Self-titration by experienced e-cigarette users: blood nicotine delivery and subjective effects (Study Data)

This is a UK laboratory study of twelve experienced e-cigarette users (11 males; 1 female; note the female participant’s data was removed from all analyses in the published paper) to understand the effects of e-liquid nicotine concentration on puffing patterns, plasma nicotine levels and subjective effects. All participants completed two vaping sessions under low (6 mg/mL) and high (24 mg/mL) nicotine e-liquid concentrations in two separate (counterbalanced) sessions at the University of East London (UEL). The data include puffing patterns (puff number, puff duration, volume of e-liquid consumed), plasma nicotine levels, craving and withdrawal symptoms after 10, 30 and 60 minutes of ad libitum vaping and self-reported positive and negative effects at 60 minutes

Cotinine-assessed second-hand smoke exposure and risk of cardiovascular disease in older adults

Objectives: To examine whether second-hand smoke (SHS) exposure measured by serum cotinine is associated with increased coronary heart disease (CHD) and stroke risk among contemporary older British adults. Design: Prospective population-based study with self-reported medical history and health behaviours. Fasting blood samples were analysed for serum cotinine and cardiovascular disease (CVD) risk markers. Setting: Primary care centres in 25 British towns in 1998–2001. Patients: 8512 60–79-year-old men and women selected from primary care registers. Main outcome measures: Fatal and non-fatal myocardial infarction (MI; n=445) and stroke (n=386) during median 7.8-year follow-up. Main exposure: Observational study of serum cotinine assayed from fasting blood sample using liquid chromatography tandem mass spectrometry method, and self-reported smoking history. Results: Among 5374 non-smokers without pre-existing CVD, geometric mean cotinine was 0.15 ng/ml (IQR 0.05–0.30). Compared with non-smokers with cotinine ≤0.05 ng/ml, higher cotinine levels (0.06–0.19, 0.2–0.7 and 0.71–15.0 ng/ml) showed little association with MI; adjusted HRs were 0.92 (95% CI 0.63 to 1.35), 1.07 (0.73 to 1.55) and 1.09 (0.69 to 1.72), p(trend)=0.69. Equivalent HRs for stroke were 0.82 (0.55 to 1.23), 0.74 (0.48 to 1.13) and 0.69 (0.41 to 1.17), p(trend)=0.065. The adjustment for sociodemographic, behavioural and CVD risk factors had little effect on the results. The HR of MI for smokers (1–9 cigarettes/day) compared with non-smokers with cotinine ≤0.05 ng/ml was 2.14 (1.39 to 3.52) and 1.03 (0.52 to 2.04) for stroke. Conclusions: In contemporary older men and women, SHS exposure (predominantly at low levels) was not related to CHD or stroke risks, but we cannot rule out the possibility of modest effects at higher exposure levels

Taming the snake in paradise: combining institutional design and leadership to enhance collaborative innovation

The growing expectations to public services and the pervasiveness of wicked problems in times characterized by growing fiscal constraints call for the enhancement of public innovation, and new research suggests that multi-actor collaboration in networks and partnerships is superior to hierarchical and market-based strategies when it comes to spurring such innovation. Collaborative innovation seems ideal as it builds on diversity to generate innovative public value outcomes, but there is a catch since diversity may clash with the need for constructing a common ground that allows participating actors to agree on a joint and innovative solution. The challenge for collaborative innovation – taming the snake in paradise – is to nurture the diversity of views, ideas and forms of knowledge while still establishing a common ground for joint learning. While we know a great deal about the dynamics of the mutually supportive processes of collaboration, learning and innovation, we have yet to understand the role of institutional design and leadership in spurring collaborative innovation and dealing with this tension. Building on extant research, the article draws suitable cases from the Collaborative Governance Data Bank and uses Qualitative Comparative Analysis to explore how multiple constellations of institutional design and leadership spur collaborative innovation. The main finding is that, even though certain institutional design features reduce the need for certain leadership roles, the exercise of hands-on leadership is more important for securing collaborative innovation outcomes than hands-off institutional design

Oligodendroglia Are Particularly Vulnerable to Oxidative Damage After Neurotrauma In Vivo.

In the paper "Oligodendroglia are particularly vulnerable to oxidative damage after neurotrauma in vivo," we determined the extent of oxidative damage to specific cellular subpopulations and structures within regions vulnerable to secondary degeneration and assessed the effect this had on oligodendroglial function. Comparative assessment of oxidative damage demonstrated selective vulnerability of oligodendroglia, specifically oligodendrocyte progenitor cells (OPCs) to DNA oxidation in vivo. Immunohistochemical fate mapping along the oligodendroglial lineage showed a transient susceptibility of these cells to DNA oxidation, protein nitration, and lipid peroxidation, with mature oligodendrocytes derived immediately after injury more vulnerable to DNA oxidation than their counterparts existing at the time of injury or later derived. In situ hybridization demonstrated a reduction in myelin regulatory factor (MyRF) messenger RNA (mRNA) fluorescence in newly derived mature oligodendrocytes, suggesting a compromise in the production and maintenance of the myelin sheath in these cells. The data imply a deficit in the normal differentiation of OPCs to myelinating oligodendrocytes, associated with a transient increase in oxidative damage, which may contribute to the dysmyelinating phenotype seen at chronic time points after injury. Identifying and understanding the sources of this oxidative damage is integral for the development of therapeutic interventions for neurotrauma

Patient expectations of fair complaint handling in hospitals: empirical data

BACKGROUND: A common finding in several studies is patients' dissatisfaction with complaint handling in health care. The reasons why are for the greater part unknown. The key to an answer may be found in a better understanding of patients' expectations. We investigated patients' expectations of complaint handling in hospitals. METHODS: Subjects were patients who had lodged a complaint at the complaint committees of 74 hospitals in the Netherlands. A total of 424 patients (response 75%) completed a written questionnaire at the start of the complaint procedures. Derived from justice theory, we asked what they expected from fair procedures, fair communication and fair outcome of complaint handling. RESULTS: The predominant reason for complainants to lodge a complaint was to prevent the incident from happening again. Complainants expected fair procedures from the complaint committee, in particular an impartial position. This was most important to 87% of the complainants. They also expected to be treated respectfully. Furthermore, they expected the hospital and the professional involved to respond to their complaint. A change in hospital performances was the most wanted outcome of complaint handling, according to 79% of the complainants. They also expected disclosure from the professionals. Professionals should admit a mistake when it had occurred. More complainants (65%) considered it most important to get an explanation than an apology (41%). Only 32% of complainants expected the professional to make an effort to restore the doctor-patient relationship. A minority of complainants (7%) wanted financial compensation. CONCLUSION: Nearly all complainants want to prevent the incident from happening again, not out of pure altruism, but in order to restore their sense of justice. We conclude that complaint handling that does not allow for change is unlikely to meet patients' expectations. Secondly, complaint handling should not be left exclusively to complaint committees, the responses of hospital and professionals are indispensable

Induction of the nicotinamide riboside kinase NAD+ salvage pathway in skeletal myopathy of H6PDH KO mice

Background: Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11β-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation. Methods: We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD+ precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO. Results: H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD+ biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD+ biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD+ levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD+/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD+ availability. Conclusions: These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD+ salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved

Haploinsufficiency for Translation Elongation Factor eEF1A2 in Aged Mouse Muscle and Neurons Is Compatible with Normal Function

Translation elongation factor isoform eEF1A2 is expressed in muscle and neurons. Deletion of eEF1A2 in mice gives rise to the neurodegenerative phenotype "wasted" (wst). Mice homozygous for the wasted mutation die of muscle wasting and neurodegeneration at four weeks post-natal. Although the mutation is said to be recessive, aged heterozygous mice have never been examined in detail; a number of other mouse models of motor neuron degeneration have recently been shown to have similar, albeit less severe, phenotypic abnormalities in the heterozygous state. We therefore examined the effects of ageing on a cohort of heterozygous +/wst mice and control mice, in order to establish whether a presumed 50% reduction in eEF1A2 expression was compatible with normal function. We evaluated the grip strength assay as a way of distinguishing between wasted and wild-type mice at 3-4 weeks, and then performed the same assay in older +/wst and wild-type mice. We also used rotarod performance and immunohistochemistry of spinal cord sections to evaluate the phenotype of aged heterozygous mice. Heterozygous mutant mice showed no deficit in neuromuscular function or signs of spinal cord pathology, in spite of the low levels of eEF1A2

PROTDES: CHARMM toolbox for computational protein design

We present an open-source software able to automatically mutate any residue positions and find the best aminoacids in an arbitrary protein structure without requiring pairwise approximations. Our software, PROTDES, is based on CHARMM and it searches automatically for mutations optimizing a protein folding free energy. PROTDES allows the integration of molecular dynamics within the protein design. We have implemented an heuristic optimization algorithm that iteratively searches the best aminoacids and their conformations for an arbitrary set of positions within a structure. Our software allows CHARMM users to perform protein design calculations and to create their own procedures for protein design using their own energy functions. We show this by implementing three different energy functions based on different solvent treatments: surface area accessibility, generalized Born using molecular volume and an effective energy function. PROTDES, a tutorial, parameter sets, configuration tools and examples are freely available at http://soft.synth-bio.org/protdes.html