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Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8(+) T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.

To implement a nurse-led sexual rehabilitation programme for gynaecological cancer (GC) survivors and to evaluate its effects on their sexual functioning, sexual distress and marital satisfaction.An assessor-blinded, randomized controlled trial.The development of the nurse-led sexual rehabilitation intervention was guided by the concept of sexual health, as stated in the Neotheoretical Framework of Sexuality; the explicit permission giving, limited information, specific suggestions and intensive therapy model; and evidence-based nursing interventions for sexuality. Four intervention sessions will be delivered along the treatment trajectory. Women newly diagnosed (within 3 months) with GC will be recruited from the gynaecological units of three hospitals in Hong Kong. The participants (N = 172) will be randomly assigned to the intervention group to receive the nurse-led sexual rehabilitation programme, or to an attention control group to receive attention on four occasions during the same period when the intervention group receives the intervention. Sexual functioning, sexual distress and marital quality will be measured at baseline, 1 month after the completion of cancer treatment, after completion of the sexual rehabilitation programme and 12 months after cancer treatment. Semi-structured interviews will be conducted with the participants in the intervention group to explore their experiences with and feelings towards the programme. The study was funded in March 2019 and ethics approval was obtained in January 2019.Positive outcomes of the nurse-led sexual rehabilitation programme will contribute to scientific and practical knowledge about nursing interventions to help GC survivors and their partners to resume a satisfying intimate relationship and adapt to changes in sexuality after treatment.This study will contribute to the evidence for and advance research on the effectiveness of nurse-led sexuality rehabilitation interventions to support women and their partners to rebuild sexuality and intimacy after treatment for GC.

This study assessed the psychological wellbeing and its associated factors amongst ethnic minorities during the coronavirus disease 2019 (COVID-19) pandemic. A total of 310 Hong Kong South Asians aged 41.3 (SD 13.7) years completed an anonymous online survey between July 2020 and February 2021. The results showed an overall moderate level of stress and high levels of depression, anxiety and post-traumatic stress disorder (PTSD) symptoms amongst South Asian minorities. Multivariable regression analyses suggested that being single/divorced, following Hinduism or other non-Muslim religions, having lower perceived knowledge of COVID-19 and having worried about losing job were significant predictors of higher levels of depression, anxiety and/or stress; additionally, being male, having a low monthly household income, having worried about losing job and healthcare collapse were significant predictors of a higher level of PTSD symptoms. The findings suggest an urgent need to alleviate the psychological impacts of the COVID-19 pandemic on ethnic minorities, specifically for those most vulnerable to these impacts.

To design and develop a complex, evidence‑based, theory‑driven, and culturally appropriate character strengths-based intervention (CSI) for breast cancer patients, following the Medical Research Council (MRC) framework.From 2018 September to 2020 November, a complex intervention perspective was adopted. The rationale, methods, and processes employed in carrying out the study were reported. The acceptability and feasibility of intervention program were evaluated as a part of subsequent pilot study. Based on piloting, a refined and optimized definitive intervention was obtained. The development of the intervention is an iterative process involving input from three key stakeholders: experts, medical staff, and patient representatives.The systematic review revealed CSIs were effective and the selected theory served as a guide and indicated theory-inspired modifications. A representative team of breast cancer patients and oncology nurses collaboratively developed and tailored the intervention content and format with attention to the acceptability and feasibility. Five main strategies, including peripheral, evidential, linguistic, constituent-involving, and sociocultural strategies, were used to achieve and strengthen the cultural appropriateness. After the pilot phase, several refinements were made on the CSI program, such as editorial changes in the booklet or alternative suggestions for difficult strengths-based activities (e.g., outdoor activities). All participants not only expressed satisfaction with the program in process evaluation, but also reported perceived benefits such as enjoyable and sociable experience, better well-being, and increased confidence.Consideration of the MRC framework, theory guidance, and suggestions from stakeholders during intervention development can optimize uptake and sustainability in the clinical setting. It is recommended that randomized controlled trial be used in future studies to assess the intervention, the process and the mechanisms of the intervention. Our approach may offer implications for the design and implementation of similar initiatives to support cancer patients.ClinicalTrials.gov Register Identifier: NCT04219267, 07/01/2020, retrospectively registered.

Exposure to air pollution causes adverse health outcomes, but the toxicity mechanisms remain unclear. Here, we investigated the dynamic toxicities of naphthalene-derived secondary organic aerosol (NSOA) in a human bronchial epithelial cell line (BEAS-2B) and identified the chemical components responsible for toxicities. The chemical composition of NSOA was found to vary with six simulated atmospheric aging conditions (C(1)–C(6)), as characterized by high-resolution mass spectrometry and ion mobility mass spectrometry. Global proteome profiling reveals dynamic evolution in toxicity: Stronger proteome-wide impacts were detected in fresh NSOA, but the effects declined along with atmospheric aging. While Nrf2-regulated proteins (e.g., NQO1) were significantly up-regulated, the majority (78 to 97%) of proteins from inflammation and other pathways were down-regulated by NSOA exposure (e.g., Rho GTPases). This pattern is distinct from the reactive oxygen species (ROS)-mediated toxicity pathway, and an alternative cysteine reaction pathway was revealed by the decreased abundance of proteins (e.g., MT1X) prone to posttranslational thiol modification. This pathway was further validated by observing decreased Nrf2 response in reporter cells, after preincubating NSOA with cysteine. Ethynyl-naphthalene probe was employed to confirm the alkylation of cellular proteome thiols on the proteome-wide level by fresh NSOA via in-gel fluorescence imaging. Nontarget analysis identified several unsaturated carbonyls, including naphthoquinones and hydroxylated naphthoquinones, as the toxic components responsible for cysteine reactivity. Our study provides insights into the dynamic toxicities of NSOA during atmospheric aging and identifies short-lived unsaturated carbonyls as the predominant toxic components at the posttranslational level.

Small molecules targeting the cereblon-containing E3 ubiquitin ligase including thalidomide, lenalidomide, and pomalidomide modulate turnover of downstream client proteins and demonstrate pre-clinical and clinical anti-myeloma activity. Different drugs that engage with cereblon hold the potential of unique phenotypic effects, and we therefore studied the novel protein homeostatic modulator (PHM™) BTX306 with a unique thiophene-fused scaffold bearing a substituted phenylurea and glutarimide. This agent much more potently reduced human-derived myeloma cell line viability, with median inhibitory concentrations in the single nanomolar range versus micromolar values for lenalidomide or pomalidomide, and more potently activated caspases 3/8/9. While lenalidomide and pomalidomide induced greater degradation of Ikaros and Aiolos in myeloma cells, BTX306 more potently reduced levels of GSPT1, eRF1, CK1α, MCL-1, and c-MYC. Suppression of cereblon or overexpression of Aiolos or Ikaros induced relative resistance to BTX306, and this agent did not impact viability of murine hematopoietic cells in an in vivo model, demonstrating its specificity for human cereblon. Interestingly, BTX306 did show some reduced activity in lenalidomide-resistant cell line models but nonetheless retained its nanomolar potency in vitro, overcame bortezomib resistance, and was equipotent against otherwise isogenic cell line models with either wild-type or knockout TP53. Finally, BTX306 demonstrated strong activity against primary CD138-positive plasma cells, showed enhanced anti-proliferative activity in combination with bortezomib and dexamethasone, and was effective in an in vivo systemic model of multiple myeloma. Taken together, the data support further translational studies of BTX306 and its derivatives to the clinic for patients with relapsed and/or refractory myeloma. KEY MESSAGES: BTX306 has a unique thiophene-fused scaffold bearing phenylurea and glutarimide. BTX306 is more potent against myeloma cells than lenalidomide or pomalidomide. BTX306 overcomes myeloma cell resistance to lenalidomide or bortezomib in vitro. BTX306 is active against primary myeloma cells, and shows efficacy in vivo.

Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC., Immune responses to pancreatic ductal adenocarcinoma can be inhibited by cancer cells. Here the authors show that high levels of progranulin in PDAC inhibits immune responses by reducing MHC class I antigen presentation through enhanced degradation of MHC class I via autophagy.

Music may be a safe and effective coping strategy for psychological management. The objectives of this review were to identify the effects of music interventions on anxiety, depression, and quality of life (QoL) among cancer patients receiving chemotherapy.Fourteen databases were searched from the inception date to December 2020 to identify eligible randomized controlled trials (RCTs). Gray literature was also examined. The protocol of this systematic review was registered with PROSPERO (registration number: CRD42021223845). Two reviewers independently assessed eligibility, extracted data, and evaluated methodological quality. Meta-analysis was done. Subgroup analysis was conducted for intervention types, the person selecting music, music delivery method, timing, and session duration.Nine RCTs were identified, among which six were eligible for the meta-analysis. All studies were at a high risk of bias, and the overall quality of evidence was low to very low. The pooled results reveal that music intervention could reduce anxiety (SMD: - 0.29, 95% CI - 0.50 to - 0.08) and improve QoL (SMD: 0.42, 95% CI 0.02 to 0.82). However, it fails to affect depression (p = 0.79). The findings demonstrate no significant difference between patient-selected music and researcher-selected music, recorded music, and live music, while a length of 15-20 min/session and offering immediately before chemotherapy are more effective on anxiety than that of 30-45 min and delivering during chemotherapy.Music intervention may be a beneficial tool for anxiety reduction and QoL among cancer patients receiving chemotherapy. More high-quality RCTs are needed to ascertain the true impact of those outcomes.

Objective: The uptake of cervical cancer screening among South Asian ethnic minorities is low, rendering them at higher risk of developing cervical cancer. Interventions should, therefore, be developed to enhance their knowledge of this disease and its prevention. We developed and implemented a Health-Belief-Model-based and culturally sensitive multimedia intervention for South Asian women in Hong Kong, and evaluated its feasibility, acceptability and effectiveness using the Reach-Effectiveness-Adoption-Implementation-Maintenance framework.Design: At post-intervention, a short survey was conducted to assess the participants' perceptions of the acceptability and effectiveness of the intervention. Focus group and/or telephone interviews with persons-in-charge of community organizations were conducted to collect feedback on the intervention's effectiveness and long-term sustainability.Results: The intervention was implemented successfully in partnership with 54 community organizations, of which 51 expressed a willingness to continue doing so at their centers. 1061 South Asian women received the intervention through attendance at the 51 health talks held. Over 90% of them agreed that the intervention was acceptable and effective.Conclusions: The intervention appeared to be feasible, and is potentially effective in enhancing participants' knowledge of cervical cancer and self-efficacy in undergoing screening.

Background International guidelines on clinical staging of gastric cancer recommend the use of chest CT for the detection of pulmonary metastases. This study assessed the clinical value of routine chest CT in the staging of gastric cancer. Methods This retrospective study included patients identified from the gastric cancer registry of Chang Gung Memorial Hospital, Linkou, Taiwan. All patients who underwent clinical staging between 2008 and 2014 were included. The pattern, site and number of metastases at initial presentation and after surgery with curative intent were evaluated. Pulmonary metastases were defined as multiple small round pulmonary nodules with a random distribution or of variable size. Results Some 1669 patients were included, of whom 478 (28·6 per cent) had metastatic disease at clinical presentation. The majority of metastases were to the peritoneum (75·7 per cent of patients) or liver (30·5 per cent), and only 27 patients (5·6 per cent) had pulmonary metastases at presentation, none of which were isolated to the lung. Of these 27 patients, 11 had primary lesions located at the cardia/fundus. In 19 patients the lung metastases were also detected on the staging chest X-ray. After surgery there were 196 cancer recurrences. Some 15 patients (7·6 per cent) had lung metastasis and this was not the only site of metastases in any patient. The prevalence of lung metastasis at presentation of the disease and after surgery was 1·6 and 1·5 per cent respectively. Conclusion This study does not support the routine use of chest CT for staging of gastric cancer as isolated pulmonary metastasis in the absence of other metastatic sites could not be detected.

Colorectal cancer screening, including faecal immunohistochemical test, is an effective method for detecting colorectal cancer early. Nevertheless, faecal immunohistochemical test uptake among South Asian ethnic minorities is low because they have limited knowledge of and face barriers in accessing colorectal cancer screening. Tailored education and appropriate messaging has potential to convey to this population group the importance of colorectal cancer screening.This study aimed to assess the acceptability and effectiveness of a family-based multimedia intervention to raise awareness of colorectal cancer screening and increase the uptake of faecal immunochemical tests among South Asian older adults.A cluster-randomised controlled trial with a wait-list control group.Three-hundred and twenty dyads of South Asian older adults and their younger family members were recruited at South Asian community centres and non-governmental organisations providing support services to local South Asians in six Hong Kong districts.Group allocation of dyads during cluster randomisation was based on the group assignment of the district where they were recruited. The intervention comprised a multimedia health talk, conveying the importance of colorectal cancer screening and support from younger family members in encouraging their older relatives to undergo screening. Site coordinators assisted participants in accessing faecal immunohistochemical test. The primary outcome was increased uptake of faecal immunohistochemical test among South Asian older adults. Secondary outcomes included younger family members' encouragement of their older relatives to undergo faecal immunohistochemical test and their readiness to assist their relatives with the test. Acceptability of the intervention was measured by dyad satisfaction with the intervention.The proportion of older adults participating in faecal immunohistochemical testing was significantly higher among intervention dyads compared with controls (71.8% vs 6.8%, p 0.001). No significant within-group change was observed on the willingness of younger family members in the intervention group to encourage older adults to undergo faecal immunohistochemical test, nor their readiness to assist older adults in doing so, although a decrease in both outcomes was observed among the control group. Most participants (86%) were satisfied with the intervention.Our findings demonstrate the acceptability and effectiveness of the intervention in enhancing faecal immunohistochemical test uptake among South Asian older adults, and the benefit of using a family-based approach in the implementation of cancer screening interventions for these individuals. Implementation of the intervention as a component of usual care within South Asian communities is recommended. Trial registration ISRCTN72829325, 10 July 2018.

The urban–rural gap in cervical cancer screening uptake is a significant public health consideration. Educational interventions are commonly adopted to promote cervical cancer screening among females in rural areas; however, the characteristics and effectiveness of these educational interventions remain unclear. In this review, we aimed to identify the characteristics of educational interventions used in rural populations and to evaluate the effects of these interventions on cervical cancer screening-related outcomes. Seven English databases were searched in January 2022. Randomized controlled trials (RCTs) and quasi-experimental studies were included. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Randomized Controlled Trials and the JBI Critical Appraisal Checklist for Quasi-Experimental Studies were used for quality appraisal. RevMan 5.4 software was used for the meta-analysis. A narrative synthesis was conducted in instances where a meta-analysis was inappropriate. Three RCTs and seven quasi-experimental studies conducted in six countries were included. A social cognitive theory-based framework, the community setting, group sessions, healthcare professional-led approaches, and culture-tailored materials were implemented in the educational interventions for cervical cancer screening. The educational content mainly included basic information on cervical cancer screening, psychological issues, barriers and strategies to overcome them, and locally available resources. Educational interventions increased the knowledge and uptake of cervical cancer screening in the rural population. However, the studies only evaluated the short-term effects of these educational interventions, with the cervical screening behavior only being assessed in one instance for each participant. Educational interventions promote cervical cancer screening among females in rural areas. Theory-driven, community-involved, group-based, and healthcare professional-led approaches should be prioritized in the application of educational interventions in rural populations. Both the short- and long-term, influences of educational interventions on the cervical cancer screening behavior of females in rural areas need to be recognized.

