Length of intensive care unit stay and the apparent efficacy of antimicrobial-based versus non-antimicrobial-based ventilator pneumonia prevention interventions within the Cochrane review database.

BACKGROUND: The risk of acquiring ventilator-associated pneumonia (VAP) increases with intensive care unit (ICU) length of stay (LOS). The objectives here are to estimate, using data derived from randomized concurrent control trials (RCCTs) of non-antimicrobial versus antimicrobial interventions, the relation of LOS with firstly, apparent VAP prevention effect, and secondly, with VAP incidence in control and intervention groups. METHODS: Control and intervention group data derived from 13 Cochrane reviews of 78 RCCTs of antimicrobial-based interventions versus 111 RCCTs of various non-antimicrobial-based VAP prevention interventions. RESULTS: In meta-regression models of VAP prevention effect versus group mean LOS, the effect size of non-antimicrobial-based interventions regress towards the null (+0.028; +0.002 to +0.054) whereas antimicrobial-based interventions regress away from the null (-0.043; -0.08 to -0.004). The day 9-10 VAP incidence increase is 1.28 (0.97-1.6) percentage points among the control groups of antimicrobial interventions per day. By contrast, these increases among antimicrobial- (0.45; 0.19-0.71) and non-antimicrobial- (0.58; 0.29-0.87) intervention groups and in control groups of non-antimicrobial- (0.76; 0.46-1.05) interventions are all similar. CONCLUSIONS: Antimicrobial-based versus non-antimicrobial-based interventions show overall greater apparent VAP prevention which is most apparent with longer group mean LOS. The basis for this surprising relationship with LOS resides, paradoxically, within the control rather than the intervention groups. This discrepancy implicates indirect (spill-over) effects, inapparent within individual antimicrobial-based RCCTs, which could spuriously conflate the appearance of VAP prevention.

Borderline personality disorder: resource utilisation costs in Ireland.

OBJECTIVES: Borderline personality disorder (BPD) is characterised by recurring crises, hospitalisations, self-harm, suicide attempts, addictions, episodes of depression, anxiety and aggression and lost productivity. The objective of this study is to determine the use of direct health care resources by persons with BPD in Ireland and the corresponding costs. METHODS: This prevalence-based micro-costing study was undertaken on a sample of 196 individuals with BPD attending publicly funded mental health services in Ireland. All health care costs were assessed using a resource utilisation questionnaire completed by mental health practitioners. A probabilistic sensitivity analysis, using a Monte Carlo simulation, was performed to examine uncertainty. RESULTS: Total direct healthcare cost per individual was €10 844 annually (ranging from 5228 to 20 609). Based on a prevalence of 1% and an adult population (18-65 years) of 2.87 million, we derived that there were 28 725 individuals with BPD in Ireland. Total yearly cost of illness was calculated to be up to €311.5 million. CONCLUSIONS: There is a dearth of data on health care resource use and costs of community mental health services in Ireland. The absence of this data is a considerable constraint to research and decision-making in the area of community mental health services. This paper contributes to the limited literature on resource use and costs in community mental health services in Ireland. The absence of productivity loss data (e.g. absenteeism and presenteeism), non-health care costs (e.g. addiction treatment), and indirect costs (e.g. informal care) from study participants is a limitation of this study.

Exosome-based liquid biopsies in cancer: opportunities and challenges.

Liquid biopsy in cancer has gained momentum in clinical research and is experiencing a boom for a variety of applications. There are significant efforts to utilize liquid biopsies in cancer for early detection and treatment stratification, as well as residual disease and recurrence monitoring. Although most efforts have used circulating tumor cells and circulating tumor DNA for this purpose, exosomes and other extracellular vesicles have emerged as a platform with potentially broader and complementary applications. Exosomes/extracellular vesicles are small vesicles released by cells, including cancer cells, into the surrounding biofluids. These exosomes contain tumor-derived materials such as DNA, RNA, protein, lipid, sugar structures, and metabolites. In addition, exosomes carry molecules on their surface that provides clues regarding their origin, making it possible to sort vesicle types and enrich signatures from tissue-specific origins. Exosomes are part of the intercellular communication system and cancer cells frequently use them as biological messengers to benefit their growth. Since exosomes are part of the disease process, they have become of tremendous interest in biomarker research. Exosomes are remarkably stable in biofluids, such as plasma and urine, and can be isolated for clinical evaluation even in the early stages of the disease. Exosome-based biomarkers have quickly become adopted in the clinical arena and the first exosome RNA-based prostate cancer test has already helped >50 000 patients in their decision process and is now included in the National Comprehensive Cancer Network guidelines for early prostate cancer detection. This review will discuss the advantages and challenges of exosome-based liquid biopsies for tumor biomarkers and clinical implementation in the context of circulating tumor DNA and circulating tumor cells.

Using epidemiology to estimate the impact and burden of exposure to air pollutants.

This paper focuses on the use of results of epidemiological studies to quantify the effects on health, particularly on mortality, of long-term exposure to air pollutants. It introduces health impact assessment methods, used to predict the benefits that can be expected from implementation of interventions to reduce emissions of pollutants. It also explains the estimation of annual mortality burdens attributable to current levels of pollution. Burden estimates are intended to meet the need to communicate the size of the effect of air pollution on public health to policy makers and others. The implications, for the interpretation of the estimates, of the assumptions and approximations underlying the methods are discussed. The paper starts with quantification based on results obtained from studies of the association of mortality risk with long-term average concentrations of particulate air pollution. It then tackles the additional methodological considerations that need to be addressed when also considering the mortality effects of other pollutants such as nitrogen dioxide (NO2). Finally, approaches that could be used to integrate morbidity and mortality endpoints in the same assessment are touched upon. This article is part of a discussion meeting issue 'Air quality, past present and future'.

Osteoarthritis year in review 2019: rehabilitation and outcomes.

OBJECTIVE: Inactivity and obesity are risk factors for osteoarthritis (OA) progression. The purpose of this review was to highlight intervention parameters of exercise and lifestyle diet interventions on clinical outcomes in OA that were published over 15 months, starting January 1, 2018. DESIGN: Systematic literature searches were performed in Medline (Pubmed, OVID), Scopus, CINAHL, CENTRAL and Embase from January 1, 2018 to April 1, 2019. Key words included osteoarthritis, exercise, physical activity, diet and nutrition. Randomized controlled designs and data synthesis papers (systematic reviews, meta-analyses, clinical guidelines) written in English, that included humans with OA of any joint were included. Trials were evaluated using the Physiotherapy Evidence Database (PEDro) critical appraisal tool and the Template for Intervention Description and Replication (TIDieR). Systematic reviews and meta-analyses were evaluated using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2). Intervention details (RCTs) and key finding from papers were summarized. RESULTS: Of 540 titles and abstracts retrieved, 147 full articles were reviewed and 53 met the inclusion criteria, comprised of 39 RCTs and 14 synthesis papers. By addressing inactivity, exercise effectively improves clinical outcomes and, based on low-moderate quality evidence, without further damage to cartilage or synovial tissue. By comparison, much less work focused on minimizing obesity. Diet must be combined with exercise to improve pain, but alone, can improve physical function. CONCLUSIONS: Future work is necessary to identify the ideal exercise frequency and intensity and lifestyle diet intervention parameters. Improved adherence to reporting guidelines in future work will greatly enhance the OA rehabilitation field.

Person-centred, integrated and pro-active care for multi-morbid elderly with advanced care needs: a propensity score-matched controlled trial.

BACKGROUND: Person-centred care (PCC) focusing on personalised goals and care plans derived from "What matters to you?" has an impact on single disease outcomes, but studies on multi-morbid elderly are lacking. Furthermore, the combination of PCC, Integrated Care (IC) and Pro-active care are widely recognised as desirable for multi-morbid elderly, yet previous studies focus on single components only, leaving synergies unexplored. The effect of a synergistic intervention, which implements 1) Person-centred goal-oriented care driven by "What matters to you?" with 2) IC and 3) pro-active care is unknown. METHODS: Inspired by theoretical foundations, complexity science, previous health service research and a patient-driven evaluation of care quality, we designed the Patient-Centred Team (PACT) intervention across primary and secondary care. The PACT team collaborate with the patient to make and deliver a person-centred, integrated and proactive multi-morbidity care-plan. The control group receives conventional care. The study design is a pragmatic six months prospective, controlled clinical trial based on hospital electronic health record data of 439 multi-morbid frail elderly at risk for emergency (re) admissions referred to PACT and 779 propensity score matched controls in Norway, 2014-2016. Outcomes are emergency admissions, the sum of emergency inpatient bed days, 30-day readmissions, planned and emergency outpatient visits and mortality at three and six months follow-up. RESULTS: The Rate Ratios (RR) for emergency admissions was 0,9 (95%CI: 0,82-0,99), for sum of emergency bed days 0,68 (95%CI:0,52-0,79) and for 30-days emergency readmissions 0,72 (95%CI: 0,41-1,24). RRs were 2,3 (95%CI: 2,02-2,55) and 0,9 (95%CI: 0,68-1,20) for planned and emergency outpatient visits respectively. The RR for death at 3 months was 0,39 (95% CI: 0,22-0,70) and 0,57 (95% CI: 0,34-0,94) at 6 months. CONCLUSION: Compared with propensity score matched controls, the care process of frail multi-morbid elderly who received the PACT intervention had a reduced risk of high-level emergency care, increased use of low-level planned care, and substantially reduced mortality risk. Further study of process differences between groups is warranted to understand the genesis of these results better. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT02541474 ), registered Sept 2015.

Recommended pre-analytical plasma glucose sampling methodology may distort gestational diabetes mellitus prevalence: implications for diagnostic thresholds.

AIM: Current International Association of the Diabetes and Pregnancy Study Groups/World Health Organization gestational diabetes mellitus (GDM) diagnostic thresholds are based on a landmark study in which the pre-analytical plasma glucose sampling methodology is unclear. Worldwide, plasma glucose pre-analytical sampling methodology practices are divergent. We considered the effects of pre-analytical plasma glucose sampling methodology on GDM prevalence and gestational outcomes. METHODS: This is a retrospective observational cohort study of 1178 pregnant women undergoing an oral glucose tolerance test (OGTT). Of the 1178 pregnant women, a subset of 892 non-GDM women with singleton births undergoing OGTT between 24 and 28 weeks' gestation were investigated for large for gestation age (LGA) outcomes. OGTT were determined using traditional methods (sodium fluoride tubes batched at roomed temperature). We modelled the potential effects of using a recommended pre-analytical plasma glucose methodology (lyophilized citrate tubes) on GDM prevalence. RESULTS: The GDM prevalence in our cohort was 13.5%. The incidence of LGA showed a linear association with maternal plasma glucose that was similar to the association observed in the Hyperglycemia and Adverse Pregnancy Outcome study. Frequency of LGA exceeded 10% at HAPO glucose category 4 (fasting, 4.8 to 4.9 mmol/l; 1-h, 8.7 to 9.5 mmol/l) for fasting and 1-h plasma glucose. The use of a recommended pre-analytical method is projected to increase the prevalence of GDM to 39.2%. CONCLUSION: We challenge the consensus that recommended pre-analytical plasma glucose methodologies are optimal for the accurate diagnosis of GDM. Recommended pre-analytical plasma glucose methods may profoundly over-diagnose GDM. Centres using recommended pre-analytical plasma glucose methodologies may need to reappraise their diagnostic thresholds.

Rapid pre-concentration of mercury in solids and water for isotopic analysis.

The precise quantification of mercury (Hg) stable isotope compositions in low concentration or dilute samples poses analytical challenges due to Hg mass limitations. Common Hg pre-concentration procedures require extended processing times, making rapid Hg stable isotope measurements challenging. Here we present a modified pre-concentration method that combines commonly used Hg reduction and gold trap amalgamation followed by semi-rapid thermal desorption (less than 1 h) and chemical trapping. This custom designed system was demonstrated to perform adequately on multiple trapping matrices including a new bromine monochloride (BrCl) wet oxidant trap (40% 3HNO3:BrCl), capable of trapping consistently in 2 mL volume over a wide range of Hg masses (5-200 ng). The procedure was also shown to work effectively on natural matrices, waters and sediments, producing comparable isotope results to the direct digestion analyses. Here, we present a method that can effectively triple sample throughput in comparison to traditional procedures, and also access lower concentration matrices without compromising the accuracy or precision of Hg isotope measurements.

Turning down the heat: An enhanced understanding of the relationship between urban vegetation and surface temperature at the city scale.

Guiding urban planners on the cooling returns of different configurations of urban vegetation is important to protect urban dwellers from adverse heat impacts. To this end, we estimated statistical models that fused multi-temporal very fine spatial (20 cm) and vertical (1 mm) resolution imagery, that captures the complexity of urban vegetation, with remotely sensed temperature data to assess how urban vegetation configuration influences urban temperatures. Perth, Western Australia, was used as a case-study for this analysis. Panel regression models showed that within a location an increase in tree and shrub cover has a larger cooling effect than grass coverage. On average, holding all else equal, an approximate 1 km2 increase in shrub (tree) cover within a location reduces surface temperatures by 12 °C (5 °C). We included a range of robustness checks for the observed relationships between urban vegetation type and temperature. Geographically weighted regression models showed spatial variation in the cooling effect of different vegetation types; this indicates that i) unobserved factors moderate temperature-vegetation relationships across urban landscapes, and ii) that urban vegetation type and temperature relationships are complex. Machine learning models (Random Forests) were used to further explore complex and non-linear relationships between different urban vegetation configurations and temperature. The Random Forests showed that vegetation type explained 31.84% of the out-of-bag variance in summer surface temperatures, that increased cover of large vegetation within a location increases cooling, and that different configurations of urban vegetation structure can lead to cooling gains. The models in this study were trained with vegetation data capturing local detail, multiple time-periods, and entire city coverage. Thus, these models illustrate the potential to develop locally-detailed and spatially explicit tools to guide planning of vegetation configuration to optimise cooling at local- and city-scales.

A hexagon in Saturn's northern stratosphere surrounding the emerging summertime polar vortex.

Saturn's polar stratosphere exhibits the seasonal growth and dissipation of broad, warm vortices poleward of ~75° latitude, which are strongest in the summer and absent in winter. The longevity of the exploration of the Saturn system by Cassini allows the use of infrared spectroscopy to trace the formation of the North Polar Stratospheric Vortex (NPSV), a region of enhanced temperatures and elevated hydrocarbon abundances at millibar pressures. We constrain the timescales of stratospheric vortex formation and dissipation in both hemispheres. Although the NPSV formed during late northern spring, by the end of Cassini's reconnaissance (shortly after northern summer solstice), it still did not display the contrasts in temperature and composition that were evident at the south pole during southern summer. The newly formed NPSV was bounded by a strengthening stratospheric thermal gradient near 78°N. The emergent boundary was hexagonal, suggesting that the Rossby wave responsible for Saturn's long-lived polar hexagon-which was previously expected to be trapped in the troposphere-can influence the stratospheric temperatures some 300 km above Saturn's clouds.

Paradoxical Acinetobacter-associated ventilator-associated pneumonia incidence rates within prevention studies using respiratory tract applications of topical polymyxin: benchmarking the evidence base.

BACKGROUND: Regimens containing topical polymyxin appear to be more effective in preventing ventilator-associated pneumonia (VAP) than other methods. AIM: To benchmark the incidence rates of Acinetobacter-associated VAP (AAVAP) within component (control and intervention) groups from concurrent controlled studies of polymyxin compared with studies of various VAP prevention methods other than polymyxin (non-polymyxin studies). METHODS: An AAVAP benchmark was derived using data from 77 observational groups without any VAP prevention method under study. Data from 41 non-polymyxin studies provided additional points of reference. The benchmarking was undertaken by meta-regression using generalized estimating equation methods. RESULTS: Within 20 studies of topical polymyxin, the mean AAVAP was 4.6% [95% confidence interval (CI) 3.0-6.9] and 3.7% (95% CI 2.0-5.3) for control and intervention groups, respectively. In contrast, the AAVAP benchmark was 1.5% (95% CI 1.2-2.0). In the AAVAP meta-regression model, group origin from a trauma intensive care unit (+0.55; +0.16 to +0.94, P = 0.006) or membership of a polymyxin control group (+0.64; +0.21 to +1.31, P = 0.023), but not membership of a polymyxin intervention group (+0.24; -0.37 to +0.84, P = 0.45), were significant positive correlates. CONCLUSIONS: The mean incidence of AAVAP within the control groups of studies of topical polymyxin is more than double the benchmark, whereas the incidence rates within the groups of non-polymyxin studies and, paradoxically, polymyxin intervention groups are more similar to the benchmark. These incidence rates, which are paradoxical in the context of an apparent effect against VAP within controlled trials of topical polymyxin-based interventions, force a re-appraisal.

Impact of selective digestive decontamination on respiratory tract Candida among patients with suspected ventilator-associated pneumonia. A meta-analysis.

The purpose here is to establish the incidence of respiratory tract colonization with Candida (RT Candida) among ICU patients receiving mechanical ventilation within studies in the literature. Also of interest is its relationship with candidemia and the relative importance of topical antibiotic (TA) use as within studies of selective digestive decontamination (SDD) versus other candidate risk factors towards it. The incidence of RT Candida was extracted from component (control and intervention) groups decanted from studies of various TA and non-TA ICU infection prevention methods with summary estimates derived using random effects. A benchmark RT Candida incidence to provide overarching calibration was derived using (observational) groups from studies without any prevention method under study. A multi-level regression model of group level data was undertaken using generalized estimating equation (GEE) methods. RT Candida data were sourced from 113 studies. The benchmark RT Candida incidence is 1.3; 0.9-1.8 % (mean and 95 % confidence intervals). Membership of a concurrent control group of a study of SDD (p = 0.02), the group-wide presence of candidemia risk factors (p < 0.001), and proportion of trauma admissions (p = 0.004), but neither the year of study publication, nor membership of any other component group, nor the mode of respiratory sampling are predictive of the RT Candida incidence. RT Candida and candidemia incidences are correlated. RT Candida incidence can serve as a basis for benchmarking. Several relationships have been identified. The increased incidence among concurrent control groups of SDD studies cannot be appreciated in any single study examined in isolation.

Understanding STAT3 signaling in cardiac ischemia.

Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research.

Advances in the management of severe aortic stenosis.

BACKGROUND: Recent developments in the management of severe aortic stenosis have resulted in a paradigm shift in the way we view the condition. Patients previously denied intervention in the form of surgical aortic valve replacement (SAVR) are now candidates for transcatheter aortic valve implantation and the risk and age profiles of those undergoing SAVR are rising with the ageing population. This review article is designed to provide an overview of developments in the surgical management of severe aortic stenosis. We also discuss the expanding role of minimally invasive surgical approaches to outline the current techniques available to treat patients with severe aortic stenosis. METHODS: PubMed was searched using the terms 'severe aortic stenosis', 'surgical aortic valve replacement', 'transcatheter aortic valve replacement', 'mechanical aortic valve replacement' and 'sutureless aortic valve replacement'. Selection of articles was based on peer review, journal and relevance. Where possible articles from high-impact factor peer review journals were included. RESULTS: Minimally invasive operative approaches include mini-sternotomy and mini-thoracotomy. Sutureless aortic prostheses reduce aortic cross-clamp time and cardiopulmonary bypass time; however, long-term follow-up data are unavailable at this time. Mechanical prostheses are advised for those under 60. CONCLUSION: Multiple advances in the surgical management of aortic stenosis have occured in the past decade. An evolving spectrum of surgical and transcatheter interventions is now available depending on patient age and operative risk.

Prevalence of founder mutations in the BRCA1 and BRCA2 genes among unaffected women from the Bahamas.

Population-based testing for BRCA1/2 mutations detects a high proportion of carriers not identified by cancer family history-based testing. We sought to determine whether population-based testing is an effective approach to genetic testing in the Bahamas, where 23% of women with breast cancer carry one of seven founder mutations in the BRCA1 or BRCA2 gene. We determined the prevalence of founder BRCA mutations in 1847 Bahamian women without a personal history of breast or ovarian cancer, unselected for age or family history. We found that 2.8% (20/705) of unaffected women with a family history of breast/ovarian cancer and 0.09% (1/1089) of unaffected women without a family history carry a BRCA mutation. A total of 38% of unaffected women with a known mutation in the family were found to carry the familial mutation. We previously suggested that all Bahamian women with breast or ovarian cancer be offered genetic testing. These current data suggest that additionally all unaffected Bahamian women with a family history of breast/ovarian cancer should be offered genetic testing for the founder BRCA mutations.

Understanding Complete Pathologic Response in Oesophageal Cancer: Implications for Management and Survival.

Despite significant improvement over recent decades, oesophageal cancer survival rates remain poor. Neoadjuvant chemoradiotherapy followed by oesophageal resection is mainstay of therapy for resectable oesophageal tumours. Operative morbidity and mortality associated with oesophagectomy remain high and complications arise in up to 60% of patients. Management strategies have moved towards definitive chemoradiotherapy for a number of tumour sites (head and neck, cervical, and rectal) particularly for squamous pathology. We undertook to perform a review of the current status of morbidity and mortality associated with oesophagectomy, grading systems determining pathologic response, and data from clinical trials managing patients with definitive chemoradiotherapy to inform a discussion on the topic.

Strategies for recruitment of relatives of BRCA mutation carriers to a genetic testing program in the Bahamas.

The prevalence of BRCA1 and BRCA2 mutations among unselected breast cancer patients in the Bahamas is 23%. It is beneficial to advise relatives of mutation carriers that they are candidates for genetic testing. Women who test positive are then eligible for preventive interventions, such as oophorectomy. It is not clear how often relatives of women with a mutation in the Bahamas wish to undergo genetic testing for the family mutation. Furthermore, it is not clear how best to communicate this sensitive information to relatives in order to maximize patient compliance. We offered genetic testing to 202 first-degree relatives of 58 mutation carriers. Of 159 women who were contacted by the proband or other family member, only 14 made an appointment for genetic testing (9%). In contrast, among 32 relatives who were contacted directly by the genetic counselor, 27 came for an appointment (84%). This study suggests that for recruitment of relatives in the Bahamas, direct contact by counselor is preferable to using the proband as an intermediary.