DOHaD: A MENAGERIE OF ADAPTATIONS AND PERSPECTIVES: Large animal models of developmental programming: sustenance, stress, and sex matter.

In brief: Developmental programming refers to the long-term programming of gene expression during fetal and postnatal development, resulting in altered organ function even into adulthood. This review describes how maternal and paternal sustenance and stress, as well as fetal sex, all matter in large animal models and affect developmental programming of the offspring. Abstract: Developmental programming is the concept that certain health outcomes throughout life can be linked to early fetal or postnatal development. Progress in understanding concepts and mechanisms surrounding developmental programming is heavily leveraged by the use of large animal models. Numerous large animal models have been developed that apply a host of different maternal stressors and, more recently, paternal stressors. Maternal nutrition is the most researched maternal stressor applied during gestation and includes both global nutrient supply and models that target specific macro- or micro- nutrients. The focus of this review is to provide an overview of the many large animal models of developmental programming and to discuss the importance of sex effects (including paternal contributions) in study design and data interpretation.

Quantifying global soil carbon losses in response to warming.

The majority of the Earth's terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12-17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon-climate feedback that could accelerate climate change.

Direct Measurements of Collisional Dynamics in Cold Atom Triads.

The introduction of optical tweezers for trapping atoms has opened remarkable opportunities for manipulating few-body systems. Here, we present the first bottom-up assembly of atom triads. We directly observe atom loss through inelastic collisions at the single event level, overcoming the substantial challenge in many-atom experiments of distinguishing one-, two-, and three-particle processes. We measure a strong suppression of three-body loss, which is not fully explained by the presently availably theory for three-body processes. The suppression of losses could indicate the presence of local anticorrelations due to the interplay of attractive short range interactions and low dimensional confinement. Our methodology opens a promising pathway in experimental few-body dynamics.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

A hyper-thermostable α-amylase from Pyrococcus furiosus accumulates in Nicotiana tabacum as functional aggregates.

BACKGROUND: Alpha amylase hydrolyzes α-bonds of polysaccharides such as starch and produces malto-oligosaccharides. Its starch saccharification applications make it an essential enzyme in the textile, food and brewing industries. Commercially available α-amylase is mostly produced from Bacillus or Aspergillus. A hyper-thermostable and Ca 2++ independent α-amylase from Pyrococcus furiosus (PFA) expressed in E.coli forms insoluble inclusion bodies and thus is not feasible for industrial applications. RESULTS: We expressed PFA in Nicotiana tabacum and found that plant-produced PFA forms functional aggregates with an accumulation level up to 3.4 g/kg FW (fresh weight) in field conditions. The aggregates are functional without requiring refolding and therefore have potential to be applied as homogenized plant tissue without extraction or purification. PFA can also be extracted from plant tissue upon dissolution in a mild reducing buffer containing SDS. Like the enzyme produced in P. furiosus and in E. coli, plant produced PFA preserves hyper-thermophilicity and hyper-thermostability and has a long shelf life when stored in lyophilized leaf tissue. With tobacco's large biomass and high yield, hyper-thermostable α-amylase was produced at a scale of 42 kg per hectare. CONCLUSIONS: Tobacco may be a suitable bioreactor for industrial production of active hyperthermostable alpha amylase.

Temporal stability in patterns of genetic diversity and structure of a marine foundation species (Zostera marina).

