Population-based screening of newborns: Findings from the NBS Expansion Study (Part One)

Each year, through population-based newborn screening (NBS), 1 in 294 newborns is identified with a condition leading to early treatment and, in some cases, life-saving interventions. Rapid advancements in genomic technologies to screen, diagnose, and treat newborns promise to significantly expand the number of diseases and individuals impacted by NBS. However, expansion of NBS occurs slowly in the United States (US) and almost always occurs condition by condition and state by state with the goal of screening for all conditions on a federally recommended uniform panel. The Newborn Screening Translational Research Network (NBSTRN) conducted the NBS Expansion Study to describe current practices, identify expansion challenges, outline areas for improvement in NBS, and suggest how models could be used to evaluate changes and improvements. The NBS Expansion Study included a workshop of experts, a survey of clinicians, an analysis of data from online repositories of state NBS programs, reports and publications of completed pilots, federal committee reports, and proceedings, and the development of models to address the study findings. This manuscript (Part One) reports on the design, execution, and results of the NBS Expansion Study. The Study found that the capacity to expand NBS is variable across the US and that nationwide adoption of a new condition averages 9.5 years. Four factors that delay and/or complicate NBS expansion were identified. A companion paper (Part Two) presents a use case for each of the four factors and highlights how modeling could address these challenges to NBS expansion

Persistent Insomnia, Abstinence, and Moderate Drinking in Alcohol‐Dependent Individuals

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86952/1/j.1521-0391.2011.00152.x.pd

Bowhead and Beluga Whale Distributions, Sighting Rates, and Habitat Associations in the Western Beaufort Sea in Summer and Fall 2009–16, with Comparison to 1982–91

We analyzed data from line-transect aerial surveys for marine mammals conducted in the western Beaufort Sea (shore to 72˚ N, 140˚–157˚ W) from July to October of 2009–16 to investigate the distribution, behaviors, sighting rates, and habitat use preferences of bowhead and beluga whales. The habitat use data allowed for direct comparison with data collected in the same area from 1982 to 1991. Both species are ice-adapted, migrating through leads in sea ice in spring, and are seasonal inhabitants of the western Beaufort Sea during summer and fall. From 2009 to 2016, bowheads were seen in all survey months, with the highest overall sighting rate (whales per km) in August. Bowhead sighting rates were highest in the whales’ preferred habitats: outer shelf habitat (51–200 m depth) in July and inner shelf-shallow habitat (≤ 20 m depth) in August, September, and October. Beluga whales were also seen in all survey months, with highest overall sighting rate in July. Beluga whales were overwhelmingly associated with continental slope habitat (201–2000 m depth) in all months. Bowhead distribution and depth preferences in summer months of 2009–16 differed from those observed in 1982–91, when bowheads were not seen during limited survey effort in July and preferred outer continental shelf habitat in August. These differences indicate that bowhead whale preference for shallow shelf habitat now occurs earlier in summer than it used to. Beluga distribution and depth preference remained similar between 1982–91 and 2009–16, with strong preference for continental slope during both periods. Differences in sea ice cover habitat association for both species are likely due more to the relative lack of sea ice in recent years compared to the earlier period than to shifts in habitat preference. Habitat partitioning between bowhead and beluga whales in the western Beaufort Sea remained evident except in July, when both species used continental slope habitat. In July – October 2009–16, the distribution, sighting rates, and behavior of both bowheads and belugas in the western Beaufort showed considerable interannual variation, which underscores the importance of annual sampling to accurate records of the complex western Beaufort Sea ecosystem.Nous avons analysé les données découlant de levés aériens de transects linéaires pour mammifères marins, levés effectués dans l’ouest de la mer de Beaufort (de la rive jusqu’à 72˚ N, et de 140˚ jusqu’à 157˚ O) de juillet à octobre 2009 à 2016. Ces levés avaient pour but d’étudier la distribution, les comportements, les taux d’observation ainsi que les préférences d’utilisation de l’habitat des baleines boréales et des bélugas. Les données relatives à l’utilisation de l’habitat ont permis d’établir des comparaisons directes avec les données recueillies dans le même secteur de 1982 à 1991. Ces deux espèces sont adaptées à la glace, migrent par des chenaux formés dans la glace de mer au printemps et sont des habitants saisonniers de l’ouest de la mer de Beaufort pendant l’été et l’automne. Entre 2009 et 2016, des baleines boréales ont été aperçues pendant tous les mois visés par les levés, le taux d’observation général le plus élevé (nombre de baleines par km) ayant été enregistré au mois d’août. Les taux d’observation des baleines boréales étaient les plus élevés dans les habitats préférés de ces baleines, soit l’habitat de la plateforme externe (de 51 m à 200 m de profondeur) en juillet et l’habitat de la plateforme interne peu profonde (≤ 20 m de profondeur) en août, en septembre et en octobre. Des bélugas ont également été aperçus pendant tous les mois visés par les levés, le taux d’observation général le plus élevé ayant été enregistré en juillet. Les bélugas étaient massivement associés à l’habitat de la pente continentale (de 201 m à 2 000 m de profondeur) pendant tous les mois. La distribution et les préférences de profondeur des baleines boréales pendant les mois d’été 2009 à 2016 différaient de celles observées de 1982 à 1991, lorsque les baleines boréales n’ont pas été aperçues dans le cadre des quelques levés qui ont été effectués en juillet et préféraient leur habitat de la plateforme continentale externe en août. Ces différences indiquent que la préférence des baleines boréales pour l’habitat de la plateforme peu profonde se manifeste maintenant plus tôt l’été qu’auparavant. De 1982 à 1991 et de 2009 à 2016, la distribution des bélugas et leur préférence de profondeur sont restées semblables, avec une préférence marquée pour la pente continentale pendant les deux périodes. Pour les deux espèces, les différences sur le plan de l’association de la couverture de glace marine sont vraisemblablement davantage attribuables au manque relatif de glace de mer ces dernières années comparativement à la période précédente plutôt qu’à une variation de la préférence de l’habitat. Dans l’ouest de la mer de Beaufort, la séparation de l’habitat entre les baleines boréales et les bélugas demeurait évidente, sauf en juillet, quand les deux espèces utilisaient l’habitat de la pente continentale. De juillet à octobre 2009 à 2016, la distribution, les taux d’observation et le comportement des baleines boréales et des bélugas dans l’ouest de la mer de Beaufort ont affiché une variation considérable d’une année à l’autre, ce qui fait ressortir l’importance de faire des échantillonnages annuels afin d’obtenir des données précises au sujet de l’écosystème complexe de l’ouest de la mer de Beaufort

