Grain structure control during metal 3D printing by high-intensity ultrasound.

Additive manufacturing (AM) of metals, also known as metal 3D printing, typically leads to the formation of columnar grain structures along the build direction in most as-built metals and alloys. These long columnar grains can cause property anisotropy, which is usually detrimental to component qualification or targeted applications. Here, without changing alloy chemistry, we demonstrate an AM solidification-control solution to printing metallic alloys with an equiaxed grain structure and improved mechanical properties. Using the titanium alloy Ti-6Al-4V as a model alloy, we employ high-intensity ultrasound to achieve full transition from columnar grains to fine (~100 µm) equiaxed grains in AM Ti-6Al-4V samples by laser powder deposition. This results in a 12% improvement in both the yield stress and tensile strength compared with the conventional AM columnar Ti-6Al-4V. We further demonstrate the generality of our technique by achieving similar grain structure control results in the nickel-based superalloy Inconel 625, and expect that this method may be applicable to other metallic materials that exhibit columnar grain structures during AM.

Regulation of biosimilar medicines and current perspectives on interchangeability and policy.

Competition arising from the increasing availability of biosimilar medicines has resulted in healthcare savings and has provided greater patient access to high cost therapeutics in Europe. The biosimilar market in the USA is relatively new so the full impact of biosimilar availability remains to be seen. Educational initiatives relating to the use of biosimilar medicines are currently being undertaken by regulators, policy makers and industry. The debate on biosimilars has moved on from the appropriateness of the regulatory framework which governs their approval, to the practice of interchangeability. Interchangeability is an important issue for healthcare professionals but different definitions and regulatory frameworks exist in the USA and Europe. In the USA, an interchangeable biological product is a biosimilar which may be substituted by a pharmacist, subject to local State policies. The interchangeability of a biosimilar with its reference medicine will be evaluated by the United States Food and Drug Administration (FDA) in cases where approval as an 'interchangeable product' is sought. In contrast, the European Medicines Agency (EMA) does not assess or make recommendations on interchangeability, therefore, in Europe, interchangeability does not mean substitution but is generally physician-led or driven by national policy. This paper provides an overview of the regulation of biosimilar medicines. Challenges associated with the demonstration of interchangeability and practical considerations relating to switching are also discussed. Finally, we present policies that have been adopted to date in several European countries, the USA and Australia, which aim to promote the use of biosimilar medicines.

Fine-mapping host genetic variation underlying outcomes to Mycobacterium bovis infection in dairy cows.

BACKGROUND: Susceptibility to Mycobacterium bovis infection in cattle is governed in part by host genetics. However, cattle diagnosed as infected with M. bovis display varying signs of pathology. The variation in host response to infection could represent a continuum since time of exposure or distinct outcomes due to differing pathogen handling. The relationships between host genetics and variation in host response and pathological sequelae following M. bovis infection were explored by genotyping 1966 Holstein-Friesian dairy cows at 538,231 SNPs with three distinct phenotypes. These were: single intradermal cervical comparative tuberculin (SICCT) test positives with visible lesions (VLs), SICCT-positives with undetected visible lesions (NVLs) and matched controls SICCT-negative on multiple occasions. RESULTS: Regional heritability mapping identified three loci associated with the NVL phenotype on chromosomes 17, 22 and 23, distinct to the region on chromosome 13 associated with the VL phenotype. The region on chromosome 23 was at genome-wide significance and candidate genes overlapping the mapped window included members of the bovine leukocyte antigen class IIb region, a complex known for its role in immunity and disease resistance. Chromosome heritability analysis attributed variance to six and thirteen chromosomes for the VL and NVL phenotypes, respectively, and four of these chromosomes were found to explain a proportion of the phenotypic variation for both the VL and NVL phenotype. By grouping the M. bovis outcomes (VLs and NVLs) variance was attributed to nine chromosomes. When contrasting the two M. bovis infection outcomes (VLs vs NVLs) nine chromosomes were found to harbour heritable variation. Regardless of the case phenotype under investigation, chromosome heritability did not exceed 8% indicating that the genetic control of bTB resistance consists of variants of small to moderate effect situated across many chromosomes of the bovine genome. CONCLUSIONS: These findings suggest the host genetics of M. bovis infection outcomes is governed by distinct and overlapping genetic variants. Thus, variation in the pathology of M. bovis infected cattle may be partly genetically determined and indicative of different host responses or pathogen handling. There may be at least three distinct outcomes following M. bovis exposure in dairy cattle: resistance to infection, infection resulting in pathology or no detectable pathology.

