European legislation impedes critical care research and fails to protect patients' rights

The European Clinical Trials Directive requires an informed consent from the patient or a proxy in drug trials. Although informed consent is a valuable tool to protect patients' rights in clinical trials, this requirement largely impedes research in critical care settings, and if pursued in this context, it does not provide the patient with adequate protection. Instead of insisting on informed consent, we suggest that the focus should be shifted towards two other ethically relevant elements in human experimentation: risk assessment and selection of research subjects. When reviewing protocols in which a waiver of consent is deemed necessary, the Ethical Review Board should ensure that non-therapeutic risks are minimal, that the research is specifically designed to benefit critically ill patients, and that it cannot be conducted under circumstances where an informed consent can be obtained. If the European Directive is changed accordingly, this permits clinical trials in critical care settings, while adequate protection from risky non-therapeutic procedures is ensured and exploitation of the patient as an easily accessible research subject is prevented

Real-world evidence was feasible for estimating effectiveness of chemotherapy in breast cancer; a cohort study

Objective: Evidence-based guidelines recommend adjuvant chemotherapy in early stage breast cancer whenever treatment benefit is considered sufficient to outweigh the associated risks. However, many groups of patients were either excluded from or underrepresented in the clinical trials that form the evidence base for this recommendation. This study aims to determine whether using administrative healthcare data – Real World Data (RWD) - and econometric methods for causal analysis to provide ‘Real World Evidence’ (RWE) are feasible methods for addressing this gap.Methods: Cases of primary breast cancer in women from 2001 to 2015 were extracted from the Scottish cancer registry (SMR06) and linked to other routine health records (inpatient and outpatient visits). Four methods were used to estimate the effect of adjuvant chemotherapy on disease-specific and overall mortality: (1) regression with adjustment for covariates (2) propensity score matching (3) instrumental variables analysis and (4) regression discontinuity design. Hazard ratios for breast cancer mortality and all-cause mortality were compared to those from a meta-analysis of randomised trials.Results: 39,805 cases included in the analyses. Regression adjustment, propensity score matching and instrumental variables were feasible while regression discontinuity was not. Effectiveness estimates were similar between RWE and randomised trials for breast cancer mortality but not for all-cause mortality.Conclusions: RWE methods are a feasible means to generate estimates of effectiveness of adjuvant chemotherapy in early stage breast cancer. However, such estimates must be interpreted in the context of the available randomised evidence and the potential biases of the observational methods.<br/

Combining visible near-infrared spectroscopy and water vapor sorption for soil specific surface area estimation

Abstract The soil specific surface area (SSA) is a fundamental property governing a range of soil processes relevant to engineering, environmental, and agricultural applications. A method for SSA determination based on a combination of visible near‐infrared spectroscopy (vis‐NIRS) and vapor sorption isotherm measurements was proposed. Two models for water vapor sorption isotherms (WSIs) were used: the Tuller–Or (TO) and the Guggenheim–Anderson–de Boer (GAB) model. They were parameterized with sorption isotherm measurements and applied for SSA estimation for a wide range of soils (N = 270) from 27 countries. The generated vis‐NIRS models were compared with models where the SSA was determined with the ethylene glycol monoethyl ether (EGME) method. Different regression techniques were tested and included partial least squares (PLS), support vector machines (SVM), and artificial neural networks (ANN). The effect of dataset subdivision based on EGME values on model performance was also tested. Successful calibration models for SSATO and SSAGAB were generated and were nearly identical to that of SSAEGME. The performance of models was dependent on the range and variation in SSA values. However, the comparison using selected validation samples indicated no significant differences in the estimated SSATO, SSAGAB, and SSAEGME, with an average standardized RMSE (SRMSE = RMSE/range) of 0.07, 0.06 and 0.07, respectively. Small differences among the regression techniques were found, yet SVM performed best. The results of this study indicate that the combination of vis‐NIRS with the WSI as a reference technique for vis‐NIRS models provides SSA estimations akin to the EGME method

Bedside rationing by general practitioners: A postal survey in the Danish public healthcare system

<p>Abstract</p> <p>Background</p> <p>It is ethically controversial whether medical doctors are morally permitted to ration the care of their patients at the bedside. To explore whether general practitioners in fact do ration in this manner we conducted a study within primary care in the Danish public healthcare system. The purpose of the study was to measure the extent to which general practitioners (GPs) would be willing to factor in cost-quality trade-offs when prescribing medicine, and to discover whether, and if so to what extent, they believe that patients should be informed about this.</p> <p>Methods</p> <p>Postal survey of 600 randomly selected Danish GPs, of which 330 responded to the questionnaire. The Statistical Package for the Social Sciences (SPSS, version 14.0) was used to produce general descriptive statistics. Significance was calculated with the McNemar and the chi-square test. The main outcome measures of the study were twofold: an assessment of the proportion of GPs who, in a mainly hypothetical setting, would consider cost-quality trade-offs relevant to their clinical decision-making given their economic impact on the healthcare system; and a measure of the extent to which they would disclose this information to patients.</p> <p>Results</p> <p>In the hypothetical setting 95% of GPs considered cost-quality trade-offs relevant to their clinical decision-making given the economic impact of such trade-offs on the healthcare system. In all 90% stated that this consideration had been relevant in clinical decision-making within the last month. In the hypothetical setting 55% would inform their patients that they considered a cost-quality trade-off relevant to their clinical decisions given the economic impact of such trade-offs on the healthcare system. The most common reason (68%) given for not wanting to inform patients about this matter was the belief that the information would not prove useful to patients. In the hypothetical setting cost-quality trade-offs were considered relevant significantly more often in connection with concerns about costs to the patient (86%) than they were in connection with concerns about costs to the healthcare system (55%; p < 0.001).</p> <p>Conclusion</p> <p>Although readiness to consider cost-quality trade-offs relevant to clinical decisions is prevalent among GPs in Denmark, only half of GPs would disclose to patients that they consider this relevant to their clinical decision-making. The results of this study raise two important ethical problems. First, under Danish law physicians are required to inform patients about all equal treatments. The fact that only a few GPs would inform their patients about all of the relevant treatments therefore seems to contravene Danish law. Second, it is ethically controversial that physicians act as economic gatekeepers.</p

Allocating Family Responsibilities for Dependent Older People in Mexico and Peru

This paper applies different analytical frameworks to explore processes of family bargaining about providing care for dependent older people in Mexico and Peru. These frameworks include cultural norms, life course effects and material exchange. The paper is based on 19 in-depth qualitative family case studies, which are linked to a wider set of quantitative survey data. Care arrangements and bargaining processes are revealed to be highly gendered, and largely conform to prevailing cultural norms. Rather than neutral and objective, the self-identified role as main carer is found to be subjective and potentially ambiguous. The few men who self-identify as main carers are more likely to play an indirect, organisational role than engage directly in daily care. As such, bargaining mainly relates to which woman performs the main care role, and large family networks mean that there is usually more than one candidate carer. Bargaining can occur inter-generationally and conjugally, but bargaining between siblings is of particular importance. Bargaining is framed by the uncertain trajectory of older people’s care needs, and arrangements are sometimes reconfigured in response to changing care needs or family circumstances. Taking the narratives at face value, the influence of life course effects on bargaining and care arrangements is more obvious than material exchange. There are, however, indications that economic considerations, particularly inheritance, still play an important behind the scenes role

A reversible light- and genotype-dependent acquired thermotolerance response protects the potato plant from damage due to excessive temperature

A powerful acquired thermotolerance response in potato was demonstrated and characterised in detail, showing the time course required for tolerance, the reversibility of the process and requirement for light. Potato is particularly vulnerable to increased temperature, considered to be the most important uncontrollable factor affecting growth and yield of this globally significant crop. Here, we describe an acquired thermotolerance response in potato, whereby treatment at a mildly elevated temperature primes the plant for more severe heat stress. We define the time course for acquiring thermotolerance and demonstrate that light is essential for the process. In all four commercial tetraploid cultivars that were tested, acquisition of thermotolerance by priming was required for tolerance at elevated temperature. Accessions from several wild-type species and diploid genotypes did not require priming for heat tolerance under the test conditions employed, suggesting that useful variation for this trait exists. Physiological, transcriptomic and metabolomic approaches were employed to elucidate potential mechanisms that underpin the acquisition of heat tolerance. This analysis indicated a role for cell wall modification, auxin and ethylene signalling, and chromatin remodelling in acclimatory priming resulting in reduced metabolic perturbation and delayed stress responses in acclimated plants following transfer to 40 °C

Orbital redistribution in molecular nanostructures mediated by metal-organic bonds

Dicyanovinyl-quinquethiophene (DCV5T-Me) is a prototype conjugated oligomer for highly efficient organic solar cells. This class of oligothiophenes are built up by an electron-rich donor (D) backbone and terminal electron-deficient acceptor (A) moieties. Here, we investigated its structural and electronic properties when it is adsorbed on a Au(111) surface using low temperature scanning tunneling microscopy/spectroscopy (STM/STS) and atomic force microscopy (AFM). We find that DCV5T-Me self-assembles in extended chains, stabilized by intercalated Au atoms. The effect of metal-ligand hybridization with Au adatoms causes an energetic downshift of the DCV5T-Me lowest unoccupied molecular orbital (LUMO) with respect to the uncoordinated molecules on the surface. The asymmetric coordination of a gold atom to only one molecular end group leads to an asymmetric localization of the LUMO and LUMO+1 states at opposite sides. Using model density functional theory (DFT) calculations, we explain such orbital reshaping as a consequence of linear combinations of the original LUMO and LUMO+1 orbitals, mixed by the attachment of a bridging Au adatom. Our study shows that the alignment of molecular orbitals and their distribution within individual molecules can be modified by contacting them to metal atoms in specific sites

The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease