Echocardiographic estimation of mean pulmonary artery pressure in critically ill patients

BACKGROUND: Indirect assessment of mean pulmonary arterial pressure (MPAP) may assist management of critically ill patients with pulmonary hypertension and right heart dysfunction. MPAP can be estimated as the sum of echocardiographically derived mean right ventricular to right atrial systolic pressure gradient and right atrial pressure; however, this has not been validated in critically ill patients. METHODS: This prospective validation study was conducted in patients undergoing pulmonary artery catheterisation during intensive care admission. Pulmonary artery catheter (PAC) measurements of MPAP were contemporaneously compared to MPAP estimated utilising transthoracic echocardiography (TTE)-derived mean right ventricular to right atrial systolic pressure gradient added to invasively measured right atrial pressure. RESULTS: Of 53 patients assessed, 23 had estimable MPAP using TTE. The mean difference between TTE- and PAC-derived MPAP was 1.9 mmHg (SD 5.0), with upper and lower limits of agreement of 11.6 and −7.9 mmHg, respectively. The median absolute percentage difference between TTE- and PAC-derived MPAP was 7.5%. Inter-rater reliability assessment was performed for 15 patients, giving an intra-class correlation coefficient of 0.96 (95% confidence intervals, 0.89 to 0.99). CONCLUSIONS: This echocardiographic method of estimating MPAP in critically ill patients was not equivalent to invasively measured MPAP, based on our predefined clinically acceptable range (±5 mmHg). The accuracy of this method in critically ill patients was similar to the results obtained in ambulatory patients and compared favourably with regard to the accuracy with echocardiographic estimation of systolic pulmonary arterial pressure. The utility of this technique is limited by frequent inability to obtain an adequate tricuspid regurgitant time-velocity integral in critically ill patients

Organising health care services for people with an acquired brain injury: an overview of systematic reviews and randomised controlled trials

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background Acquired brain injury (ABI) is the leading cause of disability worldwide yet there is little information regarding the most effective way to organise ABI health care services. The aim of this review was to identify the most up-to-date high quality evidence to answer specific questions regarding the organisation of health care services for people with an ABI. Methods We conducted a systematic review of English papers using MEDLINE, EMBASE, PsycINFO, CINAHL and the Cochrane Library. We included the most recently published high quality systematic reviews and any randomised controlled trials, non-randomised controlled trials, controlled before after studies or interrupted time series studies published subsequent to the systematic review. We searched for papers that evaluated pre-defined organisational interventions for adults with an ABI. Organisational interventions of interest included fee-for-service care, integrated care, integrated care pathways, continuity of care, consumer engagement in governance and quality monitoring interventions. Data extraction and appraisal of included reviews and studies was completed independently by two reviewers. Results A total of five systematic reviews and 21 studies were included in the review; eight of the papers (31%) included people with a traumatic brain injury (TBI) or ABI and the remaining papers (69%) included only participants with a diagnosis of stroke. We found evidence supporting the use of integrated care to improve functional outcome and reduce length of stay and evidence supporting early supported discharge teams for reducing morbidity and mortality and reducing length of stay for stroke survivors. There was little evidence to support case management or the use of integrated care pathways for people with ABI. We found evidence that a quality monitoring intervention can lead to improvements in process outcomes in acute and rehabilitation settings. We were unable to find any studies meeting our inclusion criteria regarding fee-for-service care or engaging consumers in the governance of the health care organisation. Conclusions The review found evidence to support integrated care, early supported discharge and quality monitoring interventions however, this evidence was based on studies conducted with people following stroke and may not be appropriate for all people with an ABI

Throwing the rascals out? Problems of accountability in two-party systems

This article critically examines the concept of 'accountability' as it is understood in two-party systems and majoritarian democracy - namely the ability of voters to remove governments that violate their mandates or otherwise perform poorly. Voters' capacity to 'throw the rascals out' is one of the main normative appeals of two-partism and the single-member plurality (SMP) electoral system. However, this article uses a spatial model to show that in at least two types of situation voters are left in a bind when confronted with a mandate-breaking governing party: (1) when both major parties undertake unexpected non-centrist shifts in opposing directions after an election, leaving centrist voters with an unappealing choice; and (2) when a governing party that had won an election on a non-centrist platform undertakes a post-election shift to the centre, leaving its more radical supporters dissatisfied. In each case, voters have four imperfect options: punish the governing party by throwing the rascals out, but in doing so vote for a party that is ideologically more distant; abstain, and withdraw from the democratic process; vote for a minor party that has no hope of influencing government formation, but which might detach enough votes to allow the ideologically more distant major opposition party to win; and forgive the governing party its mandate-breaking. All of these options represent accountability failures. The problems are illustrated with two case studies from two-party systems: the United Kingdom in the mid-1980s and New Zealand in the period 1984-1993. In both instances, many voters found it difficult to 'throw the rascals out' without harming their own interests in the process. The article concludes that accountability may sometimes be better achieved if voters can force a party to share power in coalition with another party in order to 'keep it honest' instead of removing it from government completely, as can happen in multi-party systems based on proportional representation. Thus, although two-partism based on plurality voting is normally regarded as superior to multi-partism and proportional representation on the criterion of accountability, in some instances, the reverse can be true. The article therefore undermines a core normative argument advanced by supporters of majoritarian democracy and SMP

Third-Party Strategy under Plurality Rule: The British Liberal Democrats and the New Zealand Social Credit Party

This paper examines the strategic options facing small centrist third parties in two-party parliamentary systems operating under the single-member district plurality (SMDP) electoral system. It uses a spatial model to show that centrist third parties are better off targeting the 'safe' districts of a major party rather than marginal districts. Furthermore, it is optimal to target one party's districts, not both, to benefit from tactical and protest voting. The paper also questions the implicit conclusion of the median-legislator theorem that pivotality-seeking is the best strategy for a third party, at least under SMDP, because that would usurp voters' ability to select the executive directly, a key feature of two-partism. Finally, the paper shows that third parties can damage themselves if they 'flip' from opposition to one major party to support for it. Evidence is provided for the British Liberal Democrats and New Zealand?s historic Social Credit Party

Molecular Dynamics Simulations Suggest that Electrostatic Funnel Directs Binding of Tamiflu to Influenza N1 Neuraminidases

Oseltamivir (Tamiflu) is currently the frontline antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase, a flu protein responsible for the release of newly synthesized virions. However, oseltamivir resistance has become a critical problem due to rapid mutation of the flu virus. Unfortunately, how mutations actually confer drug resistance is not well understood. In this study, we employ molecular dynamics (MD) and steered molecular dynamics (SMD) simulations, as well as graphics processing unit (GPU)-accelerated electrostatic mapping, to uncover the mechanism behind point mutation induced oseltamivir-resistance in both H5N1 “avian” and H1N1pdm “swine” flu N1-subtype neuraminidases. The simulations reveal an electrostatic binding funnel that plays a key role in directing oseltamivir into and out of its binding site on N1 neuraminidase. The binding pathway for oseltamivir suggests how mutations disrupt drug binding and how new drugs may circumvent the resistance mechanisms

Functional significance of the hemadsorption activity of influenza virus neuraminidase and its alteration in pandemic viruses

Human influenza viruses derive their genes from avian viruses. The neuraminidase (NA) of the avian viruses has, in addition to the catalytic site, a separate sialic acid binding site (hemadsorption site) that is not present in human viruses. The biological significance of the NA hemadsorption activity in avian influenza viruses remained elusive. A sequence database analysis revealed that the NAs of the majority of human H2N2 viruses isolated during the influenza pandemic of 1957 differ from their putative avian precursor by amino acid substitutions in the hemadsorption site. We found that the NA of a representative pandemic virus A/Singapore/1/57 (H2N2) lacks hemadsorption activity and that a single reversion to the avian-virus-like sequence (N367S) restores hemadsorption. Using this hemadsorption-positive NA, we generated three NA variants with substitutions S370L, N400S and W403R that have been found in the hemadsorption site of human H2N2 viruses. Each substitution abolished hemadsorption activity. Although, there was no correlation between hemadsorption activity of the NA variants and their enzymatic activity with respect to monovalent substrates, all four hemadsorption-negative NAs desialylated macromolecular substrates significantly slower than did the hemadsorption-positive counterpart. The NA of the 1918 pandemic virus A/Brevig Mission/1/18 (H1N1) also differed from avian N1 NAs by reduced hemadsorption activity and less efficient hydrolysis of macromolecular substrates. Our data indicate that the hemadsorption site serves to enhance the catalytic efficiency of NA and they suggest that, in addition to changes in the receptor-binding specificity of the hemagglutinin, alterations of the NA are needed for the emergence of pandemic influenza viruses

Preschool hyperactivity specifically elevates long-term mental health risks more strongly in males than females: a prospective longitudinal study through to young adulthood

Evidence of continuities between preschool hyperactivity and adult mental health problems highlight the potential value of targeting early identification and intervention strategies. However, specific risk factors are currently unclear. This large-scale prospective longitudinal study aimed to identify which hyperactive preschoolers are at greatest long-term risk of poor mental health. One hundred and seventy children (89 females) rated as hyperactive by their parents and 88 non-hyperactive controls (48 females) were identified from a community sample of 4,215 3 year-olds. Baseline data relating to behavioral/emotional problems and background characteristics were collected. Follow-up mental health and functional impairment outcomes were collected between 14 and 25 years of age. At age 3 years, males and females in the hyperactive group had similarly raised levels of hyperactivity and other behavior problems. In adolescence/young adulthood, these individuals showed elevated symptoms of ADHD, conduct disorder, mood disorder, anxiety and autism, as well as functional impairment. Preschool hyperactivity was strongly predictive of poor adolescent/adult outcomes for males across domains with effects being specifically driven by hyperactivity. For females, the effects of preschool hyperactivity were smaller and dropped to non-significant levels when other preschool problems were taken into account. Environmental risk factors also differed between the sexes, although these may also have been mediated by genetic risk. In conclusion, these results demonstrate marked sex differences in preschool predictors of later adolescent/adult mental health problems. Future research should include a measure of preschool inattention as well hyperactivity. The findings highlight the potential value of tailored approaches to early identification strategies