactosidase in living cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Past research has demonstrated the positive effects of visual and performing arts on health professionals' observational acuity and associated diagnostic skills, well-being and professional identity. However, to date, the use of arts for the development of non-technical skills, such as teamwork and communication, has not been studied thoroughly., Methods: In partnership with a community print and media arts organisation, Centre[3], we used a phenomenological approach to explore front-line mental health and social service workers' experiences with a creative professional development workshop based on the visual and performing arts. Through preworkshop and postworkshop interviews with participants and postworkshop interviews with their managers, we sought to examine how participants' perceptions of the workshop compared with their preworkshop expectations, specific impacts of the workshop with respect to participants' teamwork and communication skills and changes in their perceptions regarding the use of the arts in professional development., Results: Our workshops were successful in enhancing teamwork skills among participants and showed promise in the development of communication skills, though observable changes in workplace communication could not be confirmed. The workshop facilitated teamwork and collegiality between colleagues, creating a more enjoyable and accepting work environment. The workshops also helped participants identify the strengths and weaknesses of their communication skills, made them more comfortable with different communication styles and provided them with strategies to enhance their communication skills., Conclusions: Participation in the arts can be beneficial for the development of interpersonal skills such as teamwork and communication among health professionals., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Patients with chronic hepatitis B (CHB) infection are at an increased risk of developing hepatocellular carcinoma (HCC). Risk scores have been developed in Asian populations to predict HCC risk over time., Aim: To assess the performance of HCC risk prediction models in a heterogeneous population of patients with CHB., Methods: Scores were calculated at baseline using CU-HCC, REACH-B, NGM1-HCC, NGM2-HCC and GAG-HCC models and the incidence of HCC was determined. The predictive ability of each score was evaluated using the area under the receiver operating characteristic curve (AUROC), Cox regression and plots of observed versus predicted HCC. The predictive value of the scores was compared between Asian and non-Asian patients and between cirrhotic versus non-cirrhotic with and without treatment., Results: Of 2105 patients, 70 developed HCC. Increasing risk score was associated with HCC in all models. The CU-HCC model had the highest AUROC in Asian (0.85) and non-Asian (0.91) patients. Patients identified as low risk by any model had a very low incidence of HCC (0-0.15 per year), with the highest proportion of patients identified as low risk using CU-HCC (67%) or GAG-HCC (78%). The risk of HCC was similar to predicted for low-risk and medium-risk patients but was lower than predicted for high-risk patients. Treated patients had a lower than predicted risk of HCC, particularly in non-cirrhotic high-risk patients with longer follow-up., Conclusions: Although all models predicted the risk of HCC, models that incorporated parameters of liver function or cirrhosis (CU-HCC/GAG-HCC) were most accurate. Low-risk patients likely require reduced HCC surveillance., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Insulin aggregates under storage conditions via disulfide interchange reaction. It is also known to form aggregates at the site of repeated injections in diabetes patients, leading to injection amyloidosis. This has fueled research in pharmaceutical and biotechnology industry as well as in academia to understand factors that modulate insulin stability and aggregation. The main aim of this study is to understand the factors that modulate aggregation propensity of insulin under conditions close to physiological and measure effect of "seeds" on aggregation kinetics. We explored the aggregation kinetics of insulin at pH 7.2 and 37 °C in the presence of disulfide-reducing agent dithiothreitol (DTT), using spectroscopy (UV-visible, fluorescence, and Fourier transform infrared spectroscopy) and microscopy (scanning electron microscopy, atomic force microscopy) techniques. We prepared insulin "seeds" by incubating disulfide-reduced insulin at pH 7.2 and 37 °C for varying lengths of time (10 min to 12 h). These seeds were added to the native protein and nucleation-dependent aggregation kinetics was measured. Aggregation kinetics was fastest in the presence of 10 min seeds suggesting they were nascent. Interestingly, intermediate seeds (30 min to 4 h incubation) resulted in formation of transient fibrils in 4 h that converted to amorphous aggregates upon longer incubation of 24 h. Overall, the results show that insulin under disulfide reducing conditions at pH and temperature close to physiological favors amorphous aggregate formation and seed "maturity" plays an important role in nucleation dependent aggregation kinetics.

