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Objective This longitudinal study examined changes in psychological outcomes of perioperative frontline healthcare workers at one of Australia’s most COVID-19 affected hospitals, following the surge and decline of a pandemic wave. Method A single-centred longitudinal online survey was conducted between 26 May and 17 November 2020. Recruitment was via poster advertisement and email invitation. The survey was sent out every 4 weeks, resulting in seven time-points. Results In total, 385 survey results were analysed from 193 staff (about 64% response rate), 72 (37%) of whom completed the survey more than once. The prevalence of moderate-to-severe anxiety and depressive symptoms peaked at 27% and 25%, respectively, during the pandemic surge. Up to 35% displayed post-traumatic stress disorder (PTSD) symptoms. Although not statistically significant, the trend of depressive and PTSD symptoms worsened over time, especially among females and anaesthetic/surgical trainees, despite subsidence of the pandemic curve. Technicians and anaesthetic/scrub nurses were the at-risk groups with worst psychological outcomes. Conclusion We found persistent mental health impacts on frontline perioperative HCWs despite subsidence of the pandemic wave. Further research is needed to determine the extent and trajectory of such impacts with larger sample sizes to determine generalisability to frontline HCWs in general.

To compare the performance of four N95 respirator types with respect to quantitative fit test pass rate and health care worker-rated usability and comfort.Health care workers who participated in the respiratory protection program at the Royal Melbourne Hospital, 1 October 2020 - 31 May 2021. Participants underwent quantitative N95 respirator fit testing (at least three of four types: semi-rigid cup, flat-fold cup, duckbill, and three-panel flat-fold types), and were invited to complete an online usability and comfort assessment for respirators for which their fit test results were passes.Fit test pass rate, and user-rated overall comfort and assessment ratings (five-point Likert scales), by N95 respirator type.A total of 2161 health care workers underwent quantitative fit testing (women, 1586 [73.4%]; nurses, 1271 [58.8%]). The overall fit test pass rates were 65.0% for the semi-rigid cup respirators (1029/1583 tests), 32.4% for the flat-fold respirator (660/2035 tests), 59.2% for the duckbill respirators (2005/3387 tests), and 96.4% for the three-panel flat-fold respirator (1876/1946 tests). 378 health care workers completed the comfort and usability survey. Overall comfort and assessment ratings each differed by respirator group (P 0.001); the median overall comfort (4; IQR, 3-4) and overall assessment values (4; IQR, 3-5) were highest for the three-panel flat-fold respirator and lowest for the semi-rigid cup respirators (comfort: 2 [IQR, 1-3]; assessment: 2 [IQR, 2-3]).The three-panel flat-fold N95 respirator outperformed the three alternative types with regard to fit test pass rate and user-rated comfort and usability. To maximise respiratory protection for health care workers, these factors should be considered when making respirator procurement decisions.

Background General practitioners (GPs) play a central role during the COVID-19 pandemic, and yet awareness of their mental health is limited. Methods A nationwide online survey of self-identified frontline healthcare workers was conducted between 27 August and 23 October 2020. Participants were recruited through health and professional organisations, colleges, universities, government contacts, and media. A subset of the findings on GPs and hospital medical staff (HMS) was used for this study. Results Of 9518 responses, there were 389 (4%) GPs and 1966 (21%) HMS. Compared with HMS, GPs received significantly less training on personal protective equipment usage or care for COVID-19 patients, and less support or communication within their workplace. GPs were significantly more concerned about household income, disease transmission to family and being blamed by colleagues if they became infected, all of which were associated with worse psychological outcomes. Significantly more GPs reported burnout, and experienced moderate-to-severe emotional exhaustion than HMS. Both groups used similar coping strategies, except fewer GPs than HMS used digital health applications or increased alcohol consumption. Less than 25% of either group sought professional help. Conclusions GPs are vital in our healthcare systems, yet face unique workplace challenges and mental health stressors during the pandemic. Targeted workplace and psychological support is essential to protect wellbeing among the primary care workforce.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has had a profound and prolonged impact on healthcare services and healthcare workers.AimsThe Australian COVID-19 Frontline Healthcare Workers Study aimed to investigate the severity and prevalence of mental health issues, as well as the social, workplace and financial disruptions experienced by Australian healthcare workers during the COVID-19 pandemic.MethodsA nationwide, voluntary, anonymous, single timepoint, online survey was conducted between 27 August and 23 October 2020. Individuals self-identifying as frontline healthcare workers in secondary or primary care were invited to participate. Participants were recruited through health organisations, professional associations or colleges, universities, government contacts and national media. Demographics, home and work situation, health and psychological well-being data were collected.ResultsA total of 9518 survey responses were received; of the 9518 participants, 7846 (82.4%) participants reported complete data. With regard to age, 4110 (52.4%) participants were younger than 40 years; 6344 (80.9%) participants were women. Participants were nurses (n=3088, 39.4%), doctors (n=2436, 31.1%), allied health staff (n=1314, 16.7%) or in other roles (n=523, 6.7%). In addition, 1250 (15.9%) participants worked in primary care. Objectively measured mental health symptoms were common: mild to severe anxiety (n=4694, 59.8%), moderate to severe burnout (n=5458, 70.9%) and mild to severe depression (n=4495, 57.3%). Participants were highly resilient (mean (SD)=3.2 (0.66)). Predictors for worse outcomes on all scales included female gender; younger age; pre-existing psychiatric condition; experiencing relationship problems; nursing, allied health or other roles; frontline area; being worried about being blamed by colleagues and working with patients with COVID-19.ConclusionsThe COVID-19 pandemic is associated with significant mental health symptoms in frontline healthcare workers. Crisis preparedness together with policies and practices addressing psychological well-being are needed.