Unidirectional heterologous receptor desensitization between both the fMLP and C5a receptor and the IL‐8 receptor

During inflammation neutrophils receive multiple signals that are integrated, allowing a single modified response. One mechanism for this discrimination is receptor desensitization, a process whereby ligand‐receptor binding is disassociated from cell activation. We examined the effect of heterologous receptor desensitization on neutrophil Chemotaxis, calcium mobilization, and arachidonic acid production, using interleukin‐8 (IL‐8), C5a, and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP). We observed reciprocal inhibition with respect to Chemotaxis. We demonstrated that homologous desensitization, with respect to the mobilization of intracellular calcium stores, lasted approximately 15 min. Heterologous desensitization between the fMLP receptor and the C5a receptor was reciprocal; either stimulant would diminish the cells9 response to stimulation by the other for approximately 3–5 min. However, we observed a unidirectional heterologous desensitization of the IL‐8 receptor by both the fMLP and the C5a receptor. This unidirectional heterologous desensitization was observed with respect to both calcium mobilization and arachidonic acid production (i.e., prestimulation of the IL‐8 receptor had no effect on subsequent stimulation by either fMLP or C5a).Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141009/1/jlb0088.pd

PLA2 promotes fusion between PMN‐specific granules and complex liposomes

Neutrophil stimulation results in the activation of a variety of phospholipases, including phospholipase A2 (PLA2), which releases arachidonic acid from the 2 position of membrane phospholipids, leaving a lysophospholipid. Because arachidonic acid is known to be a potent fusogen in vitro, we examined the effect of metabolism by PLA2 on the fusion of complex liposomes (liposomes prepared with a phospholipid composition similar to that found in neutrophil plasma membrane). We observed that PLA2 augmented the fusion of complex liposomes with each other as well as with specific granules isolated from human neutrophils, lowering the Ca2+ requirement for fusion by three orders of magnitude. Furthermore, although lysophospholipids inhibited fusion, the incorporation of arachidonic acid into liposome membranes overcame the inhibitory effects of the lysophospholipids. Thus with PLA2 and annexins we were able to obtain fusion of complex liposomes at concentations of Ca2+ that are close to physiological. Our data suggest that the activation of PLA2 and the generation of arachidonic acid may be the major fusion‐promoting event mediating neutrophil degranulation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141645/1/jlb0663.pd

Chasing Migration Genes: A Brain Expressed Sequence Tag Resource for Summer and Migratory Monarch Butterflies (Danaus plexippus)

North American monarch butterflies (Danaus plexippus) undergo a spectacular fall migration. In contrast to summer butterflies, migrants are juvenile hormone (JH) deficient, which leads to reproductive diapause and increased longevity. Migrants also utilize time-compensated sun compass orientation to help them navigate to their overwintering grounds. Here, we describe a brain expressed sequence tag (EST) resource to identify genes involved in migratory behaviors. A brain EST library was constructed from summer and migrating butterflies. Of 9,484 unique sequences, 6068 had positive hits with the non-redundant protein database; the EST database likely represents ∼52% of the gene-encoding potential of the monarch genome. The brain transcriptome was cataloged using Gene Ontology and compared to Drosophila. Monarch genes were well represented, including those implicated in behavior. Three genes involved in increased JH activity (allatotropin, juvenile hormone acid methyltransfersase, and takeout) were upregulated in summer butterflies, compared to migrants. The locomotion-relevant turtle gene was marginally upregulated in migrants, while the foraging and single-minded genes were not differentially regulated. Many of the genes important for the monarch circadian clock mechanism (involved in sun compass orientation) were in the EST resource, including the newly identified cryptochrome 2. The EST database also revealed a novel Na+/K+ ATPase allele predicted to be more resistant to the toxic effects of milkweed than that reported previously. Potential genetic markers were identified from 3,486 EST contigs and included 1599 double-hit single nucleotide polymorphisms (SNPs) and 98 microsatellite polymorphisms. These data provide a template of the brain transcriptome for the monarch butterfly. Our “snap-shot” analysis of the differential regulation of candidate genes between summer and migratory butterflies suggests that unbiased, comprehensive transcriptional profiling will inform the molecular basis of migration. The identified SNPs and microsatellite polymorphisms can be used as genetic markers to address questions of population and subspecies structure

Newborn Sequencing in Genomic Medicine and Public Health

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening