Genetics of phenological development and implications for seed yield in lentil.

Understanding phenology, its genetics and agronomic consequences, is critical for crop adaptation. Here we aim at (1) characterising lentil response to photoperiod with a focus on five loci: the lentil ELF3 ortholog Sn, two loci linked to clusters of lentil FT orthologs and two loci without candidates in chromosomes 2 and 5 (exp. 1: 36 lines, short and long day in phytotron); (2) establishing phenology-yield relationship (exp. 2: 25 lines, 11 field environments). A vintage perspective, where we quantify time trends in phenotype over three decades of breeding, links both experiments. Yield increased linearly from older to newer varieties at 29 kg ha-1 yr-1 or 1.5% yr-1, correlated negatively with flowering time in both winter- and summer-rainfall regimes, and decoupled from biomass in favourable environments. Time to flowering shortened from older to newer varieties at -0.56 % yr-1 in the field, and -0.42 % yr-1 (short day) and -0.99 % yr-1 (long day) in the phytotron. Early-flowering lines of diverse origin carried multiple early alleles for the five loci, indicating that at least some of these loci affect phenology additively. Current germplasm primarily features the early flowering haplotype for an FTb cluster region, hence the potential to increase phenological diversity with yield implications.

Neurosurgical resection of multiple brain metastases: outcomes, complications, and survival rates in a retrospective analysis.

PURPOSE: This study investigates the outcomes of microsurgical resection of multiple brain metastasis (BMs). METHODS: This retrospective, monocentric analysis included clinical data from all consecutive BM patients, who underwent simultaneous resection of ≥ 2 BMs between January 2018 and May 2023. Postoperative neurological and functional outcomes, along with perioperative complications, as well as survival data were evaluated. RESULTS: A total of 47 patients, with a median age of 61 years (IQR 48-69), underwent 73 craniotomies (median 2; range 1-3) for resection of 104 BMs. Among patients, 80.8% presented with symptomatic BMs, causing focal neurological deficits in 53% of cases. Gross total resection was achieved in 87.2% of BMs. Karnofsky Performance Scale (KPS) scores improved in 42.6% of patients, remained unchanged in 46.8%, and worsened in 10.6% after surgery. Perioperative complications were observed in 29.8% of cases, with transient complications occurring in 19.2% and permanent deficits in 10.6%. The 30-days mortality rate was 2.1%. Logistic regression identified eloquent localization (p = 0.036) and infratentorial craniotomy (p = 0.018) as significant predictors of postoperative complications. Concerning overall prognosis, patients with permanent neurological deficits post-surgery (HR 11.34, p = 0.007) or progressive extracranial disease (HR: 4.649; p = 0.006) exhibited inferior survival. CONCLUSION: Microsurgical resection of multiple BMs leads to clinical stabilization or functional improvement in most patients. Although transient complications do not affect overall survival, the presence of persistent neurological deficits (> 3 months post-surgery) and progressive extracranial disease negatively impact overall survival. This highlights the importance of careful patient selection for resection of multiple BMs.

Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

Promising functional outcomes following anterior cruciate ligament repair with suture augmentation.