Introduction In the era of the COVID-19 pandemic, the avoidance of aerosol generating procedures (AGPs) is paramount to reduce the risk of viral transmission to staff and other patients. Perioperative management of a new tracheostomy is challenging as routine care, such as suctioning, frequently involves AGPs. Method We developed and implemented an apparatus called the heat and moisture exchanger (HME) filter-protected open circuit. This enabled closed suctioning to be performed and allowed spontaneously breathing patients to be managed with an open circuit in a shared environment while reducing the risk of viral aerosolisation. We performed a prospective observational study of 20 cases, recording the incidence of desaturation (

Aim We investigated whether acute carbohydrate ingestion reduced arterial potassium concentration ([K+]) during and after intense exercise and delayed fatigue. Methods In a randomized, double‐blind crossover design, eight males ingested 300 ml water containing 75 g glucose (CHO) or placebo (CON); rested for 60 min, then performed high‐intensity intermittent cycling (HIIC) at 130% V˙O2peak, comprising three 45‐s exercise bouts (EB), then a fourth EB until fatigue. Radial arterial (a) and antecubital venous (v) blood was sampled at rest, before, during and after HIIC and analyzed for plasma ions and metabolites, with forearm arteriovenous differences (a‐v diff) calculated to assess inactive forearm muscle effects. Results Glucose ingestion elevated [glucose]a and [insulin]a above CON (p = .001), being, respectively, ~2‐ and ~5‐fold higher during CHO at 60 min after ingestion (p = .001). Plasma [K+]a rose during and declined following each exercise bout in HIIC (p = .001), falling below baseline at 5 min post‐exercise (p = .007). Both [K+]a and [K+]v were lower during CHO (p = .036, p = .001, respectively, treatment main effect). The [K+]a‐v diff across the forearm widened during exercise (p = .001), returned to baseline during recovery, and was greater in CHO than CON during EB1, EB2 (p = .001) and EB3 (p = .005). Time to fatigue did not differ between trials. Conclusion Acute oral glucose ingestion, as used in a glucose tolerance test, induced a small, systemic K+‐lowering effect before, during, and after HIIC, that was detectable in both arterial and venous plasma. This likely reflects insulin‐mediated, increased Na+,K+‐ATPase induced K+ uptake into non‐contracting muscles. However, glucose ingestion did not delay fatigue., Acute glucose intake substantially elevated insulin, with a systemic K+‐lowering effect evident in arterial and antecubital venous plasma before, during, and post‐exercise. An increased arterio‐venous K+ difference across the relatively inactive forearm musculature with glucose ingestion was consistent with increased K+ uptake in non‐active muscle; this was likely mediated via insulin‐induced activation of sodium‐potassium ATPase.

Author(s): Brunt, Elizabeth; Aishima, Shinichi; Clavien, Pierre-Alain; Fowler, Kathryn; Goodman, Zachary; Gores, Gregory; Gouw, Annette; Kagen, Alex; Klimstra, David; Komuta, Mina; Kondo, Fukuo; Miksad, Rebecca; Nakano, Masayuki; Nakanuma, Yasuni; Ng, Irene; Paradis, Valerie; Nyun Park, Young; Quaglia, Alberto; Roncalli, Massimo; Roskams, Tania; Sakamoto, Michiie; Saxena, Romil; Sempoux, Christine; Sirlin, Claude; Stueck, Ashley; Thung, Swan; Tsui, WMS; Wang, Xin-Wei; Wee, Aileen; Yano, Hirohisa; Yeh, Matthew; Zen, Yoh; Zucman-Rossi, Jessica; Theise, Neil | Abstract: Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation.ConclusionIt is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (HaE); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).

Whether copyrights should exist in content generated by an artificial intelligence is a frequently discussed issue in the legal literature. Most of the discussion focuses on economic rights, whereas the relationship of artificial intelligence and moral rights remains relatively obscure. However, as moral rights traditionally aim at protecting the author’s “personal sphere”, the question whether the law should recognize such protection in the content produced by machines is pressing; this is especially true considering that artificial intelligence is continuously further developed and increasingly hard to comprehend for human beings. This paper first provides the background on the protection of moral rights under existing international, U.S. and European copyright laws. On this basis, the paper then proceeds to highlight special issues in connection with moral rights and content produced by artificial intelligence, in particular whether an artificial intelligence itself, the creator or users of an artificial intelligence should be considered as owners of moral rights. Finally, the present research discusses possible future solutions, in particular alternative forms of attribution rights or the introduction of related rights.

The ursane triterpenoids, asiatic acid 1 and madecassic acid 2, are the major pharmacological constituents of Centella asiatica, commonly known as Gotu Kola, which is used traditionally for the treatment of anxiety and for the improvement of cognition and memory. Using the two-electrode voltage-clamp technique, these triterpenes, and some semisynthetic derivatives, were found to exhibit selective negative modulation of different subtypes of the GABAA receptor expressed in Xenopus laevis oocytes. Despite differing by only one hydroxyl group, asiatic acid 1 was found to be a negative modulator of the GABA-induced current at α1 β2 γ2L, α2 β2 γ2L and α5 β3 γ2L GABAA receptors, while madecassic acid 2 was not. Asiatic acid 1 exhibited the greatest effect at α1 β2 γ2L (IC50 37.05 μm), followed by α5 β3 γ2L (IC50 64.05 μm) then α2 β2 γ2L (IC50 427.2 μm) receptors. Conversion of the carboxylic acid group of asiatic acid 1 to a carboxamide group (2α,3β,23-trihydroxy-urs-12-en-28-amide 5) resulted in enhanced inhibition at both the α1 β2 γ2L (IC50 14.07 μm) and α2 β2 γ2L receptor subtypes (IC50 28.41 μm). The results of this study, and the involvement of α5 -containing GABAA receptors in cognition and memory, suggest that asiatic acid 1 may be a lead compound for the enhancement of cognition and memory.

This paper is a response to the Singapore Personal Data Protection Commission consultation on a draft AI Governance Framework. It analyses the five data trust models proposed by the UK Open Data Institute and identifies that only the contractual and corporate models are likely to be legally suitable for achieving the aims of a data trust. The paper further explains how data trusts might be used as in the governance of AI, and investigates the barriers which Singapore's data protection law presents to the use of data trusts and how those barriers might be overcome. Its conclusion is that a mixed contractual/corporate model, with an element of regulatory oversight and audit to ensure consumer confidence that data is being used appropriately, could produce a useful AI governance tool.

The common law presumption that a boy under the age of 14 is incapable of sexual intercourse has provoked controversial debates in Hong Kong. This article describes a 6-step advocacy journey to examine how community efforts have helped modify this law so that juvenile male sexual offenders under the age of 14 who have committed the crime of having sexual intercourse with underage females can be sentenced to receive appropriate treatment. Seven court cases provided by the magistrates' courts in Hong Kong were used in this advocacy effort for the removal of the presumption in July 2012. Although this effort has yet to reveal signs of effectiveness, it represents greater public awareness about providing rehabilitation appropriate for juvenile sex offenders through a formal sentence. Restorative justice, as opposed to retributive or punitive justice, places an emphasis on rehabilitation of the offender and restoration of victims to a place of wholeness.

In the era of the mobile apps and IoT, huge quantities of data about individuals and their activities offer a wave of opportunities for economic and societal value creation. However, the current personal data ecosystem is fragmented and inefficient. On one hand, end-users are not able to control access (either technologically, by policy, or psychologically) to their personal data which results in issues related to privacy, personal data ownership, transparency, and value distribution. On the other hand, this puts the burden of managing and protecting user data on apps and ad-driven entities (e.g., an ad-network) at a cost of trust and regulatory accountability. In such a context, data holders (e.g., apps) may take advantage of the individuals’ inability to fully comprehend and anticipate the potential uses of their private information with detrimental effects for aggregate social welfare. In this paper, we investigate the problem of the existence and design of efficient ecosystems (modeled as markets in this paper) that aim to achieve a maximum social welfare state among competing data holders by preserving the heterogeneous privacy preservation constraints up to certain compromise levels, induced by their clients, and at the same time satisfying requirements of agencies (e.g., advertisers) that collect and trade client data for the purpose of targeted advertising, assuming the potential practical inevitability of some amount inappropriate data leakage on behalf of the data holders. Using concepts from supply-function economics, we propose the first mathematically rigorous and provably optimal privacy market design paradigm that always results in unique equilibrium (i.e, stable) market states that can be either economically efficient or inefficient, depending on whether privacy trading markets are monopolistic or oligopolistic in nature. Subsequently, we characterize in closed form, the efficiency gap (if any) at market equilibrium.

Optimal patient management benefits from comprehensive and accurate pathology reports that contribute to cancer staging and prognostication. Proforma reports are used in many countries, but these vary in their structure and implementation. The International Collaboration on Cancer Reporting (ICCR) is an alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer the European Society of Pathology and the American Society of Clinical Pathology (ASCP), with the aim of developing an evidence-based reporting data set for each cancer site. It is argued that this should reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardised cancer reporting data sets. The resultant standardisation of cancer reporting will benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of a cancer data set by the ICCR expert panel for the reporting of the main malignant liver tumours: intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma and hepatocellular carcinoma and present the 'required' and 'recommended' elements to be included in the report with an explanatory commentary. This data set incorporates definitions and classifications in the most recent World Health Organisation (WHO) publication on hepatic malignancies (4th edition) and the recently published tumour-node-metastasis (TNM)8 staging system. Widespread adoption and implementation of this data set will enable consistent and accurate data collection, comparison of epidemiological and pathological parameters between different populations, facilitate research and ultimately result in better patient outcomes.

We investigated whether potassium (K+) disturbances during and following intense exercise may be pronounced when utilizing a large contracting muscle mass, examining maximal 2,000-m rowing exercise effects on radial arterial plasma K+ concentration ([K+]a) in 11 healthy adults. Blood was sampled at baseline, preexercise, each 30 s during rowing, and for 30 min postexercise. Time to complete 2,000 m was 7.26 ± 0.59 min; power output at 30 s was 326 ± 81 W (mean ± SD). With exercise time expressed in deciles, power output fell 16.5% from the first to fourth decile ( P < 0.05) and 19.9% at the ninth decile ( P < 0.05); EMG median frequency declined 4.6% by the third decile and 5.5% by the eighth decile ( P < 0.05). Plasma [K+]a increased from 3.89 ± 0.13 mM at rest to 6.13 ± 0.46 mM by 90 s rowing ( P < 0.001) and was then sustained until end exercise ( P < 0.001). In recovery, [K+]a decreased abruptly, reaching 3.33 ± 0.22 mM at 5 min postexercise ( P < 0.001) and remaining below preexercise after 30 min ( P < 0.005). At end exercise, blood [lactate]a (preexercise 0.64 ± 0.18 mM) reached 10.87 ± 1.33 mM, plasma volume decreased 9.7 ± 2.3% from preexercise, and pHa decreased to 7.10 ± 0.07 units ( P < 0.001). In conclusion, arterial hyperkalemia was sustained during exhaustive rowing reflecting a balance between K+ release and reuptake in contracting muscles and K+ uptake by inactive muscles. While high, the [K+]a was lower than anticipated compared with maximal cycling or sprinting, possibly reflecting greater adrenergic response and Na+,K+-ATPase activity in contracting muscles; fatigue was evidenced by reduced power output and EMG median frequency. A prolonged hypokalemia after rowing likely reflected continuing muscular Na+,K+-ATPase activity.

A series of 4-arylimidazolones have been accessed via late-stage, palladium-mediated arylation of acetone- and cyclohexanone-derived 4-chloroimidazolones. The 4-chloroimidazolones were prepared via a novel rearrangement of the corresponding imidazolone N-oxides. This communication serves as an expansion of chemistry originally developed for our glucagon receptor antagonist program.

A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%-13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133⁻ counterparts, CD133(+) cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133(+) cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133(+) tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133(+) and CD133⁻ cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133(+) TICs. Functional studies on miR-130b lentiviral-transduced CD133⁻ cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133(+) TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133⁻ cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133(+) liver TICs, in part, via silencing TP53INP1.

The outcomes of hepatitis B virus (HBV)-related hepatitis after liver transplantation (LT) without hepatitis B immune globulin (HBIG) is not well documented. This study aims to determine the outcomes of chronic hepatitis B (CHB) patients using an HBIG-free regimen. All biopsies performed 3 months or more after LT in consecutive CHB patients transplanted from 2003 to 2012 were reviewed. None of the patients received HBIG. Results of all liver histologies were reviewed to determine the cause of graft dysfunction. Of the 435 patients transplanted during this period, 263 liver biopsies were performed in 144 patients. Thirty-six patients were positive for hepatitis B surface antigen (HBsAg) with undetectable HBV DNA at the time of biopsy, and none had histological evidence of HBV infection. Of the 263 biopsies, 44 (17%) had evidence of fibrosis. There was a significantly higher rate of fibrosis in those with large duct obstruction compared to those without (51% versus 9%, respectively; P

BACKGROUND: Acute kidney injury (AKI) is common in patients undergoing cardiac surgery among whom it is associated with poor outcomes, prolonged hospital stays and increased mortality. Statin drugs can produce more than one effect independent of their lipid lowering effect, and may improve kidney injury through inhibition of postoperative inflammatory responses. OBJECTIVES: This review aimed to look at the evidence supporting the benefits of perioperative statins for AKI prevention in hospitalised adults after surgery who require cardiac bypass. The main objectives were to 1) determine whether use of statins was associated with preventing AKI development; 2) determine whether use of statins was associated with reductions in in-hospital mortality; 3) determine whether use of statins was associated with reduced need for RRT; and 4) determine any adverse effects associated with the use of statins. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared administration of statin therapy with placebo or standard clinical care in adult patients undergoing surgery requiring cardiopulmonary bypass and reporting AKI, serum creatinine (SCr) or need for renal replacement therapy (RRT) as an outcome were eligible for inclusion. All forms and dosages of statins in conjunction with any duration of pre-operative therapy were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: All authors extracted data independently and assessments were cross-checked by a second author. Likewise, assessment of study risk of bias was initially conducted by one author and then by a second author to ensure accuracy. Disagreements were arbitrated among authors until consensus was reached. Authors from two of the included studies provided additional data surrounding post-operative SCr as well as need for RRT. Meta-analyses were used to assess the outcomes of AKI, SCr and mortality rate. Data for the outcomes of RRT and adverse effects were not pooled. Adverse effects taken into account were those reported by the authors of included studies. MAIN RESULTS: We included seven studies (662 participants) in this review. All except one study was assessed as being at high risk of bias. Three studies assessed atorvastatin, three assessed simvastatin and one investigated rosuvastatin. All studies collected data during the immediate perioperative period only; data collection to hospital discharge and postoperative biochemical data collection ranged from 24 hours to 7 days. Overall, pre-operative statin treatment was not associated with a reduction in postoperative AKI, need for RRT, or mortality. Only two studies (195 participants) reported postoperative SCr level. In those studies, patients allocated to receive statins had lower postoperative SCr concentrations compared with those allocated to no drug treatment/placebo (MD 21.2 µmol/L, 95% CI -31.1 to -11.1). Adverse effects were adequately reported in only one study; no difference was found between the statin group compared to placebo. AUTHORS' CONCLUSIONS: Analysis of currently available data did not suggest that preoperative statin use is associated with decreased incidence of AKI in adults after surgery who required cardiac bypass. Although a significant reduction in SCr was seen postoperatively in people treated with statins, this result was driven by results from a single study, where SCr was considered as a secondary outcome. The results of the meta-analysis should be interpreted with caution; few studies were included in subgroup analyses, and significant differences in methodology exist among the included studies. Large high quality RCTs are required to establish the safety and efficacy of statins to prevent AKI after cardiac surgery.

Background and Aim: Decrease in expression of the E-cadherin–catenin complex is an important element in gastric carcinogenesis. However, the expression of the complex in gastric precancerous lesions has not been well studied. The present study aimed to examine the serial change in expression of E-cadherin–catenin complex in the precancerous lesions of gastric cancer patients. Methods: Gastrectomy specimens of 40 patients with gastric cancer were retrieved. Areas with chronic gastritis, atrophic gastritis, intestinal metaplasia and adenocarcinoma were identified and immunostained for α-catenin, β-catenin and E-cadherin. The results were scored semiquantitatively by two independent pathologists using a validated scoring system. Results: A significant decrease in score was observed in 5% (1/22) of α-catenin, 0% (0/22) of β-catenin and 9% (2/22) of E-cadherin in chronic atrophic gastritis patients, and in 28% (5/18) of α-catenin, 67% (10/15) of β-catenin and 57% (8/14) of E-cadherin in intestinal metaplasia patients. The scoring of α-catenin, β-catenin and E-cadherin correlated with each other. Forty-three percent of patients had concordant changes of scores along the gastritis–adenocarcinoma sequence. There was no association between Helicobacter pylori status and E-cadherin–catenin complex expression. Conclusion: Deregulation of the E-cadherin–catenin complex was observed in the majority of precancerous lesions in patients with gastric adenocarcinoma, which has potential diagnostic and therapeutic implications. © 2003 Blackwell Publishing Asia Pty Ltd

Research carried out on effective schools have pointed out that school leadership is ranked as the second most important influence amongst school-related factors that affect student learning. As rightly cautioned by Hallinger, while research does serve its purpose in informing practices and “some parts of the ‘global’ (i.e. Western) knowledge base may be highly relevant across national and cultural contexts, we know little about which theories and findings are ‘universally’ applicable and which are context dependent” (p. 83). Other studies have also highlighted the need for researchers to take into consideration the contextual influences of the school, such as the school culture and student background. Indeed, educators often remark that certain theories, originating from the west, cannot be applied within the local context because both the system and the culture are different. Nevertheless, since researches such as those done by Dwyer and Hallinger and Murphy have indicated that successful school principals habitually engage in instructional leadership practices, it will be worthwhile investigating these practices in the context of Singapore so that policies and programmes such as the Leadership in Education Programme, attended by all would-be principals, can focus on the type of training that would bring about positive school outcomes.

Introduction: Increasing numbers of hospital admissions is a complex issue of significant concern to health systems around the world, as a significant cost driver of healthcare is inpatient cost[i]. In Singapore, patients who are frequently admitted to hospitals, although comprising a small number, account for a disproportionately high use of scarce healthcare resources. While national efforts are currently underway to provide care planning and coordination to such patients, evidence shows that there is a need for case-finding of at-risk patients before they deteriorate[ii]. To date, most predictive models for frequent admissions are derived using administrative and clinical data, and little is known about the psychosocial, behavioural and environmental factors which contribute to frequent admissions in the local context[iii]. Aims: This study aims to Understand how psychosocial, behavioural and environmental factors contribute to frequent admissions, and identify the gaps in current services to address these factors; and Understand how frequent admitters and their caregivers cope with physical, mental and financial stress. Methods: A qualitative approach was used, where in-depth, semi-structured interviews (n=42) and focus group discussions (n=2) were conducted with 41 health and community care providers, and 13 frequent admitters (defined as patients with three or more admissions in a year) and/or caregivers recruited from both the National University Hospital and community care sectors through purposive sampling. Data analysis was done using a deductive approach[iv]. Results and Key Findings: Key psychosocial factors contributing to frequent admissions included social isolation, the lack of caregiver support or capability, anxious caregivers, caregiver stress and perceptionsthat hospital care was superior to community care. Behavioural factors included lack of motivation for self-care while environmental factors included poor communication during care transition between healthcare settings, and financial subsidy schemes which favour hospital rather than community care. Neighbours and friends were found to be an importance source of social support in preventing readmissions, while religion was found to have mixed impact on how patients or caregivers coped with illness. Discussion and Lessons Learnt: This study highlights the importance ofaddressing social isolation, and that informal networks such as neighbours and friends are an often overlooked source of psychosocial support for patients and their caregivers. Secondly, caregiver training, education and provision of respite services should also be in place to support caregivers in the community. Thirdly, a concerted effort is needed to address patients’ socio-cultural beliefs and perceptions about healthcare, while concurrently improving care integration between healthcare settings. Limitations: Comparatively more healthcare professionals than patients and caregivers were interviewed in this study, as many patients were too ill to be interviewed. Suggestions for Future Research: The findings of this study could be used to develop asurvey to understand the prevalence of factors identified in this study among frequent admitters. A screening tool could then be developed to screen individuals at-risk for frequent admissions so that pre-emptive interventions could be instituted. References: 1- Longman JM, Singer JB, Gao Y, Barclay LM, Passey ME, Pirotta JP, et al. Community based service providers' perspectives on frequent and/or avoidable admission of older people with chronic disease in rural NSW: a qualitative study. BMC Health Services Research. 2011Dec;11(1) 2- Ross S, Curry N, Goodwin N. Case management. What it is and how it can best be implemented. London: The King’s Fund; 2011. [Cited 12 Dec 2011]. Available from: http://www.kingsfund.org.uk/publications/case_management.html. 3- Low LL, Liu N, Wang S, Thumboo J, Ong MEH, Lee KH. Predicting frequent hospital admission risk in Singapore: a retrospective cohort study to investigate the impact of comorbidities, acute illness burden and social determinants of health. BMJ Open. 2016;6(10) 4- Pope C. Qualitative research in health care: Analysing qualitative data. BMJ. 2000 Aug;320(7227):114–6

