Effector-independent Representations Guide Sequential Target Selection Biases in Action.

Previous work shows that automatic attention biases toward recently selected target features transfer across action and perception and even across different effectors such as the eyes and hands on a trial-by-trial basis. Although these findings suggest a common neural representation of selection history across effectors, the extent to which information about recently selected target features is encoded in overlapping versus distinct brain regions is unknown. Using fMRI and a priming of pop-out task where participants selected unpredictable, uniquely colored targets among homogeneous distractors via reach or saccade, we show that color priming is driven by shared, effector-independent underlying representations of recent selection history. Consistent with previous work, we found that the intraparietal sulcus (IPS) was commonly activated on trials where target colors were switched relative to those where the colors were repeated; however, the dorsal anterior insula exhibited effector-specific activation related to color priming. Via multivoxel cross-classification analyses, we further demonstrate that fine-grained patterns of activity in both IPS and the medial temporal lobe encode information about selection history in an effector-independent manner, such that ROI-specific models trained on activity patterns during reach selection could predict whether a color was repeated or switched on the current trial during saccade selection and vice versa. Remarkably, model generalization performance in IPS and medial temporal lobe also tracked individual differences in behavioral priming sensitivity across both types of action. These results represent a first step to clarify the neural substrates of experience-driven selection biases in contexts that require the coordination of multiple actions.

Predictability and durability of mitral valve repair in patients with severe degenerative mitral regurgitation in medium sized centres.

INTRODUCTION: Mitral valve repair (MVr) is now the treatment of choice to correct severe degenerative mitral regurgitation (MR). Repair rates vary greatly from centre to centre, and the concept of heart valve centres of excellence has been established. OBJECTIVE: The purpose of this study was to see whether large international centre repair rates, and outcomes, are transferrable to medium-sized centres with an interest in mitral repair. METHODS: Between 2011 and 2018, a total of 346 patients underwent mitral valve surgery by a single surgeon. Of these, 238 consecutive patients had repairs, or attempted repairs for degenerative MR, and are included in this study. RESULTS: The study sample consisted of 71% male patients and had a mean age of 64.4 ± 12.3 years; 66% of the study population had concomitant procedures. The overall repair rate in this cohort is 99%. Mean follow up was 3.7 ± 1.9 years. At 5 years, the freedom from MR ≥ 3+ was 95.9 ± 1.9% and at 7 years 91.1 ± 3.8%. Freedom from reoperation at 5 years was 92.9 ± 3.7%, while the 5 years actuarial survival was 89.1 ± 3.7%. On a multivariate analysis, predischarge echo grade was associated with higher risk of future reoperation (odds ratio (OR) = 21.82, p = 0.05). Only age (OR = 1.3, p = 0.03) was predictive of long-term survival. CONCLUSIONS: In specialised medium-sized heart centres, where the surgical team have undergone specialist mitral training, favourable short- and long-term outcomes are achievable with mitral repair rates similar to those from large international centres of excellence. In these heart centres, early surgery should be considered for all patients with severe degenerative MR.

Vancomycin-Resistant Enterococci in Patients Attending for Colonoscopy: An Estimate of Community Prevalence.

Aims Ireland has the highest vancomycin-resistant Enterococcus faecium (VRE) bloodstream infection prevalence in Europe. Two patterns of VRE carriage are recognised. European, with widespread community prevalence and North American, where carriage is predominantly nosocomial. It is unclear which pattern is dominant in Ireland. This uncertainty limits infection control measures. This study sought to explore this issue via a cross sectional point prevalence study. Methods Asymptomatic community volunteers, represented by patients undergoing elective outpatient colonoscopy testing, were opportunistically screened for VRE. Demographic and risk factor data were collected via a patient survey. Rectal swabs were collected before colonoscopy and VRE was identified using the VITEK MS system. Results 102 patients were cultured. A single patient tested positive, representing a prevalence rate of 0.98% (95% CI <0.01-5.8%). This patient demonstrated traditional risk factors, suggesting nosocomial rather than community acquisition. 94% (N=94) of patients had no knowledge of VRE, while 83% (N=83) had low levels of concern regarding hospital acquired infections. Conclusion There is a low incidence of VRE in the Irish community setting, in contrast to other European Countries, suggesting asymptomatic community colonization is not responsible for the high rates of VRE seen in Ireland. Wider screening or atypical infection control measures would not be supported by this data.

Re-assessing the importance of linear type traits in predicting genetic merit for survival in an aging Holstein-Friesian dairy cow population.

