Predicting subacute ruminal acidosis from milk mid-infrared estimated fatty acids and machine learning on Canadian commercial dairy herds.

Our objective was to validate the possibility of detecting SARA from milk Fourier transform mid-infrared spectroscopy estimated fatty acids (FA) and machine learning. Subacute ruminal acidosis is a common condition in modern commercial dairy herds for which the diagnostic remains challenging due to its symptoms often being subtle, nonexclusive, and not immediately apparent. This observational study aimed at evaluating the possibility of predicting SARA by developing machine learning models to be applied to farm data and to provide an estimated portrait of SARA prevalence in commercial dairy herds. A first data set composed of 488 milk samples of 67 cows (initial DIM = 8.5 ± 6.18; mean ± SD) from 7 commercial dairy farms and their corresponding SARA classification (SARA+ if rumen pH <6.0 for 300 min, else SARA-) was used for the development of machine learning models. Three sets of predictive variables: i) milk major components (MMC), ii) milk FA (MFA), and iii) MMC combined with MFA (MMCFA) were submitted to 3 different algorithms, namely Elastic net (EN), Extreme gradient boosting (XGB), and Partial least squares (PLS), and evaluated using 3 different scenarios of cross-validation. Accuracy, sensitivity, and specificity of the resulting 27 models were analyzed using a linear mixed model. Model performance was not significantly affected by the choice of algorithm. Model performance was improved by including fatty acids estimations (MFA and MMCFA as opposed to MMC alone). Based on these results, one model was selected (algorithm: EN; predictive variables: MMCFA; 60.4, 65.4, and 55.3% of accuracy, sensitivity, and specificity, respectively) and applied to a large data set comprising the first test-day record (milk major components and FA within the first 70 DIM of 211,972 Holstein cows (219,503 samples) collected from 3001 commercial dairy herds. Based on this analysis, the within-herd SARA prevalence of commercial farms was estimated at 6.6 ± 5.29% ranging from 0 to 38.3%. A subsequent linear mixed model was built to investigate the herd-level factors associated to higher within-herd SARA prevalence. Milking system, proportion of primiparous cows, herd size and seasons were all herd-level factors affecting SARA prevalence. Furthermore, milk production was positively, and milk fat yield negatively associated with SARA prevalence. Due to their moderate levels of accuracy, the SARA prediction models developed in our study, using data from continuous pH measurements on commercial farms, are not suitable for diagnostic purpose. However, these models can provide valuable information at the herd level.

The hidden cost of disease: II. Impact of the first incidence of lameness on production and economic indicators of primiparous dairy cows.

Lameness is a persistent and underreported health and welfare problem in the dairy industry, resulting in reduced cow performance and profitability as well as early culling. The study objectives were (1) to quantify the impact of the first instance of lameness, at different stages of lactation, on production and economic performance, and (2) to further quantify the impacts of the first instance of lameness when only cows that remain in the herd for at least 100 d in milk (DIM) and those that remain for 305 DIM are included in the analysis. A retrospective longitudinal study was conducted using pre-existing data from animal health records and Dairy Herd Improvement Association records. Data were edited based on selected inclusion criteria, yielding a data set containing records from 15,159 first-lactation Holstein cows from 120 herds with year of first calving between 2003 and 2014. Lame cows were assigned to 1 of 4 groups based on when in the lactation the first event of lameness occurred: transition (1-21 DIM), early lactation (22-100 DIM), mid-lactation (101-200 DIM), or late lactation (201+ DIM). Mid- and late-lactation lame cows were also stratified by cumulative milk yield before the lameness event. Healthy cows (i.e., no recorded lameness event) were randomly assigned for each lactation stage, with mid-lactation healthy and late-lactation healthy cows similarly stratified. Production performance (cumulative milk, fat, and protein yield) and economic performance [milk value, margin over feed cost (MOFC), and gross profit] were analyzed using a mixed model with herd as a random effect. Cumulative milk yields were 811 to 1,290 kg lower for lame cows than for healthy cows, with milk component yields undergoing similar reductions. Reductions in milk yield contributed to losses in milk value (-Can$527 to -Can$1,083; -US$419 to -US$862) and MOFC (-Can$510 to -Can$774; -US$406 to -US$616). Higher losses were reported using gross profit (-Can$753 to -Can$1,052; -US$599 to -US$837), which includes all lameness-related costs. Production and performance losses were smaller when 100 DIM and 305 DIM thresholds were applied (i.e., exclusion of cows culled before 100 and 305 DIM, respectively), however, mid- and late-lactation lame cows maintained high levels of significant losses for all 6 variables analyzed. Lameness also led to higher levels of culling, masking losses for transition and early-lactation lame cows in the 305-DIM analysis. Increasing producer understanding of the costs associated with lameness not only serves to provide insight to producers for more informed culling decisions, but may also help producers weigh the costs of adopting new methods and technologies targeted at reducing on-farm lameness.