Application of high-dimensional feature selection: evaluation for genomic prediction in man.

In this study, we investigated the effect of five feature selection approaches on the performance of a mixed model (G-BLUP) and a Bayesian (Bayes C) prediction method. We predicted height, high density lipoprotein cholesterol (HDL) and body mass index (BMI) within 2,186 Croatian and into 810 UK individuals using genome-wide SNP data. Using all SNP information Bayes C and G-BLUP had similar predictive performance across all traits within the Croatian data, and for the highly polygenic traits height and BMI when predicting into the UK data. Bayes C outperformed G-BLUP in the prediction of HDL, which is influenced by loci of moderate size, in the UK data. Supervised feature selection of a SNP subset in the G-BLUP framework provided a flexible, generalisable and computationally efficient alternative to Bayes C; but careful evaluation of predictive performance is required when supervised feature selection has been used.

Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis.

Tuberculosis (TB) caused by Mycobacterium bovis is a re-emerging disease of livestock that is of major economic importance worldwide, as well as being a zoonotic risk. There is significant heritability for host resistance to bovine TB (bTB) in dairy cattle. To identify resistance loci for bTB, we undertook a genome-wide association study in female Holstein-Friesian cattle with 592 cases and 559 age-matched controls from case herds. Cases and controls were categorised into distinct phenotypes: skin test and lesion positive vs skin test negative on multiple occasions, respectively. These animals were genotyped with the Illumina BovineHD 700K BeadChip. Genome-wide rapid association using linear and logistic mixed models and regression (GRAMMAR), regional heritability mapping (RHM) and haplotype-sharing analysis identified two novel resistance loci that attained chromosome-wise significance, protein tyrosine phosphatase receptor T (PTPRT; P=4.8 × 10(-7)) and myosin IIIB (MYO3B; P=5.4 × 10(-6)). We estimated that 21% of the phenotypic variance in TB resistance could be explained by all of the informative single-nucleotide polymorphisms, of which the region encompassing the PTPRT gene accounted for 6.2% of the variance and a further 3.6% was associated with a putative copy number variant in MYO3B. The results from this study add to our understanding of variation in host control of infection and suggest that genetic marker-based selection for resistance to bTB has the potential to make a significant contribution to bTB control.

Implementing biosecurity measures on dairy farms in Ireland.

Dairy farms in Ireland are expanding in preparation for a new era of unrestricted milk production with the elimination of the European Union (EU) production quotas in 2015. Countries experiencing a changing agricultural demographic, including farm expansion, can benefit from documenting the implementation of on-farm biosecurity. The objectives of this study were to document and describe influences on biosecurity practices and related opinions on dairy farms. A representative response rate of 64% was achieved to a nationwide telesurvey of farmers. A 20% discrepancy was found between self-declared and truly 'closed' herds indicating a lack of understanding of the closed herd concept. Although >72% of farmers surveyed considered biosecurity to be important, 53% stated that a lack of information might prevent them from improving their biosecurity. Logistic regression highlighted regional, age, and farm-size related differences in biosecurity practices and opinions towards its implementation. Farmers in the most dairy cattle dense region were three times more likely to quarantine purchased stock than were their equivalents in regions where dairy production was less intense (P=0.012). Younger farmers in general were over twice as likely as middle-aged farmers to implement biosecurity guidelines (P=0.026). The owners of large enterprises were almost five times more likely to join a voluntary animal health scheme (P=0.003), and were over three times more likely to pay a premium price for health accredited animals (P=0.02) than were those farming small holdings. The baseline data recorded in this survey will form the basis for more detailed sociological and demographic research which will facilitate the targeting of future training of the farming community in biosecurity.

Bias, accuracy, and impact of indirect genetic effects in infectious diseases.

Selection for improved host response to infectious disease offers a desirable alternative to chemical treatment but has proven difficult in practice, due to low heritability estimates of disease traits. Disease data from field studies is often binary, indicating whether an individual has become infected or not following exposure to an infectious disease. Numerous studies have shown that from this data one can infer genetic variation in individuals' underlying susceptibility. In a previous study, we showed that with an indirect genetic effect (IGE) model it is possible to capture some genetic variation in infectivity, if present, as well as in susceptibility. Infectivity is the propensity of transmitting infection upon contact with a susceptible individual. It is an important factor determining the severity of an epidemic. However, there are severe shortcomings with the Standard IGE models as they do not accommodate the dynamic nature of disease data. Here we adjust the Standard IGE model to (1) make expression of infectivity dependent on the individuals' disease status (Case Model) and (2) to include timing of infection (Case-ordered Model). The models are evaluated by comparing impact of selection, bias, and accuracy of each model using simulated binary disease data. These were generated for populations with known variation in susceptibility and infectivity thus allowing comparisons between estimated and true breeding values. Overall the Case Model provided better estimates for host genetic susceptibility and infectivity compared to the Standard Model in terms of bias, impact, and accuracy. Furthermore, these estimates were strongly influenced by epidemiological characteristics. However, surprisingly, the Case-Ordered model performed considerably worse than the Standard and the Case Models, pointing toward limitations in incorporating disease dynamics into conventional variance component estimation methodology and software used in animal breeding.

Genetic correlations between measures of Mycobacterium bovis infection and economically important traits in Irish Holstein-Friesian dairy cows.

Mycobacterium bovis is the primary agent of tuberculosis (TB) in cattle. The failure of Ireland and some other countries to reach TB-free status indicates a need to investigate complementary control strategies. One such approach would be genetic selection for increased resistance to TB. Previous research has shown that considerable genetic variation exists for susceptibility to the measures of M. bovis infection, confirmed M. bovis infection, and M. bovis-purified protein derivative (PPD) responsiveness. The objective of this study was to estimate the genetic and phenotypic correlations between economically important traits and these measures of M. bovis infection. A total of 20,148 and 17,178 cows with confirmed M. bovis infection and M. bovis-PPD responsiveness records, respectively, were available for inclusion in the analysis. First- to third-parity milk, fat, and protein yields, somatic cell count, calving interval, and survival, as well as first-parity body condition score records, were available on cows that calved between 1985 and 2007. Bivariate linear-linear and threshold-linear sire mixed models were used to estimate (co)variance components. The genetic correlations between economically important traits and the measures of M. bovis infection estimated from the linear-linear and threshold-linear sire models were similar. The genetic correlations between susceptibility to confirmed M. bovis infection and economically important traits investigated in this study were all close to zero. Mycobacterium bovis-PPD responsiveness was positively genetically correlated with fat production (0.39) and body condition score (0.36), and negatively correlated with somatic cell score (-0.34) and survival (-0.62). Hence, selection for increased survival may indirectly reduce susceptibility to M. bovis infection, whereas selection for reduced somatic cell count and increased fat production and body condition score may increase susceptibility to M. bovis infection.

Genetics of tuberculosis in Irish Holstein-Friesian dairy herds.

Information is lacking on genetic parameters for tuberculosis (TB) susceptibility in dairy cattle. Mycobacterium bovis is the principal agent of tuberculosis in cattle. The objective of this study was to quantify the genetic variation present among Irish Holstein-Friesian dairy herds in their susceptibility to M. bovis infection. A total of 15,182 cow and 8,104 heifer single intradermal comparative tuberculin test (SICTT, a test for M. bovis exposure and presumed infection) records from November 1, 2002, to October 31, 2005, were available for inclusion in the analysis. Data on observed carcass TB lesions from abattoirs were also available for inclusion in the analysis. The only animals retained were those present in a herd during episodes in which at least 2 animals showed evidence of infection; this ensured a high likelihood of exposure to M. bovis. Linear animal models, and sire and animal threshold models were used to estimate the variance components for susceptibility to M. bovis-purified protein derivative (PPD) responsiveness and confirmed M. bovis infection. The heritability estimates from the threshold sire models were biased upward because the relatedness between dam-daughter pairs was ignored. The threshold animal model produced heritability estimates of 0.14 in cows and 0.12 in heifers for susceptibility to M. bovis-PPD responsiveness, and 0.18 in cows for confirmed M. bovis infection susceptibility. Therefore, exploitable genetic variation exists among Irish dairy cows for susceptibility to M. bovis infection. Sire rankings from the linear and threshold animal models were similar, indicating that either model could be used for the analysis of susceptibility to M. bovis-PPD responsiveness. A favorable genetic correlation close to unity was observed between susceptibility to confirmed M. bovis infection and M. bovis-PPD responsiveness, indicating that direct selection for resistance to M. bovis-PPD responsiveness will indirectly reduce susceptibility to confirmed M. bovis infection. Data from the national TB eradication program could be used routinely to estimate breeding values for susceptibility to M. bovis infection.