Genetic diversity and population structure reflect complex interactions among a diverse set of processes that may vary temporally, limiting their potential to predict ecological and evolutionary outcomes. Yet, the stability of these patterns is rarely tested. We resampled eelgrass (Zostera marina) meadows from published studies to determine variability in genetic diversity and structure within and between meadows over 5-12 years. The meadows sampled (San Francisco, Tomales and Bodega Bays in California and the Virginia coastal bays) represent a range of life histories (annual vs perennial), age (well-established vs restored) and environments (rural vs urbanized). In all of these systems, neither diversity nor differentiation (FST) changed over time. Differences among tidal heights within Bodega Bay were also remarkably consistent, with the high intertidal being more diverse than the subtidal, and tidal height differentiation being modest but significant at both time points. Historical studies used only a few microsatellite loci; therefore, our temporal comparisons were based on 4-5 loci. However, analysis of the current data using a set of 12 loci show that 4-5 loci are sufficient to describe diversity and differentiation patterns in this system. This temporal consistency was not because of the resampling of large clones, underscoring the feasibility and relevance of understanding drivers of the differences. Because seagrasses are declining at rapid rates, restoration and conservation are increasingly a coastal management priority. Our results argue that surveys of eelgrass genetic structure and diversity at decadal scales can provide accurate depictions of populations, increasing the utility of published genetic data for restoration and designing networks of reserves.

Within-day and between-day Reproducibility of Baroreflex Sensitivity in Healthy Adult Males.

Within-day and between-day reproducibility of supine and tilt baroreflex sensitivity were investigated utilising sequence and spectral indices in 46 healthy adult males employing 3 repeat measures; baseline, +60 min and +24 h. Reproducibility was assessed via the 95% limits of agreement and by the technical error of the measurement. For spectral parameters, the limits of agreement indicated same day was marginally better than between-day reproducibility. For sequence parameters, between-day had marginally better agreement than same-day reproducibility. Tilt markedly improved reproducibility across all outcome measures. Precision expressed by the technical error of the measurement for all spectral outcomes was good in both supine and tilt baroreflex sensitivity (<6%). Precision was lower, but acceptable, for sequence baroreflex sensitivity outcomes in both positions (<11%). Baroreflex sensitivity transfer gain provided the best agreement and reproducibility during supine and tilt conditions. These findings suggest time and spectral techniques may be employed to assess within-day and between-day baroreflex sensitivity changes in healthy individuals. The inclusion of a tilt manoeuvre may improve the reproducibility of the outcome measure, which may aid in the detection of modest baroreflex sensitivity changes in studies employing limited sample sizes.

A pilot study examining the effects of consuming a high-protein vs normal-protein breakfast on free-living glycemic control in overweight/obese 'breakfast skipping' adolescents.

To examine whether the daily consumption of normal-protein (NP) vs higher-protein (HP) breakfasts improve free-living glycemic control in overweight/obese, 'breakfast skipping' adolescents. Twenty-eight healthy, but overweight, teens (age: 19±1 year; BMI: 29.9±0.8 kg m(-2)) completed a 12-week randomized parallel-arm study in which the adolescents consumed either a 350 kcal NP breakfast (13 g protein) or HP breakfast (35 g protein). Pre- and post-study 24-h blood glucose measures were assessed using continuous glucose monitoring. Although no main effects of time or group were detected, time by group interactions were observed. Post hoc pairwise comparisons assessing the post-pre changes revealed that the daily consumption of the HP breakfasts tended to reduce the 24-h glucose variability (s.d.) vs NP (-0.17±0.09 vs +0.09±0.10 s.d.; P=0.06) and tended to reduce the time spent above the high glucose limit (-292±118 vs -24±80 min; P=0.09). The consumption of the HP breakfasts also reduced the 24-h maximal (peak) glucose response (-0.94±0.36 vs +0.30±0.18 mmol l(-1); P<0.01) and reduced postprandial glucose fluctuations (-0.88±0.44 vs +0.49±0.34 mmol l(-1); P<0.03) vs NP. These data suggest that the daily addition of a HP breakfast, containing 35 g of high-quality protein, has better efficacy at improving free-living glycemic control compared with a NP breakfast in overweight/obese, but otherwise healthy, 'breakfast skipping' adolescents.

Predicting the patients who will struggle with anal incontinence: sensitivity to disgust matters.

AIM: Quality of life varies in patients with anal incontinence. The severity of symptoms is a surprisingly modest predictor, but they reliably elicit disgust. The current work assessed prospectively whether dispositional sensitivity to disgust predicted the quality of life in patients with anal incontinence. METHOD: Seventy-five patients with anal incontinence identified from the waiting list for the pelvic floor clinic at the Greenlane Clinical Centre, Auckland, New Zealand, completed questionnaires assessing symptom severity (Fecal Incontinence Severity Index) and disgust sensitivity (Disgust Sensitivity-Revised scale) prior to a first appointment. Three months later incontinence-specific (Fecal Incontinence Quality of Life Scale, FI QLS) and general quality of life (World Health Organization Quality of Life-BREF, WHOQOL-BREF) were assessed. RESULTS: Greater severity of symptoms prospectively predicted lower incontinence-specific quality of life (FI QLS lifestyle domain) and lower general quality of life (WHOQOL-BREF environmental domain). Greater disgust sensitivity predicted poorer psychological and environmental well-being, and moderated the link between symptom severity and outcome. Persons low in disgust sensitivity reported a higher quality of life when symptom severity was low, but those with a high disgust sensitivity had a low quality of life regardless of symptom severity. CONCLUSION: The functional status of patients with anal incontinence explains some but not all of the variation in quality of life. Emotional factors such as disgust appear to have a role. Disgust sensitivity warrants further attention.

Autism in Glasgow: cumulative incidence and the effects of referral age, deprivation and geographical location.

BACKGROUND: Referrals to the Greater Glasgow Community Autism Team (CAT) made before the child's sixth birthday were analysed to obtain an estimation of the proportion of children in Greater Glasgow with childhood autism and investigate whether there were any variations in diagnosis rates, or in age at referral and diagnosis, depending on deprivation or geographical location. METHODS: An analysis was made of the database recording referrals to Greater Glasgow CAT, between 2004 and 2007 inclusive, of children referred by age 6 years, comprising 584 cases. Cumulative incidence was calculated for childhood autism. Ages at referral and diagnosis were also analysed. RESULTS: For this subset of children, there were 246 diagnosed cases of childhood autism, a cumulative incidence from 2004 until 2007 of 11.1 per year per 10,000 children aged 0-6 years. Of children with an eventual diagnosis of autism by age 6, 72% were referred by the age of 4 years. Deprivation was found to have an association with referral and diagnostic rates, with higher rates seen in the most deprived. There was geographical variation in the cumulative incidence of autism. CONCLUSION: Given that the populations were not known to differ in any manner that would lead to a true variation, the geographical variation in the cumulative incidence of autism in children up to 6 years in Greater Glasgow observed in this study is likely to represent differences in the care pathway between areas. Such differences may also explain the observed association with deprivation. Reasons for the variation are being explored.

Containing Attachment Concerns: Does Trait Mindfulness Buffer the Links between Attachment Insecurity and Maladaptive Sexual Motivations?

Individuals reporting greater insecure attachment are more likely to report maladaptive sexual motivations, such as sex to avoid negative relational and personal outcomes (e.g., conflict). Despite the costs of such sexual motivations, research is less clear regarding what might buffer the extent to which attachment insecurities manifest in such motives. The current study examined whether trait mindfulness moderates the links between attachment insecurity and maladaptive sexual motives. Participants (N = 194) completed measures of trait mindfulness, general sexual motivations, and attachment. As predicted, the links between attachment anxiety and having sex to cope and affirm the self were eliminated among individuals reporting higher levels of the acting with awareness facet of trait mindfulness. No such buffering effects were seen for attachment avoidance. Instead, acting with awareness mindfulness appeared to increase the extent to which more avoidantly attached individuals reported coping and self-affirmation-based sexual motives. These findings contribute to knowledge regarding the potential utility and limits of mindfulness in relational and sexual contexts, perhaps suggesting that mindfulness may help anxiously attached individuals manage the extent to which attachment concerns manifest in maladaptive sexual motivations. Findings of the study may inform both theory regarding mindfulness in interpersonal functioning and how mindfulness interventions might be deployed in sex therapy contexts.

Mindfulness Between the Sheets: Does a Brief Mindfulness Intervention Improve Community-Dwelling Populations' Sexual Experiences and Motivations, and Are Effects Moderated by Attachment Insecurity?

Research is increasingly linking mindfulness with better relationship outcomes. Less clear is whether these benefits extend to the sexual domain or whether the benefits of mindfulness are moderated by individual characteristics. Accordingly, the current report tested whether a brief online mindfulness intervention improved the cognitive, affective, and behavioral aspects of sexual experiences and whether effects varied by attachment anxiety and avoidance. Participants (N = 90) first completed a measure of attachment before reporting their sexual experiences each day for 7-days. Participants then listened to a mindfulness recording every day for 4 weeks. Finally, sexual experiences were reported on every day for 7 days again. Consistent with previous studies, no benefits of the mindfulness intervention were detected for more avoidant persons. Less consistent with expectation, however, the mindfulness intervention did not improve sexual outcomes in general, nor did it buffer other-focused avoidance-based sexual motivations or bolster sexual communal strength among more anxiously attached persons. However, the intervention did increase reports of positive sexuality among more anxious persons. Results are discussed in terms of the differential utility and limits of short mindfulness interventions looking to enhance sexual functioning in different populations and the potential mechanisms behind the presence and absence of effects.

Effect of ewe birth litter size and estimation of genetic parameters on ewe reproductive life traits.

Ewe lifetime productivity has economic implications for producers because shorter lifetime productivity results in less profit. Productive years of ewes from extensive, range-based systems of the United States West are generally less than ewes from more temperate regions of the United States. Accordingly, ewes from range-based systems, especially those employing shed-lambing strategies, have been selected for increased litter size to offset decreased lifetime productivity. However, the relationship of the ewe's birth litter size (ELSB) has not been considered a potential contributor to lifetime productivity. Longevity (number of productive years, n = 1 per population) and stayability (probability to survive to the next age; ages 2-7 years, n = 6 per population) were investigated to understand ELSB effects on productive life. Columbia, Polypay, Rambouillet, and Targhee breeds were used in this study. Across-breed (n = 11 550) and within-breed (Columbia, n = 4 398; Polypay, n = 4 534; Rambouillet, n = 5 922; Targhee, n = 6 482) analyses were used. Depending on the population, records spanned from 1950 to 2008, where ewe's birth year was included as a fixed effect in the animal model using restricted maximum likelihood estimation procedures. Fixed effects investigated included ELSB (single-, twin-, or triplet-born) and ewe breed (across-breed analyses only). Regardless of trait or population used, heritability ranged from 0.06 ± 0.02 to 0.34 ± 0.03, where stayability at younger ages had the highest estimates. The breed effect was significant in all across-breed analyses (0.0001 ≤ P ≤ 0.038; n = 7), where Polypay, a breed selected for accelerated lambing and increased fertility, averaged shorter productive life or had a lower probability of survival to the next age compared with other breeds (longevity: 0.009 ≤ P ≤ 0.223; stayability: 0.000 ≤ P ≤ 0.842). The ELSB was significant in 60% (n = 5) and 37% (n = 30) of longevity and stayability analyses, respectively. Except for Targhee, all analyses showed ewes born in smaller litter sizes were associated with longer productive lives or higher probability of surviving to the next age, particularly in across-breed analyses (e.g., longevity: single- vs twin-born ewes, P = 0.004; vs triplet-born ewes, P = 0.003). This study provides evidence that increasing prolificacy in ewes from extensive, range-based production systems may impact productive life. Due to the low heritability of these traits, additional investigation into modeling these traits with dominance effects and litter size needs to be conducted.

Role of the placenta in developmental programming: Observations from models using large animals.

Developmental programming, which proposes that "insults" or "stressors" during intrauterine or postnatal development can have not only immediate but also long-term consequences for healthy and productivity, has emerged as a major biological principle, and based on studies in many animal species also seems to be a universal phenomenon. In eutherians, the placenta appears to be programmed during its development, which has consequences for fetal growth and development throughout pregnancy, and likewise has long-term consequences for postnatal development, leading to programming of organ function of the offspring even into adulthood. This review summarizes our current understanding of the placenta's role in developmental programming, the mechanisms involved, and the challenges remaining.

Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling.

The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.

Methadone and buprenorphine-related deaths among people prescribed and not prescribed Opioid Agonist Therapy during the COVID-19 pandemic in England.

BACKGROUND: The coronavirus pandemic resulted in many changes which had the potential to impact mortality related to opioid agonist therapy (OAT; methadone, buprenorphine), including changes in the prescribing and dispensing of OAT and patterns of drug availability and use. We aimed to assess the impact of the first lockdown (initiated March 23rd 2020) on methadone- and buprenorphine-related deaths in England in people both prescribed and not prescribed OAT using data from the National Programme on Substance Abuse Deaths. METHODS: This was a retrospective post-mortem toxicology study of OAT-related deaths which occurred in the 3-month period March 23rd to June 22nd in the years 2016-2020. Provisional data regarding numbers accessing treatment for opioid use disorder was provided by the National Drug Treatment Monitoring System. RESULTS: We found a 64% increase in methadone-related deaths in March to June 2020 compared to March to June 2019 (2019 n = 96; 2020 projected n = 157). There were increases in the mortality rate of both in-treatment decedents (22% increase; 2019 n = 45; an exponential smoothing model of the 2016-19 trend [α=0.5] predicted 44 deaths in 2020, 55 were reported) and decedents not prescribed methadone (74% increase; 2019 n = 46; 2016-19 trend predicted 43 deaths in 2020, 80 were reported). There was no increase in buprenorphine-related deaths (2019 n = 9/529; 2020 n = 11/566). There were no changes in the numbers of deaths where other opioids or multiple substances were detected, or in methadone levels detected. Numbers of people accessing treatment for opioid use disorder in 2020 did not decrease relative to previous years (p >0.05). CONCLUSIONS: Methadone-related deaths in non-prescribed individuals, but not prescribed individuals, increased considerably above the annual trend forecast for 2020 during the first COVID-19 lockdown in England. Further studies are thus needed to understand this difference.

Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults.

BACKGROUND: Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer's Disease and amyotrophic lateral sclerosis. OBJECTIVES: This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects. DESIGN: Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design. SETTING: Single site in the United States. PARTICIPANTS: Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), ≥ 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability). TREATMENT: In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects. MEASUREMENTS: Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only. RESULTS: Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated. CONCLUSIONS: The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer's Disease and other neurodegenerative diseases.

Supranutritional selenium increases mammary gland vascularity in postpartum ewe lambs.

Objectives were to determine the effects of maternal dietary supranutritional Se and nutritional plane during gestation on capillary surface density, capillary area density, and angiogenic factor expression in the developing mammary gland of primiparous ewes. Selenium treatments were initiated at breeding [adequate Se (ASe; 9.5 µg/kg of body weight) vs. high Se (HSe; 81.8 µg/kg of body weight)] and nutritional planes at d 50 of gestation [Low, 60%; moderate (Mod), 100%; and High, 140% of requirements). Mammary glands were collected within 24h postpartum. Vascular development was assessed in the glandular portion of the mammary gland. Vascularity was determined for mammary tissue with the following measurements taken: the cross-sectional capillary area density (total capillary area as a proportion of tissue area) and capillary surface density (CSD; total capillary circumference per unit of tissue area). High-Se ewes had greater capillary surface and area densities compared with ASe ewes. A tendency existed for an Se × plane of nutrition interaction for CSD with maternal diet not affecting CSD in HSe ewes, but Low ewes had a decreased CSD compared with Mod ewes, with High being intermediate in ASe ewes. Moreover, HSe-Low and HSe-High ewes had increased CSD compared with ASe-Low and ASe-High, respectively. Although Se status did not influence angiogenic factor mRNA expression, mammary glands from Low ewes tended to have increased VEGF and FLT1 mRNA expression compared with High ewes, with Mod being intermediate. Maternal plane of nutrition did not affect mammary gland glutathione peroxidase activity, but it was increased in HSe compared with ASe ewes. Increased mammary capillary nutrient exchange area may contribute to previously observed changes in colostrum quality.

