Pharmacokinetic models for propofol-defining and illuminating the devil in the detail

The recently introduced open-target-controlled infusion (TCI) systems can be programmed with any pharmacokinetic model, and allow either plasma- or effect-site targeting. With effect-site targeting the goal is to achieve a user-defined target effect-site concentration as rapidly as possible, by manipulating the plasma concentration around the target. Currently systems are pre-programmed with the Marsh and Schnider pharmacokinetic models for propofol. The former is an adapted version of the Gepts model, in which the rate constants are fixed, whereas compartment volumes and clearances are weight proportional. The Schnider model was developed during combined pharmacokinetic-pharmacodynamic modelling studies. It has fixed values for V1, V3, k(13), and k(31), adjusts V2, k(12), and k(21) for age, and adjusts k(10) according to total weight, lean body mass (LBM), and height. In plasma targeting mode, the small, fixed V1 results in very small initial doses on starting the system or on increasing the target concentration in comparison with the Marsh model. The Schnider model should thus always be used in effect-site targeting mode, in which larger initial doses are administered, albeit still smaller than for the Marsh model. Users of the Schnider model should be aware that in the morbidly obese the LBM equation can generate paradoxical values resulting in excessive increases in maintenance infusion rates. Finally, the two currently available open TCI systems implement different methods of effect-site targeting for the Schnider model, and in a small subset of patients the induction doses generated by the two methods can differ significantly

Polyandry in nature: a global analysis

A popular notion in sexual selection is that females are polyandrous and their offspring are commonly sired by more than a single male. We now have large-scale evidence from natural populations to be able to verify this assumption. Although we concur that polyandry is a generally common and ubiquitous phenomenon, we emphasise that it remains variable. In particular, the persistence of single paternity, both within and between populations, requires more careful consideration. We also explore an intriguing relation of polyandry with latitude. Several recent large-scale analyses of the relations between key population fitness variables, such as heterozygosity, effective population size (Ne), and inbreeding coefficients, make it possible to examine the global effects of polyandry on population fitness for the first time

Sex ratio distorting microbes exacerbate arthropod extinction risk in variable environments

Maternally-inherited sex ratio distorting microbes (SRDMs) are common among arthropod species. Typically, these microbes cause female-biased sex ratios in host broods, either by; killing male offspring, feminising male offspring, or inducing parthenogenesis. As a result, infected populations can experience drastic ecological and evolutionary change. The mechanism by which SRDMs operate is likely to alter their impact on host evolutionary ecology; despite this, the current literature is heavily biased towards a single mechanism of sex ratio distortion, male-killing. Furthermore, amidst the growing concerns surrounding the loss of arthropod diversity, research into the impact of SRDMs on the viability of arthropod populations is generally lacking. In this study, using a theoretical approach, we model the epidemiology of an understudied mechanism of microbially-induced sex ratio distortion—feminisation—to ask an understudied question—how do SRDMs impact extinction risk in a changing environment? We constructed an individual-based model and measured host population extinction risk under various environmental and epidemiological scenarios. We also used our model to identify the precise mechanism modulating extinction. We find that the presence of feminisers increases host population extinction risk, an effect that is exacerbated in highly variable environments. We also identified transmission rate as the dominant epidemiological trait responsible for driving extinction. Finally, our model shows that sex ratio skew is the mechanism driving extinction. We highlight feminisers and, more broadly, SRDMs as important determinants of the resilience of arthropod populations to environmental change

Socioeconomic Inequality in Malnutrition in Developing Countries

Epidemiological evidence points to a small set of primary causes of child mortality that are the main killers of children aged less than 5 years: pneumonia, diarrhoea, low birth weight, asphyxia and, in some parts of the world, HIV and malaria. Malnutrition is the underlying cause of one out of every two such deaths. The evidence also shows that child death and malnutrition are not equally distributed throughout the world. They cluster in sub-Saharan Africa and south Asia, and in poor communities within these regions. Disparities in health outcomes between the poor and the rich are increasingly attracting attention from researchers and policy-makers, thereby fostering a substantial growth in the literature on health equity. “Socioeconomic inequality” in malnutrition refers to the degree to which childhood malnutrition rates differ between more and less socially and economically advantaged groups. This is different from “pure inequality”, which takes into account all factors influencing childhood malnutrition. The available literature documenting socioeconomic inequality in malnutrition focuses mainly on individual countries or regions. At a more global level, Wagstaff and Watanabe provided evidence on socioeconomic inequality in malnutrition across 20 developing countries. Other relevant cross-country studies include those of Pradhan et al., who describe total inequality, and Smith et al., who describe inequalities between urban and rural populations. The latter two studies, however, provide no evidence on socioeconomic inequality within developing countries

