Missed Cystic Fibrosis Newborn Screening Cases due to Immunoreactive Trypsinogen Levels below Program Cutoffs: A National Survey of Risk Factors.

Testing immunoreactive trypsinogen (IRT) is the first step in cystic fibrosis (CF) newborn screening. While high IRT is associated with CF, some cases are missed. This survey aimed to find factors associated with missed CF cases due to IRT levels below program cutoffs. Twenty-nine states responded to a U.S-wide survey and 13 supplied program-related data for low IRT false screen negative cases (CFFN) and CF true screen positive cases (CFTP) for analysis. Rates of missed CF cases and odds ratios were derived for each factor in CFFNs, and two CFFN subgroups, IRT above ("high") and below ("low") the CFFN median (39 ng/mL) compared to CFTPs for this entire sample set. Factors associated with "high" CFFN subgroup were Black race, higher IRT cutoff, fixed IRT cutoff, genotypes without two known CF-causing variants, and meconium ileus. Factors associated with "low" CFFN subgroup were older age at specimen collection, Saturday birth, hotter season of newborn dried blood spot collection, maximum ≥ 3 days laboratories could be closed, preterm birth, and formula feeding newborns. Lowering IRT cutoffs may reduce "high" IRT CFFNs. Addressing hospital and laboratory factors (like training staff in collection of blood spots, using insulated containers during transport and reducing consecutive days screening laboratories are closed) may reduce "low" IRT CFFNs.

Ancient marine sediment DNA reveals diatom transition in Antarctica.

Antarctica is one of the most vulnerable regions to climate change on Earth and studying the past and present responses of this polar marine ecosystem to environmental change is a matter of urgency. Sedimentary ancient DNA (sedaDNA) analysis can provide such insights into past ecosystem-wide changes. Here we present authenticated (through extensive contamination control and sedaDNA damage analysis) metagenomic marine eukaryote sedaDNA from the Scotia Sea region acquired during IODP Expedition 382. We also provide a marine eukaryote sedaDNA record of ~1 Mio. years and diatom and chlorophyte sedaDNA dating back to ~540 ka (using taxonomic marker genes SSU, LSU, psbO). We find evidence of warm phases being associated with high relative diatom abundance, and a marked transition from diatoms comprising <10% of all eukaryotes prior to ~14.5 ka, to ~50% after this time, i.e., following Meltwater Pulse 1A, alongside a composition change from sea-ice to open-ocean species. Our study demonstrates that sedaDNA tools can be expanded to hundreds of thousands of years, opening the pathway to the study of ecosystem-wide marine shifts and paleo-productivity phases throughout multiple glacial-interglacial cycles.

Episodes of Early Pleistocene West Antarctic Ice Sheet Retreat Recorded by Iceberg Alley Sediments.

Ice loss in the Southern Hemisphere has been greatest over the past 30 years in West Antarctica. The high sensitivity of this region to climate change has motivated geologists to examine marine sedimentary records for evidence of past episodes of West Antarctic Ice Sheet (WAIS) instability. Sediments accumulating in the Scotia Sea are useful to examine for this purpose because they receive iceberg-rafted debris (IBRD) sourced from the Pacific- and Atlantic-facing sectors of West Antarctica. Here we report on the sedimentology and provenance of the oldest of three cm-scale coarse-grained layers recovered from this sea at International Ocean Discovery Program Site U1538. These layers are preserved in opal-rich sediments deposited ∼1.2 Ma during a relatively warm regional climate. Our microCT-based analysis of the layer's in-situ fabric confirms its ice-rafted origin. We further infer that it is the product of an intense but short-lived episode of IBRD deposition. Based on the petrography of its sand fraction and the Phanerozoic 40Ar/39Ar ages of hornblende and mica it contains, we conclude that the IBRD it contains was likely sourced from the Weddell Sea and/or Amundsen Sea embayment(s) of West Antarctica. We attribute the high concentrations of IBRD in these layers to "dirty" icebergs calved from the WAIS following its retreat inland from its modern grounding line. These layers also sit at the top of a ∼366-m thick Pliocene and early Pleistocene sequence that is much more dropstone-rich than its overlying sediments. We speculate this fact may reflect that WAIS mass-balance was highly dynamic during the ∼41-kyr (inter)glacial world.

Antiphased dust deposition and productivity in the Antarctic Zone over 1.5 million years.

The Southern Ocean paleoceanography provides key insights into how iron fertilization and oceanic productivity developed through Pleistocene ice-ages and their role in influencing the carbon cycle. We report a high-resolution record of dust deposition and ocean productivity for the Antarctic Zone, close to the main dust source, Patagonia. Our deep-ocean records cover the last 1.5 Ma, thus doubling that from Antarctic ice-cores. We find a 5 to 15-fold increase in dust deposition during glacials and a 2 to 5-fold increase in biogenic silica deposition, reflecting higher ocean productivity during interglacials. This antiphasing persisted throughout the last 25 glacial cycles. Dust deposition became more pronounced across the Mid-Pleistocene Transition (MPT) in the Southern Hemisphere, with an abrupt shift suggesting more severe glaciations since ~0.9 Ma. Productivity was intermediate pre-MPT, lowest during the MPT and highest since 0.4 Ma. Generally, glacials experienced extended sea-ice cover, reduced bottom-water export and Weddell Gyre dynamics, which helped lower atmospheric CO2 levels.

Epigenetic targeting of Waldenström macroglobulinemia cells with BET inhibitors synergizes with BCL2 or histone deacetylase inhibition.

Aim: Waldenström macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by overproduction of monoclonal IgM. To date, there are no therapies that provide a cure for WM patients, and therefore, it is important to explore new therapies. Little is known about the efficiency of epigenetic targeting in WM. Materials & methods: WM cells were treated with BET inhibitors (JQ1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. Results: BET inhibition reduces growth of WM cells, with little effect on survival. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. Conclusion: Our studies identify BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition.

The association between newborn screening analytes as measured on a second screen and childhood autism in a Texas Medicaid population.

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case-control study examined data on 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Subjects were linked to their 2007-2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain.

The association between newborn screening analytes and childhood autism in a Texas Medicaid population, 2010-2012.

Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. It is commonly diagnosed at 3 or 4 years of age. We explored whether there was an association of any analytes measured by newborn screening tests with a later diagnosis of ASD. A database was compiled of 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Two controls (without any ASD diagnosis) were matched to each case by infant sex and birth year/month. All study subjects were linked to their 2007-2009 birth and newborn screening laboratory records, including values for 36 analytes or analyte ratios. We examined the association of analytes/ratios with a later diagnosis of ASD. Among 3,258 cases and 6,838 controls, seven analytes (e.g., 17-hydroxyprogesterone, acylcarnitines) were associated with a later ASD diagnosis. In this exploratory study, an ASD diagnosis was associated with 7 of 36 newborn screening analytes/ratios. These findings should be replicated in other population-based datasets.

The Holocene retreat dynamics and stability of Petermann Glacier in northwest Greenland.

Submarine glacial landforms in fjords are imprints of the dynamic behaviour of marine-terminating glaciers and are informative about their most recent retreat phase. Here we use detailed multibeam bathymetry to map glacial landforms in Petermann Fjord and Nares Strait, northwestern Greenland. A large grounding-zone wedge (GZW) demonstrates that Petermann Glacier stabilised at the fjord mouth for a considerable time, likely buttressed by an ice shelf. This stability was followed by successive backstepping of the ice margin down the GZW's retrograde backslope forming small retreat ridges to 680 m current depth (∼730-800 m palaeodepth). Iceberg ploughmarks occurring somewhat deeper show that thick, grounded ice persisted to these water depths before final breakup occurred. The palaeodepth limit of the recessional moraines is consistent with final collapse driven by marine ice cliff instability (MICI) with retreat to the next stable position located underneath the present Petermann ice tongue, where the seafloor is unmapped.

Preferences for self-management support: findings from a survey of diabetes patients in safety-net health systems.

OBJECTIVE: We sought to identify interest in different modes of self-management support among diabetes patients cared for in public hospitals, and to assess whether demographic or disease-specific factors were associated with patient preferences. We explored the possible role of a perceived communication need in influencing interest in self-management support. METHODS: Telephone survey of a random sample of 796 English and Spanish-speaking diabetes patients (response rate 47%) recruited from four urban US public hospital systems. In multivariate models, we measured the association of race/ethnicity, primary language, self-reported health literacy, self-efficacy, and diabetes-related factors on patients' interest in three self-management support strategies (telephone support, group medical visits, and Internet-based support). We explored the extent to which patients believed that better communication with providers would improve their diabetes control, and whether this perception altered the relationship between patient factors and self-management support acceptance. RESULTS: Sixty-nine percent of respondents reported interest in telephone support, 55% in group medical visits, and 42% in Internet. Compared to Non-Hispanic Whites, Spanish-speaking Hispanics were more interested in telephone support (OR 3.45, 95% CI 1.97-6.05) and group medical visits (OR 2.45, 95% CI 1.49-4.02), but less interested in Internet self-management support (OR 0.56, 95% CI 0.33-0.93). African-Americans were more interested than Whites in all three self-management support strategies. Patients with limited self-reported health literacy were more likely to be interested in telephone support than those not reporting literacy deficits. Forty percent reported that their diabetes would be better controlled if they communicated better with their health care provider. This perceived communication benefit was independently associated with interest in self-management support (p<0.001), but its inclusion in models did not alter the strengths of the main associations between patient characteristics and self-management support preferences. CONCLUSION: Many diabetes patients in safety-net settings report an interest in receiving self-management support, but preferences for modes of delivery of self-management support vary by race/ethnicity, language proficiency, and self-reported health literacy. PRACTICE IMPLICATIONS: Public health systems should consider offering a range of self-management support services to meet the needs of their diverse patient populations. More broad dissemination and implementation of self-management support may help address the unmet need for better provider communication among diabetes patients in these settings.