Disulfide bonds are naturally formed in more than 50% of amyloidogenic proteins, but the exact role of disulfide bonds in protein aggregation is still not well-understood. The intracellular reducing agents and/or improper use of antioxidants in extracellular environment can break proteins disulfide bonds, making them unstable and prone to misfolding and aggregation. In this study, we report the effect of disulfide-reducing agent dithiothreitol (DTT) on hen egg white lysozyme (lysozyme) and bovine serum albumin (BSA) aggregation at pH 7.2 and 37 °C. BSA and lysozyme proteins treated with disulfide-reducing agents form very distinct amorphous aggregates as observed by scanning electron microscope. However, proteins with intact disulfide bonds were stable and did not aggregate over time. BSA and lysozyme aggregates show unique but measurable differences in 8-anilino-1-naphthalenesulfonic acid (ANS) and 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) fluorescence, suggesting a loose and flexible aggregate structure for lysozyme but a more compact aggregate structure for BSA. Scrambled disulfide-bonded protein aggregates were observed by nonreducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) for both proteins. Similar amorphous aggregates were also generated using a nonthiol-based reducing agent, tris(2-carboxyethyl)phosphine (TCEP), at pH 7.2 and 37 °C. In summary, formation of distinct amorphous aggregates by disulfide-reduced BSA and lysozyme suggests an alternate pathway for protein aggregation that may be relevant to several proteins.

We have previously demonstrated that rat type-1 cerebellar astrocytes express a very active Na(+)/Ca(2+) exchanger which accounts for most of the total plasma membrane Ca(2+) fluxes and for the clearance of Ca (i) (2+) induced by physiological agonist. In this chapter, we have explored the mechanism by which the reverse Na(+)/Ca(2+) exchange is involved in agonist-induced Ca(2+) signalling in rat cerebellar astrocytes. Laser-scanning confocal microscopy experiments using immunofluorescence labelling of Na(+)/Ca(2+) exchanger and RyRs demonstrated that they are highly co-localized. The most important finding presented in this chapter is that L-glutamate activates the reverse mode of the Na(+)/Ca(2+) exchange by inducing a Na(+) entry through the electrogenic Na(+)-glutamate co-transporter and not through the ionophoric L-glutamate receptors as confirmed by pharmacological experiments with specific blockers of ionophoric L-glutamate receptors, electrogenic glutamate transporters and the Na/Ca exchange.

Providing patient care for the unconscious population in the intensive care unit can be very challenging. Over time, some nurses may face barriers that prevent them from providing caring behaviors, such as communication. Review of the literature found the attitude of a nurse, hospital technology, and the working environment are barriers that prevent therapeutic nurse-patient communication with a patient who is unconscious or sedated and ventilated. Becoming more knowledgeable about how communication can help and what can be done if such barriers present themselves in the hospital setting is beneficial to improving nurses' care in the intensive care unit.

Background: The effect of chronic hepatitis B (CHB) infection on health-related quality of life (HRQoL) and health state utilities has not been well characterized., Objective: To measure utility scores and HRQoL across disease states associated with CHB infection., Methods: Patients attending four tertiary care clinics for CHB were approached between July 2007 and March 2009. Respondents completed version 2 of the Short-Form 36 Health Survey, the EQ5D, a visual analogue scale, the Health Utilities Index Mark 3, standard gamble, and demographics and risk factor surveys in English, Cantonese or Mandarin. Charts were reviewed to determine disease stage and comorbidities., Results: A total of 433 patients were studied: 294 had no cirrhosis; 79 had compensated cirrhosis; seven had decompensated cirrhosis; 23 had hepatocellular carcinoma; and 30 had received a liver transplant. The mean standard gamble utilities for these disease states were 0.89, 0.87, 0.82, 0.84 and 0.86, respectively. HRQoL scores in noncirrhotic patients were similar to those of the general population. Scores of patients with compensated cirrhosis were not significantly lower; however, patients with decompensated cirrhosis and hepatocellular carcinoma had significantly lower HRQoL scores compared with noncirrhotic patients (P<0.05). Similar scores were observed among patients on and off oral antiviral treatment. Post-liver transplant patients had a higher HRQoL than patients with decompensated cirrhosis. Age, number of comorbidities and relationship status were significantly associated with HRQoL scores., Conclusions: HRQoL in CHB patients is only impaired in the later stages of liver disease. Neither CHB infection nor antiviral treatment is associated with a lower quality of life.

Because firing properties and metabolic rates vary widely, neurons require different transport rates from their Na(+)/K(+) pumps in order to maintain ion homeostasis. In this study we show that Na(+)/K(+) pump activity is tightly regulated by a novel process, RNA editing. Three codons within the squid Na(+)/K(+) ATPase gene can be recoded at the RNA level, and the efficiency of conversion for each varies dramatically, and independently, between tissues. At one site, a highly conserved isoleucine in the seventh transmembrane span can be converted to a valine, a change that shifts the pump's intrinsic voltage dependence. Mechanistically, the removal of a single methyl group specifically targets the process of Na(+) release to the extracellular solution, causing a higher turnover rate at the resting membrane potential., Competing Interests: The authors have declared that no competing interests exist.