The hidden cost of disease: I. Impact of the first incidence of mastitis on production and economic indicators of primiparous dairy cows.

Mastitis is a highly prevalent disease, which negatively affects cow performance, profitability, welfare, and longevity. The objectives of this study were (1) to quantify the impact of the first instance of mastitis, at different stages of lactation, on production and economic performance, and (2) to further quantify the impact of the first instance of mastitis when only cows that remain in the herd for at least 100 d in milk (DIM) and those that remain for 305 DIM are included in the analysis. A retrospective longitudinal study was conducted using data from existing animal health record files and Dairy Herd Improvement records. After editing based on selected inclusion criteria and completeness of health records, data consisted of records from first-lactation Holstein cows, from 120 herds, that calved for the first time between 2003 and 2014, inclusive. Mastitic cows were assigned to 1 of 4 groups based on when in the lactation the first event of mastitis occurred: transition (1-21 DIM), early lactation (22-100 DIM), mid lactation (101-200 DIM), or late lactation (201+ DIM). Mid-lactation and late-lactation mastitic cows were also stratified by cumulative milk yield before the mastitis event. Healthy cows (i.e., no recorded mastitis event) were randomly assigned for each lactation stage, with mid-lactation healthy and late-lactation healthy cows similarly stratified. Production performance (cumulative milk, fat, and protein yield) and economic performance [milk value, margin over feed cost (MOFC), and gross profit] were analyzed using a mixed model with herd as a random effect. Significant losses in cumulative milk yield (-382 to -989 kg) and correspondingly lower fat and protein yields were found in mastitic cows, with transition and late-lactation mastitic cows having the highest losses. Drops in production translated to significant reductions in cumulative milk value (-Can$287 to -Can$591; -US$228 to -US$470), MOFC (-Can$243 to -Can$540; -US$193 to -US$429), and gross profit (-Can$649 to -Can$908; -US$516 to -US$722) for mastitic cows at all stages. Differences between mastitic and healthy cows in the early lactation and transition stages remained for all variables in the 100-DIM analysis, but, aside from gross profit, were nonsignificant in the 305-DIM analysis. Gross profit accounted for all costs associated with mastitis and thus continued to be lower for mastitic cows at all stages, even in the 305-DIM analysis in which culled cows were omitted (-Can$485 to -Can$979; -US$386 to -US$779). The research reflects the performance implications of mastitis, providing more information upon which the producer can make informed culling decisions and maximize both herd profitability and cow longevity.

A broad-scale spatial analysis of the environmental benefits of fertiliser closed periods implemented under the Nitrates Directive in Europe.

Nutrient pollution from agriculture has been an ongoing challenge for decades, contributing to numerous negative environmental impacts. In the European Union policies have been developed to address nutrient pollution, including Nitrate Action Programmes under Council Directive 91/676/EEC. Although Member States report on progress on implementation, there have been few studies that explore how measures have been implemented; the environmental implications of any differences; and how they vary spatially on a European scale. This study aims to address this gap with respect to fertiliser closed periods (1155 different closed periods across 69 Nitrate Action Programmes). This included the development of an approach that can be applied using readily available spatial data. Each closed period was scored for its coverage of risk periods for losses of nitrate; organic material; nitrous oxide and ammonia. Closed periods were then matched to relevant combinations of spatial data for each environmental zone and fertiliser type. The scores for each combination were used to create maps and calculate spatial statistics. The results show that in addition to nitrate, closed periods also reduce the risk of organic material run-off, emissions of nitrous oxide and to a lesser extent ammonia. However, risk reduction is spatially variable across all the impacts and the scope for synergy is also variable (e.g. nitrate loss does not always correlate with nitrous oxide or ammonia risk reduction). Regions in the Atlantic, Lustanian and some areas within the Mediterranean zones appear to provide the greatest combined risk reduction, with other zones, especially in eastern Europe, having a lower combined risk reduction (due to a combination of different risk periods coupled with lower coverage of individual risks). The spatial analysis within this study is relatively simple; is based on a snapshot of closed periods during 2019-2020; and only explores one measure. However, it does provide some useful data and insights that could support policy development in the future. This includes scope for Member States and regions to learn from others where greater coverage of risk periods has been achieved; and highlighting how a more holistic perspective can be taken to the environmental management of nutrients. As we strive towards developing sustainable production systems, farmers and policy makers need to take a more integrated approach to incorporate additional environmental objectives; which increases the complexity of the challenge. Consequently, the demand for pragmatic approaches that take a more holistic approach is likely to increase in the future.

