Fondaparinux is an effective alternative to other non-heparin anticoagulants in the treatment of heparin-induced thrombocytopenia

A critical appraisal and clinical application of Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2014;125(6):924-929. doi: 10.1182/blood-2014-09-599498

The relationship between EQ-5D, HAQ and pain in patients with rheumatoid arthritis: further validation and development of the limited dependent variable, mixture model approach

Objective: To provide robust estimates of EQ-5D as a function of the Health Assessment Questionnaire (HAQ) and pain in patients with rheumatoid arthritis. Method: Repeated observations of patients diagnosed with RA in a US observational cohort (n=100,398 observations) who provided data on HAQ, pain on a visual analogue scale and the EQ-5D questionnaire. We use a bespoke mixture modelling approach to appropriately reflect the characteristics of the EQ-5D instrument and compare this to results from linear regression. Results: The addition of pain alongside HAQ as an explanatory variable substantially improves explanatory power. The preferred model is a four component mixture. Unlike the linear regression it exhibits very good fit to the data, does not suffer from problems of bias or predict values outside the feasible range. Conclusions: It is appropriate to model the relationship between HAQ and EQ-5D but only if suitable statistical methods are applied. Linear models underestimate the QALY benefits, and therefore the cost effectiveness, of therapies. The bespoke mixture model approach outlined here overcomes this problem. The addition of pain as an explanatory variable greatly improves the estimates

Structural studies reveal the enantiospecific recognition of a DNA G-quadruplex by a ruthenium polypyridyl complex

Using X-ray crystallography, we show an enantiospecificity in DNA G-quadruplex binding, using the complexes Λ/∆-[Ru(TAP)2(dppz-11-CN)]2+ (TAP=1,4,5,8-tetraazaphenanthrene) containing the dppz (dipyridophenazine) ligand, paralleling the specificity of the complexes with duplex DNA. The Λ complex crystallises with the normally parallel stranded d(TAGGGTTA) tetraplex to give the first such antiparallel strand assembly in which syn-guanosine is adjacent to the complex at the 5’ end of the quadruplex core. SRCD measurements confirm that the same conformational switch occurs in solution. The Δ enantiomer, by contrast, is present in the structure but stacked at the ends of the assembly. In addition, we report the structure of Λ-[Ru(phen)2(11-CN-dppz)]2+ bound to d(TCGGCGCCGA), a duplex forming sequence, and use both structural models to aid in the elucidation of the motif-specific luminescence response of the isostructural phen analogue enantiomers

Electrostatic phase separation: a review

The current understanding and developments in the electrostatic phase separation are reviewed. The literature covers predominantly two immiscible and inter-dispersed liquids following the last review on the topic some 15 years. Electrocoalescence kinetics and governing parameters, such as the applied field, liquid properties, drop shape and flow, are considered. The unfavorable effects, such as chain formation and partial coalescence, are discussed in detail. Moreover, the prospects of microfluidics platforms, non-uniform fields, coalescence on the dielectric surfaces to enhance the electrocoalescence rate are also considered. In addition to the electrocoalescence in water-in-oil emulsions the research in oil-in-oil coalescence is also discussed. Finally the studies in electrocoalescer development and commercial devices are also surveyed. The analysis of the literature reveals that the use of pulsed DC and AC electric fields is preferred over constant DC fields for efficient coalescence; but the selection of the optimum field frequency a priori is still not possible and requires further research. Some recent studies have helped to clarify important aspects of the process such as partial coalescence and drop–drop non-coalescence. On the other hand, some key phenomena such as thin film breakup and chain formation are still unclear. Some designs of inline electrocoalescers have recently been proposed; however with limited success: the inadequate knowledge of the underlying physics still prevents this technology from leaving the realm of empiricism and fully developing in one based on rigorous scientific methodology

The Impact of Moving from EQ-5D-3L to -5L in NICE Technology Appraisals

Background: The EuroQol-5 Dimension (EQ-5D) instrument is the National Institute for Health and Care Excellence (NICE)’s preferred measure of health-related quality of life (QoL) in adults. The three-level (3L) value set is currently recommended for use, but the five-level (5L) set is increasingly being used in practice. Objective: We aimed to explore the impact of moving from 3L to 5L in NICE appraisals. Methods: We adapted our existing mapping for use with health state utility values derived from a population where the original distribution of utilities was unknown. We used this mapping to estimate 5L utilities for 21 comparisons of interventions from models used in NICE technology appraisal decision making, covering a range of disease areas. Results: All utilities increased using 5L, and the differences between highest and lowest utilities decreased. In ten oncology comparisons, using 5L generally increased the incremental quality-adjusted life-years (QALYs) as the benefit from improving survival increased. In four non-oncology comparisons where the intervention improved QoL only, the incremental QALYs decreased as the benefit of improving QoL was reduced. In seven non-oncology comparisons where interventions improved survival and QoL, there was a trade-off between increasing the benefit from survival and decreasing the benefit from improving QoL. Conclusion: 3L and 5L lead to substantially different estimates of incremental QALYs and cost effectiveness. The direction and magnitude of the change is not consistent across case studies. Using 5L instead of 3L may lead to different reimbursement decisions. NICE will face inconsistencies in decision making if it uses 3L and 5L concurrently

Genetic Organisation, Mobility and Predicted Functions of Genes on Integrated, Mobile Genetic Elements in Sequenced Strains of Clostridium difficile

Background: Clostridium difficile is the leading cause of hospital-associated diarrhoea in the US and Europe. Recently the incidence of C. difficile-associated disease has risen dramatically and concomitantly with the emergence of 'hypervirulent' strains associated with more severe disease and increased mortality. C. difficile contains numerous mobile genetic elements, resulting in the potential for a highly plastic genome. In the first sequenced strain, 630, there is one proven conjugative transposon (CTn), Tn5397, and six putative CTns (CTn1, CTn2 and CTn4-7), of which, CTn4 and CTn5 were capable of excision. In the second sequenced strain, R20291, two further CTns were described.Results: CTn1, CTn2 CTn4, CTn5 and CTn7 were shown to excise from the genome of strain 630 and transfer to strain CD37. A putative CTn from R20291, misleadingly termed a phage island previously, was shown to excise and to contain three putative mobilisable transposons, one of which was capable of excision. In silico probing of C. difficile genome sequences with recombinase gene fragments identified new putative conjugative and mobilisable transposons related to the elements in strains 630 and R20291. CTn5-like elements were described occupying different insertion sites in different strains, CTn1-like elements that have lost the ability to excise in some ribotype 027 strains were described and one strain was shown to contain CTn5-like and CTn7-like elements arranged in tandem. Additionally, using bioinformatics, we updated previous gene annotations and predicted novel functions for the accessory gene products on these new elements.Conclusions: The genomes of the C. difficile strains examined contain highly related CTns suggesting recent horizontal gene transfer. Several elements were capable of excision and conjugative transfer. The presence of antibiotic resistance genes and genes predicted to promote adaptation to the intestinal environment suggests that CTns play a role in the interaction of C. difficile with its human host

Valuing health at the end of life: A stated preference discrete choice experiment

A source of debate in the field of health care priority setting is whether health gains should be weighted differently for different groups of patients. The debate has recently focused on the relative value of life extensions for patients with short life expectancy. However, few studies have examined empirically whether society is prepared to fund life-extending end-of-life treatments that would not meet the reimbursement criteria used for other treatments. A web-based discrete choice experiment was conducted in 2012 using a sample of 3969 members of the general public in England and Wales. The study design was informed by the National Institute for Health and Care Excellence's supplementary policy for the appraisal of life-extending end-of-life treatments. The choice tasks involved asking respondents which of two hypothetical patients they would prefer to treat, assuming that the health service has enough funds to treat only one of them. Conditional logit regressions were used for modelling. Choices about which patient to treat were influenced more by the sizes of treatment gains than by patients' life expectancy without treatment. Some respondents appear to support a health-maximisation type objective throughout, whilst a small minority always seek to treat those who are worse off without treatment. The majority of respondents, however, seem to advocate a mixture of the two approaches. Overall, we find little evidence that members of the general public prefer to give higher priority to life-extending end-of-life treatments than to other types of treatment. When asked to make decisions about the treatment of hypothetical patients with relatively short life expectancies, most people's choices are driven by the size of the health gains offered by treatment

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p<0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p<0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication