Northern Sydney Local Health District

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.For example, 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 versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase 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. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.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. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. 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 assays, we hope to encourage technical innovation in the field.

BACKGROUND & AIMS: Although functional gastrointestinal disorders (FGIDs), now called disorders of gut-brain interaction, have major economic effects on health care systems and adversely affect quality of life, little is known about their global prevalence and distribution. We investigated the prevalence of and factors associated with 22 FGIDs, in 33 countries on 6 continents. METHODS: Data were collected via the Internet in 24 countries, personal interviews in 7 countries, and both in 2 countries, using the Rome IV diagnostic questionnaire, Rome III irritable bowel syndrome questions, and 80 items to identify variables associated with FGIDs. Data collection methods differed for Internet and household groups, so data analyses were conducted and reported separately. RESULTS: Among the 73,076 adult respondents (49.5% women), diagnostic criteria were met for at least 1 FGID by 40.3% persons who completed the Internet surveys (95% confidence interval [CI], 39.9-40.7) and 20.7% of persons who completed the household surveys (95% CI, 20.2-21.3). FGIDs were more prevalent among women than men, based on responses to the Internet survey (odds ratio, 1.7; 95% CI, 1.6-1.7) and household survey (odds ratio, 1.3; 95% CI, 1.3-1.4). FGIDs were associated with lower quality of life and more frequent doctor visits. Proportions of subjects with irritable bowel syndrome were lower when the Rome IV criteria were used, compared with the Rome III criteria, in the Internet survey (4.1% vs 10.1%) and household survey (1.5% vs 3.5%). CONCLUSIONS: In a large-scale multinational study, we found that more than 40% of persons worldwide have FGIDs, which affect quality of life and health care use. Although the absolute prevalence was higher among Internet respondents, similar trends and relative distributions were found in people who completed Internet vs personal interviews.

BACKGROUND: falls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. Current guidelines are inconsistent, with no up-to-date, globally applicable ones present. OBJECTIVES: to create a set of evidence- and expert consensus-based falls prevention and management recommendations applicable to older adults for use by healthcare and other professionals that consider: (i) a person-centred approach that includes the perspectives of older adults with lived experience, caregivers and other stakeholders; (ii) gaps in previous guidelines; (iii) recent developments in e-health and (iv) implementation across locations with limited access to resources such as low- and middle-income countries. METHODS: a steering committee and a worldwide multidisciplinary group of experts and stakeholders, including older adults, were assembled. Geriatrics and gerontological societies were represented. Using a modified Delphi process, recommendations from 11 topic-specific working groups (WGs), 10 ad-hoc WGs and a WG dealing with the perspectives of older adults were reviewed and refined. The final recommendations were determined by voting. RECOMMENDATIONS: all older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for community-dwelling older adults. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations. CONCLUSIONS: the core set of recommendations provided will require flexible implementation strategies that consider both local context and resources.

BACKGROUND: Hip fractures are an increasingly common consequence of falls in older people that are associated with a high risk of death and reduced function. This review aims to quantify the impact of hip fracture on older people's abilities and quality of life over the long term. METHODS: Studies were identified through PubMed and Scopus searches and contact with experts. Cohort studies of hip fracture patients reporting outcomes 3 months post-fracture or longer were included for review. Outcomes of mobility, participation in domestic and community activities, health, accommodation or quality of life were categorised according to the World Health Organization's International Classification of Functioning and synthesised narratively. Risk of bias was assessed according to four items from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. RESULTS: Thirty-eight studies from 42 publications were included for review. Most followed a clearly defined sample from the time of fracture. Hip fracture survivors experienced significantly worse mobility, independence in function, health, quality of life and higher rates of institutionalisation than age matched controls. The bulk of recovery of walking ability and activities for daily living occurred within 6 months after fracture. Between 40 and 60 % of study participants recovered their pre-fracture level of mobility and ability to perform instrumental activities of daily living, while 40-70 % regained their level of independence for basic activities of daily living. For people independent in self-care pre-fracture, 20-60 % required assistance for various tasks 1 and 2 years after fracture. Fewer people living in residential care recovered their level of function than those living in the community. In Western nations, 10-20 % of hip fracture patients are institutionalised following fracture. Few studies reported impact on participation in domestic, community, social and civic life. CONCLUSIONS: Hip fracture has a substantial impact on older peoples' medium- to longer-term abilities, function, quality of life and accommodation. These studies indicate the range of current outcomes rather than potential improvements with different interventional approaches. Future studies should measure impact on life participation and determine the proportion of people that regain their pre-fracture level of functioning to investigate strategies for improving these important outcomes.

