Royal Hobart Hospital

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

BACKGROUND: Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults. METHODS: We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. RESULTS: A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. CONCLUSIONS: The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).

The human immune system displays substantial variation between individuals, leading to differences in susceptibility to autoimmune disease. We present single-cell RNA sequencing (scRNA-seq) data from 1,267,758 peripheral blood mononuclear cells from 982 healthy human subjects. For 14 cell types, we identified 26,597 independent cis-expression quantitative trait loci (eQTLs) and 990 trans-eQTLs, with most showing cell type-specific effects on gene expression. We subsequently show how eQTLs have dynamic allelic effects in B cells that are transitioning from naïve to memory states and demonstrate how commonly segregating alleles lead to interindividual variation in immune function. Finally, using a Mendelian randomization approach, we identify the causal route by which 305 risk loci contribute to autoimmune disease at the cellular level. This work brings together genetic epidemiology with scRNA-seq to uncover drivers of interindividual variation in the immune system.

The World Allergy Organization (WAO) Guidelines for the assessment and management of anaphylaxis provide a unique global perspective on this increasingly common, potentially life-threatening disease. Recommendations made in the original WAO Anaphylaxis Guidelines remain clinically valid and relevant, and are a widely accessed and frequently cited resource. In this 2015 update of the evidence supporting recommendations in the Guidelines, new information based on anaphylaxis publications from January 2014 through mid- 2015 is summarized. Advances in epidemiology, diagnosis, and management in healthcare and community settings are highlighted. Additionally, new information about patient factors that increase the risk of severe and/or fatal anaphylaxis and patient co-factors that amplify anaphylactic episodes is presented and new information about anaphylaxis triggers and confirmation of triggers to facilitate specific trigger avoidance and immunomodulation is reviewed. The update includes tables summarizing important advances in anaphylaxis research.

CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

OBJECTIVE: To examine whether past high sun exposure is associated with a reduced risk of multiple sclerosis. DESIGN: Population based case-control study. SETTING: Tasmania, latitudes 41-3 degrees S. PARTICIPANTS: 136 cases with multiple sclerosis and 272 controls randomly drawn from the community and matched on sex and year of birth. MAIN OUTCOME MEASURE: Multiple sclerosis defined by both clinical and magnetic resonance imaging criteria. RESULTS: Higher sun exposure when aged 6-15 years (average 2-3 hours or more a day in summer during weekends and holidays) was associated with a decreased risk of multiple sclerosis (adjusted odds ratio 0.31, 95% confidence interval 0.16 to 0.59). Higher exposure in winter seemed more important than higher exposure in summer. Greater actinic damage was also independently associated with a decreased risk of multiple sclerosis (0.32, 0.11 to 0.88 for grades 4-6 disease). A dose-response relation was observed between multiple sclerosis and decreasing sun exposure when aged 6-15 years and with actinic damage. CONCLUSION: Higher sun exposure during childhood and early adolescence is associated with a reduced risk of multiple sclerosis. Insufficient ultraviolet radiation may therefore influence the development of multiple sclerosis.

OBJECTIVE: Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function. RESEARCH DESIGN AND METHODS: This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures. RESULTS: T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes (all P < 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed (P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume. CONCLUSIONS: Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.

