ShcA promotes chondrocyte hypertrophic commitment and osteoarthritis in mice through RunX2 nuclear translocation and YAP1 inactivation.

OBJECTIVE: Chondrocyte hypertrophic differentiation, a key process in endochondral ossification, is also a feature of osteoarthritis leading to cartilage destruction. Here we investigated the role of the adaptor protein Src homology and Collagen A (ShcA) in chondrocyte differentiation and osteoarthritis. METHODS: Mice ablated for ShcA in osteochondroprogenitor cells were generated by crossing mice carrying the Twist2-Cre transgene with ShcAflox/flox mice. Their phenotype (n = 5 to 14 mice per group) was characterized using histology, immuno-histology and western-blot. To identify the signaling mechanisms involved, in vitro experiments were conducted on wild type and ShcA deficient chondrocytes (isolated from n = 4 to 7 littermates) and the chondroprogenitor cell line ATDC5 (n = 4 independent experiments) using western-blot, cell fractionation and confocal microscopy. RESULTS: Deletion of ShcA decreases the hypertrophic zone of the growth plate (median between group difference -11.37% [95% confidence interval -17.34 to -8.654]), alters the endochondral ossification process, and leads to dwarfism (3 months old male mice nose-to-anus length -1.48 cm [-1.860 to -1.190]). ShcA promotes ERK1/2 activation, nuclear translocation of RunX2, the master transcription factor for chondrocyte hypertrophy, while maintaining the Runx2 inhibitor, YAP1, in its cytosolic inactive form. This leads to hypertrophic commitment and expression of markers of hypertrophy, such as Collagen X. In addition, loss of ShcA protects from age-related osteoarthritis development in mice (2 years old mice OARSI score -6.67 [-14.25 to -4.000]). CONCLUSION: This study reveals ShcA as a new player in the control of chondrocyte hypertrophic differentiation and its deletion slows down osteoarthritis development.

The SAFEST review: a mixed methods systematic review of shock-absorbing flooring for fall-related injury prevention.

BACKGROUND: Shock-absorbing flooring may minimise impact forces incurred from falls to reduce fall-related injuries; however, synthesized evidence is required to inform decision-making in hospitals and care homes. METHODS: This is a Health Technology Assessment mixed methods systematic review of flooring interventions targeting older adults and staff in care settings. Our search incorporated the findings from a previous scoping review, MEDLINE, AgeLine, and Scopus (to September 2019) and other sources. Two independent reviewers selected, assessed, and extracted data from studies. We assessed risk of bias using Cochrane and Joanna Briggs Institute tools, undertook meta-analyses, and meta-aggregation. RESULTS: 20 of 22 included studies assessed our outcomes (3 Randomised Controlled Trials (RCTs); 7 observational; 5 qualitative; 5 economic), on novel floors (N = 12), sports floors (N = 5), carpet (N = 5), and wooden sub-floors (N = 1). Quantitative data related to 11,857 patient falls (9 studies), and 163 staff injuries (1 study). One care home-based RCT found a novel underlay produced similar injurious falls rates (high-quality evidence) and falls rates (moderate-quality evidence) to a plywood underlay with vinyl overlay and concrete sub-floors. Very low-quality evidence suggested that shock-absorbing flooring may reduce injuries in hospitals (Rate Ratio 0.55, 95% CI 0.36 to 0.84, 2 studies; 27.1% vs. 42.4%; Risk Ratio (RR) = 0.64, 95% CI 0.44 to 0.93, 2 studies) and care homes (26.4% vs. 33.0%; RR 0.80, 95% CI 0.70 to 0.91, 3 studies), without increasing falls. Economic evidence indicated that if injuries are fewer and falls not increased, then shock-absorbing flooring would be a dominant strategy. Fracture outcomes were imprecise; however, hip fractures reduced from 30 in 1000 falls on concrete to 18 in 1000 falls on wooden sub-floors (OR 0.59, 95% CI 0.45 to 0.78; one study; very low-quality evidence). Staff found moving wheeled equipment harder on shock-absorbing floors leading to workplace adaptations. Very low-quality evidence suggests staff injuries were no less frequent on rigid floors. CONCLUSION: Evidence favouring shock-absorbing flooring is uncertain and of very low quality. Robust research following a core outcome set is required, with attention to wider staff workplace implications. TRIAL REGISTRATION: PROSPERO CRD42019118834 .

Better care for less money: cost-effectiveness of integrated care in multi-episode patients with severe psychosis.

OBJECTIVE: To compare cost-effectiveness of integrated care with therapeutic assertive community treatment (IC-TACT) versus standard care (SC) in multiple-episode psychosis. METHOD: Twelve-month IC-TACT in patients with schizophrenia-spectrum and bipolar I disorders were compared with a historical control group. Primary outcomes were entropy-balanced cost-effectiveness based on mental healthcare costs from a payers' perspective and quality-adjusted life years (QALYs) as a measure of health effects during 12-month follow-up. RESULTS: At baseline, patients in IC-TACT (n = 214) had significantly higher illness severity and lower functioning than SC (n = 56). Over 12 months, IC-TACT had significantly lower days in inpatient (10.3 ± 20.5 vs. 28.2 ± 44.9; P = 0.005) and day-clinic care (2.6 ± 16.7 vs. 16.4 ± 33.7; P = 0.004) and correspondingly lower costs (€-55 084). Within outpatient care, IC-TACT displayed a higher number of treatment contacts (116.3 ± 45.3 vs. 15.6 ± 6.3) and higher related costs (€+1417). Both resulted in lower total costs in IC-TACT (mean difference = €-13 248 ± 2975, P < 0.001). Adjusted incremental QALYs were significantly higher for IC-TACT versus SC (+0.10 ± 0.37, P = 0.05). The probability of cost-effectiveness of IC-TACT was constantly higher than 99%. CONCLUSION: IC-TACT was cost-effective compared with SC. The use of prima facies 'costly' TACT teams is highly recommended to improve outcomes and save total cost for patients with severe psychotic disorders.

Cognitive and emotional empathy in individuals at clinical high risk of psychosis.

BACKGROUND: Impairments of social cognition are considered core features of schizophrenia and are established predictors of social functioning. However, affective aspects of social cognition including empathy have far less been studied than its cognitive dimensions. The role of empathy in the development of schizophrenia remains largely elusive. METHODS: Emotional and cognitive empathy were investigated in large sample of 120 individuals at Clinical High Risk of Psychosis (CHR-P) and compared with 50 patients with schizophrenia and 50 healthy controls. A behavioral empathy assessment, the Multifaceted Empathy Test, was implemented, and associations of empathy with cognition, social functioning, and symptoms were determined. RESULTS: Our findings demonstrated significant reductions of emotional empathy in individuals at CHR-P, while cognitive empathy appeared intact. Only individuals with schizophrenia showed significantly reduced scores of cognitive empathy compared to healthy controls and individuals at CHR-P. Individuals at CHR-P were characterized by significantly lower scores of emotional empathy and unspecific arousal for both positive and negative affective valences compared to matched healthy controls and patients with schizophrenia. Results also indicated a correlation of lower scores of emotional empathy and arousal with higher scores of prodromal symptoms. CONCLUSION: Findings suggest that the tendency to 'feel with' an interaction partner is reduced in individuals at CHR-P. Altered emotional reactivity may represent an additional, early vulnerability marker, even if cognitive mentalizing is grossly unimpaired in the prodromal stage. Different mechanisms might contribute to reductions of cognitive and emotional empathy in different stages of non-affective psychotic disorders and should be further explored.

Understanding longer-term disability outcomes for Maori and non-Maori after hospitalisation for injury: results from a longitudinal cohort study.

OBJECTIVES: The objectives are to (1) describe disability outcomes at 24 months after injury and (2) identify factors contributing to disability outcomes at 24 months after injury, for Maori and non-Maori who have been hospitalised for injury. STUDY DESIGN: This is a prospective cohort study. METHODS: Prospective Outcomes of Injury Study participants were injured New Zealanders aged 18-64 years and recruited from New Zealand's no-fault injury insurer, the Accident Compensation Corporation's entitlement claims register. Data about a number of pre-injury, injury-related and early post-injury characteristics were collected from interviews held at 3 and 24 months after injury. Disability was measured using the World Health Organization Disability Assessment Schedule (WHODAS). Modified Poisson regression modelling was used to estimate relative risks (RRs) of disability for Maori and non-Maori who were hospitalised for injury. RESULTS: Analyses were restricted to 375 Maori and 1824 non-Maori participants for whom complete data were available. Of these, 105 (28%) Maori and 446 (24%) non-Maori were hospitalised for their injury. Of these hospitalised groups, 26% of Maori and 10% of non-Maori were experiencing disability (WHODAS ≥10) at 24 months after injury. Maori who were hospitalised for injury and who were not working for pay before their injury (RR = 2.7; 95% confidence interval [CI] 1.4-4.9), who were experiencing disability before their injury (RR = 3.1; 95% CI 1.6-5.8) or who reported trouble accessing healthcare services for their injury (RR = 2.6; 95% CI 1.3-5.2) were independently at increased risk of disability 24 months after injury. Non-Maori who were hospitalised for injury and who had inadequate household income before injury (RR = 2.4; 95% CI 1.4-4.1), less than the secondary school qualifications (RR = 2.0; 95% CI 1.1-3.8), were not working for pay before injury (RR = 2.8; 95% CI 1.5-5.1), were experiencing disability before their injury (RR = 3.0; 95% CI 1.7-5.2), had ≥2 chronic conditions (RR = 3.5; 95% CI 2.0-6.4) or had body mass index ≥30 kg/m2/undisclosed (RR = 2.4; 95% CI 1.3-4.4) were at increased risk of disability 24 months after injury. CONCLUSIONS: Variables predicting disability 24 months after injury for Maori, also predict disability 24 months after injury for non-Maori, with one notable exception-trouble accessing healthcare services. Our findings show that having access to healthcare services for injury plays an important role after injury and must be focussed on to ensure that the burden of poor injury-related outcomes and injury-related inequities are reduced and ultimately eliminated.

Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients.

OBJECTIVE: To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD). METHODS: A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. RESULTS: Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42-62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). CONCLUSION: TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

Working while unwell: Workplace impairment in people with severe asthma.

BACKGROUND: Severe asthma affects quality of life; however, its impact on workplace productivity is poorly understood. OBJECTIVE: To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma. METHODS: The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years; 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated. RESULTS: At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P < .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P < .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P < .01). CONCLUSION AND CLINICAL RELEVANCE: Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age.

Anticoagulation withdrawal in antiphospholipid syndrome: a retrospective matched-control study.

Background/Purpose Long-term anticoagulation is the standard treatment for thrombotic antiphospholipid syndrome (APS). However, in daily practice, the question of withdrawing anticoagulation may arise, without any evidence-based recommendations. This study aimed to assess outcomes in APS patients after anticoagulation withdrawal. Methods Thrombotic APS patients followed in our centre, whose anticoagulation was withdrawn after APS diagnosis, were retrospectively selected, and were match-controlled with patients under anticoagulation, based on sex, age, APS clinical phenotype and disease duration. Results Thirty cases with anticoagulation withdrawal were included. Median follow-up was 51 months (12-124). The risk of thrombotic relapse was higher in cases compared to controls (7.3% versus 1.5% patient-year ( p = 0.01); hazard ratio 4.8; 95% confidence interval (1.4-16.7)). Male gender, anti-ß2GP1 and triple positivity at inclusion were predictive factors for thrombotic relapse. Conversely, aspirin prescription was a protective factor against relapses. Persistence of LA, anti-ß2GP1 and triple positivity over time were associated with a higher risk of thrombosis and aPL disappearance with a lower risk. Conclusion In our study, anticoagulation withdrawal was associated with an increased risk of thrombotic relapse. Our findings emphasize the influence of anti-ß2GP1 and triple positivity persistence over time on the risk of relapse and the benefit of aspirin prescription when anticoagulation has been withdrawn.

Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome.

Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low-molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068.

Head-to-head trials of antibiotics for bronchiectasis.

BACKGROUND: The diagnosis of bronchiectasis is defined by abnormal dilation of the airways related to a pathological mechanism of progressive airway destruction that is due to a 'vicious cycle' of recurrent bacterial infection, inflammatory mediator release, airway damage, and subsequent further infection. Antibiotics are the main treatment option for reducing bacterial burden in people with exacerbations of bronchiectasis and for longer-term eradication, but their use is tempered against potential adverse effects and concerns regarding antibiotic resistance. The comparative effectiveness, cost-effectiveness, and safety of different antibiotics have been highlighted as important issues, but currently little evidence is available to help resolve uncertainty on these questions. OBJECTIVES: To evaluate the comparative effects of different antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified randomised controlled trials (RCTs) through searches of the Cochrane Airways Group Register of trials and online trials registries, run 30 April 2018. We augmented these with searches of the reference lists of published studies. SELECTION CRITERIA: We included RCTs reported as full-text articles, those published as abstracts only, and unpublished data. We included adults and children (younger than 18 years) with a diagnosis of bronchiectasis by bronchography or high-resolution computed tomography who reported daily signs and symptoms, such as cough, sputum production, or haemoptysis, and those with recurrent episodes of chest infection; we included studies that compared one antibiotic versus another when they were administered by the same delivery method. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial selection, data extraction, and risk of bias. We assessed overall quality of the evidence using GRADE criteria. We made efforts to collect missing data from trial authors. We have presented results with their 95% confidence intervals (CIs) as mean differences (MDs) or odds ratios (ORs). MAIN RESULTS: Four randomised trials were eligible for inclusion in this systematic review - two studies with 83 adults comparing fluoroquinolones with ß-lactams and two studies with 55 adults comparing aminoglycosides with polymyxins.None of the included studies reported information on exacerbations - one of our primary outcomes. Included studies reported no serious adverse events - another of our primary outcomes - and no deaths. We graded this evidence as low or very low quality. Included studies did not report quality of life. Comparison between fluoroquinolones and ß-lactams (amoxicillin) showed fewer treatment failures in the fluoroquinolone group than in the amoxicillin group (OR 0.07, 95% CI 0.01 to 0.32; low-quality evidence) after 7 to 10 days of therapy. Researchers reported that Pseudomonas aeruginosa infection was eradicated in more participants treated with fluoroquinolones (Peto OR 20.09, 95% CI 2.83 to 142.59; low-quality evidence) but provided no evidence of differences in the numbers of participants showing improvement in sputum purulence (OR 2.35, 95% CI 0.96 to 5.72; very low-quality evidence). Study authors presented no evidence of benefit in relation to forced expiratory volume in one second (FEV1). The two studies that compared polymyxins versus aminoglycosides described no clear differences between groups in the proportion of participants with P aeruginosa eradication (OR 1.40. 95% CI 0.36 to 5.35; very low-quality evidence) or improvement in sputum purulence (OR 0.16, 95% CI 0.01 to 3.85; very low-quality evidence). The evidence for changes in FEV1 was inconclusive. Two of three trials reported adverse events but did not report the proportion of participants experiencing one or more adverse events, so we were unable to interpret the information. AUTHORS' CONCLUSIONS: Limited low-quality evidence favours short-term oral fluoroquinolones over beta-lactam antibiotics for patients hospitalised with exacerbations. Very low-quality evidence suggests no benefit from inhaled aminoglycosides verus polymyxins. RCTs have presented no evidence comparing other modes of delivery for each of these comparisons, and no RCTs have included children. Overall, current evidence from a limited number of head-to-head trials in adults or children with bronchiectasis is insufficient to guide the selection of antibiotics for short-term or long-term therapy. More research on this topic is needed.

Dual antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation of the smaller airways and associated with a mortality rate greater than twice that of the general population. Antibiotics serve as front-line therapy for managing bacterial load, but their use is weighed against the development of antibiotic resistance. Dual antibiotic therapy has the potential to suppress infection from multiple strains of bacteria, leading to more successful treatment of exacerbations, reduced symptoms, and improved quality of life. Further evidence is required on the efficacy of dual antibiotics in terms of management of exacerbations and extent of antibiotic resistance. OBJECTIVES: To evaluate the effects of dual antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified studies from the Cochrane Airways Group Specialised Register (CAGR), which includes the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine (AMED), and PsycINFO, as well as studies obtained by handsearching of journals/abstracts. We also searched the following trial registries: US National Institutes of Health Ongoing Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform. We imposed no restriction on language of publication. We conducted our search in October 2017. SELECTION CRITERIA: We searched for randomised controlled trials comparing dual antibiotics versus a single antibiotic for short-term (< 4 weeks) or long-term management of bronchiectasis diagnosed in adults and/or children by bronchography, plain film chest radiography, or high-resolution computed tomography. Primary outcomes included exacerbations, length of hospitalisation, and serious adverse events. Secondary outcomes were response rates, emergence of resistance to antibiotics, systemic markers of infection, sputum volume and purulence, measures of lung function, adverse events/effects, deaths, exercise capacity, and health-related quality of life. We did not apply outcome measures as selection criteria. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of 287 records, along with the full text of seven reports. Two studies met review inclusion criteria. Two review authors independently extracted outcome data and assessed risk of bias. We extracted data from only one study and conducted GRADE assessments for the following outcomes: successful treatment of exacerbation; response rates; and serious adverse events. MAIN RESULTS: Two randomised trials assessed the effectiveness of oral plus inhaled dual therapy versus oral monotherapy in a total of 118 adults with a mean age of 62.8 years. One multi-centre trial compared inhaled tobramycin plus oral ciprofloxacin versus ciprofloxacin alone, and one single-centre trial compared nebulised gentamicin plus systemic antibiotics versus a systemic antibiotic alone. Published papers did not report study funding sources.Effect estimates from one small study with 53 adults showed no evidence of treatment benefit with oral plus inhaled dual therapy for the following primary outcomes at the end of the study: successful management of exacerbation - cure at day 42 (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.22 to 2.01; 53 participants; one study; very low-quality evidence); number of participants with Pseudomonas aeruginosa eradication at day 21 (OR 2.33, 95% CI 0.66 to 8.24; 53 participants; one study; very low-quality evidence); and serious adverse events (OR 0.48, 95% CI 0.08 to 2.87; 53 participants; one study; very low-quality evidence). Similarly, researchers provided no evidence of treatment benefit for the following secondary outcomes: clinical response rates - relapse at day 42 (OR 0.57, 95% CI 0.12 to 2.69; 53 participants; one study; very low-quality evidence); microbiological response rate at day 21 - eradicated (OR 2.40, 95% CI 0.67 to 8.65; 53 participants; one study; very low-quality evidence); and adverse events - incidence of wheeze (OR 5.75, 95% CI 1.55 to 21.33). Data show no evidence of benefit in terms of sputum volume, lung function, or antibiotic resistance. Outcomes from a second small study with 65 adults, available only as an abstract, were not included in the quantitative data synthesis. The included studies did not report our other primary outcomes: duration; frequency; and time to next exacerbation; nor our secondary outcomes: systemic markers of infection; exercise capacity; and quality of life. We did not identify any trials that included children. AUTHORS' CONCLUSIONS: A small number of studies in adults have generated high-quality evidence that is insufficient to inform robust conclusions, and studies in children have provided no evidence. We identified only one dual-therapy combination of oral and inhaled antibiotics. Results from this single trial of 53 adults that we were able to include in the quantitative synthesis showed no evidence of treatment benefit with oral plus inhaled dual therapy in terms of successful treatment of exacerbations, serious adverse events, sputum volume, lung function, and antibiotic resistance. Further high-quality research is required to determine the efficacy and safety of other combinations of dual antibiotics for both adults and children with bronchiectasis, particularly in terms of antibiotic resistance.

Continuous versus intermittent antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic airway disease characterised by a destructive cycle of recurrent airway infection, inflammation and tissue damage. Antibiotics are a main treatment for bronchiectasis. The aim of continuous therapy with prophylactic antibiotics is to suppress bacterial load, but bacteria may become resistant to the antibiotic, leading to a loss of effectiveness. On the other hand, intermittent prophylactic antibiotics, given over a predefined duration and interval, may reduce antibiotic selection pressure and reduce or prevent the development of resistance. This systematic review aimed to evaluate the current evidence for studies comparing continuous versus intermittent administration of antibiotic treatment in bronchiectasis in terms of clinical efficacy, the emergence of resistance and serious adverse events. OBJECTIVES: To evaluate the effectiveness of continuous versus intermittent antibiotics in the treatment of adults and children with bronchiectasis, using the primary outcomes of exacerbations, antibiotic resistance and serious adverse events. SEARCH METHODS: On 1 August 2017 and 4 May 2018 we searched the Cochrane Airways Review Group Specialised Register (CAGR), CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and AMED. On 25 September 2017 and 4 May 2018 we also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal, conference proceedings and the reference lists of existing systematic reviews. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) of adults or children with bronchiectasis that compared continuous versus intermittent administration of long-term prophylactic antibiotics of at least three months' duration. We considered eligible studies reported as full-text articles, as abstracts only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and full-text reports. MAIN RESULTS: We identified 268 unique records. Of these we retrieved and examined 126 full-text reports, representing 114 studies, but none of these studies met our inclusion criteria. AUTHORS' CONCLUSIONS: No randomised controlled trials have compared the effectiveness and risks of continuous antibiotic therapy versus intermittent antibiotic therapy for bronchiectasis. High-quality clinical trials are needed to establish which of these interventions is more effective for reducing the frequency and duration of exacerbations, antibiotic resistance and the occurrence of serious adverse events.

Oral versus inhaled antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic inflammatory disease characterised by a recurrent cycle of respiratory bacterial infections associated with cough, sputum production and impaired quality of life. Antibiotics are the main therapeutic option for managing bronchiectasis exacerbations. Evidence suggests that inhaled antibiotics may be associated with more effective eradication of infective organisms and a lower risk of developing antibiotic resistance when compared with orally administered antibiotics. However, it is currently unclear whether antibiotics are more effective when administered orally or by inhalation. OBJECTIVES: To determine the comparative efficacy and safety of oral versus inhaled antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified studies through searches of the Cochrane Airways Group's Specialised Register (CAGR), which is maintained by the Information Specialist for the group. The Register contains trial reports identified through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, and PsycINFO, and handsearching of respiratory journals and meeting abstracts. We also searched ClinicalTrials.gov and the WHO trials portal. We searched all databases in March 2018 and imposed no restrictions on language of publication. SELECTION CRITERIA: We planned to include studies which compared oral antibiotics with inhaled antibiotics. We would have considered short-term use (less than four weeks) for treating acute exacerbations separately from longer-term use as a prophylactic (4 weeks or more). We would have considered both intraclass and interclass comparisons. We planned to exclude studies if the participants received continuous or high-dose antibiotics immediately before the start of the trial, or if they have received a diagnosis of cystic fibrosis (CF), sarcoidosis, active allergic bronchopulmonary aspergillosis or active non-tuberculous Mycobacterial infection. DATA COLLECTION AND ANALYSIS: Two review authors independently applied study inclusion criteria to the searches and we planned for two authors to independently extract data, assess risk of bias and assess overall quality of the evidence using GRADE criteria. We also planned to obtain missing data from the authors where possible and to report results with 95% confidence intervals (CIs). MAIN RESULTS: We identified 313 unique records through database searches and a further 21 records from trial registers. We excluded 307 on the basis of title and abstract alone and a further 27 after examining full-text reports. No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS: There is currently no evidence indicating whether orally administered antibiotics are more beneficial compared to inhaled antibiotics. The recent ERS bronchiectasis guidelines provide a practical approach to the use of long-term antibiotics. New research is needed comparing inhaled versus oral antibiotic therapies for bronchiectasis patients with a history of frequent exacerbations, to establish which approach is the most effective in terms of exacerbation prevention, quality of life, treatment burden, and antibiotic resistance.

Macrolide antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a chronic respiratory disease characterised by abnormal and irreversible dilatation and distortion of the smaller airways. Bacterial colonisation of the damaged airways leads to chronic cough and sputum production, often with breathlessness and further structural damage to the airways. Long-term macrolide antibiotic therapy may suppress bacterial infection and reduce inflammation, leading to fewer exacerbations, fewer symptoms, improved lung function, and improved quality of life. Further evidence is required on the efficacy of macrolides in terms of specific bacterial eradication and the extent of antibiotic resistance. OBJECTIVES: To determine the impact of macrolide antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted all searches on 18 January 2018. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least four weeks' duration that compared macrolide antibiotics with placebo or no intervention for the long-term management of stable bronchiectasis in adults or children with a diagnosis of bronchiectasis by bronchography, plain film chest radiograph, or high-resolution computed tomography. We excluded studies in which participants had received continuous or high-dose antibiotics immediately before enrolment or before a diagnosis of cystic fibrosis, sarcoidosis, or allergic bronchopulmonary aspergillosis. Our primary outcomes were exacerbation, hospitalisation, and serious adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of 103 records. We independently screened the full text of 40 study reports and included 15 trials from 30 reports. Two review authors independently extracted outcome data and assessed risk of bias for each study. We analysed dichotomous data as odds ratios (ORs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 14 parallel-group RCTs and one cross-over RCT with interventions lasting from 8 weeks to 24 months. Of 11 adult studies with 690 participants, six used azithromycin, four roxithromycin, and one erythromycin. Four studies with 190 children used either azithromycin, clarithromycin, erythromycin, or roxithromycin.We included nine adult studies in our comparison between macrolides and placebo and two in our comparison with no intervention. We included one study with children in our comparison between macrolides and placebo and one in our comparison with no intervention.In adults, macrolides reduced exacerbation frequency to a greater extent than placebo (OR 0.34, 95% confidence interval (CI) 0.22 to 0.54; 341 participants; three studies; I2 = 65%; moderate-quality evidence). This translates to a number needed to treat for an additional beneficial outcome of 4 (95% CI 3 to 8). Data show no differences in exacerbation frequency between use of macrolides (OR 0.31, 95% CI 0.08 to 1.15; 43 participants; one study; moderate-quality evidence) and no intervention. Macrolides were also associated with a significantly better quality of life compared with placebo (MD -8.90, 95% CI -13.13 to -4.67; 68 participants; one study; moderate-quality evidence). We found no evidence of a reduction in hospitalisations (OR 0.56, 95% CI 0.19 to 1.62; 151 participants; two studies; I2 = 0%; low-quality evidence), in the number of participants with serious adverse events, including pneumonia, respiratory and non-respiratory infections, haemoptysis, and gastroenteritis (OR 0.49, 95% CI 0.20 to 1.23; 326 participants; three studies; I2 = 0%; low-quality evidence), or in the number experiencing adverse events (OR 0.83, 95% CI 0.51 to 1.35; 435 participants; five studies; I2 = 28%) in adults with macrolides compared with placebo.In children, there were no differences in exacerbation frequency (OR 0.40, 95% CI 0.11 to 1.41; 89 children; one study; low-quality evidence); hospitalisations (OR 0.28, 95% CI 0.07 to 1.11; 89 children; one study; low-quality evidence), serious adverse events, defined within the study as exacerbations of bronchiectasis or investigations related to bronchiectasis (OR 0.43, 95% CI 0.17 to 1.05; 89 children; one study; low-quality evidence), or adverse events (OR 0.78, 95% CI 0.33 to 1.83; 89 children; one study), in those receiving macrolides compared to placebo. The same study reported an increase in macrolide-resistant bacteria (OR 7.13, 95% CI 2.13 to 23.79; 89 children; one study), an increase in resistance to Streptococcus pneumoniae (OR 13.20, 95% CI 1.61 to 108.19; 89 children; one study), and an increase in resistance to Staphylococcus aureus (OR 4.16, 95% CI 1.06 to 16.32; 89 children; one study) with macrolides compared with placebo. Quality of life was not reported in the studies with children. AUTHORS' CONCLUSIONS: Long-term macrolide therapy may reduce the frequency of exacerbations and improve quality of life, although supporting evidence is derived mainly from studies of azithromycin, rather than other macrolides, and predominantly among adults rather than children. However, macrolides should be used with caution, as limited data indicate an associated increase in microbial resistance. Macrolides are associated with increased risk of cardiovascular death and other serious adverse events in other populations, and available data cannot exclude a similar risk among patients with bronchiectasis.

Trends in time-loss injuries during the 2011-2016 South African Rugby Youth Weeks.

Youth rugby is a popular sport in South Africa (SA) with a high injury incidence. The annual SA Rugby Youth Week tournaments attract the top age-group players in the country providing a sample of players for reliable injury surveillance. The aim of the study was to analyze the changes in time-loss injury rates at the SA Rugby Youth Week tournaments between 2011 and 2016, differences between age-groups, and to investigate associated injury risk factors. All confirmed time-loss injuries at the 4 age-group tournaments (under-13, under-16, and 2 under-18) from 2011 to 2016 were recorded. Injury incidence densities (IID) for years, tournaments, and injury risk factors were calculated and Poisson regression analyses were performed to determine differences. Time-loss injuries (n = 494) were reported over 24 240 exposure hours, with an overall IID of 20.4 (18.6-22.2) injuries per 1000 player hours. The year 2013 had a significantly lower IID compared to 2011. Injury risk decreased with increasing age; under-13 and under-16 had significantly higher IID compared to under-18 Craven Week. Tackling was the phase of play at highest risk, with an IID of 7.4 (6.3-8.5) injuries per 1000 player hours. Central/peripheral nervous system (CNS/PNS) and, therefore, the head/neck were the most commonly occurring injuries/location injured. In conclusion, within the SA Rugby tournament structure, the older players had a decreased rate of injury. The tackle event was still the phase of play with the highest injury incidence regardless of age. This increase in incidence is largely due to an increase in CNS/PNS injuries.

Social gradient in caries experience of Belgian adults 2010.

OBJECTIVE: This study aims to explore the caries experience of the Belgian population in relation to social indicators. BASIC RESEARCH DESIGN: Data collection (2009-2010) consisted of an oral health questionnaire and examination during a home visit. PARTICIPANTS: Representative sample of the Belgian population (⟩5 years old). Only the economically active population was included for final analyses. MAIN OUTCOME MEASURES: ANOVA and multivariable regression analyses were used to reveal associations between social indicators, oral hygiene, untreated decay, DMFT and edentulousness. RESULTS: 2742 participants completed the questionnaire, of whom 2563 were examined clinically. Most (53%) were female and mean age was 43.3 years (95% CI= 41.2-45.4). In the total population, 11.1 % were caries-free (DMFT = 0) and mean DMFT was 10.8 (95% CI = 10.0-11.5). In the analysed subsample, higher educated participants had lower DMFT scores than those with low or no educational qualifications (p = 0.003). Employment status was associated with the presence of untreated tooth decay, especially in the youngest age group (p = 0.015), and with edentulousness (p = 0.02), with a higher risk among unemployed women of being completely edentulous (OR = 5.32; 95% CI = 1.75-16.12). Untreated tooth decay was related to frequency of tooth brushing and plaque index (p ⟨ 0.002 and ⟨ 0.001 respectively). CONCLUSIONS: Caries experience in Belgium, expressed as mean DMFT and proportion of untreated tooth decay, is more associated with level of education and employment status than with family income, which is still the main criterion for larger government allowances for healthcare in Belgium.

Effect of an oral healthcare programme on care staff knowledge and attitude regarding oral health: a non-randomised intervention trial.

OBJECTIVES: The objective of the study was to evaluate the effect of an oral healthcare programme in nursing homes on care staff knowledge and attitude regarding oral health. METHODS: The study sample consisted of the nurses and nurses' aides from 63 nursing homes, which either received an oral healthcare programme including mobile dental care or were on a waiting list to receive this programme. A validated questionnaire completed at baseline and again after the study period assessed the care staff knowledge and attitude. Paired t test, independent t test, general linear and linear mixed models were used to examine the changes in attitude and knowledge scores. RESULTS: In total, 546 questionnaires were completed by the same people from 36 nursing homes at baseline and on completion of the study. After the intervention period, knowledge significantly improved in both study groups (I p < 0.001; C p < 0.001), the intervention group significantly showing the largest increase (p < 0.001). The outcome variable attitude only showed a significant improvement in the intervention group (p < 0.001). The mixed models confirmed the impact of some aspects of the intervention on the attitude and the knowledge of the caregivers. CONCLUSIONS: The oral healthcare programme including a mobile dental team resulted in a significant increase of the care staff knowledge and attitude regarding oral health. CLINICAL RELEVANCE: The integration of a dental professional team in nursing home organisations should be encouraged because it could be valuable to tackle barriers for the provision of daily oral hygiene and to support the continuous integration of oral health care into general care.