OBJECTIVES: This guideline provides recommendations for the clinical management of schizophrenia and related disorders for health professionals working in Australia and New Zealand. It aims to encourage all clinicians to adopt best practice principles. The recommendations represent the consensus of a group of Australian and New Zealand experts in the management of schizophrenia and related disorders. This guideline includes the management of ultra-high risk syndromes, first-episode psychoses and prolonged psychoses, including psychoses associated with substance use. It takes a holistic approach, addressing all aspects of the care of people with schizophrenia and related disorders, not only correct diagnosis and symptom relief but also optimal recovery of social function. METHODS: The writing group planned the scope and individual members drafted sections according to their area of interest and expertise, with reference to existing systematic reviews and informal literature reviews undertaken for this guideline. In addition, experts in specific areas contributed to the relevant sections. All members of the writing group reviewed the entire document. The writing group also considered relevant international clinical practice guidelines. Evidence-based recommendations were formulated when the writing group judged that there was sufficient evidence on a topic. Where evidence was weak or lacking, consensus-based recommendations were formulated. Consensus-based recommendations are based on the consensus of a group of experts in the field and are informed by their agreement as a group, according to their collective clinical and research knowledge and experience. Key considerations were selected and reviewed by the writing group. To encourage wide community participation, the Royal Australian and New Zealand College of Psychiatrists invited review by its committees and members, an expert advisory committee and key stakeholders including professional bodies and special interest groups. RESULTS: The clinical practice guideline for the management of schizophrenia and related disorders reflects an increasing emphasis on early intervention, physical health, psychosocial treatments, cultural considerations and improving vocational outcomes. The guideline uses a clinical staging model as a framework for recommendations regarding assessment, treatment and ongoing care. This guideline also refers its readers to selected published guidelines or statements directly relevant to Australian and New Zealand practice. CONCLUSIONS: This clinical practice guideline for the management of schizophrenia and related disorders aims to improve care for people with these disorders living in Australia and New Zealand. It advocates a respectful, collaborative approach; optimal evidence-based treatment; and consideration of the specific needs of those in adverse circumstances or facing additional challenges.

IMPORTANCE: Knee osteoarthritis (OA), a common cause of chronic pain and disability, has biomechanical and inflammatory origins and is exacerbated by obesity. OBJECTIVE: To determine whether a ≥10% reduction in body weight induced by diet, with or without exercise, would improve mechanistic and clinical outcomes more than exercise alone. DESIGN, SETTING, AND PARTICIPANTS: Single-blind, 18-month, randomized clinical trial at Wake Forest University between July 2006 and April 2011. The diet and exercise interventions were center-based with options for the exercise groups to transition to a home-based program. Participants were 454 overweight and obese older community-dwelling adults (age ≥55 years with body mass index of 27-41) with pain and radiographic knee OA. INTERVENTIONS: Intensive diet-induced weight loss plus exercise, intensive diet-induced weight loss, or exercise. MAIN OUTCOMES AND MEASURES: Mechanistic primary outcomes: knee joint compressive force and plasma IL-6 levels; secondary clinical outcomes: self-reported pain (range, 0-20), function (range, 0-68), mobility, and health-related quality of life (range, 0-100). RESULTS: Three hundred ninety-nine participants (88%) completed the study. Mean weight loss for diet + exercise participants was 10.6 kg (11.4%); for the diet group, 8.9 kg (9.5%); and for the exercise group, 1.8 kg (2.0%). After 18 months, knee compressive forces were lower in diet participants (mean, 2487 N; 95% CI, 2393 to 2581) compared with exercise participants (2687 N; 95% CI, 2590 to 2784, pairwise difference [Δ](exercise vs diet )= 200 N; 95% CI, 55 to 345; P = .007). Concentrations of IL-6 were lower in diet + exercise (2.7 pg/mL; 95% CI, 2.5 to 3.0) and diet participants (2.7 pg/mL; 95% CI, 2.4 to 3.0) compared with exercise participants (3.1 pg/mL; 95% CI, 2.9 to 3.4; Δ(exercise vs diet + exercise) = 0.39 pg/mL; 95% CI, -0.03 to 0.81; P = .007; Δ(exercise vs diet )= 0.43 pg/mL; 95% CI, 0.01 to 0.85, P = .006). The diet + exercise group had less pain (3.6; 95% CI, 3.2 to 4.1) and better function (14.1; 95% CI, 12.6 to 15.6) than both the diet group (4.8; 95% CI, 4.3 to 5.2) and exercise group (4.7; 95% CI, 4.2 to 5.1, Δ(exercise vs diet + exercise) = 1.02; 95% CI, 0.33 to 1.71; P(pain) = .004; 18.4; 95% CI, 16.9 to 19.9; Δ(exercise vs diet + exercise), 4.29; 95% CI, 2.07 to 6.50; P(function )< .001). The diet + exercise group (44.7; 95% CI, 43.4 to 46.0) also had better physical health-related quality of life scores than the exercise group (41.9; 95% CI, 40.5 to 43.2; Δ(exercise vs diet + exercise) = -2.81; 95% CI, -4.76 to -0.86; P = .005). CONCLUSIONS AND RELEVANCE: Among overweight and obese adults with knee OA, after 18 months, participants in the diet + exercise and diet groups had more weight loss and greater reductions in IL-6 levels than those in the exercise group; those in the diet group had greater reductions in knee compressive force than those in the exercise group. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00381290.

OBJECTIVES: To provide guidance for the management of mood disorders, based on scientific evidence supplemented by expert clinical consensus and formulate recommendations to maximise clinical salience and utility. METHODS: Articles and information sourced from search engines including PubMed and EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (MDC) (e.g., books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Information was reviewed and discussed by members of the MDC and findings were then formulated into consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous successive consultation and external review involving: expert and clinical advisors, the public, key stakeholders, professional bodies and specialist groups with interest in mood disorders. RESULTS: The Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders (Mood Disorders CPG) provide up-to-date guidance and advice regarding the management of mood disorders that is informed by evidence and clinical experience. The Mood Disorders CPG is intended for clinical use by psychiatrists, psychologists, physicians and others with an interest in mental health care. CONCLUSIONS: The Mood Disorder CPG is the first Clinical Practice Guideline to address both depressive and bipolar disorders. It provides up-to-date recommendations and guidance within an evidence-based framework, supplemented by expert clinical consensus. MOOD DISORDERS COMMITTEE: Professor Gin Malhi (Chair), Professor Darryl Bassett, Professor Philip Boyce, Professor Richard Bryant, Professor Paul Fitzgerald, Dr Kristina Fritz, Professor Malcolm Hopwood, Dr Bill Lyndon, Professor Roger Mulder, Professor Greg Murray, Professor Richard Porter and Associate Professor Ajeet Singh. INTERNATIONAL EXPERT ADVISORS: Professor Carlo Altamura, Dr Francesco Colom, Professor Mark George, Professor Guy Goodwin, Professor Roger McIntyre, Dr Roger Ng, Professor John O'Brien, Professor Harold Sackeim, Professor Jan Scott, Dr Nobuhiro Sugiyama, Professor Eduard Vieta, Professor Lakshmi Yatham. AUSTRALIAN AND NEW ZEALAND EXPERT ADVISORS: Professor Marie-Paule Austin, Professor Michael Berk, Dr Yulisha Byrow, Professor Helen Christensen, Dr Nick De Felice, A/Professor Seetal Dodd, A/Professor Megan Galbally, Dr Josh Geffen, Professor Philip Hazell, A/Professor David Horgan, A/Professor Felice Jacka, Professor Gordon Johnson, Professor Anthony Jorm, Dr Jon-Paul Khoo, Professor Jayashri Kulkarni, Dr Cameron Lacey, Dr Noeline Latt, Professor Florence Levy, A/Professor Andrew Lewis, Professor Colleen Loo, Dr Thomas Mayze, Dr Linton Meagher, Professor Philip Mitchell, Professor Daniel O'Connor, Dr Nick O'Connor, Dr Tim Outhred, Dr Mark Rowe, Dr Narelle Shadbolt, Dr Martien Snellen, Professor John Tiller, Dr Bill Watkins, Dr Raymond Wu.

