Lifestyle factors and small intestine adenocarcinoma risk: a systematic review and meta-analysis.

Background: Although the incidence of small intestinal adenocarcinoma (SIA) is low, rates are increasing and little information regarding modifiable lifestyle risk factors is available.

Aim: To provide a systematic review of lifestyle factors and SIA risk.

Methods: Ovid MEDLINE, EMBASE and WEB OF SCIENCE were searched from inception to Week 1 October 2013. Nine publications that reported on SIA risk in relation to alcohol intake (n=6), tobacco smoking (n=6), diet (n=5), body mass (n=3), physical activity (n=1), hormone use (n=1) and/or socio-economic status (n=3) were retrieved. Results for alcohol, smoking and SIA risk were pooled using random-effects meta-analyses to produce relative risks (RR) and 95% confidence intervals (CI).

Results: The summary RR for individuals consuming the highest versus lowest category of alcohol intake was 1.51 (95% CI 0.83-2.75; n=5 studies) with significant increased risks emerging in sensitivity analysis with reduced heterogeneity (RR: 1.82, 95% CI: 1.05-3.15; n=4 studies). The pooled SIA RR for individuals in the highest versus lowest category of smoking was 1.24 (95% CI 0.71-2.17; n=5 studies). In relation to dietary factors, high fibre intakes and normal body weight may be protective, while high intakes of red/processed meat and sugary drinks may increase SIA risk. Evidence on socio-economic status and SIA risk was equivocal. Data on other factors were too sparse to draw any conclusions.

Conclusions: Alcohol may be associated with an increased risk of SIA. Further investigation of lifestyle factors, particularly alcohol, smoking and diet, in the aetiology of this cancer is warranted in large consortial studies.

Processes influencing surface interaction and photocatalytic destruction of microcystins on titanium dioxide photocatalysts

Microcystins are a family of hepatotoxic peptides produced by freshwater cyanobacteria. Their occurrence in drinking water is of concern since chronic exposure to these toxins causes tumor promotion. It is therefore essential to establish a reliable treatment strategy that will ensure their removal from potable water. We have previously described the rapid destruction of microcystin-LR using TiO₂ photocatalysis, however, since there are at least 70 microcystin variants it is essential that the destruction of a number of microcystins be evaluated. In this study the dark adsorption and destruction of four microcystins was followed over a range of pH. All four microcystins were destroyed although the efficiency of their removal varied. The two more hydrophobic microcystins (-LW and -LF) were found to have high dark adsorption (98 and 91% at pH 4) in contrast to microcystin-RR, which was found to have almost no (only 2-3%) dark adsorption across all pH. 

Primary care organisational interventions for secondary prevention of IHD: a systematic review and meta-analysis.

Background: Ischaemic heart disease (IHD) is the most common cause of death worldwide.

Aim: To determine the long-term impact of organisational interventions for secondary prevention of IHD.

Design and setting: Systematic review and meta-analysis of studies from CENTRAL, MEDLINE®, Embase, and CINAHL published January 2007 to January 2013.

Method: Searches were conducted for randomised controlled trials of patients with established IHD, with long-term follow-up, of cardiac secondary prevention programmes targeting organisational change in primary care or community settings. A random-effects model was used and risk ratios were calculated.

Results: Five studies were included with 4005 participants. Meta-analysis of four studies with mortality data at 4.7–6 years showed that organisational interventions were associated with approximately 20% reduced mortality, with a risk ratio (RR) for all-cause mortality of 0.79 (95% confidence interval [CI] = 0.66 to 0.93), and a RR for cardiac-related mortality of 0.74 (95% CI = 0.58 to 0.94). Two studies reported mortality data at 10 years. Analysis of these data showed no significant differences between groups. There were insufficient data to conduct a meta-analysis on the effect of interventions on hospital admissions. Additional analyses showed no significant association between organisational interventions and risk factor management or appropriate prescribing at 4.7–6 years.

Conclusion: Cardiac secondary prevention programmes targeting organisational change are associated with a reduced risk of death for at least 4–6 years. There is insufficient evidence to conclude whether this beneficial effect is maintained indefinitely.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND: Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

METHODS: We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

FINDINGS: We received data on 18 766 women (18 206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02).

INTERPRETATION: Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

FUNDING: Cancer Research UK, Medical Research Council.

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

BACKGROUND: The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.

METHODS: We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).

FINDINGS: In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar.

INTERPRETATION: Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment.

FUNDING: Cancer Research UK, Medical Research Council.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.

PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.

RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).

CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer

PURPOSE: There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.

EXPERIMENTAL DESIGN: A total of 132 patients treated with first-line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR).

RESULTS: The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31-0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36-0.99; adjusted P = 0.046, respectively). The minor allele of HIF1α rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (P(act) = 0.003).

CONCLUSION: In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy.

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals

Background: Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke. 

Methods We identified published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-effects meta-analysis to combine effect estimates from published and unpublished data. 

Findings We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603 838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528 908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5·1 million person-years (mean 8·5 years), in which 4768 events were recorded, and for stroke was 3·8 million person-years (mean 7·2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35-40 h per week), working long hours (≥55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1·13, 95% CI 1·02-1·26; p=0·02) and incident stroke (1·33, 1·11-1·61; p=0·002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and different methods of stroke ascertainment (range of RR estimates 1·30-1·42). We recorded a dose-response association for stroke, with RR estimates of 1·10 (95% CI 0·94-1·28; p=0·24) for 41-48 working hours, 1·27 (1·03-1·56; p=0·03) for 49-54 working hours, and 1·33 (1·11-1·61; p=0·002) for 55 working hours or more per week compared with standard working hours (p_trend<0·0001).

Interpretation Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours. 

Effectiveness of a short message reminder in increasing compliance with pediatric cataract treatment:A randomized trial

Objective: Regular follow-up is essential to successful management of childhood cataract. We sought to assess whether a mobile phone short message service (SMS) for parents of children with cataract could improve follow-up adherence and the proportion of procedures performed in timely fashion. Design: Randomized, controlled trial. This trial is registered with ClinicalTrials.gov, NCT01417819. Participants: We included 258 parent-child pairs involved in the Childhood Cataract Program of the Chinese Ministry of Health. Methods: Participants were randomized (1:1) to a mobile phone SMS intervention or standard follow-up appointments. All participants were scheduled to attend <4 follow-up appointments according to the protocol. Parents in the intervention group received SMS automated reminders before scheduled appointments. The control group parents did not receive SMSs or any alternative reminder of scheduled appointments. Regular ocular examinations and analyses were performed by investigators masked to group allocation; however, study participants and the manager in charge of randomization and sending SMSs were not masked. Main Outcome Measures: Number of follow-up appointments attended, additional surgeries, laser treatments, changes in eyeglasses prescription, and occurrence of secondary ocular hypertension. Results: Among parent-child participants, 135 were randomly assigned to the SMS intervention and 123 to standard appointments. Attendance rates for the SMS group (first visit, 97.8%; second, 91.9%; third, 92.6%; fourth, 83%) were significantly higher than those for the control group (first visit, 87.8%; second, 69.9%; third, 56.9%; fourth, 33.3%). The increase in attendance rate for total number of follow-up visits with SMS reminders was 47.2% (relative risk [RR] for attendance, 1.47; 95% confidence interval [CI], 1.16-1.78; P = 0.003). The number needed to remind (NNR) to gain 1 additional visit by 1 child was 3 (95% CI, 1.8-4.2). A total of 247 clinical interventions were carried out in the SMS group and 134 in the control group (RR, 1.68; 95% CI, 1.37-1.99; P = 0.007). The NNR to result in 1 additional clinical intervention was 5 (95% CI, 3.5-6.5). Conclusions: The SMS reminders significantly improved follow-up adherence in pediatric cataract treatment. Using readily available mobile phone resources may be an effective and economic strategy to improve management of childhood cataract in China. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2012 American Academy of Ophthalmology.

Prevalence of the different types of age-related cataract in an African population.

PURPOSE: To describe the prevalence of different types of cataract and their association with visual acuity in a Tanzanian population aged 40 years and older. METHODS: A prevalence survey for lens opacity, glaucoma, and visual impairment was carried out on all residents age 40 and older of six villages in Kongwa, Tanzania. One examiner graded the lens for presence of nuclear (NSC), posterior subcapsular (PSC), and cortical cataract (CC), using the new WHO Simplified Cataract Grading System. Visual acuity was measured in each eye, both presenting and best corrected, using an illiterate E chart. RESULTS: The proportion of eligible subjects participating was 90% (3268/3641). The prevalence of cataract was as follows: NSC, 15.6%; CC, 8.8%; and PSC, 1.9%. All types of cataract increased with age, from NSC, 1.7%; CC, 2.4%; and PSC, 0.4% for those aged 40 to 49 years to NSC, 59.2%; CC, 23.5%; and PSC, 5.9% for those aged 70 years and older (P < 0.0001 for all cataract types, chi(2) test for trend). Cataract prevalence was higher among women than men for NSC (P = 0.0001), but not for CC (P = 0.15) or PSC (P = 0.25), after adjusting for age. Prevalence rates of visual impairment (BCVA < 6/12), US blindness (< or = 6/60) and WHO blindness (< 6/120) for this population were 13.3%, 2.1%, and 1.3%, respectively. Older age and each of the major types of pure and mixed cataract were independently associated with worse vision in regression modeling. CONCLUSIONS: Unlike African-derived populations in Salisbury and Barbados, NSC rather than CC was most prevalent in this African population. The seeming lower prevalence of CC may to some extent be explained by different grading schemes, differential availability of cataract surgery, the younger mean age of the Tanzanian subjects, and a higher prevalence of NSC in this population.

Risk factors (excluding hormone therapy) for endometrial hyperplasia: a systematic review.

Objective: To conduct a systematic review of risk factors associated with the development of Endometrial Hyperplasia (EH).

Data sources: Ovid MEDLINE, EMBASE and Web of Science databases were searched from inception to 30 June 2015.

Study eligibility: Fifteen observational studies that reported on EH risk in relation to lifestyle factors (n=14), medical history (n=11), reproductive and menstrual history (n=9) and measures of socio-economic status (n=2) were identified. Pooled relative risk estimates and corresponding 95% confidence intervals (CI) were able to be derived for EH and Body Mass Index (BMI), smoking, diabetes and hypertension, using random effects models comparing high versus low categories.

Results: The pooled relative risk for EH when comparing women with the highest versus lowest BMI was 1.82 (95% CI 1.22–2.71; n=7 studies, I2=90.4%). No significant associations were observed for EH risk for smokers compared with non-smokers (RR 0.88, 95% CI 0.66-1.17; n=3, I2=0.0%), hypertensive versus normotensive women (RR 1.51, 95% CI 0.72–3.15; n=5 studies, I2=79.1%), or diabetic versus non-diabetic women (RR 1.77, 95% CI 0.79–3.96; n=5 studies, I2=31.8%) respectively although the number of included studies was limited. There were mixed reports on the relationship between age and risk of EH. Too few studies reported on other factors to reach any conclusions in relation to EH risk.

Conclusions: A high BMI was associated with an increased risk of EH, providing additional rationale for women to maintain a normal body weight. No significant associations were detected for other factors and EH risk, however relatively few studies have been conducted and few of the available studies adequately adjusted for relevant confounders. Therefore, further aetiological studies of endometrial hyperplasia are warranted.

A validated UPLC–MS/MS method for the surveillance of ten aquatic biotoxins in European brackish and freshwater systems

Over the past few decades, there has been an increased frequency and duration of cyanobacterial Harmful Algal Blooms (HABs) in freshwater systems globally. These can produce secondary metabolites called cyanotoxins, many of which are hepatotoxins, raising concerns about repeated exposure through ingestion of contaminated drinking water or food or through recreational activities such as bathing/ swimming. An ultra-performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) multi-toxin method has been developed and validated for freshwater cyanotoxins; microcystins-LR, -YR, -RR, -LA, -LY and -LF, nodularin, cylindrospermopsin, anatoxin-a and the marine diatom toxin domoic acid. Separation was achieved in around 9 min and dual SPE was incorporated providing detection limits of between 0.3 and 5.6 ng/L of original sample. Intra- and inter-day precision analysis showed relative
standard deviations (RSD) of 1.2–9.6% and 1.3–12.0% respectively. The method was applied to the analysis of aquatic samples (n = 206) from six European countries. The main class detected were the hepatotoxins; microcystin-YR (n = 22), cylindrospermopsin (n = 25), microcystin-RR (n = 17), microcystin-LR (n = 12), microcystin-LY (n = 1), microcystin-LF (n = 1) and nodularin (n = 5). For microcystins, the levels detected ranged from 0.001 to 1.51 mg/L, with two samples showing combined levels above the guideline set by the WHO of 1 mg/L for microcystin-LR. Several samples presented with multiple toxins indicating the potential for synergistic effects and possibly enhanced toxicity. This is the first published pan European survey of freshwater bodies for multiple biotoxins, including two identified for the first time; cylindrospermopsin in Ireland and nodularin in Germany, presenting further incentives for improved monitoring and development of strategies to mitigate human exposure.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review

BACKGROUND: Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents.

OBJECTIVES: To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs.

DATA SOURCES: We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014.

METHODS: Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis.

RESULTS: Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001).

LIMITATIONS: Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors.

CONCLUSIONS: Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014101.

FUNDING: The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Regularization and Bang-bang conjugate times in optimal control

Consideramos o problema de controlo óptimo de tempo mínimo para sistemas de controlo mono-entrada e controlo afim num espaço de dimensão finita com condições inicial e final fixas, onde o controlo escalar toma valores num intervalo fechado. Quando aplicamos o método de tiro a este problema, vários obstáculos podem surgir uma vez que a função de tiro não é diferenciável quando o controlo é bang-bang. No caso bang-bang os tempos conjugados são teoricamente bem definidos para este tipo de sistemas de controlo, contudo os algoritmos computacionais directos disponíveis são de difícil aplicação. Por outro lado, no caso suave o conceito teórico e prático de tempos conjugados é bem conhecido, e ferramentas computacionais eficazes estão disponíveis. Propomos um procedimento de regularização para o qual as soluções do problema de tempo mínimo correspondente dependem de um parâmetro real positivo suficientemente pequeno e são definidas por funções suaves em relação à variável tempo, facilitando a aplicação do método de tiro simples. Provamos, sob hipóteses convenientes, a convergência forte das soluções do problema regularizado para a solução do problema inicial, quando o parâmetro real tende para zero. A determinação de tempos conjugados das trajectórias localmente óptimas do problema regularizado enquadra-se na teoria suave conhecida. Provamos, sob hipóteses adequadas, a convergência do primeiro tempo conjugado do problema regularizado para o primeiro tempo conjugado do problema inicial bang-bang, quando o parâmetro real tende para zero. Consequentemente, obtemos um algoritmo eficiente para a computação de tempos conjugados no caso bang-bang.

A influência da estimulação auditiva na pessoa em coma

Este estudo teve como finalidade compreender os efeitos da estimulação auditiva com uma voz desconhecida e familiar, na pessoa em coma nos parâmetros e curvas monitorizados em ambiente de cuidados intensivos. A revisão da literatura acerca da comunicação verbal em cuidados intensivos e consequente análise de conteúdo foi utilizada para construir a mensagem estímulo, que foi refinada e validada por um grupo de peritos. Esta mensagem é constituída por três partes: apresentação e orientação, informação e avaliação funcional e estimulação, e serviu como referência para a gravação das mensagens no estudo que se seguiu. Neste estudo também foi traduzida, adaptada para a realidade Portuguesa e convertida em linguagem CIPE® a Coma Recovery Scale – Revised, que deu origem ao Instrumento de Avaliação da Recuperação do Coma da Universidade de Aveiro (IARCUA), que foi sujeito a testes de fiabilidade.Os resultados da análise sugerem que o referido instrumento pode ser utilizado com fiabilidade, mesmo quando existem algumas flutuações no estado clínico das pessoas. A correlação dos scores das subescalas foi elevada e superior aos resultados apresentados para a escala original, indicando que esta escala é um instrumento indicado para a avaliação da função neuro-comportamental. O estudo da influência da estimulação auditiva foi realizado com uma amostra de 10 pessoas em coma internadas no Serviço de Cuidados Intensivos do Hospital de Santo António, no ano de 2009, com total autorização da Comissão de Ética do referido Hospital, sendo a selecção baseada numa avaliação preliminar através do instrumento referido e avaliação dos potenciais evocados auditivos do tronco cerebral. A pessoa significativa foi seleccionada através da aplicação de testes sociométricos. A todos os participantes foram dadas informações escritas acerca do estudo e foi concedido um período de tempo para reflexão e posterior decisão acerca da autorização ou não da aplicação do estudo. O tempo total de recolha de dados foi de 45 minutos distribuídos equitativamente por três períodos: pré-estimulação, estimulação e pós-estimulação. Os valores recolhidos foram os das curvas de ECG, das pressões arteriais e pletismografia de pulso e dos parâmetros de frequência cardíaca, pressão arterial sistólica, diastólica e média, temperatura corporal periférica e saturação parcial de oxigénio, utilizando-se o programa Datex-Ohmeda S/5 Collect para o efeito. A análise estatística e clínica dos dados, foi realizada por períodos de estimulação e fases da mensagem estímulo, aplicando-se testes estatísticos e uma análise baseada em critérios de relevância clínica.Os resultados demonstraram que na estimulação com uma voz desconhecida se verificou um aumento dos valores da frequência cardíaca, dos valores das pressões arteriais sistólicas, diastólicas e médias, na transição entre os períodos de préestimulação e estimulação e que estes valores tendem a normalizar quando termina a estimulação. Estas alterações foram corroboradas pela análise dos intervalos RR e da curva de pressões arteriais. Em relação à estimulação com uma voz familiar, as pessoas também reagiram aquando da estimulação com aumento dos valores da frequência cardíaca e dos valores das pressões arteriais sistólicas, diastólicas e médias. No entanto em alguns casos verificámos que os valores destes parâmetros continuaram a aumentar no período de pós-estimulação, o que revela que os utentes desenvolveram episódios de ansiedade de separação. Relativamente à temperatura corporal periférica e saturação parcial de oxigénio, em ambos os casos, não verificámos alterações aquando da estimulação. Relativamente às fases da mensagem estímulo, durante a estimulação com uma voz desconhecida, os participantes apresentaram uma maior variabilidade nos valores da frequência cardíaca, pressões arteriais sistólica, diastólica e média na fase de avaliação funcional e estimulação. Esta constatação é corroborada pela análise das curvas monitorizadas. Em relação à estimulação com uma voz familiar, além de reagirem nos mesmos parâmetros com maior intensidade na fase de avaliação funcional e estimulação, os participantes também reagiram de forma relevante na fase de apresentação e orientação. Este estudo contribui para a reflexão sobre a prática comunicacional com as pessoas inconscientes, no sentido de sensibilizar os enfermeiros e outros profissionais de saúde para a importância da comunicação nas unidades de cuidados intensivos e contribuir igualmente para a melhoria da qualidade de cuidados.