Persistent triple antiphospholipid antibody positivity as a strong risk factor of first thrombosis, in a long-term follow-up study of patients without history of thrombosis or obstetrical morbidity.

Introduction The long-term risk of first thrombosis and benefit of prophylaxis in antiphospholipid antibody (aPL) carriers without history of thrombosis or obstetrical morbidity is poorly known. This study aimed to evaluate the long-term rate and risk factors associated with a first thrombosis in those patients. Patients and methods After a prior study ended in December 2005 and was already published, we extended the follow-up period of our cohort of aPL carriers. Results Ninety-eight of the 103 patients of the previous study were included. The annual first thrombosis rate was 2.3% per patient-year during a median of 13 years (6-17). None of the baseline characteristics was predictive of risk of first thrombosis, but persistent aPL over time were associated with an increased risk. The stronger association was found in triple aPL-positive carriers: OR 3.38 (95% CI: 1.24-9.22). Of note, conversely to our previous findings, no benefit of aspirin prophylaxis was observed. Conclusion The risk of first thrombosis in aPL carriers without history of thrombosis or obstetrical morbidity was significant, persisted linearly over time and was associated with persistent aPL. This risk was especially increased in triple aPL-positive carriers, in whom a close follow-up seems to be necessary. Nevertheless, the benefit of aspirin prophylaxis remained unclear.

Long term use of metformin in idiopathic cyclic edema, report of thirteen cases and review of the literature.

INTRODUCTION: Idiopathic cyclic edema (ICE) is a rare cause of edema. To date, there is no standard of care. The physiopathology of ICE could be explained by an impairment of capillary permeability. In 1995, a study demonstrated the efficacy of metformin on symptoms and capillary permeability. We evaluated ICE-patients who were treated with metformin in our department. METHODS: We retrospectively included patients diagnosed for ICE between January 1997 and October 2013. ICE was diagnosed in the presence of edema after excluding other etiologies. LANDIS test was used to support ICE diagnosis in all patients. The absence of edema at follow-up was considered as complete response (CR), partial decreased was considered as partial response (PR). Adverse events were recorded. RESULTS: Thirteen patients have accepted to use metformin. The median treatment duration was 28.5 months [8-167] and the median follow-up of treated patients was 40.5 months [14-167]. CR was reached in 10 patients (77%), and PR in 2 patients (15%). Two patients reported side-effects as diarrheas and one of them stopped the treatment due to mild diarrhea. CONCLUSION: We report the interest and tolerance of the long-term use of metformin in ICE. No severe adverse events were noticed. A prospective study is needed to confirm the efficacy of metformin in ICE-patients.

Early detection and integrated care for adolescents and young adults with psychotic disorders: the ACCESS III study.

OBJECTIVE: The objective of the study was to investigate whether a combined intervention composed of early detection plus integrated care (EDIC) enhances outcomes in patients with early psychosis compared to standard care (SC). METHODS: ACCESS III is a prospective non-randomized historical control design 1-year study examining the efficacy of EDIC (n = 120) vs. SC (n = 105) in patients aged 12-29 years. Primary outcome was the rate of ≥6 months combined symptomatic and functional remission. Additional outcomes comprised the reduction of DUP and course of psychopathology, functioning, quality of life, and satisfaction with care. RESULTS: In observed cases, 48.9% in the EDIC and 15.2% in the SC group reached the primary endpoint. Remission was predicted by EDIC (OR = 6.8, CI: 3.15-14.53, P < 0.001); younger age predicted non-remission (OR = 1.1, CI: 1.01-1.19, P = 0.038). Linear regressions indicated a reduction of DUP in EDIC (P < 0.001), but not in SC (P = 0.41). MMRMs showed significantly larger improvements in PANSS positive (P < 0.001) and GAF (P < 0.01) scores in EDIC vs. SC, and in EDIC over time in CGI-Severity (P < 0.001) and numerically in Q-LES-Q-18 (P = 0.052). CONCLUSIONS: EDIC lead to significantly higher proportions of patients achieving combined remission. Moderating variables included a reduction of DUP and EDIC, offering psychotherapeutic interventions.