Investigation of the mechanisms by which hot isostatic pressing improves the fatigue performance of powder bed fused Ti-6Al-4V.

Hot isostatic pressing (HIP) is often needed to obtain powder bed fused (PBF) Ti-6Al-4V parts with good fatigue performance. This manuscript attempts to clarify the mechanisms through which HIP treatment acts to improve high cycle fatigue performance. Several mechanisms are considered and examined against experimental data sets available in the literature. The results suggest that HIP may act most significantly by decreasing the fraction of the defect population that can initiate fatigue cracks, both by decreasing defect sizes below a threshold and by changing the microstructure that surrounds defects. Given the novelty of the latter conclusion, an electron backscatter diffraction microscopy study was performed for validation. The gained understanding provides initial guidance on the choice of optimum HIP soak parameters (Temperature-Pressure-Time) for the high cycle fatigue performance of PBF Ti-6Al-4V.

Early hatching enhances survival despite beneficial phenotypic effects of late-season developmental environments.

Seasonal shifts in environmental conditions provide predictable cues to which organisms can respond in adaptive ways. For example, seasonal changes in temperature can induce phenotypes at different times of the year that have season-specific fitness benefits. Here, we tested the hypothesis that embryo responses to seasonal changes in thermal environments are adaptively matched to the timing of reproduction (environmental-matching hypothesis). We collected eggs of the brown anole lizard (Anolis sagrei) from early and late seasons, and exposed them to early and late thermal regimes that mimic nest temperatures. After measuring offspring morphology and performance, we quantified their survival in the field. Females had higher fecundity, but produced smaller eggs, early in the season compared with late in the season. Late-season eggs exposed to late thermal regimes had relatively high survival, but early-season eggs exposed to early thermal regimes had similar survival rates to those exposed to mismatched conditions. Late-season nest temperatures and late-season eggs produced offspring that were relatively large and fast runners. However, despite phenotypic benefits of late-season conditions, early-season hatchlings had greater survival in the field. Our results do not fully support the environmental-matching hypothesis but suggest that selection favours seasonal shifts in reproductive investment of mothers (high early-season fecundity) over plastic responses of embryos to seasonal environmental changes.

Association between exposure to anaesthesia and surgery and long-term cognitive trajectories in older adults: report from the Mayo Clinic Study of Aging.

BACKGROUND: The link between exposure to general anaesthesia and surgery (exposure) and cognitive decline in older adults is debated. We hypothesised that it is associated with cognitive decline. METHODS: We analysed the longitudinal cognitive function trajectory in a cohort of older adults. Models assessed the rate of change in cognition over time, and its association with exposure to anaesthesia and surgery. Analyses assessed whether exposure in the 20 yr before enrolment is associated with cognitive decline when compared with those unexposed, and whether post-enrolment exposure is associated with a change in cognition in those unexposed before enrolment. RESULTS: We included 1819 subjects with median (25th and 75th percentiles) follow-up of 5.1 (2.7-7.6) yr and 4 (3-6) cognitive assessments. Exposure in the previous 20 yr was associated with a greater negative slope compared with not exposed (slope: -0.077 vs -0.059; difference: -0.018; 95% confidence interval: -0.032, -0.003; P=0.015). Post-enrolment exposure in those previously unexposed was associated with a change in slope after exposure (slope: -0.100 vs -0.059 for post-exposure vs pre-exposure, respectively; difference: -0.041; 95% confidence interval: -0.074, -0.008; P=0.016). Cognitive impairment could be attributed to declines in memory and attention/executive cognitive domains. CONCLUSIONS: In older adults, exposure to general anaesthesia and surgery was associated with a subtle decline in cognitive z-scores. For an individual with no prior exposure and with exposure after enrolment, the decline in cognitive function over a 5 yr period after the exposure would be 0.2 standard deviations more than the expected decline as a result of ageing. This small cognitive decline could be meaningful for individuals with already low baseline cognition.

In vitro gas and methane production in rumen fluid from dairy cows fed grass silages differing in plant maturity, compared to in vivo data.