PURPOSE: There has been a renewed interest in the repair of the torn anterior cruciate ligament (ACL). Purpose of this study was to evaluate the functional outcome of arthroscopic ACL repair with additional suture augmentation (SA), hypothesizing that isolated ACL ruptures would yield superior patient-reported outcome measures (PROMs) compared to those with concomitant meniscal and/or ligamentous injuries. METHODS: This is a retrospective analysis of 93 consecutive patients (67 female, median age 42 years) who underwent arthroscopic ACL repair with SA between January 2017 and March 2019 for an acute traumatic ACL tear confirmed by magnetic resonance imaging (MRI). Patients with pre- or intraoperative mid-substance or distal ACL tears and/or poor tissue quality of the ACL remnant were not considered for ACL repair but were scheduled for an ACL reconstruction with a tendon autograft. In patients who underwent ACL repair with SA, the SA construct was proximally stabilized with a flip-button and distally with a suture anchor. Surgery was preferably performed on the day of injury and all surgeries were performed by the same surgeon. Postoperative rehabilitation included partial weight-bearing (20 kg) for 6 weeks and immobilization in a brace limited at 90-degrees of knee flexion for 4 weeks. Patient-reported outcome measures (PROMs) were determined using International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form, Lysholm Score (LS), Tegner Activity Score (TS) and Forgotten Joint Score (FJS). Knee-laxity was assessed using the KT-1000 arthrometer (Med Metrics Corp. Inc., San Diego, USA). RESULTS: Nine patients underwent revision surgery for a traumatic re-tear (four patients) and chronic instability (five patients) and were excluded from further functional analysis. Functional results of 77 patients (54 female) with a median age of 44 years (IQR 33-51) on the day of surgery were available for follow-up after a median time of 35 months (IQR 33-44). Concomitant injuries were observed in 66 Patients (86%), meniscal injuries in 43 patients (55%) and ligamentous injuries in 50 patients (65%). Median interval from injury to surgery was 1 day (IQR 0-1) with 81% (62/77) of patients being treated within 24 h of injury. The median IKDC was 92 (IQR 86-99), the median LS was 95 (IQR 86-100), the median pre-traumatic TS was 7 (IQR 6-7), the median post-traumatic TS was 6 (IQR 5-7) with a non-significant median difference (TSDiff) of 0 (IQR 0-1). The median FJS was 95 (IQR 78-98). KT-1000 measurements were available in 34 of 77 patients with a median postoperative laxity compared to the uninjured side of 1 mm (IQR 0-2). Interval from injury to surgery, patients' age, body mass index (BMI), knee laxity and concomitant ligamentous or meniscal injuries had no statistically significant impact on postoperative PROMs (n.s.). CONCLUSION: Following arthroscopic ACL repair with SA good-to-excellent functional results were observed. However, a failure rate of 10% cannot be neglected and warrants further attention. Concomitant injuries to the meniscus and/or collateral ligaments do not seem to be associated with inferior PROMs. LEVEL OF EVIDENCE: Level IV.

Ultrastructural analysis of explanted CyPass microstents and correlation with clinical findings.

PURPOSE: The purpose of this study was to obtain insight into cellular processes after CyPass microstent implantation into the supraciliary space. With this knowledge, we expected to find some reason for surgical failure. METHODS: Nine CyPass microstents of 8 patients with primary open-angle glaucoma (n = 1), pseudoexfoliation glaucoma (n = 5), uveitic glaucoma (n = 1), and posttraumatic open-angle glaucoma (n = 1) were explanted due to recurrence of IOP elevation, corneal decompensation, or persistent hypotony. The explants were processed for light and transmission electron microscopy. RESULTS: Fibrotic material, consisting of collagen fibrils, microfibrils, pseudoexfoliation fibrils produced by activated fibroblasts, was detected in the stent lumen of 4/5 pseudoexfoliation glaucoma patients and also in posttraumatic open-angle glaucoma. Fibrotic material was also present on the outer surface and within fenestrations of the majority of stents. Complete absence of fibrotic reaction was noticed in 3 of 9 microstents. CONCLUSION: Although MIGS is known to be less invasive than conventional surgery, implants placed in the suprachoroidal space may be adversely affected by a fibrotic tissue reaction resulting in implant failure. Understanding mechanisms and risk factors leading to fibrotic scarring following antiglaucomatous surgery may help to develop novel strategies that improve surgical outcome.

A retrospective audit of postoperative days alive and out of hospital, including before and after implementation of the WHO surgical safety checklist.