Circulating-water garment or the combination of a circulating-water mattress and forced-air cover to maintain core temperature during major upper-abdominal surgery.

BACKGROUND: A recent heat-balance study in volunteers suggested that greater efficacy of circulating-water garments (CWGs) results largely from increased heat transfer across the posterior skin surface since heat transfer across the anterior skin surface was similar with circulating-water and forced-air. We thus tested the hypothesis that the combination of a circulating-water mattress (CWM) and forced-air warming prevents core temperature reduction during major abdominal surgery no worse than a CWG does. METHODS: Fifty adult patients aged between 18 and 85 yr old, undergoing major abdominal surgery, were randomly assigned to intraoperative warming with a combination of forced-air and a CWM or with a CWG (Allon ThermoWrap). Core temperature was measured in the distal oesophagus. Non-inferiority of the CWM to the CWG on change from baseline to median intraoperative temperature was assessed using a one-tailed Student's t-test with an equivalency buffer of -0.5°C. RESULTS: Data analysis was restricted to 16 CWG and 20 CWM patients who completed the protocol. Core temperature increased in both groups during the initial hours of surgery. We had sufficient evidence (P=0.001), to conclude that the combination of a CWM and forced-air warming was non-inferior to a CWG in preventing temperature reduction, with mean (95% CI) difference in the temperature change between the CWM and the CWG groups (CWM-CWG) of 0.46°C (-0.09°C, 1.00°C). CONCLUSIONS: The combination of a CWM and forced-air warming is significantly non-inferior in maintaining intraoperative core temperature than a CWG. TRIAL REGISTRY: This trial has been registered at clinical trials.gov, identifier: NCT 00651898.

Role of antimicrobial restrictions in bacterial resistance control: a systematic literature review.

BACKGROUND: Antimicrobial stewardship is considered as one of the most fundamental aspects of bacterial resistance control. Among the multitude of initiatives, restrictive strategies have been widely practiced in hospital settings. However, data concerning their potential effectiveness have not been methodically collected and evaluated to date. AIM: To identify, collect and evaluate the available evidence regarding the impact of restrictive policies on bacterial resistance in hospital settings. METHODS: A systematic literature review was conducted using the PubMed/Medline, Embase, Global Health and CINAHL Plus databases. FINDINGS: In total, 5555 papers were retrieved in the search process, and 29 studies were included in the final analysis. There were no randomized studies, and the inherent limitations of the observational designs employed impede the deduction of safe conclusions. Seemingly beneficial interventions encompass the restriction of broad-spectrum cephalosporins in favour of beta-lactam/lactamase inhibitor combinations as well as the restriction of fluoroquinolones. Antimicrobial restrictions might also play a role in the control of vancomycin-resistant enterococci, while carbapenem stewardship in the form of the preferred use of ertapenem did not produce the anticipated results. Complex restrictions are not offered for informative comparative analyses. Hospital-wide policies could perhaps be superior to those confined to high-risk departments. Carbapenem-resistant Acinetobacter baumannii might be difficult to control through solely formulary interventions. CONCLUSION: The presumably effective restrictive strategies rely mainly on inadequately tested hypotheses and low-quality evidence. Therefore, systematic, high-quality research is needed to confirm and expand comprehension of the subject so that the most successful policies are employed in the field.