Breast cancer is the most common cancer among women. Mammography screening greatly reduce breast cancer mortality in women between the ages of 50 and 69. Despite the well publicized importance of attending mammography, screening rates in British Columbia (BC) continue to remain below an ideal 70% screening rate. This study examines the factors that influence mammography screening participation in women between the ages of 45 to 65, living in different regions of BC. Literature review has shown that age, ethnicity, socioeconomic status, obesity, smoking, urban and rural living, previous Pap smear screening, having a regular family doctor, and recent physician access affect screening attendance. Data from the 2006 Canadian National Census and the 2005 Canadian Community Health Survey was obtained in order to determine the influence of factors in regions of BC. Results showed that increasing obesity and low education were significantly correlated with lower mammography screening rates in BC, confirming previous literature trends. Older age was found to correlate with increased mammography screening attendance. Knowledge of factors that influence mammography screening in specific regions of BC can help provide region-specific recommendations and improve screening attendance, thereby increasing the likelihood of early detection and reducing breast cancer mortality.

Kiasuism (from the adjective, kiasu; meaning “the fear of losing out”) is a much talked‐about topic in Singapore. This study seeks to assess the situation in Singapore and in a major city in Australia, define this cultural concept and explore the possible repercussions on society. Data collected from undergraduates in Singapore and Australia by using a questionnaire survey were analysed using statistical techniques such as multiple regression analysis and t‐tests of sample means. Qualitative methods such as content analyses and critical incident technique for instrument development were also employed. The study consisted of two phases: a phase one pilot study and a phase two questionnaire designed to determine the degree of kiasuism in the two samples and its effect on general wellbeing, academic performance and satisfaction with performance. Results indicated that kiasuism is not unique to Singapore, and may well be a behaviour exhibited by people around the world.

A series of 4-arylimidazolones have been accessed via late-stage, palladium-mediated arylation of acetone- and cyclohexanone-derived 4-chloroimidazolones. The 4-chloroimidazolones were prepared via a novel rearrangement of the corresponding imidazolone N-oxides. This communication serves as an expansion of chemistry originally developed for our glucagon receptor antagonist program.

Purpose: To examine the effect of hormone use, pregnancy and menopausal status on clinical outcomes following excimer laser surgery for myopia and myopic astigmatism. Methods: Participants comprised all female patients of the Melbourne Excimer Laser Group (MELG). A standardised surgical protocol was followed by the 27 MELG members, using the VisX 20/20 excimer laser and included the prospective collection of the following information preoperatively and one, three, six and 12 months after the procedure: uncorrected and best corrected visual acuity with a LogMAR chart; best manifest refraction: and subjective assessment of corneal clarity. A survey that elicited information about oral contraceptive (OC) use, pregnancy history, surgical and natural menopause, and use of hormone replacement therapy (HRT) was mailed to all the women. Results: A 77% response to the mailed survey was achieved. Two women were pregnant at the time of surgery, one became pregnant during the first month after surgery, and all three women were excluded from further analyses, although a review of two of the case histories revealed suboptimal clinical outcomes. Women taking OC were included in the control group after OC use was shown not to be associated with outcome. Women were grouped accordingly: control, n=225; pre-menopausal on HRT, n=7; post-menopausal not on HRT, n=34; and post-menopausal on HRT, n=21. The groups differed significantly with regard to age and preoperative spherical equivalent. After controlling for age and preoperative spherical equivalent, the mean number of uncorrected LogMAR letters read one year after surgery was significantly lower for the post-menopausal women on HRT in comparison with the control group. Best corrected acuity and corneal clarity were not significantly different among the groups. Discussion: These preliminary results suggest that the interaction of menopausal and HRT status could decrease the effectiveness of PRK and PARK, but require confirmation with a further study in a prospective manner using objective measures of corneal epithelial healing and serum hormone levels.

Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Frequent relapse and drug resistance accounts for the poor prognosis, which could be attributed by the presence of cancer stem cells (CSCs), a subpopulation that harbor the properties of self-renewal, clonal tumor initiation and long-term repopulation capacity. Toll like receptors (TLRs) are widely expressed on immune cells and TLR/Interleukin-1 receptor associated kinase (IRAK) pathway was originally best known for their role in the induction of innate immune responses, but it was recently found to be frequently up-regulated in various cancers, although its role in cancer development remains largely unexplored. By RNA sequencing analysis of 16 pairs of HCC clinical samples, we found IRAK1 to be significantly overexpressed in HCC among all members of IRAK family. By quantitative PCR and western blot analyses, overexpression of IRAK1 at both mRNA and protein level was confirmed, which correlated with advanced tumor stage (p = 0.04). By lentiviral-based over-expression and knockdown approaches, we demonstrated that IRAK1 promoted cell proliferation and invasiveness. Interestingly, IRAK1 regulated CSC properties including tumorigenicity, self-renewal, drug resistance and expression of liver CSC markers including CD24 and CD47. To further examine the therapeutic potentials of targeting IRAK1 in HCC, we treated HCC cells with IRAK1/4 inhibitor. Suppression of IRAK1 at 10μM not only consistently inhibited CSC properties, but also augmented the effect of sorafenib, a molecularly targeted drug for treatment of advanced HCC. The cancer-promoting and drug desensitization effect of IRAK1 could be partly explained by activation of NF-κB signaling pathway as well as down-regulation of apoptotic cascade. Conclusion: Overexpression of IRAK1 in HCC promotes cancer progression by enhancing proliferation and invasiveness; Importantly, IRAK1 may promote cancer stemness and confers resistance to sorafenib. All in all, targeting IRAK1 with specific small molecule inhibitor alone or in combination with other drugs may be a novel therapeutic regimen for treatment of HCC. Citation Format: Yik Ling Bowie Cheng, Oi Lin Irene Ng, Kin Wah Terence Lee. Inhibition of TLR/IRAK pathway in hepatocellular carcinoma augmented therapeutic responses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5152.

Purpose: The natural products resveratrol and trans- e-viniferin have been reported to have many beneficial effects, which include the enhancement of cognition and memory. There have been no studies which have reported the effects of these compounds on the different GABA A receptor subtypes and this study aimed to address this. Methods: The effects of both resveratrol, and its dimer, trans- e-viniferin, have been investigated on different GABA A receptor subtypes expressed in Xenopus laevis oocytes, using the two-electrode voltage clamp technique. Results: Resveratrol induced a current of 22 ± 3.53 nA in the α 1 β 2 γ 2L subtype of the GABA A receptor (but not in the α 5 β 3 γ 2L and α 2 β 2 γ 2L subtypes) when applied alone. It also positively modulated the GABA-induced current ( I GABA ) in α 1 β 2 γ 2L receptors, in adose-dependent manner (EC 50 58.24 μM). The effects of resveratrol were not sensitive to the benzodiazepine antagonist flumazenil. trans- e-Viniferin exhibited a different pattern of activity to resveratrol; it alone had no effect on any of the subtypes, but it did negatively modulate the GABA-induced current ( I GABA ) in all three subtypes. The greatest inhibition was found in the α 1 β 2 γ 2L subtype (IC 50 5.79 μM), with the inhibition in the α 2 β 2 γ 2L (IC 50 of 19.08 μM) and α 5 β 3 γ 2L (IC 50 of 21.05 μM) subtypes being similar. The effects of trans- e-viniferin in α 1 β 2 γ 2L and α 2 β 2 γ 2L receptors werealso not sensitive to the benzodiazepine antagonist flumazenil while, in the α 5 β 3 γ 2L subtype the effect was not sensitive to the inverse agonist L-655,708, indicating different binding sites for this molecule. Conclusions: The results of the present study indicate that both resveratrol and trans- e-viniferin modulate the GABA-induced current in different ways, and that trans- e-viniferin may be a lead compound for the discovery of agents which selectively inhibit the GABA-induced current in α 1 -containing subtypes. This article is open to POST-PUBLICATION REVIEW . Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Introduction: PIN1 is a peptidyl-prolyl cis/trans isomerase (PPlase) that regulates multiple signaling pathways to control cell fate. It is found to be up-regulated in hepatocellular carcinomas (HCC), leading to increased cell proliferation and inhibition of apoptosis. However, the regulation of PIN1 remains poorly defined. MicroRNA (miRNA) plays a pivotal role in carcinogenesis by regulating tumor suppressor genes and oncogenes via targeting the 3′UTR of their encoded mRNAs. Therefore, we aimed at identifying miRNAs regulating PIN1 expression, and determining the contributions of these miRNAs to tumorigenesis through PIN1. Methods: Potential miRNAs regulating PIN1 were identified through sequence prediction using the online database TargetScan Release 6.2. Western immunoblotting and qRT-PCR were used to assess PIN1 expression in HCC cells with over-expression of identified miRNAs. Dual-Luciferase reporter assay was conducted to examine the direct interaction between the identified miRNAs and PIN1 3′UTR. The tumor suppressive role of the identified miRNAs in HCC cells was investigated using MTT cell proliferation assay, colony formation assay and Annexin V apoptosis detection assay. To investigate the correlation between the levels of PIN1 and the identified miRNAs, qRT-PCR was used to determine the mRNA levels of PIN1 and the identified miRNAs in 20 pairs of normal liver tissue and HCC. Results: We identified miR-296-5p and miR-874-3p as important negative regulators of PIN1. Consequently, over-expression of miR-296-5p and miR-874-3p enhanced cellular apoptosis, and inhibited cell growth and colony formation in HCC cells. Furthermore, the cellular functions of miR-296-5p and miR-874-3p were abrogated by over-expression of PIN1. Importantly, the expression of PIN1 was negatively correlated with that of miR-296-5p and miR-874-3p in HCC tissues, consistent with the regulatory role of miR-295-5p and miR-874-3p on PIN1 expression. Conclusion: Taken together, our data showed that miR-296-5p and miR-874-3p controlled cell proliferation and apoptosis in HCC by regulating PIN1 expression. Citation Format: Ka Wai Leong, Chi Wai Cheng, Chun Ming Wong, Oi Lin Irene Ng, Yok Lam Kwong, Eric Wai Choi Tse. miR-296-5p and miR-874-3p control cell proliferation and apoptosis in HCC via regulation of PIN1 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3119. doi:10.1158/1538-7445.AM2015-3119