This paper presents the results of experimental research using concrete produced by substituting part of the natural coarse aggregates with recycled aggregates from concrete demolition. The influence of the quality of the recycled aggregate (amount of declassified and source of aggregate), the percentage of replacement on the targeted quality of the concrete to be produced (strength and workability) has been evaluated. The granular structure of concrete and replacement criteria were analyzed in this study, factors which have not been analyzed in other studies. The following properties of recycled concretes were analyzed: density, absorption, compressive strength, elastic modulus, amount of occluded air, penetration of water under pressure and splitting tensile strength. A simplified test program was designed to control the costs of the testing while still producing sufficient data to develop reliable conclusions in order to make the number of tests viable whilst guaranteeing the reliability of the conclusions. Several factors were analyzed including the type of aggregate, the percentage of replacement, the type of sieve curve, the declassified content, the strength of concrete and workability of concrete and the replacement criteria. The type of aggregate and the percentage of replacement were the only factors that showed a clear influence on most of the properties. Compressive strength is clearly affected by the quality of recycled aggregates. If the water-cement ratio is kept constant and the loss of workability due to the effect of using recycled aggregate is compensated for with additives, the percentage of replacement of the recycled aggregate will not affect the compressive strength. The elastic modulus is affected by the percentage of replacement. If the percentage of replacement does not exceed 50%, the elastic modulus will only change slightly.

Background: Despite the availability of screening for chronic hepatitis B (CHB) infection and effective treatments now available, many at-risk individuals fail to seek appropriate medical attention., Objective: To identify the barriers to care for CHB infection in a Chinese Canadian community., Methods: A survey conducted in English or Chinese collected information from individuals with CHB infection that evaluated the level of understanding and identified the barriers that may prevent Chinese patients from undergoing monitoring, screening and/or treatment for CHB infection., Results: Among the 204 patients enrolled, common misconceptions were that sharing food transmits hepatitis B and that patients with severe disease are always symptomatic. Patients with a better understanding of hepatitis B were better educated, younger and were being followed at a tertiary care centre (P<0.01 for all). Prominent barriers to health care were time, inconvenience and language difficulties. Patients under the care of family physicians who had extended office hours were less likely to cite time (P=0.06) and distance (P=0.05) as barriers., Conclusion: Patient misconceptions that severe liver disease due to hepatitis B infection is symptomatic may factor into the unwillingness to spare the time and undergo the inconvenience associated with regular medical follow-up. Implementation of programs that increase awareness of the silent progression of CHB infection and provide culturally responsive clinics, better able to work within patients' time constraints may improve Chinese patients' access to health care.

In the past decade, there has been an increasing emphasis by researchers regarding the stigmatization of people who are hepatitis C positive as they seek health care. Because the vast majority of people with hepatitis C have a history of injection drug use, they are frequently assumed by practitioners to be injection drug users (IDUs), blamed for acquiring the disease, and viewed as irresponsible, immoral, and unworthy. Such stigmatization may cause people who have hepatitis C to avoid testing, treatment and care, as well as to not disclose their hepatitis C or injection drug use to practitioners. The purpose of this paper is to critically examine the representation of stigmatization in 21 published research reports from 1995 to 2006, with a specific focus on how these depictions have shaped the current understanding of interventions to address stigmatization of people with hepatitis C by health care practitioners. We will identify two themes in this literature: (1) hepatitis C-related stigmatization in health care settings arises primarily from practitioners' negative views of injection drug use, and (2) practitioners' negative attitudes toward people with hepatitis C are the result of their lack of awareness and/or information about the disease and/or about injection drug use. We will illustrate that similar themes have informed anti-stigma initiatives in other diseases, notably HIV/AIDS and mental illness, which have had little sustained effect in changing practitioners' behaviour toward the stigmatized population. In conclusion, we will call for research that considers factors beyond the individual practitioner as contributing to the stigmatization of people with hepatitis C, such as social, structural and institutional forces that shape practitioners' interactions with people with hepatitis C in health care settings.