OBJECTIVES: To compare standard high flow oxygen treatment with titrated oxygen treatment for patients with an acute exacerbation of chronic obstructive pulmonary disease in the prehospital setting. DESIGN: Cluster randomised controlled parallel group trial. SETTING: Ambulance service in Hobart, Tasmania, Australia. PARTICIPANTS: 405 patients with a presumed acute exacerbation of chronic obstructive pulmonary disease who were treated by paramedics, transported, and admitted to the Royal Hobart Hospital during the trial period; 214 had a diagnosis of chronic obstructive pulmonary disease confirmed by lung function tests in the previous five years. INTERVENTIONS: High flow oxygen treatment compared with titrated oxygen treatment in the prehospital (ambulance/paramedic) setting. MAIN OUTCOME MEASURE: Prehospital or in-hospital mortality. RESULTS: In an intention to treat analysis, the risk of death was significantly lower in the titrated oxygen arm compared with the high flow oxygen arm for all patients (high flow oxygen n=226; titrated oxygen n=179) and for the subgroup of patients with confirmed chronic obstructive pulmonary disease (high flow n=117; titrated n=97). Overall mortality was 9% (21 deaths) in the high flow oxygen arm compared with 4% (7 deaths) in the titrated oxygen arm; mortality in the subgroup with confirmed chronic obstructive pulmonary disease was 9% (11 deaths) in the high flow arm compared with 2% (2 deaths) in the titrated oxygen arm. Titrated oxygen treatment reduced mortality compared with high flow oxygen by 58% for all patients (relative risk 0.42, 95% confidence interval 0.20 to 0.89; P=0.02) and by 78% for the patients with confirmed chronic obstructive pulmonary disease (0.22, 0.05 to 0.91; P=0.04). Patients with chronic obstructive pulmonary disease who received titrated oxygen according to the protocol were significantly less likely to have respiratory acidosis (mean difference in pH 0.12 (SE 0.05); P=0.01; n=28) or hypercapnia (mean difference in arterial carbon dioxide pressure -33.6 (16.3) mm Hg; P=0.02; n=29) than were patients who received high flow oxygen. CONCLUSIONS: Titrated oxygen treatment significantly reduced mortality, hypercapnia, and respiratory acidosis compared with high flow oxygen in acute exacerbations of chronic obstructive pulmonary disease. These results provide strong evidence to recommend the routine use of titrated oxygen treatment in patients with breathlessness and a history or clinical likelihood of chronic obstructive pulmonary disease in the prehospital setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Register ACTRN12609000236291.

BACKGROUND: Previous randomised trials and meta-analyses have shown that nasal continuous positive airway pressure (NCPAP) is a useful method for providing respiratory support after extubation. However, this treatment sometimes 'fails' in infants, and they may require endotracheal re-intubation with its attendant risks and expense. Nasal intermittent positive pressure ventilation (NIPPV) can augment NCPAP by delivering ventilator breaths via nasal prongs. Older children and adults with chronic respiratory failure benefit from NIPPV, and the technique has been applied to neonates. However, serious side effects including gastric perforation have been reported with older methods of providing NIPPV. OBJECTIVES: Primary objective To compare effects of management with NIPPV versus NCPAP on the need for additional ventilatory support in preterm infants whose endotracheal tube was removed after a period of intermittent positive pressure ventilation. Secondary objectives To compare rates of gastric distension, gastrointestinal perforation, necrotising enterocolitis and chronic lung disease; duration of hospitalisation; and rates of apnoea, air leak and mortality for NIPPV and NCPAP. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 9), MEDLINE via PubMed (1966 to 28 September 2015), Embase (1980 to 28 September 2015) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 28 September 2015). We also searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing use of NIPPV versus NCPAP in extubated preterm infants. NIPPV included non-invasive support delivered by a mechanical ventilator or a bilevel device in a synchronised or non-synchronised way. Participants included ventilated preterm infants who were ready to be extubated to non-invasive respiratory support. Interventions compared were NIPPV, delivered by short nasal prongs or nasopharyngeal tube, and NCPAP, delivered by the same methods.Types of outcomes measures included failure of therapy (respiratory failure, rates of endotracheal re-intubation); gastrointestinal complications (i.e. abdominal distension requiring cessation of feeds, gastrointestinal perforation or necrotising enterocolitis); pulmonary air leak; chronic lung disease (oxygen requirement at 36 weeks' postmenstrual age) and mortality. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data regarding clinical outcomes including extubation failure; endotracheal re-intubation; rates of apnoea, gastrointestinal perforation, feeding intolerance, necrotising enterocolitis, chronic lung disease and air leak; and duration of hospital stay. We analysed trials using risk ratio (RR), risk difference (RD) and the number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: Through the search, we identified 10 trials enrolling a total of 1431 infants and comparing extubation of infants to NIPPV or NCPAP. Three trials had methodological limitations and possible selection bias.Five trials used the synchronised form of NIPPV, four used the non-synchronised form and one used both methods. Eight studies used NIPPV delivered by a ventilator, one used a bilevel device and one used both methods. When all studies were included, meta-analysis demonstrated a statistically and clinically significant reduction in the risk of meeting extubation failure criteria (typical RR 0.70, 95% CI 0.60 to 0.80; typical RD -0.13, 95% CI -0.17 to -0.08; NNTB 8, 95% CI 6 to 13; 10 trials, 1431 infants) and needing re-intubation (typical RR 0.76, 95% CI 0.65 to 0.88; typical RD -0.10, 95% CI -0.15 to -0.05; NNTB 10, 95% CI 7 to 20; 10 trials, 1431 infants). We graded evidence for these outcomes as moderate, as all trial interventions were unblinded. Although methods of synchronisation varied (Graseby capsule or pneumotachograph/flow-trigger), the five trials that synchronised NIPPV showed a statistically significant benefit for infants extubated to NIPPV in terms of prevention of extubation failure up to one week after extubation.Unsynchronised NIPPV also reduced extubation failure. NIPPV provided via a ventilator is more beneficial than that provided by bilevel devices in reducing extubation failure during the first week. When comparing interventions, investigators found no significant reduction in rates of chronic lung disease (typical RR 0.94, 95% CI 0.80 to 1.10; typical RD -0.02, 95% CI -0.08 to 0.03) or death, and no difference in the incidence of necrotising enterocolitis. Air leaks were reduced in infants randomised to NIPPV (typical RR 0.48, 95% CI 0.28 to 0.82; typical RD -0.03, 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100). We graded evidence quality as moderate (unblinded studies) or low (imprecision) for secondary outcomes. AUTHORS' CONCLUSIONS: Implications for practice NIPPV reduces the incidence of extubation failure and the need for re-intubation within 48 hours to one week more effectively than NCPAP; however, it has no effect on chronic lung disease nor on mortality. Synchronisation may be important in delivering effective NIPPV. The device used to deliver NIPPV may be important; however, data are insufficient to support strong conclusions. NIPPV does not appear to be associated with increased gastrointestinal side effects. Implications for research Large trials should establish the impact of synchronisation of NIPPV on safety and efficacy of the technique and should compare the efficacy of bilevel devices versus a ventilator for providing NIPPV.

