Maternal age at birth and childhood type 1 diabetes: a pooled analysis of 30 observational studies

OBJECTIVE - The aim if the study was to investigate whether children born to older mothers have an increased risk of type 1 diabetes by performing a pooled analysis of previous studies using individual patient data to adjust for recognized confounders.
RESEARCH DESIGN AND METHODS - Relevant studies published before June 2009 were identified from MEDLINE, Web of Science, and EMBASE. Authors of studies were contacted and asked to provide individual patient data or conduct prespecified analyses. Risk estimates of type 1 diabetes by maternal age were calculated for each study, before and after adjustment for potential confounders. Meta-analysis techniques were used to derive combined odds ratios and to investigate heterogeneity among studies.
RESULTS - Data were available for 5 cohort and 25 case-control studies, including 14,724 cases of type 1 diabetes. Overall, there was, on average, a 5% (95% CI 2-9) increase in childhood type 1 diabetes odds per 5-year increase in maternal age (P = 0.006), but there was heterogeneity among studies (heterogeneity I 2 = 70%). In studies with a low risk of bias, there was a more marked increase in diabetes odds of 10% per 5-year increase in maternal age. Adjustments for potential confounders little altered these estimates. CONCLUSIONS - There was evidence of a weak but significant linear increase in the risk of childhood type 1 diabetes across the range of maternal ages, but the magnitude of association varied between studies. A very small percentage of the increase in the incidence of childhood type 1 diabetes in recent years could be explained by increases in maternal age.

Patterns of alcohol consumption and ischaemic heart disease in culturally divergent countries: The Prospective Epidemiological Study of Myocardial Infarction (PRIME)

Objective: To investigate the effect of alcohol intake patterns on ischaemic heart disease in two countries with contrasting lifestyles, Northern Ireland and France.
Design: Cohort data from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) were analysed. Weekly alcohol consumption, incidence of binge drinking (alcohol >50 g on at least one day a week), incidence of regular drinking (at least one day a week, and alcohol <50 g if on only one occasion), volume of alcohol intake, frequency of consumption, and types of beverage consumed were assessed once at inclusion. All coronary events that occurred during the 10 year follow-up were prospectively registered. The relation between baseline characteristics and incidence of hard coronary events and angina events was assessed by Cox's proportional hazards regression analysis.
Setting: One centre in Northern Ireland (Belfast) and three centres in France (Lille, Strasbourg, and Toulouse).
Participants: 9778 men aged 50-59 free of ischaemic heart disease at baseline, who were recruited between 1991 and 1994.
Main outcome measures: Incident myocardial infarction and coronary death ("hard" coronary events), and incident angina pectoris.
Results: A total of 2405 men from Belfast and 7373 men from the French centres were included in the analyses, 1456 (60.5%) and 6679 (90.6%) of whom reported drinking alcohol at least once a week, respectively. Among drinkers, 12% (173/1456) of men in Belfast drank alcohol every day compared with 75% (5008/6679) of men in France. Mean alcohol consumption was 22.1 g/day in Belfast and 32.8 g/day in France. Binge drinkers comprised 9.4% (227/2405) and 0.5% (33/7373) of the Belfast and France samples, respectively. A total of 683 (7.0%) of the 9778 participants experienced ischaemic heart disease events during the 10 year follow-up: 322 (3.3%) hard coronary events and 361 (3.7%) angina events. Annual incidence of hard coronary events per 1000 person years was 5.63 (95% confidence interval 4.69 to 6.69) in Belfast and 2.78 (95% CI 2.41 to 3.20) in France. After multivariate adjustment for classic cardiovascular risk factors and centre, the hazard ratio for hard coronary events compared with regular drinkers was 1.97 (95% CI 1.21 to 3.22) for binge drinkers, 2.03 (95% CI 1.41 to 2.94) for never drinkers, and 1.57 (95% CI 1.11 to 2.21) for former drinkers for the entire cohort. The hazard ratio for hard coronary events in Belfast compared with in France was 1.76 (95% CI 1.37 to 2.67) before adjustment, and 1.09 (95% CI 0.79 to 1.50) after adjustment for alcohol patterns and wine drinking. Only wine drinking was associated with a lower risk of hard coronary events, irrespective of the country.
Conclusions: Regular and moderate alcohol intake throughout the week, the typical pattern in middle aged men in France, is associated with a low risk of ischaemic heart disease, whereas the binge drinking pattern more prevalent in Belfast confers a higher risk.

Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children (Review)

Abstract
Background: Automated closed loop systems may improve adaptation of the mechanical support to a patient's ventilatory needs and
facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of
ventilation.

Objectives: To compare the duration of weaning from mechanical ventilation for critically ill ventilated adults and children when managed
with automated closed loop systems versus non-automated strategies. Secondary objectives were to determine differences
in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1948 to August 2011); EMBASE (OvidSP) (1980 to August 2011); CINAHL (EBSCOhost) (1982 to August 2011); and the Latin American and Caribbean Health Sciences Literature (LILACS). In addition we received and reviewed auto-alerts for our search strategy in MEDLINE, EMBASE, and CINAHL up to August 2012. Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles.

Selection criteria: We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning
strategies including non-protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an intensive care unit (ICU).

Data collection and analysis: Two authors independently extracted study data and assessed risk of bias. We combined data into forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria.

Main results: Pooled data from 15 eligible trials (14 adult, one paediatric) totalling 1173 participants (1143 adults, 30 children) indicated that automated closed loop systems reduced the geometric mean duration of weaning by 32% (95% CI 19% to 46%, P =0.002), however heterogeneity was substantial (I2 = 89%, P < 0.00001). Reduced weaning duration was found with mixed or
medical ICU populations (43%, 95% CI 8% to 65%, P = 0.02) and Smartcare/PS™ (31%, 95% CI 7% to 49%, P = 0.02) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (17%, 95% CI 8% to 26%) and ICU length of stay (LOS) (11%, 95% CI 0% to 21%). There was no difference in mortality rates or hospital LOS. Overall the quality of evidence was high with the majority of trials rated as low risk.

Authors' conclusions: Automated closed loop systems may result in reduced duration of weaning, ventilation, and ICU stay. Reductions are more
likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized
controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.

Development and independent validation of a prognostic assay for stage ii colon cancer using formalin-fixed paraffin-embedded tissue

Purpose: Current prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray-based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples. Patients and Methods: A gene signature was developed from a balanced set of 73 patients with recurrent disease (high risk) and 142 patients with no recurrence (low risk) within 5 years of surgery. Results: The 634-probe set signature identified high-risk patients with a hazard ratio (HR) of 2.62 (P <.001) during cross validation of the training set. In an independent validation set of 144 samples, the signature identified high-risk patients with an HR of 2.53 (P <.001) for recurrence and an HR of 2.21 (P = .0084) for cancer-related death. Additionally, the signature was shown to perform independently from known prognostic factors (P <.001). Conclusion: This gene signature represents a novel prognostic biomarker for patients with stage II colon cancer that can be applied to FFPE tumor samples. © 2011 by American Society of Clinical Oncology.

Cognitive-behavioural interventions for children who have been sexually abused

Background: Despite differences in how it is defined, there is a general consensus amongst clinicians and researchers that the sexual abuse of children and adolescents (’child sexual abuse’) is a substantial social problem worldwide. The effects of sexual abuse manifest in a wide range of symptoms, including fear, anxiety, post-traumatic stress disorder and various externalising and internalising behaviour problems, such as inappropriate sexual behaviours. Child sexual abuse is associated with increased risk of psychological problems in adulthood. Cognitive-behavioural approaches are used to help children and their non-offending or ’safe’ parent tomanage the sequelae of childhood sexual abuse. This review updates the first Cochrane review of cognitive-behavioural approaches interventions for children who have been sexually abused, which was first published in 2006.

Objectives: To assess the efficacy of cognitive-behavioural approaches (CBT) in addressing the immediate and longer-term sequelae of sexual abuse on children and young people up to 18 years of age.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011 Issue 4); MEDLINE (1950 to November Week
3 2011); EMBASE (1980 to Week 47 2011); CINAHL (1937 to 2 December 2011); PsycINFO (1887 to November Week 5 2011); LILACS (1982 to 2 December 2011) and OpenGrey, previously OpenSIGLE (1980 to 2 December 2011). For this update we also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP).

Selection criteria: We included randomised or quasi-randomised controlled trials of CBT used with children and adolescents up to age 18 years who had experienced being sexually abused, compared with treatment as usual, with or without placebo control.

Data collection and analysis: At least two review authors independently assessed the eligibility of titles and abstracts identified in the search. Two review authors independently extracted data from included studies and entered these into Review Manager 5 software. We synthesised and presented data in both written and graphical form (forest plots).

Main results: We included 10 trials, involving 847 participants. All studies examined CBT programmes provided to children or children and a nonoffending parent. Control groups included wait list controls (n = 1) or treatment as usual (n = 9). Treatment as usual was, for the most part, supportive, unstructured psychotherapy. Generally the reporting of studies was poor. Only four studies were judged ’low risk of bias’ with regards to sequence generation and only one study was judged ’low risk of bias’ in relation to allocation concealment. All studies were judged ’high risk of bias’ in relation to the blinding of outcome assessors or personnel; most studies did not report on these, or other issues of bias. Most studies reported results for study completers rather than for those recruited.

Depression, post-traumatic stress disorder (PTSD), anxiety and child behaviour problems were the primary outcomes. Data suggest that CBT may have a positive impact on the sequelae of child sexual abuse, but most results were not statistically significant. Strongest evidence for positive effects of CBT appears to be in reducing PTSD and anxiety symptoms, but even in these areas effects tend to be 'moderate’ at best. Meta-analysis of data from five studies suggested an average decrease of 1.9 points on the Child Depression Inventory immediately after intervention (95% confidence interval (CI) decrease of 4.0 to increase of 0.4; I2 = 53%; P value for heterogeneity = 0.08), representing a small to moderate effect size. Data from six studies yielded an average decrease of 0.44 standard deviations on a variety of child post-traumatic stress disorder scales (95% CI 0.16 to 0.73; I2 = 46%; P value for heterogeneity = 0.10). Combined data from five studies yielded an average decrease of 0.23 standard deviations on various child anxiety scales (95% CI 0.3 to 0.4; I2=0%; P value for heterogeneity = 0.84). No study reported adverse effects.

Authors’ conclusions: The conclusions of this updated review remain the same as those when it was first published. The review confirms the potential of CBT to address the adverse consequences of child sexual abuse, but highlights the limitations of the evidence base and the need for more carefully conducted and better reported trials.

High-volume haemofiltration for sepsis.

Background: Severe sepsis and septic shock are leading causes of death in the intensive care unit (ICU). This is despite advances in the management of patients with severe sepsis and septic shock including early recognition, source control, timely and appropriate administration of antimicrobial agents, and goal directed haemodynamic, ventilatory and metabolic therapies. High-volume haemofiltration (HVHF) is a blood purification technique which may improve outcomes in critically ill patients with severe sepsis or septic shock. The technique of HVHF has evolved from renal replacement therapies used to treat acute kidney injury (AKI) in critically ill patients in the ICU.

Objectives: This review assessed whether HVHF improves clinical outcome in adult critically ill patients with sepsis in an ICU setting.

Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, Issue 7); MEDLINE (1990 to August 2011), EMBASE (1990 to August 2011); LILACS (1982 to August 2011), Web of Science (1990 to August 2011), CINAHL (1982 to August 2011) and specific websites.

Selection criteria: We included randomized controlled trials (RCTs) and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to standard or usual dialysis therapy; and RCTs and quasi-randomized trials comparing HVHF or high-volume haemodiafiltration to no similar dialysis therapy. The studies involved adults in critical care units.

Data collection and analysis: Three review authors independently extracted data and assessed trial quality. We sought additional information as required from trialists.

Main results: We included three randomized trials involving 64 participants. Due to the small number of studies and participants, it was not possible to combine data or perform sub-group analyses. One trial reported ICU and 28-day mortality, one trial reported hospital mortality and in the third, the number of deaths stated did not match the quoted mortality rates. No trials reported length of stay in ICU or hospital and one reported organ dysfunction. No adverse events were reported. Overall, the included studies had a low risk of bias.

Authors' conclusions: There were no adverse effects of HVHF reported.There is insufficient evidence to recommend the use of HVHF in critically ill patients with severe sepsis and or septic shock except as interventions being investigated in the setting of a randomized clinical trial. These trials should be large, multi-centred and have clinically relevant outcome measures. Financial implications should also be assessed.

Language development at 3 years in pre-term children of birth weight below 1000 g

Language development at 3 years of pre-term children born below 1000 g birth weight was compared with full-term controls matched for social background. The pre-term group used less complex expressive language and showed lower receptive understanding, auditory memory and verbal reasoning. Language outcome was related to intraventricular haemorrhage but not to global indication of postnatal illness such as number of days on the ventilator. Average verbal intelligence in environmentally low risk, extremely low birth weight children is an insufficient indicator of complex language functioning.

The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC(50) of 0.55 mu mol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgV(II) genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15-induced apoptosis. Pharmacologic inhibition of c-jun NH(2)-terminal kinase inhibited PBOX-15-induced apoptosis in mutated IgV(II) and ZAP-70(-) CLL cells but not in unmutated IgV(II) and ZAP-70(+) cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential.

The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes

OBJECTIVE To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.

RESULTS Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).

CONCLUSIONS These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.

Preeclampsia is characterized by the development of hypertension and new-onset proteinuria during the second half of pregnancy (1,2), leading to increased maternal morbidity and mortality (3). Women with type 1 diabetes are at increased risk for development of preeclampsia during pregnancy, with rates being two-times to four-times higher than that of the background maternity population (4,5). Small advances have come from preventive measures, such as low-dose aspirin in women at high risk (6); however, delivery remains the only effective intervention, and preeclampsia is responsible for up to 15% of preterm births and a consequent increase in infant mortality and morbidity (7).

Although the etiology of preeclampsia remains unclear, abnormal placental vascular remodeling and placental ischemia, together with maternal endothelial dysfunction, hemodynamic changes, and renal pathology, contribute to its pathogenesis (8). In addition, over the past decade accumulating evidence has suggested that an imbalance between angiogenic factors, such as placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), plays a key role in the pathogenesis of preeclampsia (8,9). In women at low risk (10–13) and women at high risk (14,15), concentrations of angiogenic and antiangiogenic factors are significantly different between women who later develop preeclampsia (lower PlGF, higher sFlt-1, and higher sEng levels) compared with women who do not.

Few studies have specifically focused on circulating angiogenic factors and risk of preeclampsia in women with diabetes, and the results have been conflicting. In a small study, higher sFlt-1 and lower PlGF were reported at the time of delivery in women with diabetes who developed preeclampsia (16). In a longitudinal prospective cohort of pregnant women with diabetes, Yu et al. (17) reported increased sFlt-1 and reduced PlGF in the early third trimester as potential predictors of preeclampsia in women with type 1 diabetes, but they did not show any difference in sEng levels in women with preeclampsia compared with women without preeclampsia. By contrast, Powers et al. (18) reported only increased sEng in the second trimester in women with pregestational diabetes who developed preeclampsia.

The aim of this study, which was significantly larger than the previous studies highlighted, was to assess the association between circulating angiogenic (PlGF) and antiangiogenic (sFlt-1 and sEng) factors and the risk of preeclampsia in women with type 1 diabetes. A further aim was to evaluate the added predictive ability and clinical usefulness of angiogenic factors and established risk factors for preeclampsia risk prediction in women with type 1 diabetes.

Protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in critically ill paediatric patients

Background:Mechanical ventilation is a critical component of paediatric intensive care therapy. It is indicated when the patient’s spontaneous ventilation is inadequate to sustain life. Weaning is the gradual reduction of ventilatory support and the transfer of respiratory control back to the patient. Weaning may represent a large proportion of the ventilatory period. Prolonged ventilation is associated with significant morbidity, hospital cost, psychosocial and physical risks to the child and even death. Timely and effective weaning may reduce the duration of mechanical ventilation and may reduce the morbidity and mortality associated with prolonged ventilation. However, no consensus has been reached on criteria that can be used to identify when patients are ready to wean or the best way to achieve it.Objectives:To assess the effects of weaning by protocol on invasively ventilated critically ill children. To compare the total duration of invasive mechanical ventilation of critically ill children who are weaned using protocols versus those weaned through usual (non-protocolized) practice. To ascertain any differences between protocolized weaning and usual care in terms of mortality, adverse events, intensive care unit length of stay and quality of life.Search methods:We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 10, 2012), MEDLINE (1966 to October 2012), EMBASE (1988 to October 2012), CINAHL (1982 to October 2012), ISI Web of Science and LILACS. We identified unpublished data in the Web of Science (1990 to October 2012), ISI Conference Proceedings (1990 to October 2012) and Cambridge Scientific Abstracts (earliest to October 2012). We contacted first authors of studies included in the review to obtain further information on unpublished studies or work in progress. We searched reference lists of all identified studies and review papers for further relevant studies. We applied no language or publication restrictions.Selection criteriaWe included randomized controlled trials comparing protocolized weaning (professional-led or computer-driven) versus non-protocolized weaning practice conducted in children older than 28 days and younger than 18 years.Data collection and analysis:Two review authors independently scanned titles and abstracts identified by electronic searching. Three review authors retrieved and evaluated full-text versions of potentially relevant studies, independently extracted data and assessed risk of bias.Main results:We included three trials at low risk of bias with 321 children in the analysis. Protocolized weaning significantly reduced total ventilation time in the largest trial (260 children) by a mean of 32 hours (95% confidence interval (CI) 8 to 56; P = 0.01). Two other trials (30 and 31 children, respectively) reported non-significant reductions with a mean difference of -88 hours (95% CI -228 to 52; P = 0.2) and -24 hours (95% CI -10 to 58; P = 0.06). Protocolized weaning significantly reduced weaning time in these two smaller trials for a mean reduction of 106 hours (95% CI 28 to 184; P = 0.007) and 21 hours (95% CI 9 to 32; P < 0.001). These studies reported no significant effects for duration of mechanical ventilation before weaning, paediatric intensive care unit (PICU) and hospital length of stay, PICU mortality or adverse events.Authors' conclusions:Limited evidence suggests that weaning protocols reduce the duration of mechanical ventilation, but evidence is inadequate to show whether the achievement of shorter ventilation by protocolized weaning causes children benefit or harm.

The distribution of COPD in UK general practice using the new GOLD classification

The new Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 document recommends a combined assessment of chronic obstructive pulmonary disease (COPD) based on current symptoms and future risk.

A large database of primary-care COPD patients across the UK was used to determine COPD distribution and characteristics according to the new GOLD classification. 80 general practices provided patients with a Read code diagnosis of COPD. Electronic and hand searches of patient medical records were undertaken, optimising data capture.

Data for 9219 COPD patients were collected. For the 6283 patients with both forced expiratory volume in 1 s (FEV1) and modified Medical Research Council scores (mean¡SD age 69.2¡10.6 years, body mass index 27.3¡6.2 kg?m-2), GOLD 2011 group distributions were: A (low risk and fewer symptoms) 36.1%, B (low risk and more symptoms) 19.1%, C (high risk and fewer symptoms) 19.6% and D (high risk and more symptoms) 25.3%. This is in contrast with GOLD 2007 stage classification: I (mild) 17.1%, II (moderate) 52.2%, III (severe) 25.5% and IV (very severe) 5.2%. 20% of patients with FEV1 o50% predicted had more than two exacerbations in the previous 12 months. 70% of patients with FEV1 ,50% pred had fewer than two exacerbations in the previous 12 months.

This database, representative of UK primary-care COPD patients, identified greater proportions of patients in the mildest and most severe categories upon comparing 2011 versus 2007 GOLD classifications. Discordance between airflow limitation severity and exacerbation risk was observed.

Automated versus non-automated weaning for reducing the duration of mechanical ventilation in critically ill adults & children (Review)

Background Automated closed loop systems may improve adaptation of mechanical support for a patient's ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. This review was originally published in 2013 with an update published in 2014. Objectives The primary objective for this review was to compare the total duration of weaning from mechanical ventilation, defined as the time from study randomization to successful extubation (as defined by study authors), for critically ill ventilated patients managed with an automated weaning system versus no automated weaning system (usual care). Secondary objectives for this review were to determine differences in the duration of ventilation, intensive care unit (ICU) and hospital lengths of stay (LOS), mortality, and adverse events related to early or delayed extubation with the use of automated weaning systems compared to weaning in the absence of an automated weaning system. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (OvidSP) (1948 to September 2013); EMBASE (OvidSP) (1980 to September 2013); CINAHL (EBSCOhost) (1982 to September 2013); and the Latin American and Caribbean Health Sciences Literature (LILACS). Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles. The original search was run in August 2011, with database auto-alerts up to August 2012. Selection criteria We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning strategies including non-protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an ICU. Data collection and analysis Two authors independently extracted study data and assessed risk of bias. We combined data in forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria. Main results We included 21 trials (19 adult, two paediatric) totaling 1676 participants (1628 adults, 48 children) in this updated review. Pooled data from 16 eligible trials reporting weaning duration indicated that automated closed loop systems reduced the geometric mean duration of weaning by 30% (95% confidence interval (CI) 13% to 45%), however heterogeneity was substantial (I2 = 87%, P < 0.00001). Reduced weaning duration was found with mixed or medical ICU populations (42%, 95% CI 10% to 63%) and Smartcare/PS™ (28%, 95% CI 7% to 49%) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (10%, 95% CI 3% to 16%) and ICU LOS (8%, 95% CI 0% to 15%). There was no strong evidence of an effect on mortality rates, hospital LOS, reintubation rates, self-extubation and use of non-invasive ventilation following extubation. Prolonged mechanical ventilation > 21 days and tracheostomy were reduced in favour of automated systems (relative risk (RR) 0.51, 95% CI 0.27 to 0.95 and RR 0.67, 95% CI 0.50 to 0.90 respectively). Overall the quality of the evidence was high with the majority of trials rated as low risk. Authors' conclusions Automated closed loop systems may result in reduced duration of weaning, ventilation and ICU stay. Reductions are more likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PS™ and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population.

Characterisation of the frequent exacerbator phenotype in COPD patients in a large UK primary care population

BACKGROUND: The 'frequent exacerbator' is recognised as an important phenotype in COPD. Current understanding about this phenotype comes from prospective longitudinal clinical trials in secondary/tertiary care with little information reported in primary care populations.

AIMS: To characterize the frequent-exacerbator phenotype and identify associated risk factors in a large UK primary care COPD population.

METHODS: Using a large database of primary care patients from 80 UK general practices, patients were categorised using GOLD 2014 criteria into high and low risk groups based on exacerbation history. A multivariate logistic regression model was used to investigate covariates associated with the frequent-exacerbator phenotype and risk of experiencing a severe exacerbation (leading to hospitalisation).

RESULTS: Of the total study population (n = 9219), 2612 (28%) fulfilled the criteria for high risk frequent-exacerbators. Independent risk factors (adjusted odds ratio [95% CI]) for ≥2 exacerbations were: most severely impaired modified Medical Research Council (mMRC) dyspnoea score (mMRC grade 4: 4.37 [2.64-7.23]), lower FEV1 percent predicted (FEV1 <30%: 2.42 [1.61-3.65]), co-morbid cardiovascular disease (1.42 [1.19-1.68]), depression (1.56 [1.22-1.99]) or osteoporosis (1.54 [1.19-2.01]), and female gender (1.20 [1.01-1.43]). Older patients (≥75 years), those with most severe lung impairment (FEV1 <30%), those with highest mMRC score and those with co-morbid osteoporosis were identified as most at risk of experiencing exacerbations requiring hospitalisation.

CONCLUSIONS: Although COPD exacerbations occur across all grades of disease severity, female patients with high dyspnoea scores, more severely impaired lung function and co-morbidities are at greatest risk. Elderly patients, with severely impaired lung function, high mMRC scores and osteoporosis are associated with experience of severe exacerbations requiring hospitalisation.

Exercise rehabilitation following intensive care unit discharge for recovery from critical illness

Background: Skeletal muscle wasting and weakness are significant complications of critical illness, associated with the degree of illness severity and periods of reduced mobility during mechanical ventilation. They contribute to the profound physical and functional deficits observed in survivors. These impairments may persist for many years following discharge from the intensive care unit (ICU) and may markedly influence health-related quality of life. Rehabilitation is a key strategy in the recovery of patients following critical illness. Exercise based interventions are aimed at targeting this muscle wasting and weakness. Physical rehabilitation delivered during ICU admission has been systematically evaluated and shown to be beneficial. However its effectiveness when initiated after ICU discharge has yet to be established. Objectives: To assess the effectiveness of exercise rehabilitation programmes, initiated after ICU discharge, on functional exercise capacity and health-related quality of life in adult ICU survivors who have been mechanically ventilated for more than 24 hours. Search methods:We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), OvidSP MEDLINE, Ovid SP EMBASE, and CINAHL via EBSCO host to 15th May 2014. We used a specific search strategy for each database. This included synonyms for ICU and critical illness, exercise training and rehabilitation. We searched the reference lists of included studies and contacted primary authors to obtain further information regarding potentially eligible studies. We also searched major clinical trials registries (Clinical Trials and Current Controlled Trials) and the personal libraries of the review authors. We applied no language or publication restriction. We reran the search in February 2015. We will deal with any studies of interest when we update the review.  Selection criteria:We included randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs) that compared an exercise interventioninitiated after ICU discharge to any other intervention or a control or ‘usual care’ programme in adult (≥18years) survivors ofcritical illness. Data collection and analysis:We used standard methodological procedures expected by The Cochrane Collaboration. Main results:We included six trials (483 adult ICU participants). Exercise-based interventions were delivered on the ward in two studies; both onthe ward and in the community in one study; and in the community in three studies. The duration of the intervention varied according to the length of stay in hospital following ICU discharge (up to a fixed duration of 12 weeks).Risk of bias was variable for all domains across all trials. High risk of bias was evident in all studies for performance bias, although blinding of participants and personnel in therapeutic rehabilitation trials can be pragmatically challenging. Low risk of bias was at least 50% for all other domains across all trials, although high risk of bias was present in one study for random sequence generation (selection bias), incomplete outcome data (attrition bias) and other sources. Risk of bias was unclear for remaining studies across the domains.All six studies measured effect on the primary outcome of functional exercise capacity, although there was wide variability in natureof intervention, outcome measures and associated metrics, and data reporting. Overall quality of the evidence was very low. Only two studies using the same outcome measure for functional exercise capacity, had the potential for pooling of data and assessment of heterogeneity. On statistical advice, this was considered inappropriate to perform this analysis and study findings were therefore qualitatively described. Individually, three studies reported positive results in favour of the intervention. A small benefit (versus. control)was evident in anaerobic threshold in one study (mean difference, MD (95% confidence interval, CI), 1.8 mlO2/kg/min (0.4 to 3.2),P value = 0.02), although this effect was short-term, and in a second study, both incremental (MD 4.7 (95% CI 1.69 to 7.75) Watts, P value = 0.003) and endurance (MD 4.12 (95% CI 0.68 to 7.56) minutes, P value = 0.021) exercise testing demonstrated improvement.Finally self-reported physical function increased significantly following a rehabilitation manual (P value = 0.006). Remaining studies found no effect of the intervention.Similar variability in with regard findings for the primary outcome of health-related quality of life were also evident. Only two studies evaluated this outcome. Following statistical advice, these data again were considered inappropriate for pooling to determine overall effect and assessment of heterogeneity. Qualitative description of findings was therefore undertaken. Individually, neither study reported differences between intervention and control groups for health-related quality of life as a result of the intervention. Overall quality of the evidence was very low.Mortality was reported by all studies, ranging from 0% to 18.8%. Only one non-mortality adverse event was reported across all patients in all studies (a minor musculoskeletal injury). Withdrawals, reported in four studies, ranged from 0% to 26.5% in control groups,and 8.2% to 27.6% in intervention groups. Loss to follow-up, reported in all studies, ranged from 0% to 14% in control groups, and 0% to 12.5% in intervention groups. Authors’ conclusions:We are unable, at this time, to determine an overall effect on functional exercise capacity, or health-related quality of life, of an exercise based intervention initiated after ICU discharge in survivors of critical illness. Meta-analysis of findings was not appropriate. This was due to insufficient study number and data. Individual study findings were inconsistent. Some studies reported a beneficial effect of the intervention on functional exercise capacity, and others not. No effect was reported on health-related quality of life. Methodological rigour was lacking across a number of domains influencing quality of the evidence. There was also wide variability in the characteristics of interventions, outcome measures and associated metrics, and data reporting.If further trials are identified, we may be able to determine the effect of exercise-based interventions following ICU discharge, on functional exercise capacity and health-related quality of life in survivors of critical illness.

Aspirin and folic acid for the prevention of recurrent colorectal adenomas

BACKGROUND & AIMS: Although observational studies have found regular aspirin use to be associated with a reduced risk of colorectal neoplasia, results from randomized trials using aspirin have been inconsistent. Dietary folate intake also has been found to be associated with a reduced risk of colorectal neoplasms in observational studies.

METHODS: A multicenter, randomized, double-blind trial of aspirin (300 mg/day) and folate supplements (0.5 mg/day) to prevent colorectal adenoma recurrence was performed using a 2 x 2 factorial design. All patients had an adenoma (>/=0.5 cm) removed in the 6 months before recruitment and were followed-up at 4-month intervals with a second colonoscopy after approximately 3 years. The primary outcome measure was a colorectal adenoma diagnosed after baseline.

RESULTS: A total of 945 patients were recruited into the study, of whom 853 (90.3%) underwent a second colonoscopy. In total, 99 (22.8%) of 434 patients receiving aspirin had a recurrent adenoma compared with 121 (28.9%) of 419 patients receiving placebo (relative risk, 0.79; 95% confidence interval [CI], 0.63-0.99). A total of 104 patients developed an advanced colorectal adenoma; 41 (9.4%) of these were in the aspirin group and 63 (15.0%) were in the placebo group (relative risk, 0.63; 95% CI, 0.43-0.91). Folate supplementation was found to have no effect on adenoma recurrence (relative risk, 1.07; 95% CI, 0.85-1.34).

CONCLUSIONS: Aspirin (300 mg/day) but not folate (0.5 mg/day) use was found to reduce the risk of colorectal adenoma recurrence, with evidence that aspirin could have a significant role in preventing the development of advanced lesions.