How comparable are patient outcomes in the "real-world" with populations studied in pivotal AML trials?

Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.

Carfilzomib, thalidomide, and dexamethasone is safe and effective in relapsed and/or refractory multiple myeloma: final report of the single arm, multicenter phase II ALLG MM018/AMN002 study.

This multicentre, phase II study of the Australian Lymphoma and Leukaemia Group (ALLG) and the Asian Myeloma Network (AMN) investigated fixed-duration (18-month) treatment with carfilzomib (K), thalidomide (T), and dexamethasone (d; KTd) in patients with relapsed and/or refractory multiple myeloma and 1-3 prior lines of therapy. Patients received induction with up to twelve 28-day cycles of K [20mg/m2 IV cycle 1 day 1 and 2, 56mg/m2 (36mg/m2 for patients ≥75 years) from day 8 onwards), T 100mg PO nocte and weekly dexamethasone 40mg (20mg for patients ≥75 years). During maintenance T was omitted, while K continued on days 1,2,15,16 with fortnightly dexamethasone. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate, overall survival (OS), duration of response, safety, and tolerability. Ninety-three patients (median age 66.3 years (41.9 - 84.5)) were enrolled with a median follow-up of 26.4 (1.6 - 54.6) months. The median PFS was 22.3 months (95% CI 15.7 - 25.6) with a 46.3% (95% CI 35.1 - 52.8) 2-year PFS. Median OS was not reached and was 73.8% (95% CI 62.9 - 81.9) at 2 years. The overall response rate was 88% (≥ VGPR 73%). There was no difference in the depth of response, PFS or OS comparing Asian and Non-Asian cohorts (p=0.61). The safety profile for KTd was consistent with each individual drug. KTd is well tolerated and effective in patients with RRMM irrespective of Asian or non-Asian ethnicity and provides an alternative option particularly where use of KRd is limited by access, cost, or renal impairment.

Genetic diversity and phylogenetic relationship of Angus herds in Hungary and analyses of their production traits.

OBJECTIVE: This study aims to investigate the genetic structure and characteristics of the Angus cattle population in Hungary. The survey was performed with the assistance of the Hungarian Hereford, Angus, Galloway Association (HHAGA). METHODS: Genetic parameters of 1,369 animals from 16 Angus herds were analyzed using the genotyping results of 12 microsatellite markers with the aid of PowerMarker, Genalex, GDA-NT2021, and STRUCTURE software. Genotyping of DNA was performed using an automated genetic analyzer. Based on pairwise identity by state values of animals, the Python networkx 2.3 library was used for network analysis of the breed and to identify the central animals. RESULTS: The observed numbers of alleles on the 12 loci under investigation ranged from 11 to 18. The average effective number of alleles was 3.201. The overall expected heterozygosity was 0.659 and the observed heterozygosity was 0.710. Four groups were detected among the 16 Angus herds. The breeders' information validated the grouping results and facilitated the comparison of birth weight, age at first calving, number of calves born and productive lifespan data between the four groups, revealing significant differences. We identified the central animals/herd of the Angus population in Hungary. The match of our group descriptions with the phenotypic data provided by the breeders further underscores the value of cooperation between breeders and researchers. CONCLUSION: The observation that significant differences in the measured traits occurred among the identified groups paves the way to further enhancement of breeding efficiency. Our findings have the potential to aid the development of new breeding strategies and help breeders keep the Angus populations in Hungary under genetic supervision. Based on our results the efficient use of an upcoming genomic selection can, in some cases, significantly improve birth weight, age at first calving, number of calves born and the productive lifespan of animals.

Characteristics of meat production traits in the Hungarian Simmental herd selected for the simultaneous improvement of milk and meat production.

Phenotypic and genetic trends, population genetic parameters, and the heritability and breeding values of the fattening and slaughter traits - namely muscularity score (MUS), final fattening weight (FFW), weight gain per day of life (WGD), slaughter weight (SLW), carcass weight (CAR), dressing percentage (DRP), bone-meat production per day of life (BMP), SEUROP conformation and fat coverage score (EUR, FAT), and meat percentage (MEP) - of 1162 Hungarian Simmental bulls were evaluated with the progeny test database of the Association of Hungarian Simmental Breeders. Trends were calculated by weighted linear regression analysis, while the population genetic parameters and breeding values used the BLUP (best linear unbiased prediction) animal model and general linear model (GLM). According to the results, the lowest heritability value (h2=0.23) was found in FAT. In the case of MUS, EUR and MEP, the values were moderate (h2=0.32, 0.26 and 0.32), and in the case of the other traits, high heritability values (h2 = 0.42-0.52) were estimated. The phenotypic trends of the fattening and slaughter traits of bull progeny born between 2001 and 2019 showed a stagnant direction. Between the sires, the differences in the breeding values for some traits (WDG, CAR and BMP) were large, and with other traits (DRP, EUR and FAT), small differences were found. According to the data of the genetic-trend calculation, the steepness values of the evaluated traits were positive, and the genetic trends showed a slightly improving direction in the estimated period.

Effect of thickness, translucency, and substrates on the masking ability of a polymer-infiltrated ceramic-network material.

OBJECTIVE: The aim of this in vitro study is to evaluate the masking ability of polymer-infiltrated ceramic-network materials (PICN) with different translucencies and thicknesses on multiple types of substrates. MATERIALS AND METHODS: Ceramic samples were prepared of VITA ENAMIC blocks in two different translucencies (2M2-T, 2M2-HT) in a thickness range of 0.5-2.5 mm (±0.05 mm). Layered specimens were obtained using composite substrates in nine shades and transparent try-in paste. Spectral reflectance of specimens was measured using a Konica Minolta CM-3720d spectrophotometer and D65 standard illumination. CIEDE2000 color difference (ΔE00 ) between two samples was evaluated using 50%:50% perceptibility and acceptability thresholds. Specular component of the reflection was examined with Specular Component Excluded (SCE) and Included (SCI) settings. Statistical evaluation was performed by linear regression analysis, Kruskal-Wallis test, and multiplicative effect analysis. RESULTS: An increase in thickness of 0.5 mm reduces ΔE00 of HT samples to 73.5%, of T samples to 60.5% (p < 0.0001). Five substrates with HT specimens, and three substrates with T specimens had significantly different results from average (p < 0.05). There is a significant difference between SCE and SCI data depending on the wavelength (p < 0.0001). CONCLUSIONS: Masking ability of PICN materials is influenced by the thickness and translucency of the ceramic, and by the substrate. Reflection of the examined PICN material is characterized by both diffuse and specular reflection. CLINICAL SIGNIFICANCE: Although PICN materials have been available on the market for 10 years now, there is a lack of information regarding their masking ability. Acquiring in-depth data and thereby practical experience of the factors affecting the esthetics of PICN materials is essential for creating perfectly lifelike restorations.

Relationship between Some Myostatin Variants and Meat Production Related Calving, Weaning and Muscularity Traits in Charolais Cattle.

The slaughter value of live cattle can be assessed during visual conformation scoring, as well as by examining different molecular genetic information, e.g., the myostatin gene, which can be responsible for muscle development. In this study, the F94L, Q204X, nt267, nt324 and nt414 alleles of the myostatin gene (MSTN) were examined in relation to birth weight (BIW), calving ease (CAE), 205-day weaning weight (CWW), muscle score of shoulder (MSS), muscle score of back (MSB), muscle score of thigh (MST), roundness score of thigh (RST), loin thickness score (LTS), and overall muscle development percentage (OMP) of Charolais weaned calves in Hungary. Multi-trait analysis of variance (GLM) and weighted linear regression analysis were used to process the data. Calves carrying the Q204X allele in the heterozygous form achieved approximately 0.14 points higher MSB, MST and LTS, and 1.2% higher OMP, and gained 8.56 kg more CWW than their counterparts not carrying the allele (p < 0.05). As for the F94L allele, there was a difference of 4.08 kg in CWW of the heterozygous animals, but this difference could not be proved statistically. The other alleles had no significant effect on the evaluated traits.

Executive summary of consensus clinical practice guidelines for the prevention of infection in patients with multiple myeloma.

Infection remains a significant contributor to morbidity and mortality in patients with myeloma. This guideline was developed by a multidisciplinary group of clinicians who specialise in the management of patients with myeloma and infection from the medical and scientific advisory group from Myeloma Australia and the National Centre for Infections in Cancer. In addition to summarising the current epidemiology and risk factors for infection in patients with myeloma, this guideline provides recommendations that address three key areas in the prevention of infection: screening for latent infection, use of antimicrobial prophylaxis and immunoglobulin replacement and vaccination against leading respiratory infections (severe acute respiratory syndrome coronavirus 2, influenza and Streptococcus pneumoniae) and other preventable infections. This guideline provides a practical approach to the prevention of infection in patients with myeloma and harmonises the clinical approach to screening for infection, use of prophylaxis and vaccination to prevent infectious complications.

The importance of frailty assessment in multiple myeloma: a position statement from the Myeloma Scientific Advisory Group to Myeloma Australia.