We implemented the World Health Organization surgical safety checklist at Auckland City Hospital from November 2007. We hypothesised that the checklist would reduce postoperative mortality and increase days alive and out of hospital, both measured to 90 postoperative days. We compared outcomes for cohorts who had surgery during 18-month periods before vs. after checklist implementation. We also analysed outcomes during 9 years that included these periods (July 2004-December 2013). We analysed 9475 patients in the 18-month period before the checklist and 10,589 afterwards. We analysed 57,577 patients who had surgery from 2004 to 2013. Mean number of days alive and out of hospital (95%CI) in the cohort after checklist implementation was 1.0 (0.4-1.6) days longer than in the cohort preceding implementation, p < 0.001. Ninety-day mortality was 395/9475 (4%) and 362/10,589 (3%) in the cohorts before and after checklist implementation, multivariable odds ratio (95%CI) 0.93 (0.80-1.09), p = 0.4. The cohort changes in these outcomes were indistinguishable from longer-term trends in mortality and days alive and out of hospital observed during 9 years, as determined by Bayesian changepoint analysis. Postoperative mortality to 90 days was 228/5686 (4.0%) for Maori and 2047/51,921 (3.9%) for non-Maori, multivariable odds ratio (95%CI) 0.85 (0.73-0.99), p = 0.04. Maori spent on average (95%CI) 1.1 (0.5-1.7) fewer days alive and out of hospital than non-Maori, p < 0.001. In conclusion, our patients experienced improving postoperative outcomes from 2004 to 2013, including the periods before and after implementation of the surgical checklist. Maori patients had worse outcomes than non-Maori.

GP access to FIT increases the proportion of colorectal cancers detected on urgent pathways in symptomatic patients in Nottingham.

OBJECTIVE: Service evaluation of GP access to Faecal Immunochemical Test (FIT) for colorectal cancer (CRC) detection in Nottinghamshire and use of FIT for "rule out", "rule in" and "first test selection". DESIGN: Retrospective audit of FIT results, CRC outcomes and resource utilisation before and after introduction of FIT in Primary Care in November 2017. Data from the new pathway up to December 2018 was compared with previous experience. RESULTS: Between November 2017 and December 2018, 6747 GP FIT test requests yielded 5733 FIT results, of which 4082 (71.2%) were <4.0 µg Hb/g faeces, 579 (10.1%) were 4.0-9.9 µg Hb/g faeces, 836 (14.6%) were 10.0-149.9 µg Hb/g faeces, and 236 (4.1%) were ≥150.0 µg Hb/g faeces. The proportion of "rule out" results <4.0 µg Hb/g faeces was significantly higher than in the Getting FIT cohort (71.2% vs 60.4%, Chi squared 42.8, p < 0.0001) and the proportion of "rule in" results ≥150.0 µg Hb/g faeces was significantly lower (4.1% vs 8.1%, Chi squared 27.3,P < 0.0001). There was a 33% rise in urgent referrals across Nottingham overall during the evaluation period. 2 CRC diagnoses were made in 4082 patients who had FIT<4.0 µg Hb/g faeces. 58.4% of new CRC diagnoses associated with a positive FIT were early stage cancers (Stage I and II). The proportion of all CRC diagnoses that follow an urgent referral s rose after introduction of FIT. CONCLUSIONS: FIT allows GP's to select a more appropriate cohort for urgent investigation without a large number of missed diagnoses. FIT appears to promise a "stage migration" effect which may ultimately improve CRC outcomes.

Daily fluctuations in occupation with and worry about COVID-19.

In the first week after the first COVID-19 patient was reported in the Netherlands, we conducted a pre-registered momentary assessment study (7 surveys per day, 50 participants, 7 days) to study the dynamic relationship between individuals' occupation with and worries about COVID-19 in daily life, and the moderating role of neuroticism in this relationship. At the group level, higher scores on occupation and worry co-occurred, and occupation predicted worry 1 h later, but not vice versa. There were substantial individual differences in the magnitudes and directions of the effects. For instance, occupation with COVID-19 was related to increases in worry for some but decreases in worry for others. Neuroticism did not predict any of these individual differences in the links between worry and occupation. This study suggests that it is important to go beyond group-level analyses and to account for individual differences in responses to COVID-19.

Vasospasm of the basilar artery following spontaneous SAH-clinical observations and implications for vascular research.