Microfauna associated with amoebic gill disease in sea-farmed Atlantic salmon, Salmo salar L., smolts.

A study of microfauna, associated with pathological changes in the gills of Atlantic salmon, Salmo salar L., was conducted over 2001-2002. Monthly samples of 1(+) salmon smolts were taken, protozoan populations were quantified and gill health was assessed histologically. Protozoan densities were correlated with pathological changes, in order to determine their possible role in lesions in the gills. The most severe gill tissue changes were observed in summer/autumn and the least in spring. A diverse polyphyletic protozoan community was observed colonizing the gills, including Neoparamoeba sp., other amoebae, scuticociliates, Ichthyobodo-like flagellates, trichodinid ciliates and prostomatean ciliates. The earlier gill tissue changes in the gill were not always associated with the presence of these microorganisms, whereas amoebae (other than Neoparamoeba sp.), Ichthyobodo-like flagellates and trichodinid ciliates correlated with augmenting gill lesions. Neoparamoeba sp. was present, but its abundance did not correlate with the disease. This study suggests that a diversity of protozoans including Ichthyobodo-like flagellates, trichodinid ciliates and amoebae other than Neoparamoeba sp. are involved in the aetiology of amoebic gill disease in the Irish situation.

Lipid metabolism in young men after acute resistance exercise at two different intensities.

The aim of this study was to examine the effects of different resistance training loads on blood lipids. Six healthy, untrained male volunteers performed three protocols: control (no exercise), high intensity (HI) and low intensity (LI) exercise seven days apart. Each protocol comprised eight exercises. The HI protocol used a 10-repetition maximum (RM) load and 10 repetitions. In the LI protocol, the load was halved and repetitions doubled. The volume of work performed in the two exercise protocols was identical. Blood samples were collected before, immediately after, and 15 min after each protocol and analysed for total, high density (HDL-C), low density cholesterol and triglyceride. The only significant effect of exercise was to acutely increase HDL-C in the immediate post exercise sample compared with the control. There was no significant effect on any lipid fraction resulting from the LI protocol compared with the control. The results of this study suggest that intensity alone has an effect in determining the HDL-C response to acute resistance exercise.

Environmental risk factors associated with amoebic gill disease in cultured salmon, Salmo salar L., smolts in Ireland.

A 2-year study was carried out on amoebic gill disease (AGD) involving monthly samples of 1+ Atlantic salmon, Salmo salar L., smolts, histological assessment of the gills and analysis of environmental data. Gill pathology was seen before amoebae could be detected microscopically. These changes in gill integrity were associated with marine environmental conditions, particularly elevated ammonium, nitrite and chlorophyll levels. The results suggest that the environmental changes predispose salmon to colonization by amoebae and ciliates. High densities of histophagous scuticociliates were observed in the gills during periods of advanced gill pathology. A number of different amoebae were observed in close association with gill pathology. Neoparamoeba was not seen in high densities, nor was it associated with gill pathology, indicating that Neoparamoeba may not be the primary agent of the AGD in Irish salmonid culture.

Associations with Vitamin D deficiency in "at risk" Australians.

