Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines.

Numerous protocols have been described for producing neural retina from human pluripotent stem cells (hPSCs), many of which are based on the culture of 3D organoids. Although nearly all such methods yield at least partial segments of retinal structure with a mature appearance, variabilities exist within and between organoids that can change over a protracted time course of differentiation. Adding to this complexity are potential differences in the composition and configuration of retinal organoids when viewed across multiple differentiations and hPSC lines. In an effort to understand better the current capabilities and limitations of these cultures, we generated retinal organoids from 16 hPSC lines and monitored their appearance and structural organization over time by light microscopy, immunocytochemistry, metabolic imaging and electron microscopy. We also employed optical coherence tomography and 3D imaging techniques to assess and compare whole or broad regions of organoids to avoid selection bias. Results from this study led to the development of a practical staging system to reduce inconsistencies in retinal organoid cultures and increase rigor when utilizing them in developmental studies, disease modeling and transplantation.

A comprehensive phylogeny helps clarify the evolutionary history of host breadth and lure response in the Australian Dacini fruit flies (Diptera: Tephritidae).

The tribe Dacini (Diptera: Tephritidae) contains over 930 recognised species and has been widely studied due to the economic importance of some taxa, such as the Oriental fruit fly Bactrocera dorsalis. Despite the attention this group has received, very few phylogenetic reconstructions have comprehensively sampled taxa from a single biogeographic region, thereby limiting our capacity to address more targeted evolutionary questions. To study the evolution of diet breadth and male lure response, two key traits fundamental to understanding dacine diversity and the biology of pest taxa, we analysed 273 individuals representing 144 described species from Australia (80% continental coverage), the Pacific, and select close relatives from South-east Asia to estimate a dated molecular phylogenetic reconstruction of the Dacini. We utilised seven loci with a combined total of 4,332 nucleotides, to estimate both Bayesian and Maximum Likelihood phylogenies of the tribe. Consistent with other molecular phylogenies of the tribe, there was a high level of disagreement between the placement of species in the phylogeny and their current subgeneric and species-complex level taxonomies. The Australian fauna exhibit high levels of endemism, with radiations of both exclusively Australian clades, and clades that originate elsewhere (e.g. the Bactrocera dorsalis species group). Bidirectional movement of species has occurred between Papua New Guinea and Australia, with evidence for multiple incursions over evolutionary time. The Bactrocera aglaiae species group emerged sister to all other Bactrocera species examined. Divergence time estimates were âˆ¼ 30 my younger than previously reported for this group, with the tribe diverging from its most recent common ancestor âˆ¼ 43 mya. Ancestral trait reconstruction and tests for trait phylogenetic signal revealed a strong signal for the evolution of male lure response across the tree, with cue-lure/raspberry ketone lure response the ancestral trait. Methyl eugenol response has arisen on multiple, independent occasions. The evolution of host breadth exhibited a weaker signal; yet, basal groups were more likely to be host specialists. Both the evolution of lure response and host fruit use provide predictive information for the outbreak management of understudied pest fruit flies for which direct inference of these features may be lacking. Our results, which parallel those of earlier research into the closely-related African Dacus spp., demonstrate how geographically focussed taxon coverage allows Dacini phylogenetics to more explicitly test evolutionary hypotheses, thereby progressing our understanding of the evolution of this highly diverse and recently-radiated group of flies.

The impact of targeted cathodal transcranial direct current stimulation on reward circuitry and affect in Bipolar Disorder.

Bipolar Disorder is costly and debilitating, and many treatments have side effects. Transcranial Direct Current Stimulation (tDCS) is a well-tolerated neuromodulation technique that may be a useful treatment for Bipolar Disorder if targeted to neural regions implicated in the disorder. One potential region is the left ventrolateral prefrontal cortex (vlPFC), which shows abnormally elevated activity during reward expectancy in individuals with Bipolar Disorder. We used a counterbalanced repeated measures design to assess the impact of cathodal (inhibitory) tDCS over the left vlPFC on reward circuitry activity, functional connectivity, and affect in adults with Bipolar Disorder, as a step toward developing novel interventions for individuals with the disorder. -1mA cathodal tDCS was administered over the left vlPFC versus a control region, left somatosensory cortex, concurrently with neuroimaging. Affect was assessed pre and post scan in remitted Bipolar Disorder (n = 27) and age/gender-matched healthy (n = 31) adults. Relative to cathodal tDCS over the left somatosensory cortex, cathodal tDCS over the left vlPFC lowered reward expectancy-related left ventral striatal activity (F(1,51) = 9.61, p = 0.003), and was associated with lower negative affect post scan, controlling for pre-scan negative affect, (F(1,49) = 5.57, p = 0.02) in all participants. Acute cathodal tDCS over the left vlPFC relative to the left somatosensory cortex reduces reward expectancy-related activity and negative affect post tDCS. Build on these findings, future studies can determine whether chronic cathodal tDCS over the left vlPFC has sustained effects on mood in individuals with Bipolar Disorder, to guide new treatment developments for the disorder.

PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm.

PAX6 is essential for neural retina (NR) and forebrain development but how PAX6 instructs NR versus forebrain specification remains unknown. We found that the paired-less PAX6, PAX6D, is expressed in NR cells during human eye development and along human embryonic stem cell (hESC) specification to retinal cells. hESCs deficient for PAX6D failed to enter NR specification. Induced expression of PAX6D but not PAX6A in a PAX6-null background restored the NR specification capacity. ChIP-Seq, confirmed by functional assays, revealed a set of retinal genes and non-retinal neural genes that are potential targets of PAX6D, including WNT8B. Inhibition of WNTs or knocking down of WNT8B restored the NR specification capacity of neuroepithelia with PAX6D knockout, whereas activation of WNTs blocked NR specification even when PAX6D was induced. Thus, PAX6D specifies neuroepithelia to NR cells via the regulation of WNT8B.

Reproductive factors and breast arterial calcification: a systematic review and meta-analysis.

BACKGROUND: Breast arterial calcification (BAC) is a common incidental finding on screening mammography. Recent evidence suggests that BAC is associated with cardiovascular disease (CVD). We systematically reviewed the associations between BAC and reproductive factors (menopausal status, hormone replacement therapy [HRT] use, oral contraceptive [OC] use and parity). METHODS: MEDLINE and EMBASE databases, references of relevant papers and Web of Science were searched up to February 2020 for English-language studies that evaluated these associations. Study quality were determined and a random effects model was used to assess these associations. RESULTS: Nineteen observational studies (n = 47,249; three cohort studies, seven case-control studies, nine cross-sectional studies) were included. BAC was associated with menopause (nine studies; n = 15,870; odds ratio [OR] 2.67; 95% confidence interval [CI] 1.50-4.77) and parity (seven studies; n = 27,728; OR 2.50; 95% CI 1.68-3.71) and inversely with HRT use (10 studies; n = 33,156; OR 0.57; 95% CI 0.40-0.80). No association was found with OC use. Eleven studies were considered good in quality. Marked heterogeneity existed across all analyses. CONCLUSIONS: BAC is associated with HRT use, menopause and parity. However, careful interpretation is required as marked heterogeneity existed across all analyses. Traditional cardiovascular risk factors may need to be taken into account in future investigations of associations between BAC and reproductive factors. PROSPERO: CRD42020141644.

Impact of COVID-19 on radiology training: Royal College of Radiologists Junior Radiologists Forum national survey.

AIM: To obtain a national snapshot of radiology trainees' experience during the first wave of the pandemic. MATERIALS AND METHODS: A 25-item questionnaire was disseminated to representatives from all training regions across the UK in July 2020. Each representative collated the collective experiences of trainees in their training programme in key domains, including redeployment, shielding, training, and teaching. RESULTS: Ninety-five percent (38 of 40) of representatives completed the questionnaire. Trainees in up to 76% of training programmes were redeployed to wards and some trainees were shielding in 81% of programmes. Only 27% of programmes enabled remote reporting for isolating or shielding trainees. Sixty-two percent of respondents felt their well-being needs were supported. There was an overall increase in the attendance, volume, and quality of teaching and training nationally due to improved accessibility via remote-learning methods. Significant challenges were described with reporting, interventional procedures, and multidisciplinary team meeting attendance, although 62% of programmes noted an increase in service provision. Less in-person feedback was reported with in-person training still deemed necessary for practical skills. The Royal College of Radiologists Junior Radiologists Forum webinars were well received by all trainees with continuation of the series recommended. CONCLUSION: The COVID-19 pandemic has had a clear impact on many areas of radiology training in the UK. Early strategies have been adopted to mitigate the challenges faced by trainees and opportunities for future improvement are highlighted.

Observational study of pre-operative intravenous iron given to anaemic patients before elective cardiac surgery.

Cardiac surgical patients with anaemia experience increased morbidity and mortality. Iron deficiency is the most common cause of pre-operative anaemia in this group. We designed and implemented the Cardiff Pathway, a pre-assessment and treatment pathway to identify cardiac surgical patients with anaemia and iron deficiency. Patients identified with anaemia and/or iron deficiency (Hb < 130 g.l-1 and ferritin < 100 µg.l-1 ) were offered intravenous iron infusion 20 mg.kg-1 pre-operatively. Treatment success was defined as Hb ≥ 130g.l-1 on the day of surgery. We analysed data from 447 patients: 300 (67%) were not anaemic; 75 (17%) were anaemic and treated with intravenous iron; and 72 (16%) were anaemic and not treated. Haemoglobin concentration increased in successfully treated anaemic patients by a mean (95%CI) of 17 (13-21) g.l-1 and they received a median (IQR [range]) of 0 (0-2 [0-15]) units of blood peri-operatively. Transfusion was avoided in 54% of the successfully treated anaemic patients, which was significantly more than the unsuccessfully treated anaemic (22%, p = 0.005) and untreated anaemic (28%, p = 0.018) patients and similar to non-anaemic patients who received a median (IQR [range] of 0 (0-1 [0-16])) units of blood and, 63% avoided transfusion). Mean (95%CI) Hb fell between pre-assessment and surgery in the untreated anaemic (-2 (0 to -4) g.l-1 ) and non-anaemic groups (-2 (-1 to -3) g.l-1 ). Twenty-one (7%) of the non-anaemic group became newly anaemic waiting for surgery. The Cardiff Pathway reliably identified patients with anaemia and iron deficiency. Anaemic patients who had their Hb restored to normal after treatment required less blood peri-operatively and over half of them required no transfusion at all.

In-situ measurement of pyrolysis and combustion gases from biomass burning using swept wavelength external cavity quantum cascade lasers.

Broadband high-speed absorption spectroscopy using swept-wavelength external cavity quantum cascade lasers (ECQCLs) is applied to measure multiple pyrolysis and combustion gases in biomass burning experiments. Two broadly-tunable swept-ECQCL systems were used, with the first tuned over a range of 2089-2262 cm-1 (4.42-4.79 µm) to measure spectra of CO2, H2O, and CO. The second was tuned over a range of 920-1150 cm-1 (8.70-10.9 µm) to measure spectra of ammonia (NH3), ethene (C2H4), and methanol (MeOH). Absorption spectra were measured continuously at a 100 Hz rate throughout the burn process, including inhomogeneous flame regions, and analyzed to determine time-resolved gas concentrations and temperature. The results provide in-situ, dynamic information regarding gas-phase species as they are generated, close to the biomass fuel source.

A Novel Approach to Single Cell RNA-Sequence Analysis Facilitates In Silico Gene Reporting of Human Pluripotent Stem Cell-Derived Retinal Cell Types.

Cell type-specific investigations commonly use gene reporters or single-cell analytical techniques. However, reporter line development is arduous and generally limited to a single gene of interest, while single-cell RNA (scRNA)-sequencing (seq) frequently yields equivocal results that preclude definitive cell identification. To examine gene expression profiles of multiple retinal cell types derived from human pluripotent stem cells (hPSCs), we performed scRNA-seq on optic vesicle (OV)-like structures cultured under cGMP-compatible conditions. However, efforts to apply traditional scRNA-seq analytical methods based on unbiased algorithms were unrevealing. Therefore, we developed a simple, versatile, and universally applicable approach that generates gene expression data akin to those obtained from reporter lines. This method ranks single cells by expression level of a bait gene and searches the transcriptome for genes whose cell-to-cell rank order expression most closely matches that of the bait. Moreover, multiple bait genes can be combined to refine datasets. Using this approach, we provide further evidence for the authenticity of hPSC-derived retinal cell types. Stem Cells 2018;36:313-324.

Methylomic profiling and replication implicates deregulation of PCSK9 in alcohol use disorder.

Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.

Cerebellar parcellation in schizophrenia and bipolar disorder.

OBJECTIVE: The cerebellum is involved in cognitive processing and emotion control. Cerebellar alterations could explain symptoms of schizophrenia spectrum disorder (SZ) and bipolar disorder (BD). In addition, literature suggests that lithium might influence cerebellar anatomy. Our aim was to study cerebellar anatomy in SZ and BD, and investigate the effect of lithium. METHODS: Participants from 7 centers worldwide underwent a 3T MRI. We included 182 patients with SZ, 144 patients with BD, and 322 controls. We automatically segmented the cerebellum using the CERES pipeline. All outputs were visually inspected. RESULTS: Patients with SZ showed a smaller global cerebellar gray matter volume compared to controls, with most of the changes located to the cognitive part of the cerebellum (Crus II and lobule VIIb). This decrease was present in the subgroup of patients with recent-onset SZ. We did not find any alterations in the cerebellum in patients with BD. However, patients medicated with lithium had a larger size of the anterior cerebellum, compared to patients not treated with lithium. CONCLUSION: Our multicenter study supports a distinct pattern of cerebellar alterations in SZ and BD.

Physical conditions for UO formation in laser-produced uranium plumes.

We investigate the oxidation of uranium (U) species, the physical conditions leading to uranium monoxide (UO) formation and the interplay between plume hydrodynamics and plasma chemistry in a laser-produced U plasma. Plasmas are produced by ablation of metallic U using nanosecond laser pulses. An ambient gas environment with varying oxygen partial pressures in 100 Torr inert Ar gas is used for controlling the plasma oxidation chemistry. Optical emission spectroscopic analysis of U atomic and monoxide species shows a reduction in the emission intensity and persistence with increasing oxygen partial pressure. Spectral modelling is used for identifying the physical conditions in the plasma that favor UO formation. The optimal temperature for UO formation is found to be in the temperature range of ∼1500-5000 K. The spectrally integrated and spectrally filtered (monochromatic) imaging of U atomic and molecular species reveals the evolutionary paths of various species in the plasma. Our results also highlight that oxidation in U plasmas predominantly occurs at the cooler periphery and is delayed with respect to plasma formation, and the dissipation of molecular species strongly depends on oxygen partial pressure.

Data-informed targets for suicide prevention: a small-area analysis of high-risk suicide regions in Australia.

PURPOSE: To investigate small-area variation in risks associated with suicide deaths across four regional communities in New South Wales, Australia, and to determine whether these areas have unique demographic and socioeconomic risk profiles that could inform targeted means restriction suicide prevention efforts. METHODS: Archival data on suicide mortality for all deaths in New South Wales, Australia, over the period 2006-2015 were geospatially attributed to four high-risk priority regions. Deaths in the four regions were compared to each other, and to NSW, on demographic factors, indicators of economic deprivation, and suicide means. RESULTS: Priority means restriction targets were identified for all sites. In Murrumbidgee, suicide deaths were significantly more likely to involve firearms and older males (p < 0.001). The Central Coast had a greater proportion of overdose deaths (p < 0.001), which were associated with being female and unemployed. Suicide deaths in Newcastle were associated with being younger (p = 0.001) and involving 'jumping from a height' (p < 0.001), while economic deprivation was a major risk for suicide death in Illawarra Shoalhaven (p < 0.001). CONCLUSIONS: Local regions were significantly differentiated from each other, and from the State, in terms of priority populations and means of suicide, demonstrating the need for locally based, targeted interventions. There were, however, also some risk constancies across all sites (males, hanging, economic deprivation), suggesting that prevention initiatives should, optimally, be delivered within multilevel models that target risk commonalities and provide tailored initiatives that address risk specific to a region.