The basilar artery (BA), as a reference vessel for laboratory investigations of cerebral vasospasm (CVS) in many experimental models, warrants a sufficient blood supply despite hemodynamic changes during CVS. In a prospective evaluation study, we analyzed  patients who were admitted to our department with subarachnoid hemorrhage (SAH) for the occurrence and sequelae of CVS. Specifically, we sought to identify patients with CVS of the BA. As per institutional protocol, all patients with CVS detected in the posterior circulation had magnetic resonance imaging (MRI) examinations instead of CTA. Between January and December 2016, 74 patients were treated for spontaneous SAH. CVS occurred in 45 (61%) patients, and 31 (42%) patients developed associated cerebral infarctions (CI). CVS was significantly associated with CI (p < 0.0001; OR 44). In 18 (24.3%) patients, CVS significantly affected the basilar artery. Poor admission clinical state, younger age, and treatment modalities were significantly associated with BACVS. BACVS was more often detected in patients with severe CVS (p < 0.046; OR 4.4). Patients with BACVS developed cerebral infarction in a frequency comparable to other patients with CVS (61% vs. 70%, p = 0.7), but none of these infarctions occurred in the brain stem or pons even though vessel diameter was dramatically reduced according to CT- and/or MR-angiography. BACVS does not appear to be followed by cerebral infarction in the BA territory, presumably due to a vascular privilege of this vessel and its perforating branches. In contrast, brain ischemia can frequently be observed in the territories of other major arteries affected by CVS.

Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study.

Background: The vascular endothelial growth factor antibody bevacizumab (Avastin®), received approval for the treatment of recurrent glioblastoma in many countries including the USA and Switzerland, but not the European Union, in 2009. Here, we explored the hypothesis that the approval of bevacizumab improved outcome with glioblastoma on a population level. Patients and methods: The prognostic significance of epidemiological, molecular genetic, and clinical data including treatment for glioblastoma patients diagnosed from 2010 to 2014 in the Canton of Zurich, Switzerland, was retrospectively analyzed using log-rank test and Cox proportional hazards models. Data were compared with data for the years 2005-2009. Results: In total, 310 glioblastoma patients were identified in the years 2010-2014. Median overall survival was 13.5 months for patients with known isocitrate dehydrogenase (IDH) wild-type (wt) (IDH1R132H-non-mutant) tumors (N = 248), compared with 11.3 months for IDH wt patients (P = 0.761) before (2005-2009). In the IDH wt cohort, bevacizumab use at any time increased from 19% in 2005-2009 to 49% in 2010-2014. Multivariate analysis did not identify bevacizumab exposure at any time to be associated with survival. Yet, upon the second-line treatment, baseline doses of corticosteroids were reduced by more than half in 83% of patients on bevacizumab compared with 48% of the patients treated with bevacizumab-free regimens (P = 0.007). Conclusion: This epidemiological study of a small, but clinically well-annotated patient cohort fails to support the assumption that the strong increase of bevacizumab use since 2010 improved survival in glioblastoma although clinical benefit associated with decreased steroid use may have been achieved.

Dethroning the Fano Factor: A Flexible, Model-Based Approach to Partitioning Neural Variability.

Neurons in many brain areas exhibit high trial-to-trial variability, with spike counts that are overdispersed relative to a Poisson distribution. Recent work (Goris, Movshon, & Simoncelli, 2014 ) has proposed to explain this variability in terms of a multiplicative interaction between a stochastic gain variable and a stimulus-dependent Poisson firing rate, which produces quadratic relationships between spike count mean and variance. Here we examine this quadratic assumption and propose a more flexible family of models that can account for a more diverse set of mean-variance relationships. Our model contains additive gaussian noise that is transformed nonlinearly to produce a Poisson spike rate. Different choices of the nonlinear function can give rise to qualitatively different mean-variance relationships, ranging from sublinear to linear to quadratic. Intriguingly, a rectified squaring nonlinearity produces a linear mean-variance function, corresponding to responses with a constant Fano factor. We describe a computationally efficient method for fitting this model to data and demonstrate that a majority of neurons in a V1 population are better described by a model with a nonquadratic relationship between mean and variance. Finally, we demonstrate a practical use of our model via an application to Bayesian adaptive stimulus selection in closed-loop neurophysiology experiments, which shows that accounting for overdispersion can lead to dramatic improvements in adaptive tuning curve estimation.