The cumulative improvement achieved in the genetic merit for reproductive performance in dairy populations will likely improve dairy cow longevity; therefore, it is time to reassess whether linear type traits are still suitable predictors of survival in an aging dairy cow population. The objective of the present study was therefore to estimate the genetic correlations between linear type traits and survival from one parity to the next and, in doing so, evaluate if those genetic correlations change with advancing parity. After edits, 152,894 lactation survival records (first to ninth parity) were available from 52,447 Holstein-Friesian cows, along with linear type trait records from 52,121 Holstein-Friesian cows. A series of bivariate random regression models were used to estimate the genetic covariances between survival in different parities and each linear type trait. Heritability estimates for survival per parity ranged from 0.02 (SE = 0.004; first parity) to 0.05 (SE = 0.01; ninth parity). Pairwise genetic correlations between survival among different parities varied from 0.42 (first and ninth parity) to 1.00 (eighth to ninth parity), with the strength of these genetic correlations being inversely related to the interval between the compared parities. The genetic correlations between survival and the individual linear type traits varied across parities for 9 of the 20 linear type traits examined, but the correlations with only 3 of these linear type traits strengthened as the cows aged; these 3 traits were rear udder height, teat length, and udder depth. Given that linear type traits are frequently scored in first parity and are genetically correlated with survival in older parities, they may be suitable early predictors of survival, especially for later parity cows. Additionally, the direction of the genetic correlations between survival and rear udder height, teat length, and udder depth did not change between parities; hence, selection for survival in older parities using these linear type traits should not hinder genetic improvement for survival in younger parities.

Exploiting genetic variability in the trajectory of lactation yield and somatic cell score with each progressing parity.

The inclusion of reproductive performance in dairy cow breeding schemes has resulted in a cumulative improvement in genetic merit for reproductive performance; this improvement should manifest in longer productive lives through a reduced requirement for involuntary culling. Nonetheless, the average length of dairy cow productive life has not changed in most populations, suggesting that risk factors for culling, especially in older cows, are possibly more associated with lower yield or high somatic cell score (SCS) than compromised reproductive performance. The objective of the present study was to understand the dynamics of lactation yields and SCS in dairy cows across parities and, in doing so, quantify the potential to alter this trajectory through breeding. After edits, 3,470,520 305-d milk, fat, and protein yields, as well as milk fat and protein percentage and somatic cell count records from 1,162,473 dairy cows were available for analysis. Random regression animal models were used to identify the parity in which individual cows reached their maximum lactation yields, and highest average milk composition and SCS; also estimated from these models were the (co)variance components for yield, composition, and SCS per parity across parities. Estimated breeding values for all traits per parity were calculated for cows reaching ≥fifth parity. Of the cows included in the analyses, 91.0%, 92.2%, and 83.4% reached maximum milk, fat, and protein yield in fifth parity, respectively. Conversely, 95.9% of cows reached their highest average fat percentage in first parity and 62.9% of cows reached their highest average protein percentage in third parity. In contrast to both milk yield and composition traits, 98.4% of cows reached their highest average SCS in eighth parity. Individual parity estimates of heritability for milk yield traits, milk composition, and SCS ranged from 0.28 to 0.44, 0.47 to 0.69, and 0.13 to 0.23, respectively. The strength of the genetic correlations per trait among parities was inversely related to the interval between the parities compared; the weakest genetic correlation was 0.67 (standard error = 0.02) between milk yield in parities 1 and 8. Eigenvalues and eigenfunctions of the additive genetic covariance matrices for all investigated traits revealed potential to alter the trajectory of parity profiles for milk yield, milk composition, and SCS. This was further demonstrated when evaluating the trajectories of animal estimated breeding values per parity.

Correction to: Who meets national early childhood sleep guidelines in Aotearoa New Zealand? A cross-sectional and longitudinal analysis.

[This corrects the article DOI: 10.1093/sleepadvances/zpac002.].

Who meets national early childhood sleep guidelines in Aotearoa New Zealand? A cross-sectional and longitudinal analysis.

Study Objectives: To investigate the proportion of children in Aotearoa New Zealand (NZ) who do or do not meet sleep duration and sleep quality guidelines at 24 and 45 months of age and associated sociodemographic factors. Methods: Participants were children (n = 6490) from the Growing Up in New Zealand longitudinal study of child development with sleep data available at 24 and/or 45 months of age (48.2% girls, 51.8% boys; 22.4% Maori [the Indigenous people of NZ], 12.9% Pacific, 13.4% Asian, 45.2% European/Other). Relationships between sociodemographic factors and maternally reported child sleep duration (across 24 hours) and night wakings were investigated cross-sectionally and longitudinally. Estimates of children in NZ meeting sleep guidelines were calculated using a range of analytical techniques including Bayesian linear regression, negative binomial multiple regression, and growth curve models. Results: In NZ, 29.8% and 19.5% of children were estimated to have a high probability of not meeting sleep duration guidelines and 15.4% and 8.3% were estimated to have a high probability of not meeting night waking guidelines at 24 and 45 months respectively, after controlling for multiple sociodemographic variables. Factors associated cross-sectionally with children's sleep included ethnicity, socioeconomic deprivation, material standard of living, rurality, and heavy traffic, and longitudinal sleep trajectories differed by gender, ethnicity, and socioeconomic deprivation. Conclusions: A considerable proportion of young children in NZ have a high probability of not meeting sleep guidelines but this declines across the ages of 24 and 45 months. Sleep health inequities exist as early as 24 months of age in NZ.

Determining the pharmacologic window of bisphosphonates that mitigates severe injury-induced osteoporosis and muscle calcification, while preserving fracture repair.

Following severe injury, biomineralization is disrupted and limited therapeutic options exist to correct these pathologic changes. This study utilized a clinically relevant murine model of polytrauma including a severe injury with concomitant musculoskeletal injuries to identify when bisphosphonate administration can prevent the paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues, yet not interfere with musculoskeletal repair. INTRODUCTION: Systemic and intrinsic mechanisms in bone and soft tissues help promote biomineralization to the skeleton, while preventing it in soft tissues. However, severe injury can disrupt this homeostatic biomineralization tropism, leading to adverse patient outcomes due to a paradoxical decrease of biomineralization in bone and increased biomineralization in soft tissues. There remains a need for therapeutics that restore the natural tropism of biomineralization in severely injured patients. Bisphosphonates can elicit potent effects on biomineralization, though with variable impact on musculoskeletal repair. Thus, a critical clinical question remains as to the optimal time to initiate bisphosphonate therapy in patients following a polytrauma, in which bone and muscle are injured in combination with a severe injury, such as a burn. METHODS: To test the hypothesis that the dichotomous effects of bisphosphonates are dependent upon the time of administration relative to the ongoing biomineralization in reparative bone and soft tissues, this study utilized murine models of isolated injury or polytrauma with a severe injury, in conjunction with sensitive, longitudinal measure of musculoskeletal repair. RESULTS: This study demonstrated that if administered at the time of injury, bisphosphonates prevented severe injury-induced bone loss and soft tissue calcification, but did not interfere with bone repair or remodeling. However, if administered between 7 and 21 days post-injury, bisphosphonates temporally and spatially localized to sites of active biomineralization, leading to impaired fracture callus remodeling and permanence of soft tissue calcification. CONCLUSION: There is a specific pharmacologic window following polytrauma that bisphosphonates can prevent the consequences of dysregulated biomineralization, yet not impair musculoskeletal regeneration.

Perceived group size is determined by the centroids of the component elements.

To accomplish the deceptively simple task of perceiving the size of objects in the visual scene, the visual system combines information about the retinal size of the object with several other cues, including perceived distance, relative size, and prior knowledge. When local component elements are perceptually grouped to form objects, the task is further complicated because a grouped object does not have a continuous contour from which retinal size can be estimated. Here, we investigate how the visual system solves this problem and makes it possible for observers to judge the size of perceptually grouped objects. We systematically vary the shape and orientation of the component elements in a two-alternative forced-choice task and find that the perceived size of the array of component objects can be almost perfectly predicted from the distance between the centroids of the component elements and the center of the array. This is true whether the global contour forms a circle or a square. When elements were positioned such that the centroids along the global contour were at different distances from the center, perceived size was based on the average distance. These results indicate that perceived size does not depend on the size of individual elements, and that smooth contours formed by the outer edges of the component elements are not used to estimate size. The current study adds to a growing literature highlighting the importance of centroids in visual perception and may have implications for how size is estimated for ensembles of different objects.

Contribution of genetic variability to phenotypic differences in on-farm efficiency metrics of dairy cows based on body weight and milk solids yield.