Background: 'Idling' or ongoing low-level activity of the tissue factor (TF) pathway is a postulated mechanism by which the coagulation process can become active without a lag period at sites of injury., Objective: To determine whether TF around cutaneous vessels has bound factor VIIa in the absence of injury, and thus could participate in the idling process., Methods: Immunostaining of mouse skin with antibodies against a 15-residue peptide from the sequence of mouse TF, and against the whole extracellular portion of TF., Results: The whole TF antibody recognized TF in squamous epithelium and around vessels in the dermis. By contrast, the monospecific antibody only recognized TF in the squamous epithelium, but not around vessels. We also found that biotinylated, active site-inhibited FVIIa (FVIIai) bound to tissue sections in the same areas in which TF was recognized by the monospecific antibody (squamous epithelium), but did not bind around vessels. Molecular modeling revealed that FVIIa and FX binding to TF masked a significant part of the surface of the target peptide., Conclusions: In the aggregate, these data are most consistent with the interpretation that TF in perivascular sites has bound FVIIa, even in the absence of any injury. The presence of endogenously bound FVIIa prevents the subsequent binding of the monospecific antibody or exogenous FVIIai to perivascular TF.

Throughout evolution, enzymes have adapted to perform in different environments. The Na(+)/K(+) pump, an enzyme crucial for maintaining ionic gradients across cell membranes, is strongly influenced by the ionic environment. In vertebrates, the pump sees much less external Na(+) (100-160 mM) than it does in osmoconformers such as squid (450 mM), which live in seawater. If the extracellular architecture of the squid pump were identical to that of vertebrates, then at the resting potential, the pump's function would be severely compromised because the negative voltage would drive Na(+) ions back to their binding sites, practically abolishing forward transport. Here we show that four amino acids that ring the external mouth of the ion translocation pathway are more positive in squid, thereby reducing the pump's sensitivity to external Na(+) and explaining how it can perform optimally in the marine environment.

We have previously demonstrated that rat cerebellar Type-1 astrocytes express a very active genistein sensitive Na(+)/Ca(2+) exchanger, which accounts for most of the total plasma membrane Ca(2+) fluxes and for the clearance of loads induced by physiological agonists. In this work, we have explored the mechanism by which the reverse Na(+)/Ca(2+) exchange is involved in agonist-induced Ca(2+) signaling in rat cerebellar astrocytes. Microspectrofluorometric measurements of Cai(2+) with Fluo-3 demonstrate that the Cai(2+) signals associated long (> 20 s) periods of reverse operation of the Na(+)/Ca(2+) exchange are amplified by a mechanism compatible with calcium-calcium release, while those associated with short (< 20 s) pulses are not amplified. This was confirmed by pharmacological experiments using ryanodine receptors agonist (4-chloro-m-cresol) and the endoplasmic reticulum ATPase inhibitor (thapsigargin). Confocal microscopy demonstrates a high co-localization of immunofluorescent labeled Na(+)/Ca(2+) exchanger and RyRs. Low (< 50 micromol/L) or high (> 500 micromol/L) concentrations of L-glutamate (L-Glu) or L-aspartate causes a rise in which is completely blocked by the Na(+)/Ca(2+) exchange inhibitors KB-R7943 and SEA0400. The most important novel finding presented in this work is that L-Glu activates the reverse mode of the Na(+)/Ca(2+) exchange by inducing Na(+) entry through the electrogenic Na(+)-Glu-co-transporter and not through the ionophoric L-Glu receptors, as confirmed by pharmacological experiments with specific blockers of the ionophoric L-Glu receptors and the electrogenic Glu transporter.

Today, combination antiviral therapy with pegylated interferon-alpha and ribavirin (RBV) allows many patients infected with hepatitis C virus (HCV) to achieve a sustained virological response, which is equivalent to cure. Data also support the clinical benefit of combination antiviral therapy in patients coinfected with HCV and HIV, and in patients who have received a liver transplant. Antiviral therapy with pegylated interferon-alpha and RBV is, however, associated with a high incidence and significant magnitude of anemia. This anemia may have several mechanisms, including bone marrow suppression and hemolysis. In addition, patients coinfected with HIV may have both pre-existing and RBV-associated anemia. Management of anemia in patients with HCV through RBV dose reduction or treatment discontinuation may compromise the effectiveness of treatment, because studies have demonstrated that treatment adherence or maintenance of antiviral therapy dose is an important predictor of sustained virological response. Anemia associated with combination antiviral therapy in patients with HCV is frequently associated with an inadequate or blunted endogenous erythropoietin response. Accumulating evidence now supports the use of recombinant human erythropoietin (rHuEpo) to manage anemia in these patients, with the objective of maintaining the RBV dose, but clinical standards are lacking. The present article reviews the data relevant to the use of rHuEpo in this patient population and proposes a set of clinical practice standards to assist clinicians in selecting patients for rHuEpo and in implementing rHuEpo therapy effectively.