Determination of quantitative trait nucleotides by concordance analysis between quantitative trait loci and marker genotypes of US Holsteins.

Experimental designs that exploit family information can provide substantial predictive power in quantitative trait nucleotide discovery projects. Concordance between quantitative trait locus genotype as determined by the a posteriori granddaughter design and marker genotype was determined for 30 trait-by-chromosomal segment effects segregating in the US Holstein population with probabilities of <10-20 to accept the null hypotheses of no segregating gene affecting the trait within the chromosomal segment. Genotypes for 83 grandsires and 17,217 sons were determined by either complete sequence or imputation for 3,148,506 polymorphisms across the entire genome; 471 Holstein bulls had a complete genome sequence, including 64 of the grandsires. Complete concordance was obtained only for stature on chromosome 14 and daughter pregnancy rate on chromosome 18. For each quantitative trait locus, effects of the 30 polymorphisms with highest concordance scores for the analyzed trait were computed by stepwise regression for predicted transmitting abilities of 26,750 bulls with progeny test and imputed genotypes. Effects for stature on chromosome 11, daughter pregnancy rate on chromosome 18, and protein percentage on chromosome 20 met 3 criteria: complete or almost complete concordance, nominal significance of the polymorphism effect after correction for all other polymorphisms, and marker coefficient of determination >40% of total multiple-regression coefficient of determination for the 30 polymorphisms with highest concordance. An intronic variant marker on chromosome 5 at 93,945,738 bp explained 7% of variance for fat percentage and 74% of total multiple-marker regression variance but was concordant for only 24 of 30 families. The missense polymorphism Phe279Tyr in GHR at 31,909,478 bp on chromosome 20 was confirmed as the causative mutation for fat and protein concentration. For effect on fat percentage on chromosome 14, 12 additional missense polymorphisms were found that had almost complete concordance with the suggested causative polymorphism (missense mutation Ala232Glu in DGAT1). The only polymorphism found likely to improve predictive power for genomic evaluation of dairy cattle was on chromosome 15; that polymorphism had a frequency of 0.45 for the allele with economically positive effects on all production traits.

Making robust assessments of specialist trainees' workplace performance.

BACKGROUND: Workplace-based assessments should provide a reliable measure of trainee performance, but have met with mixed success. We proposed that using an entrustability scale, where supervisors scored trainees on the level of supervision required for the case would improve the utility of compulsory mini-clinical evaluation exercise (CEX) assessments in a large anaesthesia training program. METHODS: We analysed mini-CEX scores from all Australian and New Zealand College of Anaesthetists trainees submitted to an online database over a 12-month period. Supervisors' scores were adjusted for the expected supervision requirement for the case for trainees at different stages of training. We used generalisability theory to determine score reliability. RESULTS: 7808 assessments were available for analysis. Supervision requirements decreased significantly (P < 0.05) with increased duration and level of training, supporting validity. We found moderate reliability (G > 0.7) with a feasible number of assessments. Adjusting scores against the expected supervision requirement considerably improved reliability, with G > 0.8 achieved with only nine assessments. Three per cent of trainees generated average mini-CEX scores below the expected standard. CONCLUSIONS: Using an entrustment scoring system, where supervisors score trainees on the level of supervision required, mini-CEX scores demonstrated moderate reliability within a feasible number of assessments, and evidence of validity. When scores were adjusted against an expected standard, underperforming trainees could be identified, and reliability much improved. Taken together with other evidence on trainee ability, the mini-CEX is of sufficient reliability for inclusion in high stakes decisions on trainee progression towards independent specialist practice.

Invited review: A perspective on the future of genomic selection in dairy cattle.

Genomic evaluation has been successfully implemented in the United States, Canada, Great Britain, Ireland, New Zealand, Australia, France, the Netherlands, Germany, and the Scandinavian countries. Adoption of this technology in the major dairy producing countries has led to significant changes in the worldwide dairy industry. Gradual elimination of the progeny test system has led to a reduction in the number of sires with daughter records and fewer genetic ties between years. As genotyping costs decrease, the number of cows genotyped will continue to increase, and these records will become the basic data used to compute genomic evaluations, most likely via application of "single-step" methodologies. Although genomic selection has been successful in increasing rates of genetic gain, we still know very little about the genetic architecture of quantitative variation. Apparently, a very large number of genes affect nearly all economic traits, in accordance with the infinitesimal model for quantitative traits. Less emphasis in selection goals will be placed on milk production traits, and more on health, reproduction, and efficiency traits and on environmentally friendly production with reduced waste and gas emission. Genetic variance for economic traits is maintained by the increase in frequency of rare alleles, new mutations, and changes in selection goals and management. Thus, it is unlikely that a selection plateau will be reached in the near future.

Optimization of a genomic breeding program for a moderately sized dairy cattle population.

Although it now standard practice to genotype thousands of female calves, genotyping of bull calves is generally limited to progeny of elite cows. In addition to genotyping costs, increasing the pool of candidate sires requires purchase, isolation, and identification of calves until selection decisions are made. We economically optimized via simulation a genomic breeding program for a population of approximately 120,000 milk-recorded cows, corresponding to the Israeli Holstein population. All 30,000 heifers and 60,000 older cows of parities 1 to 3 were potential bull dams. Animals were assumed to have genetic evaluations for a trait with heritability of 0.25 derived by an animal model evaluation of the population. Only bull calves were assumed to be genotyped. A pseudo-phenotype corresponding to each animal's genetic evaluation was generated, consisting of the animal's genetic value plus a residual with variance set to obtain the assumed reliability for each group of animals. Between 4 and 15 bulls and between 200 and 27,000 cows with the highest pseudo-phenotypes were selected as candidate bull parents. For all progeny of the founder animals, genetic values were simulated as the mean of the parental values plus a Mendelian sampling effect with variance of 0.5. A probability of 0.3 for a healthy bull calf per mating, and a genomic reliability of 0.43 were assumed. The 40 bull calves with the highest genomic evaluations were selected for general service for 1 yr. Costs included genotyping of candidate bulls and their dams, purchase of the calves from the farmers, and identification. Costs of raising culled calves were partially recovered by resale for beef. Annual costs were estimated as $10,922 + $305 × candidate bulls. Nominal profit per cow per genetic standard deviation was $106. Economic optimum with a discount rate of 5%, first returns after 4 yr, and a profit horizon of 15 yr were obtained with genotyping 1,620 to 1,750 calves for all numbers of bull sires. However, 95% of the optimal profit can be achieved with only 240 to 300 calves. The higher reliabilities achieved through addition of genomic information to the selection process contribute not only in obtaining higher genetic gain, but also in obtaining higher absolute profits. In addition, the optimal profits are obtained for a lower number of calves born in each generation. Inbreeding, as allowed within genomic selection for the Israeli herd, had virtually no effect on genetic gain or on profits, when compared with the case of exclusion of all matings that generate inbreeding. Annual response to selection ranged from 0.35 to 0.4 genetic standard deviation for 4 to 15 bull sires, as compared with 0.25 to 0.3 for a comparable half-sib design without genomic selection.

Evaluating the ORSIM® simulator for assessment of anaesthetists' skills in flexible bronchoscopy: aspects of validity and reliability.