BACKGROUND: Falls in nursing care facilities and hospitals are common events that cause considerable morbidity and mortality for older people. OBJECTIVES: To assess the effectiveness of interventions designed to reduce falls by older people in nursing care facilities and hospitals. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (January 2009); the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 2); MEDLINE, EMBASE, and CINAHL (all to November 2008); trial registers and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials of interventions to reduce falls in older people in nursing care facilities or hospitals. Primary outcomes were rate of falls and risk of falling. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Data were pooled where appropriate. MAIN RESULTS: We included 41 trials (25,422 participants).In nursing care facilities, the results from seven trials testing supervised exercise interventions were inconsistent. This was the case too for multifactorial interventions, which overall did not significantly reduce the rate of falls (rate ratio (RaR) 0.82, 95% CI 0.62 to 1.08; 7 trials, 2997 participants) or risk of falling (risk ratio (RR) 0.93, 95% CI 0.86 to 1.01; 8 trials, 3271 participants). A post hoc subgroup analysis, however, indicated that where provided by a multidisciplinary team, multifactorial interventions reduced the rate of falls (RaR 0.60, 95% CI 0.51 to 0.72; 4 trials, 1651 participants) and risk of falling (RR 0.85, 95% CI 0.77 to 0.95; 5 trials, 1925 participants). Vitamin D supplementation reduced the rate of falls (RaR 0.72, 95% CI 0.55 to 0.95; 4 trials, 4512 participants), but not risk of falling (RR 0.98, 95% CI 0.89 to 1.09; 5 trials, 5095 participants).In hospitals, multifactorial interventions reduced the rate of falls (RaR 0.69, 95% CI 0.49 to 0.96; 4 trials, 6478 participants) and risk of falling (RR 0.73, 95% CI 0.56 to 0.96; 3 trials, 4824 participants). Supervised exercise interventions showed a significant reduction in risk of falling (RR 0.44, 95% CI 0.20 to 0.97; 3 trials, 131 participants). AUTHORS' CONCLUSIONS: There is evidence that multifactorial interventions reduce falls and risk of falling in hospitals and may do so in nursing care facilities. Vitamin D supplementation is effective in reducing the rate of falls in nursing care facilities. Exercise in subacute hospital settings appears effective but its effectiveness in nursing care facilities remains uncertain.

OBJECTIVES: To provide advice and guidance regarding the management of mood disorders, derived from scientific evidence and supplemented by expert clinical consensus to formulate s that maximise clinical utility. METHODS: Articles and information sourced from search engines including PubMed, EMBASE, MEDLINE, PsycINFO and Google Scholar were supplemented by literature known to the mood disorders committee (e.g. books, book chapters and government reports) and from published depression and bipolar disorder guidelines. Relevant information was appraised and discussed in detail by members of the mood disorders committee, with a view to formulating and developing consensus-based recommendations and clinical guidance. The guidelines were subjected to rigorous consultation and external review involving: expert and clinical advisors, key stakeholders, professional bodies and specialist groups with interest in mood disorders. RESULTS: ) provide up-to-date guidance regarding the management of mood disorders that is informed by evidence and clinical experience. The guideline is intended for clinical use by psychiatrists, psychologists, primary care physicians and others with an interest in mental health care. CONCLUSION: builds on the previous 2015 guidelines and maintains its joint focus on both depressive and bipolar disorders. It provides up-to-date recommendations and guidance within an evidence-based framework, supplemented by expert clinical consensus. MOOD DISORDERS COMMITTEE: Gin S Malhi (Chair), Erica Bell, Darryl Bassett, Philip Boyce, Richard Bryant, Philip Hazell, Malcolm Hopwood, Bill Lyndon, Roger Mulder, Richard Porter, Ajeet B Singh and Greg Murray.

