Bankstown Lidcombe Hospital

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

Hundreds of individual human cancer genome sequences are expected to be published in 2010, and thousands per year after that. The International Cancer Genome Consortium (ICGC) was launched with the aim of keeping track of the data relating to large-scale cancer genome studies of all major cancers in adults and children — a total of 50 different cancer types and/or subtypes. In this issue the ICGC team ( http://www.icgc.org ) spells out the policies and planning for the project. The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

BACKGROUND: At least one-third of community-dwelling people over 65 years of age fall each year. Exercises that target balance, gait and muscle strength have been found to prevent falls in these people. An up-to-date synthesis of the evidence is important given the major long-term consequences associated with falls and fall-related injuries OBJECTIVES: To assess the effects (benefits and harms) of exercise interventions for preventing falls in older people living in the community. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, three other databases and two trial registers up to 2 May 2018, together with reference checking and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the effects of any form of exercise as a single intervention on falls in people aged 60+ years living in the community. We excluded trials focused on particular conditions, such as stroke. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcome was rate of falls. MAIN RESULTS: We included 108 RCTs with 23,407 participants living in the community in 25 countries. There were nine cluster-RCTs. On average, participants were 76 years old and 77% were women. Most trials had unclear or high risk of bias for one or more items. Results from four trials focusing on people who had been recently discharged from hospital and from comparisons of different exercises are not described here.Exercise (all types) versus control Eighty-one trials (19,684 participants) compared exercise (all types) with control intervention (one not thought to reduce falls). Exercise reduces the rate of falls by 23% (rate ratio (RaR) 0.77, 95% confidence interval (CI) 0.71 to 0.83; 12,981 participants, 59 studies; high-certainty evidence). Based on an illustrative risk of 850 falls in 1000 people followed over one year (data based on control group risk data from the 59 studies), this equates to 195 (95% CI 144 to 246) fewer falls in the exercise group. Exercise also reduces the number of people experiencing one or more falls by 15% (risk ratio (RR) 0.85, 95% CI 0.81 to 0.89; 13,518 participants, 63 studies; high-certainty evidence). Based on an illustrative risk of 480 fallers in 1000 people followed over one year (data based on control group risk data from the 63 studies), this equates to 72 (95% CI 52 to 91) fewer fallers in the exercise group. Subgroup analyses showed no evidence of a difference in effect on both falls outcomes according to whether trials selected participants at increased risk of falling or not.The findings for other outcomes are less certain, reflecting in part the relatively low number of studies and participants. Exercise may reduce the number of people experiencing one or more fall-related fractures (RR 0.73, 95% CI 0.56 to 0.95; 4047 participants, 10 studies; low-certainty evidence) and the number of people experiencing one or more falls requiring medical attention (RR 0.61, 95% CI 0.47 to 0.79; 1019 participants, 5 studies; low-certainty evidence). The effect of exercise on the number of people who experience one or more falls requiring hospital admission is unclear (RR 0.78, 95% CI 0.51 to 1.18; 1705 participants, 2 studies, very low-certainty evidence). Exercise may make little important difference to health-related quality of life: conversion of the pooled result (standardised mean difference (SMD) -0.03, 95% CI -0.10 to 0.04; 3172 participants, 15 studies; low-certainty evidence) to the EQ-5D and SF-36 scores showed the respective 95% CIs were much smaller than minimally important differences for both scales.Adverse events were reported to some degree in 27 trials (6019 participants) but were monitored closely in both exercise and control groups in only one trial. Fourteen trials reported no adverse events. Aside from two serious adverse events (one pelvic stress fracture and one inguinal hernia surgery) reported in one trial, the remainder were non-serious adverse events, primarily of a musculoskeletal nature. There was a median of three events (range 1 to 26) in the exercise groups.Different exercise types versus controlDifferent forms of exercise had different impacts on falls (test for subgroup differences, rate of falls: P = 0.004, I² = 71%). Compared with control, balance and functional exercises reduce the rate of falls by 24% (RaR 0.76, 95% CI 0.70 to 0.81; 7920 participants, 39 studies; high-certainty evidence) and the number of people experiencing one or more falls by 13% (RR 0.87, 95% CI 0.82 to 0.91; 8288 participants, 37 studies; high-certainty evidence). Multiple types of exercise (most commonly balance and functional exercises plus resistance exercises) probably reduce the rate of falls by 34% (RaR 0.66, 95% CI 0.50 to 0.88; 1374 participants, 11 studies; moderate-certainty evidence) and the number of people experiencing one or more falls by 22% (RR 0.78, 95% CI 0.64 to 0.96; 1623 participants, 17 studies; moderate-certainty evidence). Tai Chi may reduce the rate of falls by 19% (RaR 0.81, 95% CI 0.67 to 0.99; 2655 participants, 7 studies; low-certainty evidence) as well as reducing the number of people who experience falls by 20% (RR 0.80, 95% CI 0.70 to 0.91; 2677 participants, 8 studies; high-certainty evidence). We are uncertain of the effects of programmes that are primarily resistance training, or dance or walking programmes on the rate of falls and the number of people who experience falls. No trials compared flexibility or endurance exercise versus control. AUTHORS' CONCLUSIONS: Exercise programmes reduce the rate of falls and the number of people experiencing falls in older people living in the community (high-certainty evidence). The effects of such exercise programmes are uncertain for other non-falls outcomes. Where reported, adverse events were predominantly non-serious.Exercise programmes that reduce falls primarily involve balance and functional exercises, while programmes that probably reduce falls include multiple exercise categories (typically balance and functional exercises plus resistance exercises). Tai Chi may also prevent falls but we are uncertain of the effect of resistance exercise (without balance and functional exercises), dance, or walking on the rate of falls.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

BACKGROUND AND PURPOSE: The methodological quality of randomized controlled trials (RCTs) is commonly evaluated in order to assess the risk of biased estimates of treatment effects. The purpose of this systematic review was to identify scales used to evaluate the methodological quality of RCTs in health care research and summarize the content, construction, development, and psychometric properties of these scales. METHODS: Extensive electronic database searches, along with a manual search, were performed. RESULTS: One hundred five relevant studies were identified. They accounted for 21 scales and their modifications. The majority of scales had not been rigorously developed or tested for validity and reliability. The Jadad Scale presented the best validity and reliability evidence; however, its validity for physical therapy trials has not been supported. DISCUSSION AND CONCLUSION: Many scales are used to evaluate the methodological quality of RCTs, but most of these scales have not been adequately developed and have not been adequately tested for validity and reliability. A valid and reliable scale for the assessment of the methodological quality of physical therapy trials needs to be developed.

BACKGROUND: recent studies have found that moderate intensity exercise is an effective intervention strategy for preventing falls in older people. However, research is required to determine whether supervised group exercise programmes, conducted in community settings with at-risk older people referred by their health care practitioner are also effective in improving physical functioning and preventing falls in this group. OBJECTIVES: to determine whether participation in a weekly group exercise programme with ancillary home exercises over one year improves balance, muscle strength, reaction time, physical functioning, health status and prevents falls in at-risk community-dwelling older people. METHODS: the sample comprised 163 people aged over 65 years identified as at risk of falling using a standardised assessment screen by their general practitioner or hospital-based physiotherapist, residing in South Western Sydney, Australia. Subjects were randomised into either an exercise intervention group or a control group. Physical performance and general health measures were assessed at baseline and repeated 6-months into the trial. Falls were measured over a 12-month follow-up period using monthly postal surveys. RESULTS: at baseline both groups were well matched in their physical performance, health and activity levels. The intervention subjects attended a median of 23 exercise classes over the year, and most undertook the home exercise sessions at least weekly. At retest, the exercise group performed significantly better than the controls in three of six balance measures; postural sway on the floor with eyes open and eyes closed and coordinated stability. The groups did not differ at retest in measures of strength, reaction time and walking speed or on Short-Form 36, Physical Activity Scale for the Elderly or fear of falling scales. Within the 12-month trial period, the rate of falls in the intervention group was 40% lower than that of the control group (IRR=0.60, 95% CI 0.36-0.99). CONCLUSIONS: these findings indicate that participation in a weekly group exercise programme with ancillary home exercises can improve balance and reduce the rate of falling in at-risk community dwelling older people.

OBJECTIVES: Pancreatic cancer has a very poor prognosis, largely due to its propensity for early local and distant spread. Histopathologically, most pancreatic cancers are characterized by a prominent stromal/fibrous reaction in and around tumor tissue. The aims of this study were to determine whether (1) the cells responsible for the formation of the stromal reaction in human pancreatic cancers are activated pancreatic stellate cells (PSCs) and (2) an interaction exists between pancreatic cancer cells and PSCs that may facilitate local and distant invasion of tumor. METHODS: Serial sections of human pancreatic cancer tissue were stained for desmin and glial fibrillary acidic protein (stellate cell selective markers) and alpha-smooth muscle actin (alphaSMA), a marker of activated PSC activation, by immunohistochemistry, and for collagen using Sirius Red. Correlation between the extent of positive staining for collagen and alphaSMA was assessed by morphometry. The cellular source of collagen in stromal areas was identified using dual staining methodology, ie, immunostaining for alphaSMA and in situ hybridization for procollagen alpha1I mRNA. The possible interaction between pancreatic cancer cells and PSCs was assessed in vitro by exposing cultured rat PSCs to control medium or conditioned medium from 2 pancreatic cancer cell lines (PANC-1 and MiaPaCa-2) for 24 hours. PSC activation was assessed by cell proliferation and alphaSMA expression. RESULTS: Stromal areas of human pancreatic cancer stained strongly positive for the stellate cell selective markers desmin and GFAP (indicating the presence of PSCs), for alphaSMA (suggesting that the PSCs were in their activated state) and for collagen. Morphometric analysis demonstrated a close correlation (r = 0.77; P < 0.04; 8 paired sections) between the extent of PSC activation and collagen deposition. Procollagen mRNA expression was localized to alphaSMA-positive cells in stromal areas indicating that activated PSCs were the predominant source of collagen in stromal areas. Exposure of PSCs to pancreatic cancer cell secretions in vitro resulted in PSC activation as indicated by significantly increased cell proliferation and alphaSMA expression. CONCLUSIONS: Activated PSCs are present in the stromal reaction in pancreatic cancers and are responsible for the production of stromal collagen. PSC function is influenced by pancreatic cancer cells. Interactions between tumor cells and stromal cells (PSCs) may play an important role in the pathobiology of pancreatic cancer.

BACKGROUND: Falls and fall-related injuries are common, particularly in those aged over 65, with around one-third of older people living in the community falling at least once a year. Falls prevention interventions may comprise single component interventions (e.g. exercise), or involve combinations of two or more different types of intervention (e.g. exercise and medication review). Their delivery can broadly be divided into two main groups: 1) multifactorial interventions where component interventions differ based on individual assessment of risk; or 2) multiple component interventions where the same component interventions are provided to all people. OBJECTIVES: To assess the effects (benefits and harms) of multifactorial interventions and multiple component interventions for preventing falls in older people living in the community. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, trial registers and reference lists. Date of search: 12 June 2017. SELECTION CRITERIA: Randomised controlled trials, individual or cluster, that evaluated the effects of multifactorial and multiple component interventions on falls in older people living in the community, compared with control (i.e. usual care (no change in usual activities) or attention control (social visits)) or exercise as a single intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias and extracted data. We calculated the rate ratio (RaR) with 95% confidence intervals (CIs) for rate of falls. For dichotomous outcomes we used risk ratios (RRs) and 95% CIs. For continuous outcomes, we used the standardised mean difference (SMD) with 95% CIs. We pooled data using the random-effects model. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: = 88%). Of seven trials reporting on adverse events, five found none, and six minor adverse events were reported in two.Multiple component interventions versus exerciseThis comparison was tested in five trials. There is low-quality evidence of little or no difference between the two interventions in rate of falls (1 trial) and risk of falling (RR 0.93, 95% CI 0.78 to 1.10; 3 trials; 863 participants) and very low-quality evidence, meaning we are uncertain of the effects on hospital admission (1 trial). One trial reported two cases of minor joint pain. Other falls outcomes were not reported. AUTHORS' CONCLUSIONS: Multifactorial interventions may reduce the rate of falls compared with usual care or attention control. However, there may be little or no effect on other fall-related outcomes. Multiple component interventions, usually including exercise, may reduce the rate of falls and risk of falling compared with usual care or attention control.