BACKGROUND: Developing expertise in flexible bronchoscopy is limited by inadequate opportunities to train on difficult airways. The new ORSIM bronchoscopy simulator aims to address this by creating virtual patients with difficult airways. This study aims to provide evidence on the validity and reliability of the ORSIM for assessment of subjects on both normal and abnormal airway simulations. METHODS: Novice, trainee, and expert subjects performed seven simulations of varying difficulty and scored the perceived difficulty for each. Time to completion was measured. Three blinded raters independently scored videos of each subject's performance. We measured inter-rater agreement and the difference in raters' scores between subject groups. RESULTS: We recruited 28 study subjects, generating 196 videos for analysis. Expert subjects consistently completed the scenarios faster than novices. Overall performance scores showed significant differences between subject groups (P<0.0001). Inter-rater reliability of scores was >0.8. CONCLUSIONS: Our results provide initial evidence on the validity and reliability of the ORSIM bronchoscopy simulator, supporting its potential value in training and assessment.

Identification of the sex-determining region in flathead grey mullet (Mugil cephalus).

Elucidation of the sex-determination mechanism in flathead grey mullet (Mugil cephalus) is required to exploit its economic potential by production of genetically determined monosex populations and application of hormonal treatment to parents rather than to the marketed progeny. Our objective was to construct a first-generation linkage map of the M. cephalus in order to identify the sex-determining region and sex-determination system. Deep-sequencing data of a single male was assembled and aligned to the genome of Nile tilapia (Oreochromis niloticus). A total 245 M. cephalus microsatellite markers were designed, spanning the syntenic tilapia genome assembly at intervals of 10 Mb. In the mapping family of full-sib progeny, 156 segregating markers were used to construct a first-generation linkage map of 24 linkage groups (LGs), corresponding to the number of chromosomes. The linkage map spanned approximately 1200 cM with an average inter-marker distance of 10.6 cM. Markers segregating on LG9 in two independent mapping families showed nearly complete concordance with gender (R2  = 0.95). The sex determining locus was fine mapped within an interval of 8.6 cM on LG9. The sex of offspring was determined only by the alleles transmitted from the father, thus indicating an XY sex-determination system.

Genetic analysis of calving traits by the multi-trait individual animal model.

Five alternative models were applied for analysis of dystocia and stillbirth in first and second parities. Models 1 and 2 were included only to estimate the parameters required for model 4, and models 3 and 5 are included only as comparisons to the model 4 estimates. Variance components were estimated by multi-trait REML, including cows with valid calving records for both parities. For the effects of sire of calf on first and second parities, variance components were estimated including only calvings with the same sire of calf for both parities. All heritabilities for the cow effect were quite low, but higher for dystocia than for stillbirth and higher in first parity. The sire-of-calf heritabilities were higher than the cow effect heritabilities, except for stillbirth in parity 2. Unlike the effect of cow correlations, all sire of calf correlations were >0.6, and the correlations for the same trait in parities 1 and 2 were >0.9. Thus, a multi-trait analysis should yield a significant gain in accuracy with respect to the sire of calf effects for bulls not mated to virgin heifers. A multi-trait individual animal model algorithm was developed for joint analysis of dystocia and stillbirth in first and second parities. Relationships matrices were included both for the effects of cow and sire of calf. In addition, random herd-year-season and fixed sex of calf effects were included in the model. Records were preadjusted for calving month and age. A total of 899,223 Israeli Holstein cows with first calvings since 1985 were included in the complete analysis. Approximate reliabilities were computed for both sire of cow and sire of calf effects. Correlations between these reliabilities and reliabilities obtained by direct inversion of the coefficient matrix for a sire of cow-sire of calf model were all close to 0.99. Phenotypic trends for cows born from 1983 through 2007 were economically unfavorable for dystocia and favorable for stillbirth in both parities. Genetic trends were economically unfavorable for both dystocia and stillbirth in first parity. First-parity sire of calf trends were unfavorable for dystocia, but favorable for stillbirth. All environmental trends were nearly zero. Regressions of evaluations of the complete analysis on a model including only calvings before 2011 were all >0.8. All evaluations met the Interbull Method 3 criterion for unbiasedness. Model 4, which computed genetic evaluations for all animals for all 4 traits accounting for all known relationships and correlations among the traits, is recommended for routine genetic evaluation of calving traits.