Funding Information: The consensus conference upon which this manuscript is based was funded by: IFCN, World Federation of Neurology, ALS Association, and MND Association Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

Background: Falls in care facilities and hospitals are common events that cause considerable morbidity and mortality for older people. This is an update of a review first published in 2010 and updated in 2012. Objectives: To assess the effects of interventions designed to reduce the incidence of falls in older people in care facilities and hospitals. Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (August 2017); Cochrane Central Register of Controlled Trials (2017, Issue 8); and MEDLINE, Embase, CINAHL and trial registers to August 2017. Selection criteria: Randomised controlled trials of interventions for preventing falls in older people in residential or nursing care facilities, or hospitals. Data collection and analysis: One review author screened abstracts; two review authors screened full-text articles for inclusion. Two review authors independently performed study selection, 'Risk of bias' assessment and data extraction. We calculated rate ratios (RaR) with 95% confidence intervals (CIs) for rate of falls and risk ratios (RRs) and 95% CIs for outcomes such as risk of falling (number of people falling). We pooled results where appropriate. We used GRADE to assess the quality of evidence. Main results: Thirty-five new trials (77,869 participants) were included in this update. Overall, we included 95 trials (138,164 participants), 71 (40,374 participants; mean age 84 years; 75% women) in care facilities and 24 (97,790 participants; mean age 78 years; 52% women) in hospitals. The majority of trials were at high risk of bias in one or more domains, mostly relating to lack of blinding. With few exceptions, the quality of evidence for individual interventions in either setting was generally rated as low or very low. Risk of fracture and adverse events were generally poorly reported and, where reported, the evidence was very low-quality, which means that we are uncertain of the estimates. Only the falls outcomes for the main comparisons are reported here. Care facilities Seventeen trials compared exercise with control (typically usual care alone). We are uncertain of the effect of exercise on rate of falls (RaR 0.93, 95% CI 0.72 to 1.20; 2002 participants, 10 studies; I2; = 76%; very low-quality evidence). Exercise may make little or no difference to the risk of falling (RR 1.02, 95% CI 0.88 to 1.18; 2090 participants, 10 studies; I2; = 23%; low-quality evidence). There is low-quality evidence that general medication review (tested in 12 trials) may make little or no difference to the rate of falls (RaR 0.93, 95% CI 0.64 to 1.35; 2409 participants, 6 studies; I2; = 93%) or the risk of falling (RR 0.93, 95% CI 0.80 to 1.09; 5139 participants, 6 studies; I2; = 48%). There is moderate-quality evidence that vitamin D supplementation (4512 participants, 4 studies) probably reduces the rate of falls (RaR 0.72, 95% CI 0.55 to 0.95; I2; = 62%), but probably makes little or no difference to the risk of falling (RR 0.92, 95% CI 0.76 to 1.12; I2; = 42%). The population included in these studies had low vitamin D levels. Multifactorial interventions were tested in 13 trials. We are uncertain of the effect of multifactorial interventions on the rate of falls (RaR 0.88, 95% CI 0.66 to 1.18; 3439 participants, 10 studies; I2; = 84%; very low-quality evidence). They may make little or no difference to the risk of falling (RR 0.92, 95% CI 0.81 to 1.05; 3153 participants, 9 studies; I2; = 42%; low-quality evidence). Hospitals Three trials tested the effect of additional physiotherapy (supervised exercises) in rehabilitation wards (subacute setting). The very low-quality evidence means we are uncertain of the effect of additional physiotherapy on the rate of falls (RaR 0.59, 95% CI 0.26 to 1.34; 215 participants, 2 studies; I2; = 0%), or whether it reduces the risk of falling (RR 0.36, 95% CI 0.14 to 0.93; 83 participants, 2 studies; I2; = 0%). We are uncertain of the effects of bed and chair sensor alarms in hospitals, tested in two trials (28,649 participants) on rate of falls (RaR 0.60, 95% CI 0.27 to 1.34; I2; = 0%; very low-quality evidence) or risk of falling (RR 0.93, 95% CI 0.38 to 2.24; I2; = 0%; very low-quality evidence). Multifactorial interventions in hospitals may reduce rate of falls in hospitals (RaR 0.80, 95% CI 0.64 to 1.01; 44,664 participants, 5 studies; I2; = 52%). A subgroup analysis by setting suggests the reduction may be more likely in a subacute setting (RaR 0.67, 95% CI 0.54 to 0.83; 3747 participants, 2 studies; I2; = 0%; low-quality evidence). We are uncertain of the effect of multifactorial interventions on the risk of falling (RR 0.82, 95% CI 0.62 to 1.09; 39,889 participants; 3 studies; I2; = 0%; very low-quality evidence). Authors' conclusions: In care facilities: we are uncertain of the effect of exercise on rate of falls and it may make little or no difference to the risk of falling. General medication review may make little or no difference to the rate of falls or risk of falling. Vitamin D supplementation probably reduces the rate of falls but not risk of falling. We are uncertain of the effect of multifactorial interventions on the rate of falls; they may make little or no difference to the risk of falling. In hospitals: we are uncertain of the effect of additional physiotherapy on the rate of falls or whether it reduces the risk of falling. We are uncertain of the effect of providing bed sensor alarms on the rate of falls or risk of falling. Multifactorial interventions may reduce rate of falls, although subgroup analysis suggests this may apply mostly to a subacute setting; we are uncertain of the effect of these interventions on risk of falling.