The relationship between in vitro rumen CH4 production of grass silages, using the gas production technique, and in vivo data obtained with the same cows and rations in respiration chambers was investigated. Silages were made from grass harvested in 2013 on May 6th, May 25th, July 1st and July 8th. The grass silages were used to formulate four different rations which were fed to 24 cows in early and late lactation, resulting in a slightly different dry matter intake (DMI; 16.5 kg/day vs. 15.4 kg/day). The experimental rations consisted of 70% grass silage, 10% maize silage, and 20% concentrates on a dry matter basis. Cows were adapted to the rations for 17 days before rumen fluid was collected via oesophageal tubing, and in vitro gas and CH4 production were analysed. In vitro total gas and CH4 production of the (ensiled) grass expressed as ml/g OM decreased with advancing maturity of the grass. The in vitro CH4 production after 48 hr of incubation expressed in ml/g OM did not correlate with the in vivo CH4 production expressed in g/kg organic matter intake or g/kg DMI (R2  = .00-.18, p ≥ .287). The differences in CH4 emission per unit of intake observed in vivo were rather small between the different rations, which also contributed to the observed poor relationship. Utilizing stepwise multiple regression improved the correlation only slightly. In vitro gas and CH4 production varied based on whether donor cows were previously adapted to the respective ration or not, suggesting that careful adaption to the experimental diet should be envisaged in in vitro gas and CH4 production experiments.

What do recent human studies tell us about the association between anaesthesia in young children and neurodevelopmental outcomes?

Anaesthetic and sedative drugs transiently disrupt normal neural activity to facilitate healthcare procedures in children, but they can also cause long-term brain injury in experimental animal models. The US Food and Drug Administration (FDA) has recently advised that repeated or lengthy exposures to anaesthetic and sedative drugs prior to 3 yr of age have the potential to harm the development of children's brains and added warnings to these drug labels. Paediatric anaesthesia toxicity could represent a significant public health issue, and concern about this potential injury in children has become an important issue for families, paediatric clinicians and healthcare regulators. Since late 2015, important new data from five major clinical studies have been published. This narrative review aims to provide a brief overview of the preclinical and clinical literature, including a comprehensive review of these recent additions to the human literature. We integrate these new data with prior studies to provide further insights into how these clinical findings can be applied to children.

Postoperative delirium in elderly patients is associated with subsequent cognitive impairment.

BACKGROUND: We examined the risk for postoperative delirium (POD) in patients with mild cognitive impairment (MCI) or dementia, and the association between POD and subsequent development of MCI or dementia in cognitively normal elderly patients. METHODS: Patients ≥65 yr of age enrolled in the Mayo Clinic Study of Aging who were exposed to any type of anaesthesia from 2004 to 2014 were included. Cognitive status was evaluated before and after surgery by neuropsychological testing and clinical assessment, and was defined as normal or MCI/dementia. Postoperative delirium was detected with the Confusion Assessment Method for the intensive care unit. Logistic regression analyses were performed. RESULTS: Among 2014 surgical patients, 74 (3.7%) developed POD. Before surgery, 1667 participants were cognitively normal, and 347 met MCI/dementia criteria. The frequency of POD was higher in patients with pre-existing MCI/dementia compared with no MCI/dementia {8.7 vs 2.6%; odds ratio (OR) 2.53, [95% confidence interval (CI) 1.52-4.21]; P <0.001}. Postoperative delirium was associated with lower education [OR, 3.40 (95% CI, 1.60-7.40); P =0.002 for those with <12 vs ≥16 yr of schooling]. Of the 1667 patients cognitively normal at their most recent assessment, 1152 returned for postoperative evaluation, and 109 (9.5%) met MCI/dementia criteria. The frequency of MCI/dementia at the first postoperative evaluation was higher in patients who experienced POD compared with those who did not [33.3 vs 9.0%; adjusted OR, 3.00 (95% CI, 1.12-8.05); P =0.029]. CONCLUSIONS: Mild cognitive impairment or dementia is a risk for POD. Elderly patients who have not been diagnosed with MCI or dementia but experience POD are more likely to be diagnosed subsequently with MCI or dementia.

Habitat- and season-specific temperatures affect phenotypic development of hatchling lizards.

Embryonic environments influence phenotypic development, but relatively few experiments have explored the effects of natural environmental variation. We incubated eggs of the lizard Anolis sagrei under conditions that mimicked natural spatial and temporal thermal variation to determine their effects on offspring morphology and performance. Incubation temperatures mimicked two microhabitats (open, shade) at two different times of the incubation season (April, July). Egg survival, incubation duration and offspring size were influenced by interactions between habitat- and season-specific nest temperatures, and locomotor performance was influenced primarily by temporal factors. These findings highlight the importance of spatial and temporal environmental variation in generating variation in fitness-related phenotypes.