Atmospheric oxidation of sulfur dioxide (SO2) forms sulfate-containing aerosol particles that impact air quality, climate, and human and ecosystem health. It is well-known that in-cloud oxidation of SO2 frequently dominates over gas-phase oxidation on regional and global scales. Multiphase oxidation involving aerosol particles, fog, and cloud droplets has been generally thought to scale with liquid water content (LWC) so multiphase oxidation would be negligible for aerosol particles due to their low aerosol LWC. However, recent field evidence, particularly from East Asia, shows that fast sulfate formation prevails in cloud-free environments that are characterized by high aerosol loadings. By assuming that the kinetics of cloud water chemistry prevails for aerosol particles, most atmospheric models do not capture this phenomenon. Therefore, the field of aerosol SO2 multiphase chemistry has blossomed in the past decade, with many oxidation processes proposed to bridge the difference between modeled and observed sulfate mass loadings. This review summarizes recent advances in the fundamental understanding of the aerosol multiphase oxidation of SO2, with a focus on environmental conditions that affect the oxidation rate, experimental challenges, mechanisms and kinetics results for individual reaction pathways, and future research directions. Compared to dilute cloud water conditions, this paper highlights the differences that arise at the molecular level with the extremely high solute strengths present in aerosol particles.

The 2019 novel coronavirus disease (COVID-19) epidemic originated in Wuhan, China and spread rapidly worldwide, leading the World Health Organization to declare an official global COVID-19 pandemic in March 2020. In Hong Kong, clinicians and other healthcare personnel collaborated closely to combat the outbreak of COVID-19 and minimize the cross-transmission of disease among hospital staff members. In the field of otorhinolaryngology—head and neck surgery (OHNS) and its various subspecialties, contingency plans were required for patient bookings in outpatient clinics, surgeries in operating rooms, protocols in wards and other services. Infected patients may shed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) particles into their environments via body secretions. Therefore, otolaryngologists and other healthcare personnel in this specialty face a high risk of contracting COVID-19 and must remain vigilant when performing examinations and procedures involving the nose and throat. In this article, we share our experiences of the planning and logistics undertaken to provide safe and efficient OHNS practices over the last 2 months, during the COVID-19 pandemic. We hope that our experiences will serve as pearls for otolaryngologists and other healthcare personnel working in institutes that serve large numbers of patients every day, particularly with regard to the sharing of clinical and administrative tasks during the COVID-19 pandemic.

To synthesize the characteristics and effects of couple-based intervention on sexuality and the quality of life (QOL) of cancer patients and their intimate partners and its implications for future research and practice.A systematic review and meta-analysis of randomized and non-randomized controlled studies of interventions was conducted in nine English databases and two Chinese databases, with identification of related studies published in English and Chinese. The quality of the studies was assessed using the tools of the Effective Public Health Practice Project.A total of 33 articles were identified for systematic review and 23 articles were identified for meta-analysis. For patients, the effect size was 0.42 (Hedges's g, 95% CI = 0.05-0.78, p = 0.03) for physical health. For partners, the effect size was 0.52 (Hedges's g, 95% CI = 0.06-0.98, p = 0.03) for sexual relationships. However, moderate to high heterogeneity was reported. Effects on sexual function, sexual self-concept, and mental health for couples were not significant.Couple-based interventions had small to medium-sized effects on physical health for cancer patients. Partners could derive medium effects for improvement in sexual relationships from couple-based intervention. Future research should pay more attention to sexual self-concept in cancer patients and target types of cancer that are more likely to compromise sexuality and QOL.The systematic review and meta-analysis has been registered in PROSPERO with registration number: CRD42019119047.

Wildfire smoke induces acute pulmonary distress and is of particular concern to risk groups such as the sick and elderly. Wood smoke (WS) contains many of the same toxic compounds as those found in cigarette smoke (CS) including polycyclic aromatic hydrocarbons, carbon monoxide, and free radicals. CS is a well-established risk factor for respiratory diseases such as asthma and COPD. Limited studies investigating the biological effects of WS on the airway epithelium have been performed. Using a cell culture-based model, we assessed the effects of a WS-infused solution on alveolar epithelial barrier function, cell migration, and survival. The average geometric mean of particles in the WS was 178 nm. GC/MS analysis of the WS solution identified phenolic and cellulosic compounds. WS exposure resulted in a significant reduction in barrier function, which peaked after 24 hours of continuous exposure. The junctional protein E-cadherin showed a prominent reduction in response to increasing concentrations of WS. Furthermore, WS significantly repressed cell migration following injury to the cell monolayer. There was no difference in cell viability following WS exposure. Mechanistically, WS exposure induced activation of the p44/42, but not p38, MAPK signaling pathway, and inhibition of p44/42 phosphorylation prevented the disruption of barrier function and loss of E-cadherin staining. Thus, WS may contribute to the breakdown of alveolar structure and function through a p44/42 MAPK-dependent pathway and may lead to the development and/or exacerbation of respiratory pathologies with chronic exposure.

Emerging evidence implicates a role of the gut microbiota in colorectal cancer (CRC). Peptostreptococcus anaerobius (P. anaerobius) is an anaerobic bacterium selectively enriched in the faecal and mucosal microbiota from patients with CRC, but its causative role and molecular mechanism in promoting tumorigenesis remain unestablished. We demonstrate that P. anaerobius adheres to the CRC mucosa and accelerates CRC development in Apc

Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-β. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.

Resection is the most widely used potentially curative treatment for patients with early hepatocellular carcinoma (HCC). However, recurrence within 2 years occurs in 30-50% of patients, being the major cause of mortality. Herein, we describe 2 models, both based on widely available clinical data, which permit risk of early recurrence to be assessed before and after resection.A total of 3,903 patients undergoing surgical resection with curative intent were recruited from 6 different centres. We built 2 models for early recurrence, 1 using preoperative and 1 using pre and post-operative data, which were internally validated in the Hong Kong cohort. The models were then externally validated in European, Chinese and US cohorts. We developed 2 online calculators to permit easy clinical application.Multivariable analysis identified male gender, large tumour size, multinodular tumour, high albumin-bilirubin (ALBI) grade and high serum alpha-fetoprotein as the key parameters related to early recurrence. Using these variables, a preoperative model (ERASL-pre) gave 3 risk strata for recurrence-free survival (RFS) in the entire cohort - low risk: 2-year RFS 64.8%, intermediate risk: 2-year RFS 42.5% and high risk: 2-year RFS 20.7%. Median survival in each stratum was similar between centres and the discrimination between the 3 strata was enhanced in the post-operative model (ERASL-post) which included 'microvascular invasion'.Statistical models that can predict the risk of early HCC recurrence after resection have been developed, extensively validated and shown to be applicable in the international setting. Such models will be valuable in guiding surveillance follow-up and in the design of post-resection adjuvant therapy trials.The most effective treatment of hepatocellular carcinoma is surgical removal of the tumour but there is often recurrence. In this large international study, we develop a statistical method that allows clinicians to estimate the risk of recurrence in an individual patient. This facility enhances communication with the patient about the likely success of the treatment and will help in designing clinical trials that aim to find drugs that decrease the risk of recurrence.

The sympathetic division of the autonomic nervous system includes a variety of cells including neurons, endocrine cells and glial cells. A recent study (Furlan et al. 2017) has revised thinking about the developmental origin of these cells. It now appears that sympathetic neurons and chromaffin cells of the adrenal medulla do not have an immediate common ancestor in the form a "sympathoadrenal cell", as has been long believed. Instead, chromaffin cells arise from Schwann cell precursors. This review integrates the new findings with the expanding body of knowledge on the signalling pathways and transcription factors that regulate the origin of cells of the sympathetic division of the autonomic nervous system.