PURPOSE OF REVIEW: Parkinson's disease (PD) is a complex neurodegenerative disorder, the aetiology of which is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we review recent developments around mitochondrial dysfunction in familial and sporadic PD, with a brief overview of emerging therapies targeting mitochondrial dysfunction. RECENT FINDINGS: Increasing evidence supports the critical role for mitochondrial dysfunction in the development of sporadic PD, while the involvement of familial PD-related genes in the regulation of mitochondrial biology has been expanded by the discovery of new mitochondria-associated disease loci and the identification of their novel functions. Recent research has expanded knowledge on the mechanistic details underlying mitochondrial dysfunction in PD, with the discovery of new therapeutic targets providing invaluable insights into the essential role of mitochondria in PD pathogenesis and unique opportunities for drug development.

IMPORTANCE: Systematic reviews suggest adult patients in intensive care units (ICUs) with relative contraindications to early enteral nutrition (EN) may benefit from parenteral nutrition (PN) provided within 24 hours of ICU admission. OBJECTIVE: To determine whether providing early PN to critically ill adults with relative contraindications to early EN alters outcomes. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, single-blind clinical trial conducted between October 2006 and June 2011 in ICUs of 31 community and tertiary hospitals in Australia and New Zealand. Participants were critically ill adults with relative contraindications to early EN who were expected to remain in the ICU longer than 2 days. INTERVENTIONS: Random allocation to pragmatic standard care or early PN. MAIN OUTCOMES AND MEASURES: Day-60 mortality; quality of life, infections, and body composition. RESULTS: A total of 1372 patients were randomized (686 to standard care, 686 to early PN). Of 682 patients receiving standard care, 199 patients (29.2%) initially commenced EN, 186 patients (27.3%) initially commenced PN, and 278 patients (40.8%) remained unfed. Time to EN or PN in patients receiving standard care was 2.8 days (95% CI, 2.3 to 3.4). Patients receiving early PN commenced PN a mean of 44 minutes after enrollment (95% CI, 36 to 55). Day-60 mortality did not differ significantly (22.8% for standard care vs 21.5% for early PN; risk difference, -1.26%; 95% CI, -6.6 to 4.1; P = .60). Early PN patients rated day-60 quality of life (RAND-36 General Health Status) statistically, but not clinically meaningfully, higher (45.5 for standard care vs 49.8 for early PN; mean difference, 4.3; 95% CI, 0.95 to 7.58; P = .01). Early PN patients required fewer days of invasive ventilation (7.73 vs 7.26 days per 10 patient × ICU days, risk difference, -0.47; 95% CI, -0.82 to -0.11; P = .01) and, based on Subjective Global Assessment, experienced less muscle wasting (0.43 vs 0.27 score increase per week; mean difference, -0.16; 95% CI, -0.28 to -0.038; P = .01) and fat loss (0.44 vs 0.31 score increase per week; mean difference, -0.13; 95% CI, -0.25 to -0.01; P = .04). CONCLUSIONS AND RELEVANCE: The provision of early PN to critically ill adults with relative contraindications to early EN, compared with standard care, did not result in a difference in day-60 mortality. The early PN strategy resulted in significantly fewer days of invasive ventilation but not significantly shorter ICU or hospital stays. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN012605000704695.

