Understanding the impact of interventions to prevent antimicrobial resistant infections in the long-term care facility; a review and practical guide to mathematical modelling

(1) To systematically search for all dynamic mathematical models of infectious disease transmission in long-term care facilities (LTCFs); (2) to critically evaluate models of interventions against antimicrobial resistance (AMR) in this setting; and (3) to develop a checklist for hospital epidemiologists and policy makers by which to distinguish good quality models of AMR in LTCFs. The CINAHL, EMBASE, Global Health, MEDLINE, and Scopus databases were systematically searched for studies of dynamic mathematical models set in LTCFs. Models of interventions targeting methicillin-resistant Staphylococcus aureus in LTCFs were critically assessed. Using this analysis, we developed a checklist for good quality mathematical models of AMR in LTCFs. Overall, 18 papers described mathematical models that characterized the spread of infectious diseases in LTCFs, but no models of AMR in gram-negative bacteria in this setting were described. Future models of AMR in LTCFs require a more robust methodology (ie, formal model fitting to data and validation), greater transparency regarding model assumptions, setting-specific data, realistic and current setting-specific parameters, and inclusion of movement dynamics between LTCFs and hospitals. Mathematical models of AMR in gram-negative bacteria in the LTCF setting, where these bacteria are increasingly becoming prevalent, are needed to help guide infection prevention and control. Improvements are required to develop outputs of sufficient quality to help guide interventions and policy in the future. We suggest a checklist of criteria to be used as a practical guide to determine whether a model is robust enough to test policy

An Integrated Proteomic and Transcriptomic Analysis Reveals the Venom Complexity of the Bullet Ant Paraponera clavata.

A critical hurdle in ant venom proteomic investigations is the lack of databases to comprehensively and specifically identify the sequence and function of venom proteins and peptides. To resolve this, we used venom gland transcriptomics to generate a sequence database that was used to assign the tandem mass spectrometry (MS) fragmentation spectra of venom peptides and proteins to specific transcripts. This was performed alongside a shotgun liquid chromatography-mass spectrometry (LC-MS/MS) analysis of the venom to confirm that these assigned transcripts were expressed as proteins. Through the combined transcriptomic and proteomic investigation of Paraponera clavata venom, we identified four times the number of proteins previously identified using 2D-PAGE alone. In addition to this, by mining the transcriptomic data, we identified several novel peptide sequences for future pharmacological investigations, some of which conform with inhibitor cysteine knot motifs. These types of peptides have the potential to be developed into pharmaceutical or bioinsecticide peptides

Against pragmatism: on efficacy, effectiveness and the real world

Explanatory and pragmatic trials represent ends of a continuum of attitudes about clinical trial design. Recent literature argues that pragmatic trials are more informative about clinical care in the real world. Although there is place for more pragmatic studies to inform clinical practice and health policy decision-making, we are concerned that it is generally under-appreciated that extrapolating the results of broadly inclusive pragmatic trials to the care of real patients may often be as problematic as extrapolating the results of narrowly focused explanatory or efficacy trials. Simplistic interpretation of pragmatic trials runs the risk of driving harmful policies

Pressure balance in the multiphase ISM of cosmologically simulated disc galaxies

Pressure balance plays a central role in models of the interstellar medium (ISM), but whether and how pressure balance is realized in a realistic multiphase ISM is not yet well understood. We address this question by using a set of FIRE-2 cosmological zoom-in simulations of Milky Way-mass disc galaxies, in which a multiphase ISM is self-consistently shaped by gravity, cooling, and stellar feedback. We analyse how gravity determines the vertical pressure profile as well as how the total ISM pressure is partitioned between different phases and components (thermal, dispersion/turbulence, and bulk flows). We show that, on average and consistent with previous more idealized simulations, the total ISM pressure balances the weight of the overlying gas. Deviations from vertical pressure balance increase with increasing galactocentric radius and with decreasing averaging scale. The different phases are in rough total pressure equilibrium with one another, but with large deviations from thermal pressure equilibrium owing to kinetic support in the cold and warm phases, which dominate the total pressure near the mid-plane. Bulk flows (e.g. inflows and fountains) are important at a few disc scale heights, while thermal pressure from hot gas dominates at larger heights. Overall, the total mid-plane pressure is well-predicted by the weight of the disc gas and we show that it also scales linearly with the star formation rate surface density (ςSFR). These results support the notion that the Kennicutt-Schmidt relation arises because ςSFR and the gas surface density (ςg) are connected via the ISM mid-plane pressure

Reversibility of Frailty After Bridge-to-Transplant Ventricular Assist Device Implantation or Heart Transplantation.

BACKGROUND: We recently reported that frailty is independently predictive of increased mortality in patients with advanced heart failure referred for heart transplantation (HTx). The aim of this study was to assess the impact of frailty on short-term outcomes after bridge-to-transplant ventricular assist device (BTT-VAD) implantation and/or HTx and to determine if frailty is reversible after these procedures. METHODS: Between August 2013 and August 2016, 100 of 126 consecutive patients underwent frailty assessment using Fried's Frailty Phenotype before surgical intervention: 40 (21 nonfrail, 19 frail) BTT-VAD and 77 (60 nonfrail, 17 frail) HTx-including 17 of the 40 BTT-VAD supported patients. Postprocedural survival, intubation time, intensive care unit, and hospital length of stay were compared between frail and nonfrail groups. Twenty-six frail patients were reassessed at 2 months or longer postintervention. RESULTS: Frail patients had lower survival (63 ± 10% vs 94 ± 3% at 1 year, P = 0.012) and experienced significantly longer intensive care unit (11 vs 5 days, P = 0.002) and hospital (49 vs 25 days, P = 0.003) length of stay after surgical intervention compared with nonfrail patients. Twelve of 13 frail patients improved their frailty score after VAD (4.0 ± 0.8 to 1.4 ± 1.1, P < 0.001) and 12 of 13 frail patients improved their frailty score after HTx (3.2 ± 0.4 to 0.9 ± 0.9, P < 0.001). Handgrip strength and depression improved postintervention. Only a slight improvement in cognitive function was seen postintervention. CONCLUSIONS: Frail patients with advanced heart failure experience increased mortality and morbidity after surgical intervention with BTT-VAD or HTx. Among those who survive frailty is partly or completely reversible underscoring the importance of considering this factor as a dynamic not fixed entity

Competing risk and heterogeneity of treatment effect in clinical trials

It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks – which may or may not be correlated – may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend

Phosphoenolpyruvate carboxylase dentified as a key enzyme in erythrocytic Plasmodium falciparum carbon metabolism

Phospoenolpyruvate carboxylase (PEPC) is absent from humans but encoded in thePlasmodium falciparum genome, suggesting that PEPC has a parasite-specific function. To investigate its importance in P. falciparum, we generated a pepc null mutant (D10Δpepc), which was only achievable when malate, a reduction product of oxaloacetate, was added to the growth medium. D10Δpepc had a severe growth defect in vitro, which was partially reversed by addition of malate or fumarate, suggesting that pepc may be essential in vivo. Targeted metabolomics using 13C-U-D-glucose and 13C-bicarbonate showed that the conversion of glycolytically-derived PEP into malate, fumarate, aspartate and citrate was abolished in D10Δpepc and that pentose phosphate pathway metabolites and glycerol 3-phosphate were present at increased levels. In contrast, metabolism of the carbon skeleton of 13C,15N-U-glutamine was similar in both parasite lines, although the flux was lower in D10Δpepc; it also confirmed the operation of a complete forward TCA cycle in the wild type parasite. Overall, these data confirm the CO2 fixing activity of PEPC and suggest that it provides metabolites essential for TCA cycle anaplerosis and the maintenance of cytosolic and mitochondrial redox balance. Moreover, these findings imply that PEPC may be an exploitable target for future drug discovery

Isolated and dynamical horizons and their applications

Over the past three decades, black holes have played an important role in quantum gravity, mathematical physics, numerical relativity and gravitational wave phenomenology. However, conceptual settings and mathematical models used to discuss them have varied considerably from one area to another. Over the last five years a new, quasi-local framework was introduced to analyze diverse facets of black holes in a unified manner. In this framework, evolving black holes are modeled by dynamical horizons and black holes in equilibrium by isolated horizons. We review basic properties of these horizons and summarize applications to mathematical physics, numerical relativity and quantum gravity. This paradigm has led to significant generalizations of several results in black hole physics. Specifically, it has introduced a more physical setting for black hole thermodynamics and for black hole entropy calculations in quantum gravity; suggested a phenomenological model for hairy black holes; provided novel techniques to extract physics from numerical simulations; and led to new laws governing the dynamics of black holes in exact general relativity.Comment: 77 pages, 12 figures. Typos and references correcte