A surge of vascular endothelial growth factor (VEGF) after transarterial chemoembolization (TACE) may contribute to tumor progression. Axitinib is a potent antiangiogenic agent with main activity against VEGF receptors 1 to 3. To the authors' knowledge, its role in combination with TACE for the treatment of patients with inoperable hepatocellular carcinoma (HCC) is unclear.A phase 2 clinical trial (ClinicalTrials.gov identifier NCT01352728) was conducted to evaluate the combination treatment. Patients with inoperable HCC who were potential candidates for TACE initiated treatment with axitinib at a dose of 5 mg twice daily and were evaluated for the need for TACE every 8 weeks. Axitinib was withheld 24 hours before TACE, and resumed 24 hours afterward when fulfilling predefined criteria. Radiologic assessment was conducted every 8 weeks. The primary endpoint was the 2-year overall survival (OS) rate.A total of 50 patients were recruited from March 2011 to April 2014. The mean age of the patients was 61.8 years, and 46 patients (92%) had hepatitis B infection. The Barcelona Clinic Liver Cancer stage B/C percentage was 76% (38 cases)/24% (12 cases). The 2-year OS rate was 43.7%, and the median OS was 18.8 months in the intention-to-treat population. Among the evaluable population (44 patients), 40.9% (18 patients) and 27.3% (12 patients) achieved complete and partial responses, respectively. Common grade 3 or above axitinib-related complications included hand-foot skin reaction (14%) and hypertension (24%). The presence of hypertension during treatment was found to be an independent prognosticator (hazard ratio, 0.563; P = .0073) suggestive of a contributory role of axitinib to efficacy.The combination of axitinib and TACE was potentially efficacious for patients with inoperable HCC with a high radiologic response rate. Cancer 2017;123:3977-85. © 2017 American Cancer Society.

Silicosis is a prolonged, irreversible and incurable occupational disease, and there is a significant number of newly diagnosed cases every year in Hong Kong. Due to the long latency of the disease, the diagnosis can be missed until detailed clinical examination at a later stage. For a better control of this deadly disease, detailing the pro-inflammatory and fibrotic events in the macrophage would be instrumental in understanding the pathogenesis of the disease and essential for the significant biomarkers discovery. In this in vitro study, human cell line model A549 lung epithelial cells were used. The immediate molecular events underneath the activation of quartz silica polymorphs were followed in a time course of 0, 0.5, 2, 8, 16 and 24 h. The transcriptome library was prepared and subjected to RNA-Seq analysis. Data analysis was performed by pathway analysis tools and verified by real-time PCR. The results showed that triggered genes were mainly found in the immune response and inflammatory pathways. An interesting finding was the association of the DNA-binding protein inhibitor (ID) family in the silica exposure to lung cells. The linkage of ID1, ID2 and ID3 to cancer may rationalize themselves to be the markers indicating an early response of silicosis. However, further studies are required to consolidate the roles of these genes in silicosis. Copyright © 2017 John WileySons, Ltd.

Concurrent fatty liver in hepatitis B virus (HBV)-infected patients without significant alcohol intake is a frequent and increasingly alarming problem because of the non-alcoholic fatty liver disease pandemic. The risk of HBV-related hepatocellular carcinoma (HCC) development was increased by concomitant obesity and diabetes. Direct evidence of the hepatocarcinogenic effect of fatty liver in chronic HBV remains elusive. We aimed to evaluate the risk of concurrent histologically proven fatty liver in HBV hepatocarcinogenesis.We conducted a retrospective cohort study on a liver biopsy cohort of HBV-infected patients without significant alcohol intake to evaluate the prevalence of concurrent histologically proven fatty liver and its association with subsequent HCC development. We also examined nine polymorphisms on six non-alcoholic fatty liver disease-related candidate genes (ADIPOQ, APOC3, GCKR, LEPR, PNPLA3, and PPARG).Among 270 HBV-infected patients, concurrent fatty liver was found in 107 patients (39.6%) and was associated with metabolic risks, cirrhosis (P = 0.016) and PNPLA3 rs738409 CG/GG genotype (P = 0.002). At a median follow-up of 79.9 months, 11 patients (4.1%) developed HCC, and nine of them had concurrent fatty liver. By multivariable Cox analysis, concurrent fatty liver (HR 7.27, 95% confidence interval: 1.52-34.76; P = 0.013), age, cirrhosis, and APOC3 rs2854116 TC/CC genotype (HR 3.93, 95% confidence interval: 1.30-11.84; P = 0.013) were independent factors predicting HCC development.Concurrent fatty liver is common in HBV-infected patients and an independent risk factor potentiating HBV-associated HCC development by 7.3-fold. The risk of HBV-related HCC is increased by APOC3 gene polymorphism, and further characterization is required by its role.

The albumin-bilirubin (ALBI) grade is a recently emerging alternative of the Child-Pugh (CP) grade. The Cancer of the Liver Italian Program (CLIP) was demonstrated to be a useful prognostic model for hepatocellular carcinoma (HCC) in large prospective cohorts. We aimed to investigate the feasibility of substituting the CP grade by the ALBI grade in the CLIP system and compare the prognostic performance with other existing staging systems.A large cohort of 1973 Chinese patients with HCC was recruited to evaluate the prognostic performance of CP-based CLIP (CP-CLIP) and ALBI-based CLIP (ALBI-CLIP) systems and nine other staging systems by homogeneity likelihood chi-square, c-index, and corrected Akaike information criterion.The ALBI-CLIP system provided comparable prognostic performance than the CP-CLIP system, which was indicated by homogeneity likelihood chi-squares (ALBI-CLIP 1186.35 vs CP-CLIP 1145.54), c-indices (ALBI-CLIP 0.789 vs CP-CLIP 0.785) and AICs (ALBI-CLIP 15 493.47 vs CP-CLIP 15 534.28). Among 11 staging systems, ALBI-CLIP and CP-CLIP systems were associated with the highest homogeneity chi-squares and c-indices, and the lowest corrected Akaike information criterion. Patients in ALBI-CLIP score 0-4 had better median survival than those in corresponding CP-CLIP score.The ALBI grade performs as well as the CP grade when integrating into the CLIP system. ALBI-CLIP and CP-CLIP systems are the most accurate prognostic models among 11 existing staging systems.

Current therapeutic strategies for sickle cell anemia are aimed at reactivating fetal hemoglobin. Pomalidomide, a third-generation immunomodulatory drug, was proposed to induce fetal hemoglobin production by an unknown mechanism. Here, we report that pomalidomide induced a fetal-like erythroid differentiation program, leading to a reversion of γ-globin silencing in adult human erythroblasts. Pomalidomide acted early by transiently delaying erythropoiesis at the burst-forming unit-erythroid/colony-forming unit-erythroid transition, but without affecting terminal differentiation. Further, the transcription networks involved in γ-globin repression were selectively and differentially affected by pomalidomide including BCL11A, SOX6, IKZF1, KLF1, and LSD1. IKAROS (IKZF1), a known target of pomalidomide, was degraded by the proteasome, but was not the key effector of this program, because genetic ablation of IKZF1 did not phenocopy pomalidomide treatment. Notably, the pomalidomide-induced reprogramming was conserved in hematopoietic progenitors from individuals with sickle cell anemia. Moreover, multiple myeloma patients treated with pomalidomide demonstrated increased in vivo γ-globin levels in their erythrocytes. Together, these data reveal the molecular mechanisms by which pomalidomide reactivates fetal hemoglobin, reinforcing its potential as a treatment for patients with β-hemoglobinopathies.

The Japan Integrated Staging (JIS) for hepatocellular carcinoma (HCC) has been extensively studied in hepatitis virus C-endemic Japanese population but seldom evaluated outside Japan, while albumin-bilirubin (ALBI)-based JIS (ALBI-T) has never been externally validated. We evaluate the prognostic significance of the ALBI-T score among Chinese patients with hepatitis virus B (HBV)-related HCC, and to explore its potential therapeutic application in selecting patients for appropriate treatments in addition to the Barcelona Clinic Liver Cancer (BCLC) recommendation.A cohort of 1222 HBV-associated HCC patients was evaluated to compare the prognostic performance of JIS and ALBI-T scores by homogeneity likelihood chi-square and corrected Akaike information criterion. In the subgroup analysis of each BCLC stage, Kaplan-Meier method and log-rank statistics were used to compare overall survival of patients undergoing different treatment options.The ALBI-T score showed better prognostic performance than the JIS score, which were indicated by homogeneity likelihood chi-squares (ALBI-T 580.12 vs JIS 536.35) and Akaike information criteria (ALBI-T 9836.57 vs JIS 9880.23). Treatment options significantly influenced prognosis among patients of the same BCLC stage. With the use of ALBI-T score 4 as the cutoff, the current study identified that a portion of patients (14.7%, 25.2% and 28.6% of BCLC stage B, C and D, respectively) undergoing unnecessary therapy without survival advantage.The ALBI-T score is applicable to Chinese patients with HBV-related HCC to provide reasonable prognostic information as well as potentially helping clinicians to avoid offering non-beneficial aggressive treatments.

Sickle-cell disease (SCD) and beta thalassemia constitute worldwide public health problems. New therapies, including hydroxyurea, have attempted to augment the synthesis of fetal hemoglobin (HbF) and improve current treatment. Lenalidomide and pomalidomide are members of a class of immunomodulators used as anticancer agents. Because clinical trials have demonstrated that lenalidomide reduces or eliminates the need for transfusions in some patients with disrupted blood cell production, we investigated the effects of lenalidomide and pomalidomide on erythropoiesis and hemoglobin synthesis. We used an in vitro erythropoiesis model derived from human CD34+ progenitor cells from normal and SCD donors. We found that both compounds slowed erythroid maturation, increased proliferation of immature erythroid cells, and regulated hemoglobin transcription, resulting in potent induction of HbF without the cytotoxicity associated with other HbF inducers. When combined with hydroxyurea, pomalidomide and, to a lesser extent, lenalidomide were found to have synergistic effects on HbF upregulation. Our results elucidate what we believe to be a new mechanism of action of pomalidomide and lenalidomide and support the hypothesis that pomalidomide, used alone or in combination with hydroxyurea, may improve erythropoiesis and increase the ratio of fetal to adult hemoglobin. These findings support the evaluation of pomalidomide as an innovative new therapy for beta-hemoglobinopathies.

Nodular regenerative hyperplasia (NRH) of the liver, characterized by regenerative nodules distributed throughout the liver in the absence of fibrosis, is a rare but important complication of systemic lupus erythematosus (SLE). The main consequence of NRH is non-cirrhotic portal hypertension. We describe a female patient who had immune thrombocytopenia in association with elevated liver enzymes and evidence of portal hypertension as initial manifestations of SLE. Computed tomographic scan and magnetic resonance imaging of the liver in this patient showed enhancing periportal tubular structures distributed throughout the liver. The diagnosis of NRH was eventually disclosed by transcutaneous needle liver biopsy. The pattern of radiological abnormality in this patient has not been described previously in NRH. In addition, we believe this is a first reported case of SLE presenting with immune thrombocytopenia in association with NRH.

Aims Diabetes mellitus is the most common co-morbidity associated with necrotising fasciitis. This study aims to compare the clinical presentation, investigations, Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC) score, microbiology and outcome of management of this condition in diabetic and non-diabetic patients. Patients and Methods The medical records of all patients with surgically proven necrotising fasciitis treated at our institution between 2005 and 2014 were reviewed. Diagnosis of necrotising fasciitis was made on findings of ‘dishwater’ fluid, presence of greyish necrotic deep fascia and lack of bleeding on muscle dissection found intra-operatively. Information on patients’ demographics, presenting symptoms, clinical signs, investigations, treatment and outcome were recorded and analysed. Results A total of 127 patients with surgically proven necrotising fasciitis were included in this study. In all, 78 (61.4%) were diabetic and 49 (38.6%) were non-diabetic. Diabetics tended to have polymicrobial infections (p = 0.03), renal impairment (p < 0.001), end-stage renal disease (p = 0.001) and multiple co-morbidities (p < 0.001). They presented atypically, with less tenderness (p = 0.042) and less hypotension (p = 0.034). This resulted in higher rates of misdiagnosis (p = 0.038) and a longer time to surgery (p = 0.05) leading to longer hospital stays (p = 0.043) and higher rates of amputation (p = 0.045). However, the rate of mortality is comparable (p = 0.525). A LRINEC score of > 8 appears to be more sensitive in diabetic patients (p < 0.001). However, the increased sensitivity in diabetic patients may be related to hyperglycemia and electrolyte abnormalities associated with renal impairment in these patients. Conclusion The LRINEC score must be used with caution in diagnosing necrotising fasciitis in diabetic patients. A high index of suspicion is key to the early diagnosis and subsequent management of these patients. Cite this article: Bone Joint J 2016;98-B:1563–8.

The albumin-bilirubin (ALBI) grade is a recently reported, simpler, more objective, and evidence-based alternative to the Child-Pugh (CP) score for hepatocellular carcinoma (HCC). We aimed to study whether ALBI grade could substitute for CP score in Barcelona Clinic Liver Cancer (BCLC) for HCC.An international multicentre cohort (n = 3696) was accrued to compare the prognostic performance of the CP-based and ALBI-based BCLC system, in terms of homogeneity, discriminatory ability, and monotonicity of gradients that were numerically reflected by homogeneity likelihood, linear trend chi-squares, and c-indices, respectively.The ALBI grade performed as well as CP score when integrated into the BCLC staging system in terms of predicting clinical outcome of HCC regardless of regions, etiology, and treatment options. CP-based and ALBI-based BCLC systems were highly concordant with weighted kappa value of 0.917. All restaged patients showed significantly different clinical outcomes compared with their original stage classification. In particular, ALBI-based BCLC upstaged 83 (2.2%) patients from lower CP-based BC LC stages to ALBI-based BCLC stage D, whose median overall survival was only 3 months.The overall prognostic performance of ALBI-based and CP-based BCLC systems was similar. It also potentially allows more precise patient selection for clinical trials on systemic agents.

The BALAD score is developed to provide an objective determination of prognosis for hepatocellular carcinoma (HCC) by incorporating five serum markers, namely albumin, bilirubin, alpha-fetoprotein (AFP), agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-γ-carboxy prothrombin. We aim to study the applicability of BALAD score and prognostication of the three tumor markers in hepatitis B virus-related HCC.Patients with newly diagnosed HCC were prospectively enrolled. All of the baseline characteristics and serum albumin and bilirubin level were documented at baseline. The levels of the three tumor markers (AFP, AFP-L3, and des-γ-carboxy prothrombin) were determined in archival serum samples. Patients were followed up for survivals according to local practice. The prognostic performances of the three markers and BALAD score were studied in association with overall survival (OS).A total of 198 patients with hepatitis B-related HCC were recruited. AFP and AFP-L3 levels were independent prognostic factors. The number of elevated tumor markers was also predictive of worse OS. BALAD score could stratify the cohort into different patient groups with distinct median OS. The median OS of BALAD score of 0, 1, 2, 3, and 4 was not reached, 26.6, 8.3, 2.6, and 1.9 months, respectively (P 0.0001). BALAD score could further stratify outcomes in each Barcelona Clinic Liver Cancer (BCLC) subgroup. In particular, BALAD score of 3-4 had median OS of 2.6 months only in BCLC stage C patients.BALAD score is applicable in the population of hepatitis B virus-related HCC. The combined use of BALAD score and BCLC staging system could help identify more suitable candidates for clinical trial.

Serum albumin and bilirubin are the most significant independent prognostic factors to predict hepatic events in patients with primary biliary cirrhosis (PBC). We aimed to investigate the prognostic significance of a new prognostic score, the albumin-bilirubin (ALBI) score, among PBC patients.In a retrospective longitudinal cohort of 61 Chinese PBC patients with follow-up period up to 18.3 years, the prognostic performance of the ALBI in prediction of hepatic events was compared with other well-established prognostic scores: Child-Pugh score, model of end-stage liver disease, Mayo risk score, Yale, European, and Newcastle models.Fifteen patients (24.6%) developed hepatic events during follow-up. The c-index (0.894) and χ(2) by likelihood ratio test (36.34) of the ALBI score were highest in comparison to other models. The ALBI score was the only independent prognostic factor by multivariate analysis and its adjusted hazard ratio of developing hepatic event was 27.8 (P 0.001). There were three prognostically different groups stratified by the ALBI score: ALBI grade 1 (≤ -2.60), grade 2 ( -2.60 to -1.39), and grade 3 ( -1.39) groups. The 2-, 5-, and 10-year event-free survivals for grade 1, grade 2, and grade 3 groups were 100.0% versus 100.0% versus 57.1%, 100.0% versus 88.5% versus 14.3%, and 100.0% versus 81.7% versus 0.0%, respectively (P 0.001).The ALBI score is readily derived from a blood test without using those factors evaluated subjectively or obtained by invasive procedures. It is an independent prognostic factor for PBC patients and provides better/similar prognostic performance compared with other prognostic scores.

All aqueous humor draining through the conventional outflow pathway must cross the endothelium of Schlemm's canal (SC), likely by passing through micron-sized transendothelial pores. SC pores are non-uniformly distributed along the inner wall endothelium, but it is unclear how the distribution of pores relates to the non-uniform or segmental distribution of aqueous humor outflow through the trabecular meshwork. It is hypothesized that regions in the juxtacanalicular tissue (JCT) with higher local outflow should coincide with regions of greater inner wall pore density compared to JCT regions with lower outflow. Three pairs of non-glaucomatous human donor eyes were perfused at 8 mmHg with fluorescent tracer nanospheres to decorate local patterns of outflow segmentation through the JCT. The inner wall was stained for CD31 and/or vimentin and imaged en face using confocal and scanning electron microscopy (SEM). Confocal and SEM images were spatially registered to examine the spatial relationship between inner wall pore density and tracer intensity in the underlying JCT. For each eye, tracer intensity, pore density ( n ) and pore diameter ( D ) (for both transcellular “I” and paracellular “B” pores) were measured in 4–7 regions of interest (ROIs; 50 × 150 μm each). Analysis of covariance was used to examine the relationship between tracer intensity and pore density, as well as the relationship between tracer intensity and three pore metrics ( nD , nD 2 and nD 3 ) that represent the local hydraulic conductivity of the outflow pathway as predicted by various hydrodynamic models. Tracer intensity in the JCT correlated positively with local pore density when considering total pores ( p = 0.044) and paracellular B pores on their own ( p = 0.016), but not transcellular I-pores on their own ( p = 0.54). Local hydraulic conductivity as predicted by the three hydrodynamic models all showed a significant positive correlation with tracer intensity when considering total pores and B-pores ( p p −4 ) but not I-pores ( p > 0.38). These data suggest that aqueous humor passes through micron-sized pores in the inner wall endothelium of SC. Paracellular B-pores appear to have a dominant contribution towards transendothelial filtration across the inner wall relative to transcellular I-pores. Impaired pore formation, as previously described in glaucomatous SC cells, may thereby contribute to greater outflow heterogeneity, outflow obstruction, and IOP elevation in glaucoma.

Increasing evidence suggests that chronic, subclinical inflammation plays an important role in the pathogenesis of diabetic retinopathy. We recently reported that a glycosylating enzyme, core 2 beta-1,6-N-acetylglucosaminyltransferase (core 2 GlcNAc-T), is implicated in increased leucocyte-endothelial cell adhesion in diabetic retinopathy via an upregulation mechanism controlled by TNF-alpha.We examined the functional link between circulating TNF-alpha and the activity and phosphorylation of core 2 GlcNAc-T in polymorphonuclear leucocytes of patients with type 1 and type 2 diabetes.Plasma levels of TNF-alpha, although similar in patients with type 1 and type 2 diabetes, were significantly higher than in age-matched healthy controls, and correlated well with the severity of retinopathy. Core 2 GlcNAc-T activity followed the same trend and was associated with phosphorylation of the enzyme. Finally, the observation that TNF-alpha levels are also linked to glycaemic values suggests that in patients, as well as in vitro, the glycosylation-mediated cell adhesion process that plays a role in diabetic retinopathy may involve glucose- and TNF-alpha-induced protein kinase beta2 activation, and subsequently raise activity of core 2 GlcNAc-T through increased enzyme phosphorylation.Our results reveal a novel rationale towards a specific treatment of diabetic retinopathy, based on the inhibition of core 2 GlcNAc-T activity and/or the blockage of cognate glycans.

Single nucleotide polymorphism (SNP) of the excision repair cross-complementing group 1 (ERCC1) gene has been linked with sensitivity to platinum and radiation. The authors hypothesized that the ERCC1 genotype for the SNPs cytosine-to-thymine substitution at codon 118 (C118T) and cytosine-to-adenine substitution at codon 8092 (C8092A) is prognostic in patients with nasopharyngeal carcinoma (NPC) who receive either radiotherapy (RT) or cisplatin plus RT.The authors tested their hypothesis using biomarker screening samples from the Hong Kong NPC Study Group 0502 trial, which was a prospective, multicenter clinical trial that used post-RT plasma Epstein-Bar virus (EBV) DNA (pEBV) levels to screen patients with high-risk NPC for adjuvant chemotherapy.ERCC1 SNPs were analyzed in 576 consecutive patients who were screened by pEBV. In the total biomarker population, there was no significant association of ERCC1 C118T or C8092A genotype with relapse-free survival (RFS) or overall survival (OS). There also was no correlation between ERCC1 genotype and ERCC1 protein or messenger RNA expression in a subset of patients who had available paired biopsies. Post-RT pEBV status was the only independent prognosticator for RFS and OS in multivariate analyses. However, there was a significant interaction between ERCC1 C118T genotype and post-RT pEBV status (RFS, P = .0106; OS, P = .0067). The ERCC1 C118T genotype was significantly associated with both RFS (hazard ratio, 1.67; 95% confidence interval, 1.07-2.61; P = .024) and OS (hazard ratio, 2.31; 95% confidence interval, 1.22-4.40; P = .0106) in the post-RT pEBV-negative population, but not in the pEBV-positive population.The current results prospectively validate pEBV as the most significant prognostic biomarker in NPC that can be used to select high-risk patients for adjuvant therapy. The ERCC1 C118T genotype may help to identify a favorable subgroup (approximately 7%) of pEBV-negative patients with NPC who have an excellent prognosis and can be spared the toxicities of further therapy.

Aim To examine the optimal range of International Normalized Ratio (INR) for Chinese patients receiving warfarin for moderate-intensity anticoagulation. Methods This was a retrospective cohort study conducted at the ambulatory setting of a 1400-bed public teaching hospital in Hong Kong. The INR measurements and occurrence of serious or life-threatening haemorrhagic and thromboembolic events among patients newly started on warfarin from 1 January 1999 to 30 June 2001 for indications with target INR 2–3 were analysed. The INR-specific incidence of bleeding and thromboembolism were calculated. Results A total of 491 patients were included, contributing to 453 patient-years of observation period. Forty-seven of the 491 patients experienced 25 haemorrhagic events (5.5 per 100 patient-years) and 27 thromboembolic events (6.0 per 100 patient-years). The percentage of patient-time spent within therapeutic INR range (2–3), INR 3 were 50, 44 and 6%, respectively. The incidence of either haemorrhagic or thromboembolic events was lowest (≤4 events per 100 patient-years) at INR values between 1.8 and 2.4. Conclusions An INR of 1.8–2.4 appeared to be associated with the lowest incidence rate of major bleeding or thromboembolic events in a cohort of Hong Kong Chinese patients receiving warfarin therapy for moderate-intensity anticoagulation.

Aqueous humor drains from the eye through Schlemm's canal, a small endothelial-lined collecting duct. Schlemm's canal endothelial cells may be important in controlling the pressure within the eye (and hence are of interest in glaucoma), and are subject to an unusual combination of shear stress and a basal-to-apical pressure gradient. We sought to characterize this biomechanical environment and determine its effects on F-actin architecture in situ. A theoretical model of flow in Schlemm's canal was used to estimate shear stresses applied to endothelial cells by flowing aqueous humor. Alignment of Schlemm's canal endothelial cells in human eyes was quantified by scanning electron microscopy. F-actin architecture was visualized by fluorescent labeling and compared for closely adjacent cells exposed to different biomechanical environments. We found that, despite the relatively low flow rate of aqueous humor, shear stresses experienced by Schlemm's canal endothelial cells could reach those in the arterial system. Schlemm's canal endothelial cells showed a statistically significant preferential alignment, consistent with a shear-mediated effect. Schlemm's canal endothelial cells subjected to a basal-to-apical pressure gradient due to transendothelial flow showed a prominent marginal band of F-actin with relatively few cytoplasmic filaments. Adjacent cells not subject to this gradient showed little marginal F-actin, with a denser cytoplasmic random network. We conclude that Schlemm's canal endothelial cells experience physiologically significant levels of shear stress, promoting cell alignment. We speculate that this may help control the calibre of Schlemm's canal. F-actin distribution depends critically on the presence or absence of transendothelial flow and its associated pressure gradient. In the case of this pressure gradient, mechanical reinforcement around the cell periphery by F-actin seems to be critical.

SummaryAllocation of additional resources for establishing or expanding anticoagulation clinic (AC) services is a significant concern for healthcare decision-makers when the payer is also the provider of the healthcare system. The majority of anticoagulated patients in Hong Kong are managed by routine medical care (RMC) instead of ACs, possibly due to the lack of local cost-effectiveness analysis of the AC setting. The aim was to compare the clinical and economic outcomes of anticoagulated patients who were managed by AC or RMC from the perspective of a public health organization in Hong Kong. A Markov model was designed to simulate, over 10 years, the economic and clinical outcomes of patients receiving chronic warfarin therapy managed by AC or RMC. The transition probabilities were derived from literature. Resource utilization was retrieved from patients managed by AC and RMC in Hong Kong. Sensitivity analysis was conducted to examine the robustness of the model. The total number of events per 100 patient-years and the direct medical cost per patient-year in the AC and RMC groups were 9.5 and USD 840, and, 19.3 and USD 1,179, respectively. The results of the model were sensitive to the variation of the probability of major bleeding in the AC group. In conclusion, the coordinated care provided by an anticoagulation clinic appears to be more cost-effective than routine medical care in the management of warfarin therapy from the perspective of public health organization in Hong Kong.

To examine the potential value of a creative art-based activity as a caring modality for promoting holistic well-being among chronic stroke patients, and to explore the feelings and meanings that stroke patients derived from their experience in leisure art-based creative engagement (LACE).Qualitative design.Participants were recruited through purposive and snowball sampling. Individual semi-structured interviews were conducted. Qualitative content analysis was performed. The design and implementation of LACE was guided by Watson's theory of caring.Twenty-four participants completed the study. Four themes emerged from participants' account of experiences with the LACE: (1) appreciation of opportunities, (2) appreciation of self, (3) appreciation of others, and (4) appreciation of life.From the perspective of the participants, engaging in LACE enhances their sense of enjoyment and self-expression. Furthermore, they perceived LACE as an affirmation of life and an empowering process strengthening their connection and appreciation with the self and others.This study adds evidence to existing literature on Watson's theory-guided design and implementation of caring initiatives for community rehabilitation and has laid the groundwork for developing further evidencebased research in leisure art-based caring occasions for promoting holistic well-being in stroke rehabilitation.

This review examines women's risk perception of cervical cancer, the factors influencing this perception, and the relationship between risk perception of cervical cancer and screening behavior.Integrative literature review method was used.The search procedure resulted in the identification of 42 studies, including 1 literature review and 41 primary studies. Trends and discrepancies in the literature are presented with interpretations and recommendations.Existing theories of health behavior appear inadequate for understanding screening behavior, and further studies are recommended to enrich the knowledge base of nursing diagnoses in knowledge deficit and health-seeking behavior.Efforts would be made to improve nurses' understanding of risk perception of cervical cancer within specific cultural context.

The aim of the study was to test a hypothesised model that supportive care needs (SCNs) have a mediating effect on the relationship between characteristics of (Chinese) head and neck cancer (HNC) survivors and their quality of life (QoL).A total of 285 Chinese HNC survivors who had finished cancer treatment 1 year earlier completed a self-reported survey covering demographic and clinical characteristics, the Chinese version of the Short-Form Supportive Care Needs Questionnaire (SCNS-SF34-C), the supplementary module of access to healthcare and ancillary support services and the Functional Assessment of Cancer Therapy for Head and Neck Cancer (FACT-HN).The final path model showed that optimism, educational level, any coexisting disease, number of somatic symptoms, household income, eating ability, support from others, whether the cancer is under control or not and travelling time from home to hospital have direct or indirect effects, or both, on the QoL of HNC survivors, by way of unmet SCNs in the psychological, physical and/or health system information domains, which account for 64 % of the variance in the total FACT-HN score.Our study demonstrated the mediating effects of SCNs in the association between HNC survivors and their QoL. Early needs assessment may help healthcare professionals to identify the actual needs of these survivors, and providing the information that HNC survivors want is a significant factor in meeting their psychological needs and thereby improving their overall QoL.

Does the timing of treatment affect the ocular phenotype in patients with Mucopolysaccharidosis I homozygous for the L490P mutation?

The purpose of this study is to compare health-related quality of life (HRQoL) and emotional distress among diverse cancer survivors who had completed all treatment within the previous year. A convenience sample of 353 cancers survivors (lung, head and neck, breast and prostate cancers) were recruited to complete a survey, which consisted of (i) Hospital Anxiety and Depression Scales; (ii) Chinese version of the Functional Assessment of Cancer Therapy-General version; and (iii) demographic and clinical data. The HRQoL scores were similar among the four types of survivors. Mild anxiety and depression levels were reported, but no significant difference was noted. Younger females with financial burdens and uncertain prognosis were particularly associated with HRQoL and emotional distress. Further studies are essential to identify specific problems that cancer patients experience after cancer diagnosis that might lead to the early detection of those most at risk of ongoing problems.

Purpose. Kattan and Stephenson nomograms are based on the outcomes of patients with prostate cancer recruited in the USA, but their applicability to Chinese patients is yet to be validated. We aim at studying the predictive accuracy of these nomograms in the Chinese population.Patients and Methods. A total of 408 patients who underwent laparoscopic or open radical resection of prostate from 1995 to 2009 were recruited. The preoperative clinical parameters of these patients were collected, and they were followed up regularly with PSA monitored. Biochemical recurrence was defined as two or more consecutive PSA levels >0.4 ng/mL after radical resection of prostate or secondary cancer treatment.Results. The overall observed 5-year and 10-year biochemical recurrence-free survival rates were 68.3% and 59.8%, which was similar to the predicted values by the Kattan and Stephenson nomograms, respectively. The results of our study achieved a good concordance with both nomograms (Kattan: 5-years, 0.64; Stephenson: 5-years, 0.62, 10-years, 0.71).Conclusions. The incidence of prostate cancer in Hong Kong is increasing together with the patients’ awareness of this disease. Despite the fact that Kattan nomograms were derived from the western population, it has been validated in our study to be useful in Chinese patients as well.

BACKGROUND Although advanced cancer treatments prolong survivors' lives, a significant proportion experienced poorer health-related quality of life (HRQoL) than general populations. Identifying their needs is essential to develop a health service delivery model to improve patient outcomes. OBJECTIVE The objective of this study was to examine the perceived unmet needs and HRQoL of Chinese cancer survivors who completed treatment less than 1 year ago. METHODS Three hundred seventy-six participants completed a self-report survey: the 34-item Supportive Care Needs Survey, the supplementary module of access to healthcare and ancillary support services, and the Functional Assessment of Cancer Therapy: General. Descriptive statistics were used to examine the prevalence of unmet needs. Multivariable logistic regressions were conducted to identify participants' characteristics that were associated with unmet needs. Multiple linear regression was used to delineate which domains of unmet needs were significantly associated with HRQoL with adjustment for potential confounding factors. RESULTS Healthcare information was the most common unmet needs among the survivors. Age, stage of cancer, and remission were significantly associated with 1 or more unmet need domains. Participants with unmet needs in physical, psychological, and patient care domains, on average, have poorer HRQoL. CONCLUSIONS Chinese cancer survivors have various unmet needs that might have adverse effects on their HRQoL. Younger age, more advanced stages of cancer, and remission were factors contributing to further unmet needs. IMPLICATIONS FOR PRACTICE The results provided useful information on the special needs of survivors that may affect their HRQoL, enabling clinicians to plan better how to allocate existing limited resources to those who most require them.

The combined effect of uric acid, gamma-glutamyltransferase (GGT) and cardiovascular risk factors clustering in the youth remains under-explored.The objective of this study was to examine the association between uric acid, GGT, obesity and the individual components of metabolic syndrome in children and adolescents.We performed a cross-sectional observational study of 2067 children and adolescents (875 boys and 1192 girls) aged 6-20 years who were healthy volunteers and were recruited from primary and secondary schools in Hong Kong between 2007 and 2008. Subjects were divided into two strata (75th percentile as cut-off) for comparison between odds of cardiovascular risk factors.After adjustment by multivariable logistic regression, subjects in upper stratum, i.e.,75th percentile, of either serum uric acid or GGT levels were associated with obesity, low high-density lipoprotein cholesterol (HDL-C) level and high blood pressure (adjusted odds ratios [AOR] ranged from 1.63 to 5.82, all P 0.005) compared with those in the lower stratum. There were combined effect for upper stratum of both uric acid and GGT in the association with obesity, low HDL-C and high blood pressure (AOR ranged from 2.60 to 10.69, all P 0.05) after adjustment for age, sex and body mass index z-score (except for obesity status) as well as body height (for high blood pressure).Uric acid and GGT have combined effect in association with obesity and other cardiovascular risk factors in children and adolescents.

Previous literatures on young adult survivors of childhood cancer show inconsistent findings with regards to their psychological distress and health-related quality of life (HRQOL). Much of the available data focus on negative patient outcomes following cancer treatments prescribed from 1970 to 1990. In the present study, HRQOL and psychological distress of young adult survivors in Hong Kong was examined. It focused on subjects who had received cancer treatments prescribed in the last two decades.A structured telephone survey was conducted with 614 eligible survivors and 208 sibling controls in Hong Kong.The survivors reported significantly lower mean scores in physical role and functioning, whereas their mental, social, and psychological well-being was similar to that of their sibling controls. Being female, older age, longer survival time, and specific cancer diagnoses were the factors associated with poorer physical and mental adaptation. HRQOL was negatively correlated with psychological distress.Findings of the study suggest that most survivors adjusted fairly well in mental, psychological, and social aspects. Survivors with a higher risk of poor HRQOL could benefit from appropriate screening and counseling at an early stage to mitigate their survivorship difficulties. Prospective follow-up studies on childhood cancer survivors are recommended to detect changes over longer survival periods.

The interstitial chromosome (chr.) 1q21-q22 region is frequently amplified in human cancers, where it has been reported to carry prognostic significance for patients. We attempted to delineate chr. 1q21-q22 for affected gene(s) in hepatocellular carcinoma (HCC) by array-CGH and detected copy number gains of ρ-guanine nucleotide exchange factor-H1 (GEF-H1) as most significant event. Gene expression evaluation in the HCC cohort indicated common up-regulations of GEF-H1 in 64% tumours compared to adjacent non-tumoural liver (64/100; paired t-test p0.0001). Moreover, GEF-H1 over-expressions correlated with microvascular invasion and advanced-stage tumours (p0.05). High GEF-H1 levels also predict shorter disease-free and overall survival of HCC patients (p0.03). Functional knock-down of GEF-H1 by RNAi indicated marked reduction in cell invasion through matrigel and an inhibition of cell migration (p0.035), but an effect on cell viability was not apparent. More interestingly, a mesenchymal-epithelial transition (MET) was readily observed in GEF-H1 knock-down cells, where a concomitant re-expression of epithelial markers (E-cadherin and cytokeratin 18) and cell adhesion proteins (α-catenin and γ-catenin) was found but down-regulation of mesenchymal features (N-cadherin, vimentin and fibronectin). This phenotype was accompanied by reduced filamentous actin polymerizations and diminution of the stress fibre formation. In addition, reduced active form of GTP-RhoA, together with its downstream effectors, including cleaved ROCK1 and phosphorylated MLC2, were also detected in GEF-H1-depleted cells. Taken together, our findings underscore a potent oncogenic role for GEF-H1 in promoting the metastatic potentials of HCC, possibly through activation of RhoA signalling and the EMT phenomenon.

OBJECTIVE. To assess the accuracy of the Association of Coloproctology of Great Britain and Ireland scoring system in predicting the 30-day mortality after surgery for colorectal cancer in Hong Kong elderly (aged 80 years or more) patients. DESIGN. Early mortality outcome audit in a historical cohort. SETTING. Queen Elizabeth Hospital, Hong Kong. PATIENTS. All Chinese patients (aged 80 years or more) who underwent elective or emergency surgery for colorectal cancer in the Department of Surgery between January 2005 and December 2009. MAIN OUTCOME MEASURES. Receiver operating characteristic curve analyses were used to estimate the predictive ability of the score. RESULTS. In all, 180 patients with colorectal cancer were included in this review. The overall 30-day and hospital mortality rates were 29/180 (16%) and 31/180 (17%), respectively. The Association of Coloproctology of Great Britain and Ireland score was significantly higher among patients who died within 30 days (4.2 vs 3.1, P=0.0001), and was the only independent predictor for 30-day mortality by logistic regression (P=0.009; odds ratio=2.555; 95% confidence interval, 1.277-4.932). The mean score of this study population was 3.22 (median, 3.10), giving a predicted 30-day mortality rate of 16.0 to 17.4%, which corresponded with an observed 30-day mortality of 16.1% encountered in this study. The score had a significantly larger area under the curve for the 30-day mortality rates (odds ratio=0.811; 95% confidence interval, 0.722-0.849) as compared to the American Society of Anesthesiologists score (0.664; 0.589-0.735) [P=0.0001]. CONCLUSION. The Association of Coloproctology of Great Britain and Ireland scoring system can accurately predict the 30-day mortality rate of elderly Hong Kong Chinese patients (aged 80 years or more) operated on for colorectal cancer.