Wound healing is a multistep process with four overlapping but distinct stages: hemostasis, inflammation, proliferation, and remodeling. An alteration at any stage may lead to the development of chronic non-healing wounds or excessive scar formation. Impaired wound healing presents a significant health and economic burden to millions of individuals worldwide, with diabetes mellitus and aging being major risk factors. Ongoing understanding of the mechanisms that underly wound healing is required for the development of new and improved therapies that increase repair. Chemokines are key regulators of the wound healing process. They are involved in the promotion and inhibition of angiogenesis and the recruitment of inflammatory cells, which release growth factors and cytokines to facilitate the wound healing process. Preclinical research studies in mice show that the administration of CCL2, CCL21, CXCL12, and a CXCR4 antagonist as well as broad-spectrum inhibition of the CC-chemokine class improve the wound healing process. The focus of this review is to highlight the contributions of chemokines during each stage of wound healing and to discuss the related molecular pathologies in complex and chronic non-healing wounds. We explore the therapeutic potential of targeting chemokines as a novel approach to overcome the debilitating effects of impaired wound healing.

Importance: Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective: To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants: The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions: Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures: The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results: Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, -5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, -3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, -3.0% to 4.2%]; P = .76). Conclusions and Relevance: Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516.

The results of recent large-scale clinical trials have led us to review our understanding of the metabolic response to stress and the most appropriate means of managing nutrition in critically ill patients. This review presents an update in this field, identifying and discussing a number of areas for which consensus has been reached and others where controversy remains and presenting areas for future research. We discuss optimal calorie and protein intake, the incidence and management of re-feeding syndrome, the role of gastric residual volume monitoring, the place of supplemental parenteral nutrition when enteral feeding is deemed insufficient, the role of indirect calorimetry, and potential indications for several pharmaconutrients.

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.

OBJECTIVE: Rational therapeutic development in bipolar is hampered by a lack of pathophysiological model. However, there is a wealth of converging data on the role of dopamine in bipolar disorder. This paper therefore examines the possibility of a dopamine hypothesis for bipolar disorder. METHOD: A literature search was conducted using standard search engines Embase, PyschLIT, PubMed and MEDLINE. In addition, papers and book chapters known to the authors were retrieved and examined for further relevant articles. RESULTS: Collectively, in excess of 100 articles were reviewed from which approximately 75% were relevant to the focus of this paper. CONCLUSION: Pharmacological models suggest a role of increased dopaminergic drive in mania and the converse in depression. In Parkinson's disease, administration of high-dose dopamine precursors can produce a 'maniform' picture, which switches into a depressive analogue on withdrawal. It is possible that in bipolar disorder there is a cyclical process, where increased dopaminergic transmission in mania leads to a secondary down regulation of dopaminergic receptor sensitivity over time. This may lead to a period of decreased dopaminergic transmission, corresponding with the depressive phase, and the repetition of the cycle. This model, if verified, may have implications for rational drug development.