Previous Exposure to Anesthesia and Autism Spectrum Disorder (ASD): A Puerto Rican Population-Based Sibling Cohort Study.

BACKGROUND: Autism Spectrum Disorder (ASD) is characterized by impaired social interaction and communication, and by restricted and repetitive behavior, that begins usually before a child is three years old.(1) Researchers have shown that prevalence rates in the U.S. may be as high as 1 in 68.(52) A number of studies have examined the effects of early exposure to anesthesia on brain development and subsequent impairment in neurocognitive function; yet, little is known about the possible effects of anesthetic agents on social-behavioral functioning. The association between exposure to anesthesia either in uterus, during the first years of life, or later and development of Autistic Spectrum Disorder (ASD) or its severity was determined in a retrospective population based cohort study. OBJECTIVES: Identify if children who had previous exposure to anesthesia either in uterus, first years of life during their developing brain years, or later, are at risk of developing ASD and its severe form of the disease. METHODS: Data was obtained from structured interviews administered to a sample of 515 parents/guardians distributed in two groups: ASD = 262 children diagnosed with this condition and Non-ASD: 253 children (siblings of ASD group) without diagnosis (95% confidence interval) that freely decided to participate and agreed to a consent form. Variables studied include: demographics, diagnosis and severity of ASD, exposure to anesthesia, method of childbirth, and age of exposure Children less than 2 years of age were considered into have developing brain period. Data was analyzed using Chi-square or Fisher exact test. RESULTS: In contrast to non-ASD group, most of the children within ASD group were male, 76% (p=0.0001). With regards to methods of childbirth, 64% of the ASD population were vaginal delivery (VD; Non-anesthesia exposure group) and 36% cesarean delivery (CD) compared to non-autistic population with 71% VD and 29% CD, which demonstrates no statistical difference between both groups (p=0.1113). Out of the 36% of ASD population that underwent CD, 7% were performed using general anesthesia and 93% regional anesthesia, while the 29% of the CD of non-ASD, 5% were performed using general anesthesia and 95% regional anesthesia. This reveals no statistical significance (p=0.7569) with the development of ASD and the type of anesthesia used when comparing ASD with non-ASD patients. In view of severity of autism, in VD, 56% of ASD population had mild form of the disorder, 34% moderate, and 10% severe; while CD had a 54% mild form of the disorder, 33% moderate, and 13% severe. This shows no statistical association (p=0.8069) when comparing exposure to anesthesia in uterus to subsequent severe form of ASD. Of the 262 ASD patients, 99 had exposure to anesthetics before their diagnosis, while in Non-ASD population, 110 had exposure to anesthesia, demonstrating no statistically significant association between both groups (p=0.2091). Out of 99 ASD patients exposed to anesthesia prior to their diagnosis, 72 were exposed before age 2. When compared to the 110 Non-ASD patients exposed to anesthesia, 86 had exposure during this developing brain period, which indicates no statistically significant association (p=0.4207). In addition, most of the ASD children exposed to anesthesia during developing brain were diagnosed with mild degree of the disorder when compared to ASD children without any previous exposure to anesthesia (p=0.9700) during the same period. When the exposure occurred after age 2, ASD children developed mild form of the disorder as compared with ASD children without any previous exposure to anesthesia (p=0.1699) in that period. CONCLUSIONS: Children under early exposure to anesthesia in uterus, first 2 years of life, or later are not more likely to develop neither ASD nor severe form of the disorder.

Effect of nitrogen fertilization rate and regrowth interval of grass herbage on methane emission of zero-grazing lactating dairy cows.