Multiple myeloma (MM) is a disease of older people, yet factors relating to comorbidity and frailty may threaten treatment tolerability for many of this heterogenous group. There has been increasing interest in defining specific and clinically relevant frailty assessment tools within the MM population, with the goal of using these frailty scores, not just as a prognostic instrument, but also as a predictive tool to allow for a frailty-adapted treatment approach. This paper reviews the various frailty assessment frameworks used in the evaluation of patients with MM, including the International Myeloma Working Group Frailty Index (IMWG-FI), the Mayo Frailty Index and the simplified frailty scale. While the IMWG-FI remains the most widely accepted tool, the simplified frailty scale is the most user-friendly in busy day-to-day clinics based on its ease of use. This paper summarises the recommendations from the Myeloma Scientific Advisory Group (MSAG) of Myeloma Australia, on the use of frailty assessment tools in clinical practice and proposes a frailty-stratified treatment algorithm to aid clinicians in tailoring therapy for this highly heterogeneous patient population.

Population genetic features of calving interval of the Limousin beef cattle breed in Hungary.

Variance, covariance components, heritability, breeding values (BV) and genetic trends in calving interval (CI) of the Limousin population in Hungary were evaluated. A total of 3,008 CI data of 779 cows from three herds in 1996-2016 were processed. For influencing effects GLM method, for population genetic parameters and BV estimation BLUP animal model, for trend analyses linear regression was applied. The average CI obtained was 378.8 ± 3.1 days. The variance distribution components of the phenotype were as follow: age of cow at calving 34.30%, season of calving 26.09%, year of calving 23.00%, sire 7.45%, herd 3.23%, sex of calf 0.33% and type of calving 0.30%. The heritability of CI proved to be low (h2 d = 0.04 ± 0.02 and 0.03 ± 0.02; h2 m = 0.01 ± 0.02). The repeatability was low (R = 0.03 ± 0.02). Based on the phenotypic trend calculation, the CI of cows decreased by an average of 0.60 days per year (R 2 = 0.19; P < 0.05). In case of genetic trend calculation, the average BV of sires in CI increased 0.07 and 0.17 days per year (R 2 = 0.23 and 0.27; P < 0.05).

A Multi-Analytical Approach for Studying the Effect of New LED Lighting Systems on Modern Paints: Chemical Stability Investigations.

This study aims to investigate the chemical stability of some modern paint samples exposed to a new Light Emitting Diode (LED)-lighting system and a halogen lamp by using micro-attenuated total reflectance of Fourier transform infrared spectroscopy (µ-ATR-FTIR), µ-Raman, pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS), and thermally assisted hydrolysis and methylation of GC/MS (THM-GC/MS). Those investigations were performed before and after the exposure of the samples to lightings for 1250, 2400, 3300, and 5000 h. The results obtained with µ-Raman spectroscopy show the high stability of the selected inorganic pigments after the exposure to the lighting systems; while similar to the UV/Vis/NIR results reported in a previous study, µ-ATR-FTIR and THM-GC/MS results evidence greater chemical changes occurring principally on the linseed oil binder-based mock-ups among the acrylic and alkyd-based samples. Moreover, principal component analyses (PCA) and hierarchical cluster analyses (HCA) of THM-GC/MS results highlight that those changes were mostly dependent on the exposure time and on the type of pigment, while being independent of the lighting system used. Finally, semi-quantitative µ-ATR-FTIR results show slight pigment enrichment at the paint surface due to the auto and photo-oxidative degradation of the linseed oil binder.

The effect of new LED lighting systems on the colour of modern paints.

This research focuses on the investigation of the effect of a new light emitting diode (LED)-lighting system which reproduces indoor museum conditions, on some self-made art paint colours (acrylic-, alkyd-, and linseed oil-based paints) often used in modern-contemporary art. A halogen lamp representing a traditional light source for museum lighting was also considered. Lighting-set-up and lighting optimization parameters were considered while Ultraviolet/Visible/Near Infrared (UV/Vis/NIR) spectrophotometry was used for investigating the colour change of the paint samples. Univariate analyses allowed determining the highest effect of the lighting systems on the linseed oil binder and ultramarine blue PB29 mixture upon ageing, according to the highest total colour change ΔE*ab. In a more specific and detailed way, variance analyses not only demonstrated the strong correlation between the type of binder and pigment used for the paint samples with the colour variation, but also showed that the short-wavelength blue LEDs influenced the change along the yellow-blue b* axis of the yellow and blue samples, whereas the halogen lamp mostly had an impact towards the red-green a* axis of mostly the green specimens.

Imaging of patients with multiple myeloma and associated plasma cell disorders: consensus practice statement by the Medical Scientific Advisory Group to Myeloma Australia.

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website.

Genetic parameters of gestation length trait in dromedary camels (Camelus dromedarius).

Gestation length (GL) data of dromedary camels were analysed for the period from 2007 to 2018. The database of the largest dairy camel herds (Dubai, United Arab Emirates) was used in this study. The data of 4,084 camels included in the assessment were classified into six ecotypes (Emirati, Emirati cross, Black, Pakistani, Saudi-Sudanese and Saudi cross). The aim of the study was to describe the heritability of GL of camels and the breeding value (BV) of sires for this trait. The genetic parameters of GL were estimated by the General Linear Model method and two Best Linear Unbiased Prediction (BLUP) animal models as well. The mean (±SE) of GL of camels was 384.3 ± 0.2 days. The direct heritability of GL (0.26 ± 0.06-0.36 ± 0.08) was higher than the maternal heritability (0.00 ± 0.05-0.13 ± 0.06) obtained. The maternal permanent environmental effect (0.15 ± 0.05) was similar to the results estimated previously in dromedary camel, but higher than the data reported by relevant sources in other species. Based on the results of this study it can be concluded that the GL of dromedary camels is a species-specific value similar to that in cattle, which is less affected by the maternal influence. Considerable differences (16 days) exist among male dromedaries in their BV for the GL trait.

ABO and Rhesus D blood groups in the Northern Territory of Australia.

BACKGROUND: There are no contemporary published data on the frequency of the ABO and Rhesus D (RhD) blood groups in the Northern Territory (NT) of Australia, particularly for the large Aboriginal population. AIMS: To establish the frequencies of ABO and RhD blood groups in the NT Aboriginal and non-Aboriginal populations in order to aid transfusion inventory management and clinical practice. METHODS: Retrospective data were collected from 1 January 2012 to 31 December 2012. All patients with a blood group sample processed by the NT public hospital laboratories and a recorded ABO and RhD report were included. Results were analysed using Stata 14. RESULTS: The Aboriginal and non-Aboriginal populations had significantly different ABO and RhD distributions (P < 0.001). For Aboriginal individuals, 955/1686 (56.6%) were group O and 669/1686 (39.7%) were group A. In non-Aboriginal individuals, 1201/2657 (45.2%) were group O and 986/2657 (37.1%) were group A. We found that 1646/1686 (97.6%) of Aboriginal individuals were RhD positive, compared with 2225/2657 (83.7%) of non-Aboriginal individuals. Only 62/1686 (3.7%) of Aboriginal individuals were group B or AB, compared with 470/2657 (17.7%) of non-Aboriginal individuals. In Aboriginal individuals we found that group O was more common than A in the 'Northern' NT, whereas there was similar distribution of the groups in 'Central Australia'. CONCLUSIONS: We found a significant difference in ABO and RhD blood groups between Aboriginal and non-Aboriginal individuals in the NT (P < 0.001). These findings will aid transfusion inventory management, allowing us to plan supply of blood products and reduce waste.

Genetic parameters of birth weight trait in dromedary camels (Camelus dromedarius).

Birth weight data of dromedary calves from the database of one of the world's largest dairy herds (Dubai, UAE) were analyzed for the period from 2007 to 2018. The assessment included the data of 4124 camel calves that were classified into six ecotypes (Emirate, Emirate crossed, Black, Pakistanian, Saudi-Sudanian, and Saudi crossed). The aim of the study was to describe the heritability of birth weight of calves and the breeding value of sires. Genetic parameters of birth weight were estimated by ANOVA model and two BLUP animal models as well. The mean value of the camel calves' birth weight was 34.75 ± 5.67 kg. The direct heritability of birth weight (h2d = 0.09 ± 0.04-0.11 ± 0.03) was rather low, so was the maternal heritability (h2m = 0.23 ± 0.10-0.50 ± 0.06). The maternal effect from environmental origin (c2 = 0.23 ± 0.08) far exceeded the results previously calculated in cattle. There was no difference in reliability between BLUP1 and BLUP2 models, and both of them were more accurate than the ANOVA model. Based on the results of this study, we conclude that the birth weight of dromedary calves was more influenced by the dam's intrauterine rearing capacity and by the environment, management, and feeding of the pregnant female camels than the hereditary growth potential. Considerable differences were found among male dromedaries in their breeding values for the birth weight trait.

Assessment of genetic diversity and phylogenetic relationship of Limousin herds in Hungary using microsatellite markers.

OBJECTIVE: This study was conducted to investigate basic information on genetic structure and characteristics of Limousin population in Hungary. Obtained results will be taken into consideration when adopting the new breeding strategy by the Association of Hungarian Limousin and Blonde d'Aquitaine Breeders (AHLBB). METHODS: Genetic diversity and phylogenetic relationship of 3,443 Limousin cattle from 16 different herds were investigated by performing genotyping using 18 microsatellite markers. Amplified DNA was genotyped using an automated genetic analyzer. RESULTS: Mean of effective alleles (ne) of the populations was 3.77. Population C had the lowest number of effective alleles (3.01) and the lowest inbreeding coefficient (FIS) value (-0.15). Principal component analysis of estimated genetic distance (FST) values (p<0.000) revealed two herds (C and E) distinct from the majority of other Limousin herds. The pairwise FST values of population C compared to the others (0.066 to 0.120) fell into the range of moderate genetic distance: 0.050 to 0.150, while population E displayed also moderate genetic distance (FST values in range 0.052 to 0.064) but only to six populations (G, H, J, L, N, and P). FST(C-E) was 0.148, all other pairs -excluding C and E herds- displayed low genetic distance (FST<0.049). Population D, F, I, J, K, L, N, O, and P carried private alleles, which alleles belonged to 1.1% of the individuals. Most probable number of clusters (K) were 2 and 7 determined by Structure and BAPS software. CONCLUSION: This study showed useful genetic diversity and phylogenetic relationship data that can be utilized for the development of a new breeding strategy by AHLBB. The results presented could also contribute to the proper selection of animals for further whole genome scan studies of Limousins.

The incidence and outcome of clinically significant antibodies detected in Rhesus-D positive pregnant women of the Northern Territory.

BACKGROUND: Haemolytic disease of the fetus/newborn secondary to clinically significant non-Rhesus-D antibodies has risen in importance since the advent of immunoprophylactic anti-D administration to Rhesus-D negative women. Of interest is the incidence of these antibodies in Rhesus-D positive women, who receive less frequent antenatal alloantibody screening. This is of particular concern if the antibodies arise late in pregnancy and may go undetected. AIMS: To assess the proportion of Rhesus-D positive pregnant women with late developing clinically significant antibodies for haemolytic disease of the fetus/newborn, and whether these resulted in adverse fetal outcomes. MATERIALS AND METHODS: A retrospective analysis over a 12-month period at a tertiary hospital in the Northern Territory. Group and antibody screen results in addition to clinical data regarding pregnancy/newborn were collected. RESULTS: Sixty-four of 2612 women (2.5%) had red blood cell antibodies detected during their pregnancy. Of these, 21 clinically significant antibodies were detected in 19 women (0.7% of initial cohort). The most common antibody detected was anti-c (28.5%). In six of these women (0.23% of initial cohort), the antibodies were late developing. Mild jaundice was noted in three newborns with phototherapy required in one. CONCLUSIONS: Although clinically significant antibodies were detected during pregnancy, and in a small proportion of cases as a late developing antibody undetected in the first trimester screening, clinical outcomes for the newborn were mild. As such, the cost of retesting all Rhesus-D positive pregnant women in the third trimester would be considerable and unlikely to result in any meaningful clinical benefit.

Stochastic graph Voronoi tessellation reveals community structure.

Given a network, the statistical ensemble of its graph-Voronoi diagrams with randomly chosen cell centers exhibits properties convertible into information on the network's large scale structures. We define a node-pair level measure called Voronoi cohesion which describes the probability for sharing the same Voronoi cell, when randomly choosing g centers in the network. This measure provides information based on the global context (the network in its entirety), a type of information that is not carried by other similarity measures. We explore the mathematical background of this phenomenon and several of its potential applications. A special focus is laid on the possibilities and limitations pertaining to the exploitation of the phenomenon for community detection purposes.

Enhanced Injection Molding Simulation of Advanced Injection Molds.

The most time-consuming phase of the injection molding cycle is cooling. Cooling efficiency can be enhanced with the application of conformal cooling systems or high thermal conductivity copper molds. The conformal cooling channels are placed along the geometry of the injection-molded product, and thus they can extract more heat and heat removal is more uniform than in the case of conventional cooling systems. In the case of copper mold inserts, cooling channels are made by drilling and heat removal is facilitated by the high thermal conductivity coefficient of copper, which is several times that of steel. Designing optimal cooling systems is a complex process; a proper design requires injection molding simulations, but the accuracy of calculations depends on how precise the input parameters and boundary conditions are. In this study, three cooling circuit designs and three mold materials (Ampcoloy 940, 1.2311 (P20) steel, and MS1 steel) were used and compared using numerical methods. The effect of different mold designs and materials on cooling efficiency were examined using calculated and measured results. The simulation model was adjusted to the measurement results by considering the joint gap between the mold inserts.