IMPORTANCE: Adult vulvar lichen sclerosis (VLS) may be complicated by loss of vulvar structure and vulvar carcinoma. There is a lack of evidence as to the ideal method to maintain long-term remission and prevent complications. OBJECTIVES: To determine whether long-term preventive topical corticosteroid (TCS) treatment of VLS, with a target outcome of induction and maintenance of normal skin texture and color, reduces the risk of vulvar carcinoma, relieves symptoms, improves function, and preserves vulvar architecture, and to evaluate the adverse effects of treatment. DESIGN, SETTING, AND PARTICIPANTS: A prospective longitudinal cohort study was conducted in 507 women with biopsy-proved VLS from January 2, 2008, through September 26, 2014, in the private practice of a dermatologist and a gynecologist in Sydney, Australia. INTERVENTIONS: Preventive treatment using TCSs of various potencies, adjusted to meet a target outcome of normal skin color and texture, with regular long-term follow-up by a dermatologist or gynecologist. MAIN OUTCOMES AND MEASURES: Symptoms or signs of VLS, scarring, development of malignant neoplasms, and adverse effects. RESULTS: The mean age at presentation was 55.4 years (range, 18-86 years); duration of symptoms at presentation, 5.0 years (range, 0.1-40.0 years); and duration of follow-up, 4.7 years (range, 2.0-6.8 years). Remission was induced with a potent TCS, followed by regular preventive TCS treatment of a potency titrated to achieve the target outcome. Patients were followed up at least annually. A total of 150 patients (29.6%) did not carry out the advised treatment and were considered partially compliant. A total of 357 patients (70.4%) adhered to treatment instructions and were considered compliant. Biopsy-proved squamous cell carcinoma or vulvar intraepithelial neoplasia occurred during follow-up in 0 of the compliant patients vs. 7 (4.7%) of the partially compliant patients (P < .001). Suppression of symptoms occurred in 333 (93.3%) compliant patients vs. 87 (58.0%) partially compliant patients (P < .001). Adhesions and scarring occurred during follow-up in 12 (3.4%) compliant patients and 60 (40.0%) partially compliant patients (P < .001). Reversible TCS-induced cutaneous atrophy occurred in 4 (1.1%) compliant patients and 3 (2.0%) partially compliant patients. CONCLUSIONS AND RELEVANCE: This prospective, single-center, longitudinal cohort study of adult patients with VLS suggests that individualized preventive TCS regimens that achieve objective normality of skin color and texture and are used by compliant patients who attend regular long-term follow-up visits may modify the course of the disease. There was a significant difference in symptom control, scarring, and occurrence of vulvar carcinoma between compliant and partially compliant patients. The adverse effects of TCSs were minimal.

OBJECTIVE: To present updated national birthweight percentiles by gestational age for male and female singleton infants born in Australia. DESIGN AND SETTING: Cross-sectional population-based study of 2.53 million singleton live births in Australia between 1998 and 2007. MAIN OUTCOME MEASURES: Birthweight percentiles by gestational age and sex. RESULTS: Between 1998 and 2007, women in Australia gave birth to 2 539 237 live singleton infants. Of these, 2 537 627 had a gestational age between 20 and 44 weeks, and sex and birthweight data were available. Birthweight percentiles are presented by sex and gestational age for a total of 2 528 641 births, after excluding 8986 infants with outlying birthweights. Since the publication of the previous Australian birthweight percentiles in 1999, median birthweight for term babies has increased between 0 and 25 g for boys and between 5 g and 45 g for girls. CONCLUSIONS: There has been only a small increase in birthweight percentiles for babies of both sexes and most gestational ages since 1991-1994. These national percentiles provide a current Australian reference for clinicians and researchers assessing weight at birth.