Genetic and phenotypic analysis of daily Israeli Holstein milk, fat, and protein production as determined by a real-time milk analyzer.

The objective was to test the hypothesis that more frequent but less accurately analyzed milk components may give a more representative measure of a cow's total lactation production. Daily records for milk production and fat and protein concentration collected by the AfiLab recording system (Afimilk, Kibbutz Afikim, Israel) from January 2014 to January 2016 from 47 large kibbutz (communal) herds distributed throughout Israel with a total of 37,486 Israeli Holstein cows were compared with the same statistics derived from monthly test day records derived by Bentley and Foss milk analyzers at the central laboratory of the Israel Cattle Breeders Association. The lactation means for all traits were quite similar for the 2 methods in both parities, except for fat production, which was lower for the daily records. This finding corresponded to fat lactation curves, which showed that daily results were lower with low days in milk (DIM) but almost equal to the monthly results after 125 DIM. Relative to monthly records, daily records overestimated protein percentage before 150 DIM and underestimated protein percentage in the second half of the lactation. The standard deviation for first- and second-parity daily records scored by the monthly and daily system were least similar for fat percentage, but even for this trait the difference was no more than 0.1 percentage points. The standard deviations for complete lactation production were slightly lower for the daily results for all traits but protein production. First-parity heritabilities were higher for lactations computed from daily records for all traits except for protein percentage, but differences were not significant. For daily records, coefficients of determination to predict future milk, fat, and protein lactation production from truncated lactations were greatest and root mean squared errors were least if the mean production from the last 2 weeks before the truncation date was used to estimate future production. Daily first-parity partial lactations for milk, fat, and protein production with <150 DIM predicted future lactation more accurately than corresponding monthly partial lactations. With only 30 DIM, genetic correlations between predicted and actual lactations ranged from 0.73 to 0.79 for milk, fat, and protein production. Real-time daily recording of fat and protein concentration by the daily recording system may be preferable to monthly analysis for herd-management decisions and genetic evaluation. Further study is required to compare the results of individual cows in multiple lactations.

Environmental and genetic factors affecting cow survival of Israeli Holsteins.

The objectives were to investigate the effects of various environmental factors that may affect herd-life of Israeli Holsteins, including first-calving age and season, calving ease, number of progeny born, and service sire for first calving in complete and truncated records; and to estimate heritabilities and genetic correlations between herd-life and the other traits included in the Israeli breeding index. The basic data set consisted of 590,869 cows in milk recording herds with first freshening day between 1985 and at least 8 yr before the cut-off date of September 15, 2013. Herd-life was measured as days from first calving to culling. The phenotypic and genetic trends for herd-life were 5.7 and 16.8d/yr. The genetic trend was almost linear, whereas the phenotypic trend showed 4 peaks and 3 valleys. Cows born in February and March had the shortest herd-life, whereas cows born in September had the longest herd-life. Herd-life was maximal with calving age of 23mo, which is 1mo less than the mean calving age, and minimal at 19 and 31mo of calving age. Dystocia and twinning on first-parity calving reduced herd-life by approximately180 and 120d, but the interaction effect increased herd-life by 140d. Heritability for herd-life was 0.14. Despite the fact that the service sire effect was significant in the fixed model analysis, service sire effect accounted for <0.05% of the total variance. In the analysis of 1,431,938 truncated records, the effects of dystocia and twinning rate were very similar but less than 50% of the effects found in the analysis of complete records. Pregnancy at the truncation date increased expected herd-life by 432d. The correlation between actual herd-life and predicted herd-life based on truncated records was 0.44. Genetic correlations between the truncated records and actual herd-life were 0.75 for records truncated after 6mo but approached unity for records truncated after 3 yr. The genetic correlations of herd-life with first-parity milk, fat, and protein production, somatic cell score (SCS), and female fertility were all positive, except for SCS, in which negative values are economically favorable. The highest correlations with herd-life in absolute value were with female fertility and SCS.