Background: Liver is well characterized as a major metabolic organ, the metabolic machineries driving liver cancer (hepatocellular carcinoma, HCC) progression remains poorly understood. Oxygen deprivation, hypoxia, is frequently found in regions of tumors with insufficient blood supply. Hypoxia stabilizes hypoxia-inducible factor-1α (HIF-1α) which transcriptionally activates genes that utilize glycolysis over oxidative phosphorylation for ATP production. This metabolic switch reduces mitochondrial reactive oxygen species (ROS) production that would otherwise occur due to electron imbalance through the electron transport chain (ETC) in hypoxic condition. In our transcriptome sequence analysis, among all the mitochondrial subunits in the complex I of the electron transport chain (ETC), only NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 gene (NDUFA4L2) was distinctly and significantly induced by hypoxia and over-expressed in human HCC. However, the clinical implications and functions of this gene in HCC progression remain unknown. Methods: The mRNA expression of NDUFA4L2 in an expanded cohort of 100 HCC patients was evaluated by qRT-PCR. ChIP assay was performed to study the interaction of HIF-1α with NDUFA4L2. Stable knockdown by shRNA or knockout by TALEN of HIF-1α/NDUFA4L2 was established in HCC cells to explore the roles of NDUFA4L2 in HCC. ROS, mitochondrial membrane potential, and oxygen consumption rate were measured in the HIF-1α/NDUFA4L2 knockdown or knockout HCC cells. Orthotopic implantation model was employed to evaluate the in vivo effect of NDUFA4L2 and the efficiency of HIF inhibitors. Results: NDUFA4L2 was significantly overexpressed in human HCC and was markedly induced by hypoxia. Overexpression of NDUFA4L2 in human HCC was significantly correlated with aggressive HCC clinicopathological parameters including absence of tumor encapsulation, formation of tumor microsatellite, and poorer overall survival. ChIP assay confirmed the binding of HIF-1α with hypoxia response elements (HREs) in NDUFA4L2 promoter and expression study showed that hypoxia-induced NDUFA4L2 was abolished in HIF-1αknockdown or knockout HCC cells. Genetic ablation of HIF-1α/NDUFA4L2 increased the mitochondrial activity that coupled with higher intracellular reactive oxygen species (ROS) and ROS-induced apoptosis. Knockdown of NDUFA4L2 markedly suppressed tumor growth in vitro and in vivo. HIF inhibitors, digoxin and Sorafenib, profoundly inhibited the growth of HCC that expressed high levels of NDUFA4L2. Conclusion: Over-expression of NDUFA4L2 is associated with poor clinical outcome in HCC patients. Hypoxia-induced NDUFA4L2 reduced the mitochondrial ROS production and ROS-triggered apoptosis, thereby conferring HCC cells growth advantage in hypoxic environment. Targeting HIF-1α/NDUFA4L2 pathway by HIF inhibitors represent a new therapeutic strategy for HCC. Citation Format: Kit Ho Lai, Ming Jing Xu, Pui Wah Tse, Kung Chun Chiu, Wei Lai, Chun Ming Wong, Pik Wong, Oi Lin Ng, Chak Lui Wong. HIF-1α/NDUFA4L2 promotes hepatocellular carcinoma progression through reducing oxidative stress. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1188. doi:10.1158/1538-7445.AM2015-1188

Sequence polymorphisms of hypervariable region 1 were analyzed in 100 unrelated Singaporean Chinese. Ninety-five different haplotypes resulting from 113 variable sites were found between nucleotide positions 16045 and 16364. Single nucleotide polymorphism at nucleotide positions 16223, 16045, 16129, 16362 and 16189 was amongst the five highest frequencies observed in the sequences, whilst the most frequent haplotype was 16045-16223. Based on polymorphic sites observed at HV1, haplogroups A, F1a, M7b1, B5a and D4b were the most commonly observed clusters. The haplotype, nucleotide diversity and the average number of nucleotide differences were found to be 0.999, 0.028 and 9.082, respectively. The cytosine-stretch region located around nucleotide position 16189 was observed in 22% of this population sample. Transitions were found to be more predominant than transversions.