In a study of 185 elderly living in assisted care and 192 frail aged living in the community in the Sydney metropolitan area, nursing home residents were found to be at a 3-fold and hostel dwellers at a 2-fold risk of Vitamin D [25(OH)D] deficiency (<25 nmol/L) compared to self care residents. Middle Eastern people were found to be at 4-fold risk and Vietnamese a 3-fold risk of deficiency compared to their Australian counterparts. In recently arrived Chinese immigrants, Vitamin D deficiency, was found in 28%, and marginal levels (<37 nmol/L) in 60%, compared to the 34 and 76% found in our nursing home population, and 25 and 57% in hostel care residents. Of the Middle Eastern elderly, 58% were deficient and 83% marginal; although only 18% of Vietnamese were deficient, 68% had marginal Vitamin D status. Other factors associated with Vitamin D deficiency were mobility and sun exposure in assisted care, and low dietary Vitamin D and calcium intake, reduced exercise levels and high % body fat levels in the immigrant groups.

Risk factors for coronary heart disease in two similar Indian population groups, one residing in India, and the other in Sydney, Australia.

OBJECTIVE: To identify the prevalence of coronary risk factors among South Asian Indians in Australia and India. DESIGN: Cross-sectional intercountry comparison. SUBJECTS: Healthy volunteers aged 23-75 y recruited from the Indian community in Sydney Australia (n=125), and their nominated relatives in India, (n=125). RESULTS: The two groups were of similar background with over 90% of the group in India being siblings, parents or relatives of the group in Australia. There was no difference in the populations between India and Australia with regard to mean age (40+/-11.5 vs 39+/-10.3 y), body mass index (BMI) (25+/-3.3 vs 25+/-3.5 kg/m(2)), lipoprotein (a) (178 vs 202 mg/l), total cholesterol (5.3+/-1.3 vs 5.3+/-1.2 mmol/l) or triglyceride (1.7+/-0.8 vs 1.7+/-0.8 mmol/l). The group in India had higher insulin (median values) (139 vs 83 pmol/l, P=0.0001), waist-to-hip ratio (WHR) (0.88+/-0.08 vs 0.85+/-0.09, P=0.01), exercise time (23.7+/-32.7 vs 17.2+/-23.2 h/week, P=0.07), lower waist (83+/-10.0 vs 85+/-11.1 cm, P=0.05) and high-density lipoprotein (0.9+/-0.3 vs 1.1+/-0.6 mmol/l, P=0.02). Women in India had lower BMI (22.7+/-2.9 vs 25.3+/-4.2 kg/m(2), P<0.001), higher insulin (182 vs 90 pmol/l, P<0.001), WHR (0.86+/-0.08 vs 0.77+/-0.06, P<0.001)) and prevalence of abdominal obesity (% WHR >0.8, 73 vs 23%, P<0.001; odds of waist >90 cm=2.3, P<0.05). Men in India had the same BMI, lower waist (85.5+/-8.8 vs 92.9+/-7.2 cm, P<0.001) and WHR (0.89+/-0.09 vs 0.93+/-0.05, P<0.01) but higher insulin (137 vs 76 pmol/l). CONCLUSION: The group in Australia (especially women) have a more favourable disease risk profile than those in India. The fact that the groups are of such similar background and partly related, make it unlikely that changes due to migration have a strong genetic bias. In contrast to other studies, the absence here of excessive weight gain on migration may be a key factor in disease risk prevention.

Food, activity and family--environmental vs biochemical predictors of weight gain in children.

OBJECTIVE: To identify whether measures of energy intake and expenditure predict excessive weight gain over time in children and to describe how these measures relate to similar measures in parents. DESIGN: Prospective, descriptive study over 12 months with no intervention. SETTING: University teaching hospital. SUBJECTS: Children aged between 6.0 and 9.0 y. Recruitment was through advertisement. A total of 59 children (30 F), 41 mothers and 29 fathers. In all, 41 (69%) of the children were reviewed at 12 months (20 F). RESULTS: No significant correlations were identified between body mass index (BMI) z-score change in children over 12 months for any dietary variable or for any measures of energy expenditure, including hours of television viewing or percent time spent in low-, moderate- or high-intensity activity. The BMI z-score change over 12 months was significantly correlated with LDL cholesterol and Apo B/ApoA-1 ratio, independent of percent body fat (r=0.45, P=0.01; r=0.37, P=0.03). A significant positive correlation was found for mothers and girls for percent time in moderate to high activity (r=0.44, P=0.03) and between fathers and children for percent time spent in low activity (r=0.43, P=0.005). CONCLUSIONS: The study has been unable to identify environmental predictors that indicate propensity to faster weight gain over time in this cohort of children, but has extended the evidence on lifestyle-influenced biochemical predictors that do. An overall lack of vigorous activity in this age group, and correlations between parental and child activity and inactivity have been identified.