BACKGROUND: Previous studies of adverse drug events (ADE) as a cause of hospital admission in the elderly have often been limited in their ability to assess fully the impact and potential for prevention because they either did not include all categories of ADE and/or did not assess severity and preventability. AIMS: To assess the frequency, severity and preventability of ADE causing emergency medical admissions in the elderly. METHODS: Cross-sectional survey of 219 patients aged 75 years and over who were consecutive unplanned admissions to acute medical units of the Royal Hobart Hospital in an 8-week period during August and September 1998. RESULTS: Seventy-three of 240 (30.4%) admissions may have been a result of ADE. Patients admitted because of ADE were taking more drugs than those admitted for other reasons. Most ADE were adverse drug reactions to a single (46%) or multiple drugs (25%). Non-compliance, omission or cessation of indicated treatment accounted collectively for 26% of admissions. Of all ADE admissions 53.4% were considered definitely preventable. The commonest causative drugs were cardiovascular drugs (48.4%), and the commonest manifestations were falls and postural hypotension (24.1%), heart failure (16.9%) and delirium (14.5%). ADE categories in which a high proportion of admissions was both severe and definitely preventable were non-compliance and omission of indicated treatment. CONCLUSIONS: Adverse drug events are a common preventable cause of unplanned medical admissions in the elderly. Non-compliance and omission of indicated treatment are causes of ADE-related admissions that are both preventable and frequently associated with severe ADE.

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.