Dairy cattle farming in temperate regions often relies on grass herbage (GH)-based diets but the effect of several grass management options on enteric CH4 emission has not been fully investigated yet. We investigated the combined effect of N fertilization rate and length of regrowth period of GH (predominantly ryegrass) on CH4 emission from lactating dairy cows. In a randomized block design, 28 lactating Holstein-Friesian dairy cows received a basal diet of GH and compound feed [85:15; dry matter (DM) basis]. Treatments consisted of GH cut after 3 or 5 weeks of regrowth, after receiving either a low (20kg of N/ha) or a high (90kg of N/ha) fertilization rate after initial cut. Feed intake, digestibility, milk production and composition, N and energy balance, and CH4 emission were measured during a 5-d period in climate respiration chambers after an adaptation to the diet for 12d. Cows were restricted-fed during measurements and mean DM intake was 15.0±0.16kg/d. Herbage crude protein content varied between 76 and 161g/kg of DM, and sugar content between 186 and 303g/kg of DM. Fat- and protein-corrected milk (FPCM) and feed digestibility increased with increased N fertilization rates and a shorter regrowth interval. Increasing the N fertilization rate increased daily CH4 emission per cow (+10%) and per unit of DM intake (+9%), tended to increase the fraction of gross energy intake emitted as CH4 (+7%), and (partly because of the low crude protein content for the low fertilized GH) only numerically reduced CH4 per unit of FPCM. The longer regrowth interval increased CH4 emission per unit of FPCM (+14%) compared with the shorter regrowth interval, but did not affect CH4 emission expressed in any other unit. With increasing N fertilization CH4 emission decreased per unit of digestible neutral detergent fiber intake (-13%) but not per unit of digestible organic matter intake. There was no interaction of the effect of N fertilization rate and regrowth interval on CH4 emission, but effects of N fertilization were generally most distinct with GH of 5 wk regrowth. The present results suggest that altering grass quality through an increase of N fertilization and a shorter regrowth interval can reduce CH4 emission in zero-grazing dairy cows, depending on the unit in which it is expressed. The larger amount of CH4 produced per day and cow with the more intensively managed GH is compensated by a higher feed digestibility and FPCM yield.

Previous Exposure to Anesthesia and Autism Spectrum Disorder (ASD): A Puerto Rican Population-Based Sibling Cohort Study.

BACKGROUND: Autism Spectrum Disorder (ASD) is characterized by impaired social interaction and communication, and by restricted and repetitive behavior, that begins usually before a child is three years old.1 Researchers have shown that prevalence rates in the U.S. may be as high as 1 in 68.52 A number of studies have examined the effects of early exposure to anesthesia on brain development and subsequent impairment in neurocognitive function; yet, little is known about the possible effects of anesthetic agents on social-behavioral functioning. The association between exposure to anesthesia either in uterus, during the first years of life, or later and development of Autistic Spectrum Disorder (ASD) or its severity was determined in a retrospective population based cohort study. OBJECTIVES: Identify if children who had previous exposure to anesthesia either in uterus, first years of life during their developing brain years, or later, are at risk of developing ASD and its severe form of the disease. METHODS: Data was obtained from structured interviews administered to a sample of 515 parents/guardians distributed in two groups: ASD = 262 children diagnosed with this condition and Non-ASD: 253 children (siblings of ASD group) without diagnosis (p = 0.8069) when comparing exposure to anesthesia in uterus to subsequent severe form of ASD. Of the 262 ASD patients, 99 had exposure to anesthetics before their diagnosis, while in Non-ASD population, 110 had exposure to anesthesia, demonstrating no statistically significant association between both groups (p = 0.2091). Out of 99 ASD patients exposed to anesthesia prior to their diagnosis, 72 were exposed before age 2. When compared to the 110 Non-ASD patients exposed to anesthesia, 86 had exposure during this developing brain period, which indicates no statistically significant association (p = 0.4207). In addition, most of the ASD children exposed to anesthesia during developing brain were diagnosed with mild degree of the disorder when compared to ASD children without any previous exposure to anesthesia (p = 0.9700) during the same period. When the exposure occurred after age 2, ASD children developed mild form of the disorder as compared with ASD children without any previous exposure to anesthesia (p = 0.1699) in that period. CONCLUSIONS: Children under early exposure to anesthesia in uterus, first 2 years of life, or later are not more likely to develop neither ASD nor severe form of the disorder. INDEX WORDS: Anesthesia, Autism Spectrum Disorder, Puerto Rico. (95% confidence interval) that freely decided to participate and agreed to a consent form. Variables studied, include: demographics, diagnosis and severity of ASD, exposure to anesthesia, method of childbirth, and age of exposure. Children less than 2 years of age were considered into have developing brain period. Data was analyzed using Chi-square or Fisher exact test. RESULTS: In contrast to non-ASD group, most of the children within ASD group were male, 76% (p = 0.0001). With regards to methods of childbirth, 64% of the ASD population were vaginal delivery (VD; Non-anesthesia exposure group) and 36% cesarean delivery (CD) compared to non-autistic population with 71% VD and 29% CD, which demonstrates no statistical difference between both groups (p = 0.1113). Out of the 36% of ASD population that underwent CD, 7% were performed using general anesthesia and 93% regional anesthesia, while the 29% of the CD of non-ASD, 5% were performed using general anesthesia and 95% regional anesthesia. This reveals no statistical significance (p = 0.7569) with the development of ASD and the type of anesthesia used when comparing ASD with non-ASD patients. In view of severity of autism, in VD, 56% of ASD population had mild form of the disorder, 34% moderate, and 10% severe; while CD had a 54% mild form of the disorder, 33% moderate, and 13% severe. This shows no statistical association.

Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis.

The emergence and spread of multidrug-resistant strains of Mycobacterium tuberculosis remains a major concern of tuberculosis control programmes worldwide, as treatment depends on low-efficacy, toxic compounds that often lead to poor outcomes. M. tuberculosis develops drug resistance exclusively through chromosomal mutations, in particular single-nucleotide polymorphisms. Moreover, in laboratory assays the organism exhibits a spontaneous mutation rate that is at the lower end of the bacterial spectrum. Despite this, whole-genome sequencing technology has identified unexpected genetic diversity among clinical M. tuberculosis populations. This suggests that the mycobacterial mutation rate may be modulated within the host and, in turn, implies a potential role for constitutive and/or transient mutator strains in adaptive evolution. It also raises the possibility that environmental factors might act as key mutagens during M. tuberculosis infection. Here we consider the elements that might influence the mycobacterial mutation rate in vivo and evaluate the potential roles of constitutive and transient mutator states in the generation of drug resistance mutations. In addition, we identify key research questions that will influence future efforts to develop novel therapeutic strategies for a disease that continues to impose a significant global health burden.

The adaptive significance of temperature-dependent sex determination in a reptile.

Understanding the mechanisms that determine an individual's sex remains a primary challenge for evolutionary biology. Chromosome-based systems (genotypic sex determination) that generate roughly equal numbers of sons and daughters accord with theory, but the adaptive significance of environmental sex determination (that is, when embryonic environmental conditions determine offspring sex, ESD) is a major unsolved problem. Theoretical models predict that selection should favour ESD over genotypic sex determination when the developmental environment differentially influences male versus female fitness (that is, the Charnov-Bull model), but empirical evidence for this hypothesis remains elusive in amniote vertebrates--the clade in which ESD is most prevalent. Here we provide the first substantial empirical support for this model by showing that incubation temperatures influence reproductive success of males differently than that of females in a short-lived lizard (Amphibolurus muricatus, Agamidae) with temperature-dependent sex determination. We incubated eggs at a variety of temperatures, and de-confounded sex and incubation temperature by using hormonal manipulations to embryos. We then raised lizards in field enclosures and quantified their lifetime reproductive success. Incubation temperature affected reproductive success differently in males versus females in exactly the way predicted by theory: the fitness of each sex was maximized by the incubation temperature that produces that sex. Our results provide unequivocal empirical support for the Charnov-Bull model for the adaptive significance of temperature-dependent sex determination in amniote vertebrates.

A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma.

BACKGROUND: This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer. METHODS: Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2:1 to also receive intravenous trebananib 10 mg kg(-1) once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS). RESULTS: One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ≥3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%). CONCLUSION: Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.

Passage kinetics of 13C-labeled corn silage components through the gastrointestinal tract of dairy cows.

Fractional passage rates form a fundamental element within modern feed evaluation systems for ruminants but knowledge on feed type and feed component specific passage rates are largely lacking. This study describes the use of carbon stable isotopes ((13)C) to assess component-specific passage kinetics of 6 intrinsically (13)C-labeled corn silages varying in quality (2 cultivars×3 maturity stages) in a 6×6 Latin square design using 6 rumen-fistulated lactating dairy cows. An increase in maturity increased starch and decreased neutral detergent fiber and acid detergent fiber contents of corn silages. Passage kinetics were assessed for an external (chromium mordanted fiber; Cr-NDF) and an internal marker ((13)C isotopes) collected in feces and omasal digesta. The best fit was obtained with a deterministic multicompartmental model compared with stochastic Gn and GnG1 models with increasing order of age dependency (n=1 to 5) for both sampling sites. The Cr-NDF marker yielded higher rumen fractional passage rates (K1) than did (13)C in the dry matter ((13)CDM) in feces (0.042/h vs. 0.023/h). Omasal marker excretion patterns support the conclusions based on conventional fecal marker excretions. Component-specific passage was assessed for acid detergent fiber ((13)CADF) in feces and for starch ((13)CST) in omasal digesta. The fractional passage rate based on fecal (13)CDM and (13)CADF did not differ. Omasal (13)CST provided higher K1 values (0.042/h) than omasal (13)CDM (0.034/h) but lower values than omasal Cr-NDF (0.051/h). Fractional passage rates from the proximal colon-cecum (K2) based on fecal marker concentrations showed trends similar to K1, with Cr-NDF providing a value (0.425/h) more than twice as high as that of (13)CDM (0.179/h) and (13)CADF (0.128/h). Total mean retention time in the gastrointestinal tract was approximately double for (13)CDM (64.1h) and (13)CADF (77.6h) compared with Cr-NDF (36.4h). Corn silage quality did not affect any of the estimated passage kinetic parameters. In situ fractional degradation rates did not differ among corn silages, except for a decreased fractional degradation rate of starch with advancing maturity. Results indicate that isotope labeling allows assessment of component-specific passage kinetics of carbohydrate fractions in corn silage.

Passage of stable isotope-labeled grass silage fiber and fiber-bound protein through the gastrointestinal tract of dairy cows.

Fractional passage rates are required to predict nutrient absorption in ruminants but data on nutrient-specific passage kinetics are largely lacking. With the use of the stable isotope ratio (δ) as an internal marker, we assessed passage kinetics of fiber and fiber-bound nitrogen (N) of intrinsically labeled grass silage from fecal and omasal excretion patterns of δ(13)C and δ(15)N. In a 6×6 Latin square, lactating dairy cows received grass silages [455 g/kg of total diet dry matter (DM) ] in a 2×3 factorial arrangement from ryegrass swards fertilized at low (45 kg of N/ha) or high (90 kg of N/ha) levels of N and harvested at 3 maturity stages. Feed intake (16.7±0.48 kg of DM/d; mean ± standard error of the mean) and milk yield (26.7±0.92 kg/d) increased at the high level of N fertilization and at decreasing maturity. Nutrient digestibility decreased with increasing plant maturity, particularly at the high level of N fertilization, essentially reflecting dietary treatment effects on the nutritional composition of the grass silage. Fractional rumen passage rates (K1) were highest and total mean retention time in the gastrointestinal tract (TMRT) was lowest when based on the external marker chromium mordanted fiber (Cr-NDF; 0.047/h and 38.0 h, respectively). Fecal δ(13)C in the acid detergent fiber fraction ((13)CADF) provided the lowest K1 (0.023/h) and the highest TMRT (61.1 h) and highest peak concentration time (PCT; 24.3h) among markers. In comparison, fecal fiber-bound N ((15)NADF) had a considerably higher K1 (0.032/h) and lower TMRT (46.4 h) than (13)CADF. Total N (measured with (15)NDM) had a comparable K1 (0.034/h) to that of (15)NADF but provided the highest fractional passage rates from the proximal colon-cecum (K2; 0.37/h) and lowest PCT (17.4 h) among markers. A literature review indicated unclear effects of grass silage maturity on K1 and unknown effects of N fertilization on K1. Our study indicated no effect of advancing maturity on fecal K1 and a trend for K1 to increase with the high level of N fertilization. Parameter K2 increased, whereas PCT and TMRT generally decreased with the high level of N fertilization. Omasal digesta sampling largely confirmed results based on fecal sampling. Results indicate that the use of δ(13)C and δ(15)N can describe fiber-specific passage kinetics of forage.

Driving performance of outpatients achieving discharge criteria after deep sedation is worse than these of their escort-driver: a prospective observational study on simulator.

Background: Achieving post-anesthesia discharge criteria after surgery or outpatient procedures does not mean that the patient has regained all his or her faculties, such as driving. Although mandated by many clinical guidelines, there is no evidence that escort-drivers reduce the risk of traffic accidents after deep sedation. The purpose of this study was to evaluate that hypothesis that driving performance as measured using a driving simulation would not differ between patients who had undergone deep sedation for gastrointestinal endoscopy meeting discharge criteria and their escorts. Methods: This prospective study included patients scheduled for ambulatory gastrointestinal endoscopy under deep propofol sedation (patient group) and their escorts (escort group). Driving performance of escorts and patients (when discharge criteria were met) was assessed using a driving simulator. Results: 30 patients and their escorts were included. Patients crossed the midline significantly more frequently than escorts (3 [2-4] (median [IQR]) and 2 [1-3] crossings, respectively, p=0.015]. Patients were speeding for a higher proportion of the distance traveled compared with escorts (37 (20)% (mean (SD)) and 24 (17)% in patients and escorts, respectively, p = 0.029). There were no significant differences between groups in other simulation parameters. Conclusions: The ability to stay within the traffic lanes, as measured by the number of midline crossing during a simulated driving performance, is impaired in patients who meet discharge criteria after gastrointestinal endoscopy under deep sedation compared with their escorts. This finding does not support a practice of allowing patients to drive themselves home after these procedures.