THERE has been a gradually growing awareness among policy makers and health care professionals during the past several decades of the importance of appropriate exercise habits to major public health outcomes, resulting in numerous position stands and policy recommendations that include physical activity prescriptions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). However, there is still skepticism among some clinicians and investigators as to the actual potency of exercise for disease and/or disability prevention and treatment, particularly in already frail or near frail adults (13). It is likely that some of the discrepancies among research findings, clinical practice, and policy recommendations result from a lack of appreciation of the heterogeneity of the terms “exercise” and “physical activity” as they are used in the literature. Posing the question “Does exercise prevent or treat disease in older persons?” is analogous to asking “Does medication prevent or treat disease in older persons?” The answer only makes sense when exercise is described in terms of its modality, dose (frequency and intensity), duration of exposure, and compliance with the prescription, and in relation to a specific disease, syndrome, or biological change of aging. In addition, it does not necessarily follow that the same type or dose of exercise is needed for treatment of overt or advanced disease as that which would be required for prevention. Such observations are obvious to clinicians when thinking about surgical, pharmacological, or nutritional management of disease, but lack of explicit training in exercise physiology for most physicians has often obscured this point in discussions of the value of exercise for geriatric health care problems. Therefore, in the sections that follow, a rationale for the use of exercise and physical activity for health promotion and disease prevention is offered. Exercise will be discussed in terms of the specific modalities and doses that have been studied for their role in the physiological changes of aging, disease prevention, and treatment of older persons with chronic disease and disability. Finally, an overview of the current recommendations, reflective of the current consensus of knowledge, is provided. Gaps in knowledge and controversial areas requiring further study are identified. The interaction of physical activity, exercise, and physical fitness with health and aging is complex and multifaceted. Although many questions remain about mechanisms of effect and dose-response curves (14), a synthesis of the literature indicates many potentially positive effects of participation in physical activity on the aging process. Any discussion of these issues must begin with definitions of the terminology. Physical activity has been traditionally defined as any bodily movement produced by contraction of skeletal muscle that substantially increases energy expenditure, although the intensity and duration can vary substantially (15). It should be noted that some forms of physical activity that may have particular relevance to an aging population (e.g., balance training) may not conform to this standard definition. This activity may be performed in leisure or occupational hours, and surveys for the older adult should capture both paid and unpaid (volunteer) work (16). Exercise is a subcategory of leisure time physical activity in which planned, structured, repetitive bodily movements are performed, with or without the explicit intent of improving one or more components of physical fitness. Physical fitness is defined as a set of attributes that contribute to the ability to perform physical work (e.g., cardiorespiratory endurance, muscle power, balance, flexibility, and body composition) or influence health status. “Metabolic fitness” has been advanced more recently as a term that encompasses a range of biologically important adaptations to exercise (increased insulin sensitivity, lipoprotein lipase activity, etc.) that may contribute to health status, but do not directly affect exercise capacity. Therefore, to understand the potential role of exercise in the aging process and to incorporate it into clinical practice, health care professionals should understand the risks and benefits of various modalities and doses of exercise and categories of physical activity in relation to specific health-related goals. 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"Metabolic dysfunction-associated fatty liver disease (MAFLD)" is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.