Milk solids per kilogram of body weight (BW) is growing in popularity as a measure of dairy cow lactation efficiency. Little is known on the extent of genetic variability that exist in this trait but also the direction and strength of genetic correlations with other performance traits. Such genetic correlations are important to know if producers are to consider actively selecting cows excelling in milk solids per kilogram of BW. The objective of the present study was to use a large data set of commercial Irish dairy cows to quantify the extent of genetic variability in milk solids per kilogram of BW and related traits but also their genetic and phenotypic inter-relationships. Mid-lactation BW and body condition score (BCS), along with 305-d milk solids yield (i.e., fat plus protein yield) were available on 12,413 lactations from 11,062 cows in 85 different commercial dairy herds. (Co)variance components were estimated using repeatability animal linear mixed models. The genetic correlation between milk solids and body weight was only 0.05, which when coupled with the observed large genetic variability in both traits, indicate massive potential to select for both traits in opposite directions. The genetic correlations between both milk solids and BW with BCS; however, need to be considered in any breeding strategy. The genetic standard deviation, heritability, and repeatability of milk solids per kilogram of BW was 0.08, 0.37, and 0.57, respectively. The genetic correlation between milk solids per kilogram of BW with milk solids, BW, and BCS was 0.62, -0.75, and -0.41, respectively. Therefore, based on genetic regression, each increase of 0.10 units in genetic merit for milk solids per kilogram of BW is expected to result in, on average, an increase in 16.1 kg 305-d milk solids yield, a reduction of 25.6 kg of BW and a reduction of 0.05 BCS units (scale of 1-5 where 1 is emaciated). The genetic standard deviation (heritability) for 305-d milk solids yield adjusted phenotypically to a common BW was 27.3 kg (0.22). The genetic correlation between this adjusted milk solids trait with milk solids, BW, and BCS was 0.91, -0.12, and -0.26, respectively. Once also adjusted phenotypically to a common BCS, the genetic standard deviation (heritability) for milk solids adjusted phenotypically to a common BW was 26.8 kg (0.22) where the genetic correlation with milk solids, BW and BCS was 0.91, -0.21, and -0.07, respectively. The genetic standard deviation (heritability) of BW adjusted phenotypically for differences in milk solids was 35.3 kg (0.61), which reduced to 33.2 kg when also phenotypically adjusted for differences in BCS. Results suggest considerable opportunity exists to change milk solids yield independent of BW, and vice versa. The opportunity is reduced slightly once also corrected for differences in BCS. Inter-animal BCS differences should be considered if selection on such metrics is contemplated.

The Future of Antifungal Drug Therapy: Novel Compounds and Targets.

Fungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans. However, the currently available antifungals have many limitations, including poor oral bioavailability, narrow therapeutic indices, and emerging drug resistance resulting from their use, thus making it essential to investigate the development of novel drugs which can overcome these limitations and add to the antifungal armamentarium. Advances have been made in antifungal drug discovery research and development over the past few years as evidenced by the presence of several new compounds currently in various stages of development. In the following minireview, we provide a comprehensive summary of compounds aimed at one or more novel molecular targets. We also briefly describe potential pathways relevant for fungal pathogenesis that can be considered for drug development in the near future.

An approach to teaching psychiatry to medical students in the time of Covid-19.

In this time of Covid-19, life in healthcare has changed immeasurably. It has rapidly been injected with an 'all hands-on deck' approach, to facilitate the necessary adaptations required to reduce the spread of the virus and deliver frontline clinical care. Inevitably aspects of these changes have disrupted the delivery of medical education, notably clinical placements have been cancelled and social distancing guidelines prohibit face-to-face teaching. The training of future doctors is an essential part of this effort. Indeed, the emergence of a global health threat has underlined its continued importance. For medical educators and students alike, we have been presented with a challenge. Concurrently, this presents us with an impetus and opportunity for innovation. For some time now, a transformation in medical education has been called for, with an increasing recognition of the need to prepare students for the changing landscape of healthcare systems. This has included a focus on the use of technology-enhanced and self-directed learning. As a team of educators and clinicians in psychiatry, working in the School of Medicine and Medical Sciences (SMMS) in University College Dublin (UCD), we will share how we have responded. We outline the adaptations made to our 'Psychiatry' module and consider the influence this may have on its future delivery. These changes were informed by direct student input.

Close proximity to alcohol outlets is associated with increased crime and hazardous drinking: Pooled nationally representative data from New Zealand.

This nationwide study investigated the relationship between proximity to alcohol outlets (off-licence, on-licence, and other-licence) and two adverse outcomes; hazardous drinking and crime (common assault, non-aggravated sexual assault, aggravated sexual assault, and tobacco and liquor offences). After adjustment for important individual- and area-level factors, close proximity to alcohol outlets was associated with increased risk of hazardous drinking, with strong associations for on-licence outlets. Proximity alcohol outlets was also strongly associated with all crime outcomes, often with a dose-response relationship. Nationally representative New Zealand data showed that close proximity to alcohol outlets was associated with increased crime and hazardous drinking.

Preclinical Evaluation of Acylhydrazone SB-AF-1002 as a Novel Broad-Spectrum Antifungal Agent.

The incidence of invasive fungal infections is rising due to the increase in susceptible populations. Current clinically available drugs have therapeutic limitations due to toxicity, a narrow spectrum of activity, and, more importantly, the consistent rise of fungal species that are intrinsically resistant or that develop resistance due to prolonged therapy. Thus, there is an urgent need for new broad-spectrum antifungal agents with low toxicity and a novel mechanism of action. We previously reported a new class of potent antifungal compounds, acylhydrazones, that target the fungal sphingolipid pathway. Based upon our initial lead molecules, (E)-N'-(5-bromo-2-hydroxybenzylidene)-2-methylbenzohydrazide and D13, we performed a structure-activity relationship study, synthesizing ca. 300 new compounds. Of these, 5 compounds were identified to be the most promising for further studies, based on their broad-spectrum activity and low toxicity in mammalian cells lines. Among these top 5 lead compounds, we report here the impressive in vivo activity of 2,4-dibromo-N'-(5-bromo-2-hydroxybenzylidene)benzohydrazide (SB-AF-1002) in several models of systemic fungal infection. Our data show that SB-AF-1002 is efficacious and outperforms current standard-of-care drugs in models of invasive fungal infections, such as cryptococcosis, candidiasis, and aspergillosis. Specifically, animals treated with SB-AF-1002 not only survived the infection but also showed a clearing of fungal cells from key organs. Moreover, SB-AF-1002 was very effective in an aspergillosis model as a prophylactic therapy. SB-AF-1002 also displayed acceptable pharmacokinetic properties in mice, similar to those of the parent compound, D13. These results clearly indicate that our novel acylhydrazones constitute a new class of highly potent and efficacious antifungal agents which warrant further development for the treatment of invasive fungal infections.

Association between thyroid nodule size and malignancy rate.

INTRODUCTION: The diagnostic performance of ultrasound-fine needle aspiration to identify thyroid nodules harbouring malignancy remains variable. The aim of this study was to determine thyroid nodule size and cytological classification as predictors of malignancy risk. MATERIALS AND METHODS: We conducted a retrospective cohort analysis at an academic hospital involving 499 consecutive patients who underwent thyroid surgery between 2004 and 2015. RESULTS: A total of 503 thyroid nodules (499 patients, 84% female; mean age 50.8 years, standard deviation, SD, 15.4 years) were analysed. Of these, 19.5% were malignant. The mean (± SD) nodule size was 3.28 ± 1.63 cm and 3.27 ± 1.54 cm for benign and malignant nodules, respectively. The odds of malignancy for thyroid nodules less than 3.0 cm was similar to those for nodules of 3.0 cm or greater (0.26 compared with 0.29; p=0.77). Overall, the sensitivity and specificity of fine-needle aspiration in this cohort were 71.4% and 100%, respectively. The overall false negative rate was 5.4%. When the cut-off of 3.0 cm was used, the false negative rate in thyroid nodules less than 3.0 cm was 0% compared with 7.0% in nodules of 3.0 cm or greater. Thus, class (p<0.01) but not nodule size (p=0.49), was associated with higher malignancy risk. CONCLUSIONS: Our results suggest that thyroid nodule size did not accurately predict the risk of thyroid malignancy irrespective of fine-needle aspiration cytology. Routine diagnostic thyroid lobectomy solely owing to thyroid nodule size of 3.0 cm or greater is currently not justified.

IgM in human immunity to Plasmodium falciparum malaria.

Most studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.

Psychosocial, psychiatric and work-related risk factors associated with suicide in Ireland: optimised methodological approach of a case-control psychological autopsy study.

BACKGROUND: Suicide has profound effects on families and communities, but is a statistically rare event. Psychological autopsies using a case-control design allow researchers to examine risk factors for suicide, using a variety of sources to detail the psychological and social characteristics of decedents and to compare them to controls. The Suicide Support and Information System Case Control study (SSIS-ACE) aimed to compare psychosocial, psychiatric and work-related risk factors across three groups of subjects: suicide decedents, patients presenting to hospital with a high-risk self-harm episode, and general practice controls. METHODS: The study design includes two inter-related studies; one main case-control study: comparing suicide cases to general practice (GP) controls, and one comparative study: comparing suicide cases to patients presenting with high-risk self-harm. Consecutive cases of suicide and probable suicide are identified through coroners' registration of deaths in the defined region (Cork City and County, Ireland) and are frequency-matched for age group and gender with GP patient controls recruited from the same GP practice as the deceased. Data sources for suicide cases include coroners' records, interviews with health care professionals and proxy informants; data sources for GP controls and for high-risk self-harm controls include interviews with control, with proxy informants and with health care professionals. Interviews are semi-structured and consist of quantitative and qualitative parts. The quantitative parts include a range of validated questionnaires addressing psychiatric, psychosocial and occupational factors. The study adopts several methodological innovations, including accessing multiple data sources for suicide cases and controls simultaneously, recruiting proxy informants to examine consistency across sources. CONCLUSIONS: The study allows for the investigation of consistency across different data sources and contributes to the methodological advancement of psychological autopsy research. The study will also inform clinical and public health practice. The comparison between suicide cases and controls will allow investigation of risk and protective factors for suicide more generally, while the comparison with high-risk self-harm patients will help to identify the factors associated specifically with a fatal outcome to a self-harm episode. A further enhancement is the particular focus on specific work-related risk factors for suicide.

SAR Studies on Aromatic Acylhydrazone-Based Inhibitors of Fungal Sphingolipid Synthesis as Next-Generation Antifungal Agents.

Recently, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for drug discovery of next-generation antifungal agents, and we found two aromatic acylhydrazones as effective inhibitors of GlcCer synthesis based on HTP screening. In the present work, we have designed libraries of new aromatic acylhydrazones, evaluated their antifungal activities (MIC80 and time-kill profile) against C. neoformans, and performed an extensive SAR study, which led to the identification of five promising lead compounds, exhibiting excellent fungicidal activities with very large selectivity index. Moreover, two compounds demonstrated broad spectrum antifungal activity against six other clinically relevant fungal strains. These five lead compounds were examined for their synergism/cooperativity with five clinical drugs against seven fungal strains, and very encouraging results were obtained; e.g., the combination of all five lead compounds with voriconazole exhibited either synergistic or additive effect to all seven fungal strains.

A mating advice system in dairy cattle incorporating genomic information.

This study investigated the effects of alternative mating programs that incorporate genomic information on expected progeny herd performance and inbreeding, as well as methods to include un-genotyped animals in such mating programs. A total of 54,535 Holstein-Friesian cattle with imputed high-density genotypes (547,650 SNP after edits) were available. First, to quantify the accuracy of imputing un-genotyped animals (often an issue in populations), a sub-population of 729 genotyped animals had their genotypes masked, and their allele dosages were imputed, using linear regression exploiting information on genotyped relatives. The reference population for imputation included all genotyped animals, excluding the 729 selected animals and their sires, dams, and grandsires, and had either (1) their sires' genotypes, (2) their dams' genotypes (3) both their sires' and their dams' genotypes, or (4) both their sires' and maternal grandsires' genotypes introduced into the reference population. The correlations between true genotypes and the imputed allele dosages ranged from 0.58 (sire only) to 0.68 (both sire and dam). A herd of 100 cows was then simulated (1,000 replicates) from the sub-population of 729 imputed animals. The top 10 bulls from the genotyped population, based on their total genetic merit index (TMI) were selected to be used as sires. Three mating allotment methods were investigated: (1) random mating, (2) sequential mating based on maximizing only the expected TMI of the progeny, and (3) linear programming to maximize a generated index constructed to maximize genetic merit and minimize expected progeny inbreeding as well as intra- and inter-progeny variability in genetic merit. Relationships among candidate parents were calculated using either the pedigree relationship matrix or the genomic relationship matrix; the latter was constructed using either the true genotypes of both parents or the true genotypes of the sire plus the imputed allele dosages of the dam. Using the genomic co-ancestry estimates resulted in lower average herd expected genomic inbreeding levels compared with using the pedigree-based co-ancestry estimates. Additionally, if the dams were not genotyped, using their imputed allele dosages also resulted in lower average herd expected inbreeding levels compared with using the pedigree co-ancestry estimates. The inter-progeny coefficient of variation for selected traits, milk and fertility, estimated breeding values were reduced by 12 to 65% using the linear programing method compared with sequential mating.