Comparison of a footpad analyser with a tetrapolar model for the determination of percent body fat in young men.

Since excess weight in adolescence predisposes to overweight and obesity in adulthood, a simple measure of excess adiposity in adolescents is important. Fast, inexpensive, bioelectric impedance analysers (BIA) which rely on two foot pad electrodes are now available to measure % total body fat (TBF), but are less well investigated than conventional tetrapolar models which require the subject to lie prone with four electrodes attached to hands and feet. The aim of this study was to compare the estimation of % TBF by a foot pad analyser and a tetrapolar model. Male students, n = 35, 17-19 years had height, weight, waist and hip circumferences measured and completed a questionnaire regarding age, ethnicity and time of last eating and drinking. Percent TBF was measured by a Tanita stand-on analyser (Tanita 105, Tanita Corporation, Japan) and a SEAC tetrapolar model (SEAC, SFB3, QUT, Australia). Mean age (+/- SD) of subjects = 18.2 +/- 0.6 years, BMI = 24.4 +/- 3.5 kg/m2, WHR = 0.81 +/- 0.04, % TBF, Tanita = 18.2 +/- 6.2 and SEAC = 20.4+/-4.8. Both measures of fat were correlated (r = 0.84, p<0.0001). A plot of the average versus the difference of the two analysers found the majority of differences were above zero, especially for measures of fat below 22%, indicating a negative bias for the Tanita. The limits of agreement are between -5.4 and 9% TBF. Information provided by this study will guide gymnasium operators and health professionals to comment on a relative degree of adiposity with greater confidence of data reliability.

An investigation of health behavior change in Vietnamese-born individuals living in Sydney, Australia.

OBJECTIVE: The purpose of this study was to look at rates of acculturation among Vietnamese immigrants, with particular emphasis on health behaviors. DESIGN: A volunteer sample was surveyed. SETTING/PARTICIPANTS: The participants were drawn from inner and western Sydney, Australia. Participants were asked for their perception of their English fluency as a measure of likely exposure to health promotion advertising and their food, social, exercise, drinking, and smoking habits. RESULTS: It was found that the longer the Vietnamese immigrants participants had lived in Australia, the less likely they were to smoke; in fact, the smoking rate of this population is as low as that of the Australian population as a whole. However the immigrants did not change their low rate of alcohol consumption. In addition, the Vietnamese who had lived longer in Australia significantly increased their daily exercise and started to eat more take-away foods. CONCLUSIONS: With respect to health promotion, these changes are mixed: smoking has decreased, but half the group had begun eating take-away foods; this factor, if combined with a lack of exercise, is likely to lead to obesity.

Body fat distribution and total body fat as risk factors for microalbuminuria in the obese.

BACKGROUND/AIM: Despite evidence linking type of obesity with subsequent organ malfunction, such a link with renal malfunction has not been widely researched. The aim of this study was to investigate percentage of total body fat (%TBF), and body fat distribution in relation to the renal function in overweight/obese subjects. METHODS: Body mass index (BMI), waist-to-hip ratio (WHR), TBF (by bioelectric impedance), and albumin excretion rate (AER) were determined in 77 subjects: 48 overweight/obese (BMI > or =27.8 for men and > or =27.3 for women) and 29 controls (BMI <27.8 for men and <27.3 for women). Obese subjects were subdivided into those (n = 33) with central fat distribution (WHR > or =0.81 for women and > or =0.92 for men) and those (n = 15) with peripheral fat distribution (WHR <0.81 for women and <0.92 for men). RESULTS: Obesity, irrespective of type, was significantly related to increased AER. Furthermore, in subjects who did not differ in %TBF, the age-adjusted relative risk of abnormal AER was 18 times greater in centrally obese subjects as compared with controls, while only four times greater in peripherally obese subjects. CONCLUSION: A significant difference in risk of renal malfunction was observed in individuals having the same %TBF, but differing in the distribution of this fat, with a central fat pattern being the greater risk.