Solitons on H-bonds in proteins

A model for soliton dynamics on a hydrogen-bond network in helical proteins is proposed. It employs in three dimensions the formalism of fully integrable Toda lattices which admits phonons as well as solitons along the hydrogen-bonds of the helices. A simulation of the three dimensional Toda lattice system shows that the solitons are spontaneously created and are stable and moving along the helix axis. A perturbation on one of the three H-bond lines forms solitons on the other H-bonds as well. The robust solitary wave may explain very long-lived modes in the frequency range of 100 cm$^{-1}$ which are found in recent X-ray laser experiments. The dynamics parameters of the Toda lattice are in accordance with the usual Lennard-Jones parameters used for realistic H-bond potentials in proteins.Comment: 6 pages, 7 figure

Increasing the frequency of hand washing by healthcare workers does not lead to commensurate reductions in staphylococcal infection in a hospital ward

Hand hygiene is generally considered to be the most important measure that can be applied to prevent the spread of healthcare-associated infection (HAI). Continuous emphasis on this intervention has lead to the widespread opinion that HAI rates can be greatly reduced by increased hand hygiene compliance alone. However, this assumes that the effectiveness of hand hygiene is not constrained by other factors and that improved compliance in excess of a given level, in itself, will result in a commensurate reduction in the incidence of HAI. However, several researchers have found the law of diminishing returns to apply to hand hygiene, with the greatest benefits occurring in the first 20% or so of compliance, and others have demonstrated that poor cohorting of nursing staff profoundly influences the effectiveness of hand hygiene measures. Collectively, these findings raise intriguing questions about the extent to which increasing compliance alone can further reduce rates of HAI. In order to investigate these issues further, we constructed a deterministic Ross-Macdonald model and applied it to a hypothetical general medical ward. In this model the transmission of staphylococcal infection was assumed to occur after contact with the transiently colonized hands of HCWs, who, in turn, acquire contamination only by touching colonized patients. The aim of the study was to evaluate the impact of imperfect hand cleansing on the transmission of staphylococcal infection and to identify, whether there is a limit, above which further hand hygiene compliance is unlikely to be of benefit. The model demonstrated that if transmission is solely via the hands of HCWs, it should, under most circumstances, be possible to prevent outbreaks of staphylococcal infection from occurring at a hand cleansing frequencies <50%, even with imperfect hand hygiene. The analysis also indicated that the relationship between hand cleansing efficacy and frequency is not linear - as efficacy decreases, so the hand cleansing frequency required to ensure R0<1 increases disproportionately. Although our study confirmed hand hygiene to be an effective control measure, it demonstrated that the law of diminishing returns applies, with the greatest benefit derived from the first 20% or so of compliance. Indeed, our analysis suggests that there is little benefit to be accrued from very high levels of hand cleansing and that in most situations compliance >40% should be enough to prevent outbreaks of staphylococcal infection occurring, if transmission is solely via the hands of HCWs. Furthermore we identified a non-linear relationship between hand cleansing efficacy and frequency, suggesting that it is important to maximise the efficacy of the hand cleansing process

Improving quality indicator report cards through Bayesian modeling

<p>Abstract</p> <p>Background</p> <p>The National Database for Nursing Quality Indicators^®(NDNQI^®) was established in 1998 to assist hospitals in monitoring indicators of nursing quality (eg, falls and pressure ulcers). Hospitals participating in NDNQI transmit data from nursing units to an NDNQI data repository. Data are summarized and published in reports that allow participating facilities to compare the results for their units with those from other units across the nation. A disadvantage of this reporting scheme is that the sampling variability is not explicit. For example, suppose a small nursing unit that has 2 out of 10 (rate of 20%) patients with pressure ulcers. Should the nursing unit immediately undertake a quality improvement plan because of the rate difference from the national average (7%)?</p> <p>Methods</p> <p>In this paper, we propose approximating 95% credible intervals (CrIs) for unit-level data using statistical models that account for the variability in unit rates for report cards.</p> <p>Results</p> <p>Bayesian CrIs communicate the level of uncertainty of estimates more clearly to decision makers than other significance tests.</p> <p>Conclusion</p> <p>A benefit of this approach is that nursing units would be better able to distinguish problematic or beneficial trends from fluctuations likely due to chance.</p

The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity

The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5(+) malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5(+)-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies

Minimum sample size for external validation of a clinical prediction model with a binary outcome

In prediction model research, external validation is needed to examine an existing model's performance using data independent to that for model development. Current external validation studies often suffer from small sample sizes and consequently imprecise predictive performance estimates. To address this, we propose how to determine the minimum sample size needed for a new external validation study of a prediction model for a binary outcome. Our calculations aim to precisely estimate calibration (Observed/Expected and calibration slope), discrimination (C-statistic), and clinical utility (net benefit). For each measure, we propose closed-form and iterative solutions for calculating the minimum sample size required. These require specifying: (i) target SEs (confidence interval widths) for each estimate of interest, (ii) the anticipated outcome event proportion in the validation population, (iii) the prediction model's anticipated (mis)calibration and variance of linear predictor values in the validation population, and (iv) potential risk thresholds for clinical decision-making. The calculations can also be used to inform whether the sample size of an existing (already collected) dataset is adequate for external validation. We illustrate our proposal for external validation of a prediction model for mechanical heart valve failure with an expected outcome event proportion of 0.018. Calculations suggest at least 9835 participants (177 events) are required to precisely estimate the calibration and discrimination measures, with this number driven by the calibration slope criterion, which we anticipate will often be the case. Also, 6443 participants (116 events) are required to precisely estimate net benefit at a risk threshold of 8%. Software code is provided.</p

The Goldbeter-Koshland switch in the first-order region and its response to dynamic disorder

In their classical work (Proc. Natl. Acad. Sci. USA, 1981, 78:6840-6844), Goldbeter and Koshland mathematically analyzed a reversible covalent modification system which is highly sensitive to the concentration of effectors. Its signal-response curve appears sigmoidal, constituting a biochemical switch. However, the switch behavior only emerges in the "zero-order region", i.e. when the signal molecule concentration is much lower than that of the substrate it modifies. In this work we showed that the switching behavior can also occur under comparable concentrations of signals and substrates, provided that the signal molecules catalyze the modification reaction in cooperation. We also studied the effect of dynamic disorders on the proposed biochemical switch, in which the enzymatic reaction rates, instead of constant, appear as stochastic functions of time. We showed that the system is robust to dynamic disorder at bulk concentration. But if the dynamic disorder is quasi-static, large fluctuations of the switch response behavior may be observed at low concentrations. Such fluctuation is relevant to many biological functions. It can be reduced by either increasing the conformation interconversion rate of the protein, or correlating the enzymatic reaction rates in the network.Comment: 23 pages, 4 figures, accepted by PLOS ON

A Novel BMPR2 Mutation Associated with Pulmonary Arterial Hypertension in an Octogenarian

We describe the case of an 83-year-old man with a family history of pulmonary hypertension (PH) who presented with severe pulmonary arterial hypertension (PAH) and later tested positive for a novel bone morphogenetic protein receptor 2 (BMPR2) gene mutation. To our knowledge, this may be the oldest reported patient with PAH in whom a BMPR2 mutation was initially identified

Effect of ketogenic mediterranean diet with phytoextracts and low carbohydrates/high-protein meals on weight, cardiovascular risk factors, body composition and diet compliance in Italian council employees

<p>Abstract</p> <p>Background</p> <p>There has been increased interest in recent years in very low carbohydrate ketogenic diets (VLCKD) that, even though they are much discussed and often opposed, have undoubtedly been shown to be effective, at least in the short to medium term, as a tool to tackle obesity, hyperlipidemia and some cardiovascular risk factors. For this reason the ketogenic diet represents an interesting option but unfortunately suffers from a low compliance. The aim of this pilot study is to ascertain the safety and effects of a modified ketogenic diet that utilizes ingredients which are low in carbohydrates but are formulated to simulate its aspect and taste and also contain phytoextracts to add beneficial effects of important vegetable components.</p> <p>Methods</p> <p>The study group consisted of 106 Rome council employees with a body mass index of ≥ 25, age between 18 and 65 years (19 male and 87 female; mean age 48.49 ± 10.3). We investigated the effects of a modified ketogenic diet based on green vegetables, olive oil, fish and meat plus dishes composed of high quality protein and virtually zero carbohydrate but which mimic their taste, with the addition of some herbal extracts (KEMEPHY ketogenic Mediterranean with phytoextracts). Calories in the diet were unlimited. Measurements were taken before and after 6 weeks of diet.</p> <p>Results</p> <p>There were no significant changes in BUN, ALT, AST, GGT and blood creatinine. We detected a significant (p < 0.0001) reduction in BMI (31.45 Kg/m²to 29.01 Kg/m²), body weight (86.15 kg to 79.43 Kg), percentage of fat mass (41.24% to 34.99%), waist circumference (106.56 cm to 97.10 cm), total cholesterol (204 mg/dl to 181 mg/dl), LDLc (150 mg/dl to 136 mg/dl), triglycerides (119 mg/dl to 93 mg/dl) and blood glucose (96 mg/dl to 91 mg/dl). There was a significant (p < 0.0001) increase in HDLc (46 mg/dl to 52 mg/dl).</p> <p>Conclusions</p> <p>The KEMEPHY diet lead to weight reduction, improvements in cardiovascular risk markers, reduction in waist circumference and showed good compliance.</p

Foliar δ15N values characterize soil N cycling and reflect nitrate or ammonium preference of plants along a temperate grassland gradient

The natural abundance of stable 15N isotopes in soils and plants is potentially a simple tool to assess ecosystem N dynamics. Several open questions remain, however, in particular regarding the mechanisms driving the variability of foliar δ15N values of non-N2 fixing plants within and across ecosystems. The goal of the work presented here was therefore to: (1) characterize the relationship between soil net mineralization and variability of foliar Δδ15N (δ15Nleaf − δ15Nsoil) values from 20 different plant species within and across 18 grassland sites; (2) to determine in situ if a plant’s preference for NO3− or NH4+ uptake explains variability in foliar Δδ15N among different plant species within an ecosystem; and (3) test if variability in foliar Δδ15N among species or functional group is consistent across 18 grassland sites. Δδ15N values of the 20 different plant species were positively related to soil net mineralization rates across the 18 sites. We found that within a site, foliar Δδ15N values increased with the species’ NO3− to NH4+ uptake ratios. Interestingly, the slope of this relationship differed in direction from previously published studies. Finally, the variability in foliar Δδ15N values among species was not consistent across 18 grassland sites but was significantly influenced by N mineralization rates and the abundance of a particular species in a site. Our findings improve the mechanistic understanding of the commonly observed variability in foliar Δδ15N among different plant species. In particular we were able to show that within a site, foliar δ15N values nicely reflect a plant’s N source but that the direction of the relationship between NO3− to NH4+ uptake and foliar Δδ15N values is not universal. Using a large set of data, our study highlights that foliar Δδ15N values are valuable tools to assess plant N uptake patterns and to characterize the soil N cycle across different ecosystems