Flavonoid distribution in Pyracantha coccinea plants at different growth phases

Flavonoid composition during the ontogenetic cycle was examined in Pyracantha coccinea. The flavonoid profiles of plants at different ages showed marked differences in aerial and hypogel parts. In the vegetative phase there are flavonoids (flavanones, flavones and flavonols) only in the aerial parts and they appear gradually during the plant life. These secondary metabolites are detectable in the roots exclusivelyin the reproductive phase

Interleukin-6 and Associated Cytokine Responses to An Acute Bout of High-intensity Interval Exercise: the Effect of Exercise Intensity and Volume

Acute increases in interleukin (IL)-6 following prolonged exercise are associated with the induction of a transient anti-inflammatory state (e.g., increases in IL-10) that is partly responsible for the health benefits of regular exercise. The purposes of this study were to investigate the IL-6–related inflammatory response to high-intensity interval exercise (HIIE) and to determine the impact of exercise intensity and volume on this response. Ten participants (5 males and 5 females) completed 3 exercise bouts of contrasting intensity and volume (LOW, MOD, and HIGH). The HIGH protocol was based upon standard HIIE protocols, while the MOD and LOW protocols were designed to enable a comparison of exercise intensity and volume with a fixed duration. Inflammatory cytokine concentrations were measured in plasma (IL-6, IL-10) and also determined the level of gene expression (IL-6, IL-10, and IL-4R) in peripheral blood. The plasma IL-6 response to exercise (reported as fold changes) was significantly greater in HIGH (2.70 ± 1.51) than LOW (1.40 ± 0.32) (P = 0.04) and was also positively correlated to the mean exercise oxygen uptake (r = 0.54, P < 0.01). However, there was no change in anti-inflammatory IL-10 or IL-4R responses in plasma or at the level of gene expression. HIIE caused a significant increase in IL-6 and was greater than that seen in low-intensity exercise of the same duration. The increases in IL-6 were relatively small in magnitude, and appear to have been insufficient to induce the acute systemic anti-inflammatory effects, which are evident following longer duration exercise

Accuracy of energy prediction methodologies

In the current market, the specific annual energy yield (kWh/kWp) of a PV system is gaining in importance due to its direct link to the financial returns for possible investors who typically demand an accuracy of 5% in this prediction. This paper focuses on the energy prediction of photovoltaic modules themselves, as there have been significant advances achieved with module technologies which affect the device physics in a way that might force the revisiting of device modelling. The paper reports the results of a round robin based evaluation of European modelling methodologies. The results indicate that the error in predicting energy yield for the same module at different locations was within 5% for most of the methodologies. However, this error increased significantly if the nominal nameplate rating is used in the characterization stage. For similar modules at the same location the uncertainties were much larger due to module-module variations

Pre-treatment fertility preservation and post-treatment reproduction in long-term survivors of adolescent and young adult (AYA) cancer

Purpose: To describe recall of fertility-related consultations and cryopreservation and to examine reproductive goals and reproduction post-treatment in long-term survivors of adolescent and young adult (AYA) (age, 18–39 years) cancer. Methods: This study included n = 1457 male and n = 2112 female long-term survivors (M age = 43–45 years; 5–22 years from diagnosis) who provided self-report. Clinical data were supplied by the Netherlands Cancer Registry.Results: Most male survivors (72.7%) recalled fertility-related consultations and 22.6% completed sperm cryopreservation. Younger age (OR = 2.8; 95%CI [2.2–3.6]), not having children (OR = 5.0; 95%CI [3.2–7.7]), testicular cancer or lymphoma/leukemia (OR = 2.8/2.5 relative to “others”), and more intense treatments (OR = 1.5; 95%CI [1.1–2.0]) were associated with higher cryopreservation rates. Time since diagnosis had no effect. Of men who cryopreserved, 12.1% utilized assisted reproductive technologies (ART). Most men (88.5%) felt their diagnosis did not affect their reproductive goals, but 7.6% wanted no (additional) children due to cancer. Half of female survivors (55.4%; n = 1171) recalled fertility-related consultations. Rates of cryopreservation were very low (3.6%), but increased after 2013 when oocyte cryopreservation became non-experimental. Of women who cryopreserved, 13.2% successfully utilized ART. Most women (74.8%) experienced no effects of cancer on reproductive goals, but 17.8% wanted no (additional) children due to cancer. Conclusions: Cryopreservation in men varied by patient/clinical factors and was very low in women, but data of more recently treated females are needed. Utilizing cryopreserved material through ART was rare, which questions its cost-effectiveness, but it may enhance survivors’ well-being. Implications for Cancer Survivors: The extent to which cryopreservation positively affects survivors’ well-being remains to be tested. Moreover, effects of cancer on reproductive goals require further attention, especially in women who refrain from having children due to cancer.</p

Pre-treatment fertility preservation and post-treatment reproduction in long-term survivors of adolescent and young adult (AYA) cancer

Purpose: To describe recall of fertility-related consultations and cryopreservation and to examine reproductive goals and reproduction post-treatment in long-term survivors of adolescent and young adult (AYA) (age, 18–39 years) cancer. Methods: This study included n = 1457 male and n = 2112 female long-term survivors (M age = 43–45 years; 5–22 years from diagnosis) who provided self-report. Clinical data were supplied by the Netherlands Cancer Registry.Results: Most male survivors (72.7%) recalled fertility-related consultations and 22.6% completed sperm cryopreservation. Younger age (OR = 2.8; 95%CI [2.2–3.6]), not having children (OR = 5.0; 95%CI [3.2–7.7]), testicular cancer or lymphoma/leukemia (OR = 2.8/2.5 relative to “others”), and more intense treatments (OR = 1.5; 95%CI [1.1–2.0]) were associated with higher cryopreservation rates. Time since diagnosis had no effect. Of men who cryopreserved, 12.1% utilized assisted reproductive technologies (ART). Most men (88.5%) felt their diagnosis did not affect their reproductive goals, but 7.6% wanted no (additional) children due to cancer. Half of female survivors (55.4%; n = 1171) recalled fertility-related consultations. Rates of cryopreservation were very low (3.6%), but increased after 2013 when oocyte cryopreservation became non-experimental. Of women who cryopreserved, 13.2% successfully utilized ART. Most women (74.8%) experienced no effects of cancer on reproductive goals, but 17.8% wanted no (additional) children due to cancer. Conclusions: Cryopreservation in men varied by patient/clinical factors and was very low in women, but data of more recently treated females are needed. Utilizing cryopreserved material through ART was rare, which questions its cost-effectiveness, but it may enhance survivors’ well-being. Implications for Cancer Survivors: The extent to which cryopreservation positively affects survivors’ well-being remains to be tested. Moreover, effects of cancer on reproductive goals require further attention, especially in women who refrain from having children due to cancer.</p

SNP association study in PMS2-associated Lynch syndrome

Lynch syndrome (LS) patients are at high risk of developing colorectal cancer (CRC). Phenotypic variability might in part be explained by common susceptibility loci identified in Genome Wide Association Studies (GWAS). Previous studies focused mostly on MLH1, MSH2 and MSH6 carriers, with conflicting results. We aimed to determine the role of GWAS SNPs in PMS2 mutation carriers. A cohort study was performed in 507 PMS2 carriers (124 CRC cases), genotyped for 24 GWAS SNPs, including SNPs at 11q23.1 and 8q23.3. Hazard ratios (HRs) were calculated using a weighted Cox regression analysis to correct for ascertainment bias. Discrimination was assessed with a concordance statistic in a bootstrap cross-validation procedure. Individual SNPs only had non-significant associations with CRC occurrence with HRs lower than 2, although male carriers of allele A at rs1321311 (6p21.31) may have increased risk of CRC (HR = 2.1, 95% CI 1.2–3.0). A polygenic risk score (PRS) based on 24 HRs had an HR of 2.6 (95% CI 1.5–4.6) for the highest compared to the lowest quartile, but had no discriminative ability (c statistic 0.52). Previously suggested SNPs do not modify CRC risk in PMS2 carriers. Future large studies are needed for improved risk stratification among Lynch syndrome patients