BACKGROUND: Discharge planning is a routine feature of health systems in many countries. The aim of discharge planning is to reduce hospital length of stay and unplanned readmission to hospital, and to improve the co-ordination of services following discharge from hospital.This is the third update of the original review. OBJECTIVES: To assess the effectiveness of planning the discharge of individual patients moving from hospital. SEARCH METHODS: We updated the review using the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 9), MEDLINE, EMBASE, CINAHL, the Social Science Citation Index (last searched in October 2015), and the US National Institutes of Health trial register (ClinicalTrials.gov). SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared an individualised discharge plan with routine discharge care that was not tailored to individual participants. Participants were hospital inpatients. DATA COLLECTION AND ANALYSIS: Two authors independently undertook data analysis and quality assessment using a pre-designed data extraction sheet. We grouped studies according to patient groups (elderly medical patients, patients recovering from surgery, and those with a mix of conditions) and by outcome. We performed our statistical analysis according to the intention-to-treat principle, calculating risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous data using fixed-effect meta-analysis. When combining outcome data was not possible because of differences in the reporting of outcomes, we summarised the reported data in the text. MAIN RESULTS: We included 30 trials (11,964 participants), including six identified in this update. Twenty-one trials recruited older participants with a medical condition, five recruited participants with a mix of medical and surgical conditions, one recruited participants from a psychiatric hospital, one from both a psychiatric hospital and from a general hospital, and two trials recruited participants admitted to hospital following a fall. Hospital length of stay and readmissions to hospital were reduced for participants admitted to hospital with a medical diagnosis and who were allocated to discharge planning (length of stay MD - 0.73, 95% CI - 1.33 to - 0.12, 12 trials, moderate certainty evidence; readmission rates RR 0.87, 95% CI 0.79 to 0.97, 15 trials, moderate certainty evidence). It is uncertain whether discharge planning reduces readmission rates for patients admitted to hospital following a fall (RR 1.36, 95% CI 0.46 to 4.01, 2 trials, very low certainty evidence). For elderly patients with a medical condition, there was little or no difference between groups for mortality (RR 0.99, 95% CI 0.79 to 1.24, moderate certainty). There was also little evidence regarding mortality for participants recovering from surgery or who had a mix of medical and surgical conditions. Discharge planning may lead to increased satisfaction for patients and healthcare professionals (low certainty evidence, six trials). It is uncertain whether there is any difference in the cost of care when discharge planning is implemented with patients who have a medical condition (very low certainty evidence, five trials). AUTHORS' CONCLUSIONS: A discharge plan tailored to the individual patient probably brings about a small reduction in hospital length of stay and reduces the risk of readmission to hospital at three months follow-up for older people with a medical condition. Discharge planning may lead to increased satisfaction with healthcare for patients and professionals. There is little evidence that discharge planning reduces costs to the health service.

Background: Inflammation plays a crucial role in clinical manifestations and complications of acute coronary syndromes (ACS). Colchicine, a commonly used treatment for gout, has recently emerged as a novel therapeutic option in cardiovascular medicine owing to its anti-inflammatory properties. We sought to determine the potential usefulness of colchicine treatment in patients with ACS. Methods: This was a multicenter, randomized, double-blind, placebo-controlled trial involving 17 hospitals in Australia that provide acute cardiac care service. Eligible participants were adults (18–85 years) who presented with ACS and had evidence of coronary artery disease on coronary angiography managed with either percutaneous coronary intervention or medical therapy. Patients were assigned to receive either colchicine (0.5 mg twice daily for the first month, then 0.5 mg daily for 11 months) or placebo, in addition to standard secondary prevention pharmacotherapy, and were followed up for a minimum of 12 months. The primary outcome was a composite of all-cause mortality, ACS, ischemia-driven (unplanned) urgent revascularization, and noncardioembolic ischemic stroke in a time to event analysis. Results: A total of 795 patients were recruited between December 2015 and September 2018 (mean age, 59.8±10.3 years; 21% female), with 396 assigned to the colchicine group and 399 to the placebo group. Over the 12-month follow-up, there were 24 events in the colchicine group compared with 38 events in the placebo group ( P =0.09, log-rank). There was a higher rate of total death (8 versus 1; P =0.017, log-rank) and, in particular, noncardiovascular death in the colchicine group (5 versus 0; P =0.024, log-rank). The rates of reported adverse effects were not different (colchicine 23.0% versus placebo 24.3%), and they were predominantly gastrointestinal symptoms (colchicine, 23.0% versus placebo, 20.8%). Conclusions: The addition of colchicine to standard medical therapy did not significantly affect cardiovascular outcomes at 12 months in patients with ACS and was associated with a higher rate of mortality. Registration: URL: https://www.anzctr.org.au ; Unique identifier: ACTRN12615000861550.

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

STUDY DESIGN: A reliability study and case-control study were conducted. OBJECTIVES: To determine the reliability and discriminative validity of the Biering-Sorensen test. SUMMARY OF BACKGROUND DATA: A low Biering-Sorensen score has been found to predict who will have nonspecific low back pain. However, the reliability of the test remains controversial, implying that some studies may have produced results that underestimated the magnitude of the predictive validity of this test. METHODS: Two raters measured the time holding a specific position (holding time) of 63 subjects (23 currently experiencing nonspecific low back pain, 20 who had had an episode, and 20 who were asymptomatic) while they performed the Biering-Sorensen test twice, 15 minutes apart. A standardized protocol was followed. Test-retest reliability was evaluated by calculating intra-class correlation coefficients (ICC 1,1), 95% confidence intervals (CI), and standard errors of the measurement (SEM) for the total group and for the subgroups. A three-way analysis of variance was used to determine whether test order, subject gender, or symptom status affected holding time. RESULTS: High reliability indices were obtained for the Biering-Sorensen test in subjects with current nonspecific low back pain (ICC [1,1], 0.88; 95% CI, 0.73-0.95; SEM, 11.6 seconds), in subjects who had had nonspecific low back pain (ICC [1,1], 0.77; 95% CI, 0.52-0.90; SEM, 17.5 seconds), and in asymptomatic subjects (ICC [1,1], 0.83; 95% CI, 0.62-0.93; SEM, 17.4 seconds). Results of an analysis of variance showed that subjects asymptomatic for low back pain had a significantly longer holding time than the other two groups (P < 0.05). CONCLUSIONS: The Biering-Sorensen test provides reliable measures of position-holding time and can discriminate between subjects with and without nonspecific low back pain.

BACKGROUND: It is now generally accepted that chronic pancreatic injury and fibrosis may result from repeated episodes of acute pancreatic necroinflammation (the necrosis-fibrosis sequence). Recent studies suggest that pancreatic stellate cells (PSCs), when activated, may play an important role in the development of pancreatic fibrosis. Factors that may influence PSC activation during pancreatic necroinflammation include cytokines known to be important in the pathogenesis of acute pancreatitis, such as tumour necrosis factor alpha (TNF-alpha), and the interleukins 1, 6, and 10 (IL-1, IL-6, and IL-10). AIM: To determine the effects of these cytokines on PSC activation, as assessed by cell proliferation, alpha smooth muscle actin (alpha-SMA) expression, and collagen synthesis. METHODS: Cultured rat PSCs were incubated with cytokines for 24 hours. Cell proliferation was assessed by measuring (3)H thymidine incorporation into cellular DNA, alpha-SMA expression by western blotting, and collagen synthesis by incorporation of (14)C proline into collagenase sensitive protein. mRNA levels for procollagen alpha(1)(1) in PSCs were determined by northern and dot blotting methods. RESULTS: Expression of alpha-SMA by PSCs was increased on exposure to each of the cytokines used in the study. Stellate cell proliferation was stimulated by TNF-alpha but inhibited by IL-6, while IL-1 and IL-10 had no effect on PSC proliferation. Collagen synthesis by PSCs was stimulated by TNF-alpha and IL-10, inhibited in response to IL-6, and unaltered by IL-1. Changes in collagen protein synthesis in response to TNF-alpha, IL-10, and IL-6 were not regulated at the mRNA level in the cells. CONCLUSION: This study has demonstrated that PSCs have the capacity to respond to cytokines known to be upregulated during acute pancreatitis. Persistent activation of PSCs by cytokines during acute pancreatitis may be a factor involved in the progression from acute pancreatitis to chronic pancreatic injury and fibrosis.

BACKGROUND: Whether treatment of gestational diabetes before 20 weeks' gestation improves maternal and infant health is unclear. METHODS: We randomly assigned, in a 1:1 ratio, women between 4 weeks' and 19 weeks 6 days' gestation who had a risk factor for hyperglycemia and a diagnosis of gestational diabetes (World Health Organization 2013 criteria) to receive immediate treatment for gestational diabetes or deferred or no treatment, depending on the results of a repeat oral glucose-tolerance test [OGTT] at 24 to 28 weeks' gestation (control). The trial included three primary outcomes: a composite of adverse neonatal outcomes (birth at <37 weeks' gestation, birth trauma, birth weight of ≥4500 g, respiratory distress, phototherapy, stillbirth or neonatal death, or shoulder dystocia), pregnancy-related hypertension (preeclampsia, eclampsia, or gestational hypertension), and neonatal lean body mass. RESULTS: A total of 802 women underwent randomization; 406 were assigned to the immediate-treatment group and 396 to the control group; follow-up data were available for 793 women (98.9%). An initial OGTT was performed at a mean (±SD) gestation of 15.6±2.5 weeks. An adverse neonatal outcome event occurred in 94 of 378 women (24.9%) in the immediate-treatment group and in 113 of 370 women (30.5%) in the control group (adjusted risk difference, -5.6 percentage points; 95% confidence interval [CI], -10.1 to -1.2). Pregnancy-related hypertension occurred in 40 of 378 women (10.6%) in the immediate-treatment group and in 37 of 372 women (9.9%) in the control group (adjusted risk difference, 0.7 percentage points; 95% CI, -1.6 to 2.9). The mean neonatal lean body mass was 2.86 kg in the immediate-treatment group and 2.91 kg in the control group (adjusted mean difference, -0.04 kg; 95% CI, -0.09 to 0.02). No between-group differences were observed with respect to serious adverse events associated with screening and treatment. CONCLUSIONS: Immediate treatment of gestational diabetes before 20 weeks' gestation led to a modestly lower incidence of a composite of adverse neonatal outcomes than no immediate treatment; no material differences were observed for pregnancy-related hypertension or neonatal lean body mass. (Funded by the National Health and Medical Research Council and others; TOBOGM Australian New Zealand Clinical Trials Registry number, ACTRN12616000924459.).

Hip fractures are the most serious complication of osteoporosis. Although low proximal femoral bone mineral density (BMD) does not cause hip fractures directly, it is clearly a prerequisite for the increased risk associated with aging. To investigate the mechanism of the age-related decline in proximal femoral bone mineral density, we have examined the relative importance of muscle strength, physical fitness, and body mass index (BMI) in addition to age in the determination of proximal femoral BMD in 73 healthy female volunteers age 20-75 years. Muscle strength was an independent predictor of BMD at all three sites in the proximal femur as well as in the lumbar spine and forearm; proximal femur BMD was also predicted by physical fitness. BMI was a positive predictor of bone mass at all sites. In the proximal femur, age was not an independent predictor of BMD at any site. In postmenopausal women muscle strength was a significant predictor of bone mass in the femur and forearm, but not in the spine. However, BMI remained predictive of bone mineral at all sites. Muscle strength, physical fitness, and weight appear to exert independent effects upon bone mass. Age effects may be mediated indirectly through associated changes in these factors. The integrated physical load on the skeleton may be a final common pathway.

INTRODUCTION: We undertook a systematic review to identify the best evidence for how professionalism in medicine should be taught. METHODS: Eligible studies included any articles published between 1999 and 2009 inclusive. We reviewed papers presenting viewpoints and opinions as well as empirical research. We performed a comparative and thematic synthesis on all papers meeting inclusion criteria in order to capture the best available evidence on how to teach professionalism. RESULTS: We identified 217 papers on how to teach professionalism. Of these, we determined 43 to be best evidence. Few studies provided comprehensive evaluation or assessment data demonstrating success. As yet, there has not emerged a unifying theoretical or practical model to integrate the teaching of professionalism into the medical curriculum. DISCUSSION: Evident themes in the literature are that role modelling and personal reflections, ideally guided by faculty, are the important elements in current teaching programmes, and are widely held to be the most effective techniques for developing professionalism. While it is generally held that professionalism should be part of the whole of a medical curriculum, the specifics of sequence, depth, detail, and the nature of how to integrate professionalism with other curriculum elements remain matters of evolving theory.

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

STUDY DESIGN: Cohort study. OBJECTIVE: To conduct a head-to-head comparison of the responsiveness of pain, disability, and physical impairment measures in patients with low back pain. SUMMARY OF BACKGROUND DATA: Pain, disability, and physical impairment measures are routinely measured in clinical practice and clinical research. However, to date, a head-to-head comparison has not been performed. METHODS: A numerical pain scale (0-10), the 24-item and 2 modified 18-item versions of the Roland Morris questionnaire, the patient specific functional scale, and physical impairment measures were completed by 155 patients with low back pain at baseline and then again after 6 weeks together with an 11-point global perceived effect scale. Responsiveness was evaluated by using effect sizes and t tests, correlating the change scores for each outcome with the global perceived effect score and by calculating the Guyatt responsiveness index. RESULTS: The most responsive outcome proved to be the patient specific functional scale (effect size = 1.6), followed by the numerical pain scale (effect size = 1.3) and 24-item Roland Morris questionnaire (effect size = 0.8). The responsiveness of the two 18-item Roland Morris versions was equal to the 24-item version. However, the physical impairment measures were not very responsive (effect size 0.1-0.6). The ranking of the responsiveness indices was consistent across all statistical analyses. CONCLUSIONS: Physical impairments are routinely measured in clinical practice and clinical research, but the lower responsiveness indicates that this approach is not optimal. Our findings suggest that more emphasis should be placed on change in pain and disability scores than on change in physical impairments.