Vulnerabilities in aquatic animal production.

The role of aquatic animals in global food and nutrition security is increasingly recognised. The global demand for fish is increasing, leading to a need to significantly increase its supply. Securing future fish supplies through sustainable production is a challenge as major resources such as fresh water and land are becoming limited worldwide. Aquaculture and capture fisheries face various threats from both human-mediated and natural environmental change, including climate change. Aquaculture systems and practices are vulnerable to such changes. Moreover, aquatic animal diseases are currently considered one of the most important constraints to sustainable global fish production. The need to increase global production, combined with climate change, may increase losses due to diseases. This paper examines key vulnerabilities, their impacts and management to achieve increased and sustainable global fish production. The authors focus on the need to apply international standards, and to develop biosecurity and capacity in aquatic animal health to improve global fish health. Research needed to underpin the development of improved detection and control of fish diseases is also discussed.

L'importance des animaux aquatiques pour la sécurité alimentaire et nutritionnelle mondiale est désormais reconnue. La demande mondiale en aliments issus d'animaux aquatiques ne cessant d'augmenter, il est devenu impératif de renforcer significativement l'offre du secteur. La sécurisation future de cette offre grâce à la mise en place d'une production durable constitue un défi de taille en raison de la raréfaction de certaines ressources cruciales, dont l'eau douce et les terres. L'aquaculture et la pêche de capture font face à plusieurs menaces induites par les transformations tant naturelles qu'anthropiques subies par l'environnement, y compris le changement climatique. Les systèmes et les pratiques de l'aquaculture présentent des vulnérabilités à ces changements. De plus, on considère aujourd'hui que les maladies des animaux aquatiques constituent l'une des principales entraves à une production aquacole durable au niveau mondial. Les pertes dues aux maladies vont probablement augmenter par l'effet conjoint du changement climatique et de la nécessité d'accroître les quantités produites dans le monde. Les auteurs examinent les principales vulnérabilités à l'œuvre ainsi que leur impact et les manières d'y faire face en vue d'une production aquacole mondiale accrue et durable. Ils mettent l'accent sur la nécessité de se conformer aux normes internationales et de renforcer la biosécurité et les capacités du secteur de la santé des animaux aquatiques afin d'améliorer le statut sanitaire de ces animaux à l'échelle mondiale. Ils font également le point sur les travaux de recherche qu'il convient de mener afin de mettre au point de meilleures méthodes de détection et de contrôle des maladies des animaux aquatiques.

Cada vez está más clara la función de los animales acuáticos en relación con la seguridad alimentaria y nutricional del mundo. La demanda planetaria de alimentos derivados de animales acuáticos va en aumento, lo que obliga a incrementar sustancialmente el suministro. El objetivo de asegurar el abastecimiento de animales acuáticos en el futuro gracias a una producción sostenible plantea no pocas dificultades, en la medida en que recursos importantes, como el agua dulce o las tierras, empiezan a escasear en todo el mundo. La acuicultura y la pesca de captura afrontan una serie de amenazas derivadas de los cambios ambientales, ya sean de origen natural o antrópico, en particular el cambio climático. Las praxis y los sistemas acuícolas son vulnerables a esos cambios. Están además las enfermedades de los animales acuáticos, consideradas actualmente uno de los principales frenos a la producción sostenible del sector en el mundo. La necesidad de elevar la producción mundial, combinada con el cambio climático, puede acrecentar el volumen de pérdidas debidas a enfermedades. Los autores examinan las principales fragilidades del sistema, sus consecuencias y la forma de gestionarlas para lograr una producción acuícola mundial más cuantiosa y sostenible, centrándose en la necesidad de aplicar normas internacionales y de desarrollar tanto la seguridad biológica como la capacidad en materia de sanidad de los animales acuáticos para mejorar el estado de salud de estos animales a escala mundial. También se refieren a las investigaciones necesarias para fundamentar sistemas más eficaces de detección y control de las enfermedades de los animales acuáticos.

Genomics of Parallel Experimental Evolution in Drosophila.

What are the genomic foundations of adaptation in sexual populations? We address this question using fitness-character and whole-genome sequence data from 30 Drosophila laboratory populations. These 30 populations are part of a nearly 40-year laboratory radiation featuring 3 selection regimes, each shared by 10 populations for up to 837 generations, with moderately large effective population sizes. Each of 3 sets of the 10 populations that shared a selection regime consists of 5 populations that have long been maintained under that selection regime, paired with 5 populations that had only recently been subjected to that selection regime. We find a high degree of evolutionary parallelism in fitness phenotypes when most-recent selection regimes are shared, as in previous studies from our laboratory. We also find genomic parallelism with respect to the frequencies of single-nucleotide polymorphisms, transposable elements, insertions, and structural variants, which was expected. Entirely unexpected was a high degree of parallelism for linkage disequilibrium. The evolutionary genetic changes among these sexual populations are rapid and genomically extensive. This pattern may be due to segregating functional genetic variation that is abundantly maintained genome-wide by selection, variation that responds immediately to changes of selection regime.

Standoff analysis of laser-produced plasmas using laser-induced fluorescence.

We report the use of laser-induced fluorescence (LIF) of laser ablation (LA) plumes for standoff applications. The standoff analysis of Al, as major and minor species in samples, is performed in a nanosecond laser-produced plasma created at a distance of ∼10 m. The LIF of LA plumes is carried out by resonantly exciting an Al transition at 394.4 nm (S1/22-P1/22) using a continuous wave (cw) tunable laser and by collecting the direct-line fluorescence signal at 396.15 nm. The spectral resolution of LIF is obtained by scanning the cw tunable LIF laser across the selected Al transition. Our results highlight that LIF provides enhanced signal intensity, emission persistence, and spectral resolution when compared to thermally excited emission.

Tracking of oxide formation in laser-produced uranium plasmas.

We use a spatially and temporally resolved emission tracking technique based on optical emission spectroscopy to map the evolution of emission features from uranium and its compounds in a plasma produced by a nanosecond laser. We observe quenching of the emission from neutral uranium (591.538 nm) and uranium monoxide (593.55 nm) species with increasing oxygen concentration and discuss possible reaction pathways for dissociation or formation of higher uranium oxides (UxOy). We further identify spectral features between 320 nm and 380 nm and between 520 nm and 640 nm, which we attribute to UxOy.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Clinical management of Australian adolescents and young adults with acute lymphoblastic and myeloid leukemias: A national population-based study.

BACKGROUND: While several studies have examined the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL), studies of acute myeloid leukemia (AML) are rare. Using national data for Australia, we describe (i) the number and type of treatment centers caring for AYAs, (ii) induction/first-line treatments, and (iii) survival outcomes. PROCEDURE: National population-based study assessing treatment of 15- to 24-year-olds diagnosed with ALL or AML between 2007 and 2012. Treatment details were abstracted from hospital medical records. Treatment centers were classified as pediatric or adult (adult AYA-focused or other adult; and by AYA volume [high/low]). Cox proportional hazard regression analyses examined associations between treatment and overall, event-free, and relapse-free survival outcomes. RESULTS: Forty-seven hospitals delivered induction therapy to 351 patients (181 ALL and 170 AML), with 74 (21%) treated at pediatric centers; 70% of hospitals treated less than two AYA leukemia patients per year. Regardless of treatment center, 82% of ALL patients were on pediatric protocols. For AML, pediatric protocols were not used in adult centers, with adult centers using a non-COG 7+3-type induction protocol (51%, where COG is Cooperative Oncology Group) or an ICE-type protocol (39%, where ICE is idarubicin, cytarabine, etoposide). Exploratory analyses suggested that for both ALL and AML, AYAs selected for adult protocols have worse overall, event-free, and relapse-free survival outcomes. CONCLUSIONS: Pediatric protocols were commonly used for ALL patients regardless of where they are treated, indicating rapid assimilation of recent evidence by Australian hematologists. For AML, pediatric protocols were only used at pediatric centers. Further investigation is warranted to determine the optimal treatment approach for AYA AML patients.

A pharmacogenetic investigation of intravenous furosemide in decompensated heart failure: a meta-analysis of three clinical trials.

We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.