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was &amp;gt;95% at all doses. Sustained complete (&amp;gt;95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in &amp;gt;2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Infection with Mycoplasma pneumoniae has been shown to exacerbate asthma in humans. However, the role of M. pneumoniae in the pathogenesis of chronic asthma has not been defined. Eighteen asthmatics with chronic, stable asthma and 11 nonasthmatic control subjects underwent evaluation of the upper and lower airways and serologic analysis to determine the presence of M. pneumoniae, Chlamydia pneumoniae, and seven respiratory viruses through culture, enzyme-linked immunoassay (EIA) and polymerase chain reaction (PCR). M. pneumoniae was detected by PCR in 10 of 18 asthmatics and one of 11 control subjects (p = 0.02). In nine of the 10 patients, the organism was detected in bronchoalveolar lavage or bronchial biopsies. Seven of 18 asthmatics and one of 11 control subjects were also positive for M. fermentans and M. genitalium by PCR. All patients' cultures, EIAs, and serology were negative for M. pneumoniae. All PCR and cultures were negative for C. pneumoniae, and all EIAs for respiratory viruses were negative in all subjects. Nine asthmatics and one control subject exhibited positive serology for C. pneumoniae (p = 0.05). M. pneumoniae was present in the lower airways of chronic, stable asthmatics with greater frequency than control subjects, and may play a role in the pathogenesis of chronic asthma.

BACKGROUND: High flow nasal cannulae (HFNC) are small, thin, tapered binasal tubes that deliver oxygen or blended oxygen/air at gas flows of more than 1 L/min. HFNC are increasingly being used as a form of non-invasive respiratory support for preterm infants. OBJECTIVES: To compare the safety and efficacy of HFNC with other forms of non-invasive respiratory support in preterm infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE via PubMed (1966 to 1 January 2016), EMBASE (1980 to 1 January 2016), and CINAHL (1982 to 1 January 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised trials comparing HFNC with other non-invasive forms of respiratory support in preterm infants immediately after birth or following extubation. DATA COLLECTION AND ANALYSIS: The authors extracted and analysed data, and calculated risk ratio, risk difference and number needed to treat for an additional beneficial outcome. MAIN RESULTS: We identified 15 studies for inclusion in the review. The studies differed in the interventions compared (nasal continuous positive airway pressure (CPAP), nasal intermittent positive pressure ventilation (NIPPV), non-humidified HFNC, models for delivering HFNC), the gas flows used and the indications for respiratory support (primary support from soon after birth, post-extubation support, weaning from CPAP support). When used as primary respiratory support after birth compared to CPAP (4 studies, 439 infants), there were no differences in the primary outcomes of death (typical risk ratio (RR) 0.36, 95% CI 0.01 to 8.73; 4 studies, 439 infants) or chronic lung disease (CLD) (typical RR 2.07, 95% CI 0.64 to 6.64; 4 studies, 439 infants). HFNC use resulted in longer duration of respiratory support, but there were no differences in other secondary outcomes. One study (75 infants) showed no differences between HFNC and NIPPV as primary support. Following extubation (total 6 studies, 934 infants), there were no differences between HFNC and CPAP in the primary outcomes of death (typical RR 0.77, 95% CI 0.43 to 1.36; 5 studies, 896 infants) or CLD (typical RR 0.96, 95% CI 0.78 to 1.18; 5 studies, 893 infants). There was no difference in the rate of treatment failure (typical RR 1.21, 95% CI 0.95 to 1.55; 5 studies, 786 infants) or reintubation (typical RR 0.91, 95% CI 0.68 to 1.20; 6 studies, 934 infants). Infants randomised to HFNC had reduced nasal trauma (typical RR 0.64, 95% CI 0.51 to 0.79; typical risk difference (RD) -0.14, 95% CI -0.20 to -0.08; 4 studies, 645 infants). There was a small reduction in the rate of pneumothorax (typical RR 0.35, 95% CI 0.11 to 1.06; typical RD -0.02, 95% CI -0.03 to -0.00; 5 studies 896 infants) in infants treated with HFNC. Subgroup analysis found no difference in the rate of the primary outcomes between HFNC and CPAP in preterm infants in different gestational age subgroups, though there were only small numbers of extremely preterm and late preterm infants. One trial (28 infants) found similar rates of reintubation for humidified and non-humidified HFNC, and two other trials (100 infants) found no difference between different models of equipment used to deliver humidified HFNC. For infants weaning from non-invasive respiratory support (CPAP), two studies (149 infants) found that preterm infants randomised to HFNC had a reduced duration of hospitalisation compared with infants who remained on CPAP. AUTHORS' CONCLUSIONS: HFNC has similar rates of efficacy to other forms of non-invasive respiratory support in preterm infants for preventing treatment failure, death and CLD. Most evidence is available for the use of HFNC as post-extubation support. Following extubation, HFNC is associated with less nasal trauma, and may be associated with reduced pneumothorax compared with nasal CPAP. Further adequately powered randomised controlled trials should be undertaken in preterm infants comparing HFNC with other forms of primary non-invasive support after birth and for weaning from non-invasive support. Further evidence is also required for evaluating the safety and efficacy of HFNC in extremely preterm and mildly preterm subgroups, and for comparing different HFNC devices.

CONTEXT: IL-1, IL-6, and TNF-alpha play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited. OBJECTIVE: Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults. METHODS: A total of 168 randomly selected subjects (mean 63 yr, range 52-78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: -0.18 to -0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-alpha, and the urinary PYR/Cr ratio were measured on both occasions. RESULTS: The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-alpha, as well as change in hs-CRP (beta: -0.41%/U, 95% confidence interval -0.68%, -0.15%) and IL-6 (beta: -0.62%/U, 95% confidence interval -1.01%, -0.23%). If these markers were put in the same predictive model, only IL-6 remained largely unchanged. Changes in other BMD sites were significantly predicted by IL-6 (hip and spine) and TNF-alpha (spine only). Finally, change in the PYR/Cr ratio was positively associated baseline IL-6, hs-CRP, and their changes (all P < 0.05) in women, but not men. CONCLUSIONS: Variation within the low levels of inflammatory markers observed in this study, especially IL-6, predicts bone loss and resorption, suggesting that targeted antiinflammatory therapy has potential for the prevention of osteoporosis.

Onychomycosis is a fungal infection of the nail plate or nail bed. It does not usually cure itself and it can trigger more infectious lesions in other parts of the body. The reported prevalence of onychomycosis is increasing in Western countries, presumably due to lifestyle changes and the ageing of the population. Approximately 10% of the general population, 20% of the population aged>60 years, up to 50% of people aged>70 years and up to one-third of diabetic individuals have onychomycosis. Care should be taken for the accurate diagnosis and timely treatment of toenail onychomycosis to prevent complications. Current treatment options have relatively limited therapeutic success, particularly long-term. Oral medications are associated with high recurrence rates and treatment failure, and are not suitable for many cases due to potential adverse effects. Topical medications are recommended only for mild to moderate cases. The cost of therapies may also be prohibitive in some cases. In the light of these issues, more research is warranted for the investigation and development of more effective and economical options for the treatment and prophylaxis of toenail onychomycosis. In patient populations such as diabetic individuals, where onychomycosis can provoke lower extremity complications, professional podiatry care of toenails and feet should be encouraged.

BACKGROUND AND OBJECTIVE: The aim of the Pulmonary Rehabilitation Guidelines (Guidelines) is to provide evidence-based recommendations for the practice of pulmonary rehabilitation (PR) specific to Australian and New Zealand healthcare contexts. METHODS: The Guideline methodology adhered to the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. Nine key questions were constructed in accordance with the PICO (Population, Intervention, Comparator, Outcome) format and reviewed by a COPD consumer group for appropriateness. Systematic reviews were undertaken for each question and recommendations made with the strength of each recommendation based on the GRADE (Gradings of Recommendations, Assessment, Development and Evaluation) criteria. The Guidelines were externally reviewed by a panel of experts. RESULTS: The Guideline panel recommended that patients with mild-to-severe COPD should undergo PR to improve quality of life and exercise capacity and to reduce hospital admissions; that PR could be offered in hospital gyms, community centres or at home and could be provided irrespective of the availability of a structured education programme; that PR should be offered to patients with bronchiectasis, interstitial lung disease and pulmonary hypertension, with the latter in specialized centres. The Guideline panel was unable to make recommendations relating to PR programme length beyond 8 weeks, the optimal model for maintenance after PR, or the use of supplemental oxygen during exercise training. The strength of each recommendation and the quality of the evidence are presented in the summary. CONCLUSION: The Australian and New Zealand Pulmonary Rehabilitation Guidelines present an evaluation of the evidence for nine PICO questions, with recommendations to provide guidance for clinicians and policymakers.

BACKGROUND: Risk factors represent a range of complex variables associated with the onset, development, and course of eating disorders. Understanding these risk factors is vital for the refinement of aetiological models, which may inform the development of targeted, evidence-based prevention, early intervention, and treatment programs. This Rapid Review aimed to identify and summarise research studies conducted within the last 12 years, focusing on risk factors associated with eating disorders. METHODS: The current review forms part of a series of Rapid Reviews to be published in a special issue in the Journal of Eating Disorders, funded by the Australian Government to inform the development of the National Eating Disorder Research and Translation Strategy 2021-2031. Three databases were searched for studies published between 2009 and 2021, published in English, and comprising high-level evidence studies (meta-analyses, systematic reviews, moderately sized randomised controlled studies, moderately sized controlled-cohort studies, or population studies). Data pertaining to risk factors for eating disorders were synthesised and outlined in the current paper. RESULTS: A total of 284 studies were included. The findings were divided into nine main categories: (1) genetics, (2) gastrointestinal microbiota and autoimmune reactions, (3) childhood and early adolescent exposures, (4) personality traits and comorbid mental health conditions, (5) gender, (6) socio-economic status, (7) ethnic minority, (8) body image and social influence, and (9) elite sports. A substantial amount of research exists supporting the role of inherited genetic risk in the development of eating disorders, with biological risk factors, such as the role of gut microbiota in dysregulation of appetite, an area of emerging evidence. Abuse, trauma and childhood obesity are strongly linked to eating disorders, however less conclusive evidence exists regarding developmental factors such as role of in-utero exposure to hormones. Comorbidities between eating disorders and mental health disorders, including personality and mood disorders, have been found to increase the severity of eating disorder symptomatology. Higher education attainment, body image-related factors, and use of appearance-focused social media are also associated with increased risk of eating disorder symptoms. CONCLUSION: Eating disorders are associated with multiple risk factors. An extensive amount of research has been conducted in the field; however, further studies are required to assess the causal nature of the risk factors identified in the current review. This will assist in understanding the sequelae of eating disorder development and in turn allow for enhancement of existing interventions and ultimately improved outcomes for individuals.

BACKGROUND: Nasal continuous positive airway pressure (NCPAP) is used to support preterm infants recently extubated, those experiencing significant apnoea of prematurity and those with respiratory distress soon after birth as an alternative to intubation and ventilation. This review focuses exclusively on identifying the most effective pressure source and interface for NCPAP delivery in preterm infants. OBJECTIVES: To determine which technique of pressure generation and which type of nasal interface for NCPAP delivery most effectively reduces the need for additional respiratory support in preterm infants extubated to NCPAP following intermittent positive pressure ventilation (IPPV) for respiratory distress syndrome (RDS) or in those treated with NCPAP soon after birth. SEARCH STRATEGY: The strategy included searches of MEDLINE (1966 - 2006), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2006) CINAHL, abstracts from conference proceedings, cross-referencing of previous reviews and the use of expert informants. SELECTION CRITERIA: Randomised or quasi-randomised trials comparing different techniques of NCPAP pressure generation and/or nasal interfaces in preterm infants extubated to NCPAP following IPPV for RDS or treated with NCPAP soon after birth. DATA COLLECTION AND ANALYSIS: Data was extracted and analysed by the first three authors. Dichotomous results were analysed using the relative risk (RR), risk difference (RD) and number needed to treat (NNT). MAIN RESULTS: 1. Preterm infants being extubated to NCPAP following a period of IPPV for RDS:Meta-analysis of the results from Davis 2001 and Roukema 1999a demonstrated that short binasal prongs are more effective at preventing re-intubation than single nasal or nasopharyngeal prongs [typical RR 0.59 (CI: 0.41, 0.85), typical RD -0.21 (CI: -0.35, -0.07), NNT 5 (CI: 3, 14)]. In one study comparing short binasal prong devices (Sun 1999), the re-intubation rate was significantly lower with the Infant Flow Driver than with the Medicorp prong [RR 0.33 (CI: 0.17, 0.67), RD -0.32 (CI: -0.49, -0.15), NNT 3 (CI: 2, 7)]. The other study comparing short binasal prong devices (Infant Flow Driver versus INCA prongs, Stefanescu 2003) demonstrated no significant difference in the re-intubation rate but did show a significant reduction in the total days in hospital in the Infant Flow Driver group [MD -12.60 (95% CI: -22.81, -2.39) days].2. Preterm infants primarily treated with NCPAP soon after birth:In the one trial identified, Mazzella 2001 found a significantly lower oxygen requirement and respiratory rate in those randomised to short binasal prongs when compared with CPAP delivered via nasopharyngeal prong. The requirement for intubation beyond 48 hours from randomisation was not assessed.3. Studies randomising preterm infants to different NCPAP systems using broad inclusion criteriaThe studies of Rego 2002 and Buettiker 2004 did not examine the primary outcomes of this review. Of the secondary outcomes, Rego 2002 demonstrated a significantly higher incidence of nasal hyperaemia with the use of the Argyle prong compared with Hudson prongs [RR 2.39 (95% CI: 1.27, 4.50), RD 0.28 (95% CI: 0.10, 0.46)]. One study comparing different techniques of pressure generation is awaiting further assessment as it is currently available in abstract form only. AUTHORS' CONCLUSIONS: Short binasal prong devices are more effective than single prongs in reducing the rate of re-intubation. Although the Infant Flow Driver appears more effective than Medicorp prongs the most effective short binasal prong device remains to be determined. The improvement in respiratory parameters with short binasal prongs suggests they are more effective than nasopharyngeal CPAP in the treatment of early RDS. Further studies incorporating longer-term outcomes are required. Studies are also needed to determine the optimal pressure source for the delivery of NCPAP.

CONTEXT: Severe iodine deficiency (ID) during gestation is associated with neurocognitive sequelae. The long-term impact of mild ID, however, has not been well characterized. OBJECTIVE: The purpose of this study was to determine whether children born to mothers with urinary iodine concentrations (UICs) <150 μg/L during pregnancy have poorer educational outcomes in primary school than peers whose mothers did not have gestational ID (UIC ≥150 μg/L). DESIGN: This was a longitudinal follow-up (at 9 years old) of the Gestational Iodine Cohort. Pregnancy occurred during a period of mild ID in the population, with the children subsequently growing up in an iodine-replete environment. SETTING AND PARTICIPANTS: Participants were children whose mothers attended The Royal Hobart Hospital (Tasmania) antenatal clinics between 1999 and 2001. MAIN OUTCOME MEASURES: Australian national curriculum and Tasmanian state curriculum educational assessment data for children in year 3 were analyzed. RESULTS: Children whose mothers had UIC <150 μg/L had reductions of 10.0% in spelling (-41.1 points, 95% confidence interval [CI], -68.0 to -14.3, P = .003), 7.6% in grammar (-30.9 points, 95% CI, -60.2 to -1.7, P = .038), and 5.7% in English-literacy (-0.33 points, 95% CI, -0.63 to -0.03, P = .034) performance compared with children whose mothers' UICs were ≥150 μg/L. These associations remained significant after adjustment for a range of biological factors (maternal age at birth of child, gestational length at time of birth, gestational age at time of urinary iodine collection, birth weight, and sex). Differences in spelling remained significant after further adjustment for socioeconomic factors (maternal occupation and education). CONCLUSIONS: This study provides preliminary evidence that even mild iodine deficiency during pregnancy can have long-term adverse impacts on fetal neurocognition that are not ameliorated by iodine sufficiency during childhood.