Expression levels of core spliceosomal proteins modulate the MBNL-mediated spliceopathy in DM1.

Myotonic dystrophy type 1 (DM1) is a heterogeneous multisystemic disease caused by a CTG repeat expansion in DMPK. Transcription of the expanded allele produces toxic CUG repeat RNA that sequesters the MBNL family of alternative splicing (AS) regulators into ribonuclear foci, leading to pathogenic mis-splicing. To identify genetic modifiers of toxic CUG RNA levels and the spliceopathy, we performed a genome-scale siRNA screen using an established HeLa DM1 repeat-selective screening platform. We unexpectedly identified core spliceosomal proteins as a new class of modifiers that rescue the spliceopathy in DM1. Modest knockdown of one of our top hits, SNRPD2, in DM1 fibroblasts and myoblasts, significantly reduces DMPK expression and partially rescues MBNL-regulated AS dysfunction. While the focus on the DM1 spliceopathy has centered around the MBNL proteins, our work reveals an unappreciated role for MBNL:spliceosomal protein stoichiometry in modulating the spliceopathy, revealing new biological and therapeutic avenues for DM1.

What factors are associated with infant hearing aid use? A parent survey using the Theoretical Domains Framework.

OBJECTIVE: Hearing aid use is lowest in 0-3-year-olds with hearing loss, placing spoken language development at risk. Existing interventions lack effectiveness and are typically not based on a theoretically driven, comprehensive understanding of the factors influencing infant hearing aid use. The present study is the first to address this gap in understanding. DESIGN AND STUDY SAMPLE: A 55-item online survey based on the Theoretical Domains Framework (TDF) was completed by 56 parents of 0-3-year-old hearing aid users. RESULTS: Participants reported a wide range of barriers across TDF domains, which were associated with parent-reported hearing aid use and more pronounced in parents of lower hearing aid users. The most strongly reported domains across participants were "emotion" (e.g. feelings of worry when using hearing aids), "beliefs about capabilities" (e.g. belief in ability to use hearing aids consistently), and "environmental context and resources" (e.g. child removing hearing aids). CONCLUSIONS: Parents report a wider range of barriers to infant hearing aid use than existing investigations suggest and current interventions address. Interventions would benefit from: (i) targeting a wider range of TDF domains in their design; and (ii) implementing the present TDF survey to identify and target family-specific barriers to infant hearing aid use.

Forensic Assessments of Racial-Ethnic Differences in Genuine and Malingered Psychotic Presentations.

Competent forensic practice has required continued training and professional practice in differentiating between genuine and malingered presentations, especially within the spectrum of psychotic disorders. Historically, practitioners valued racial, ethnic, and cultural differences but often considered them as peripheral matters. In contemporary forensic practice, however, language and culture play preponderant roles. This commentary is focused on core features of malingering via a cultural lens. Three core, race-informed principles, such as biases against the African American Language, are highlighted and discussed. Related subjects for forensic practice include relevant clinical constructs such as malingering bias and "imposed etics," specifically, the imposition of mainstream values and discounting of cultural differences.

First documented movement of a humpback whale between the Cape Verde Islands and West Greenland.

The endangered population of humpback whales (Megaptera novaeangliae) breeding and calving off the Cape Verde Islands (CVI) are known to migrate to feeding areas located along the eastern margin of the North Atlantic Ocean (Iceland, and Norway). Here, we report for the first time a confirmed migration of an individual humpback whale from CVI breeding ground to a western North Atlantic feeding ground of West Greenland. This individual humpback, which was photographed and identified off the coast of West Greenland in 2021, was previously documented in CVI 22 years before (1999). An annual subsistence hunt for humpbacks occurs in West Greenland and the resighting at this location with a humpback whale from CVI has strong implications for the conservation efforts of the small CVI population.

Trends in hospital admissions and mortality among inflammatory bowel disease patients with substance use disorder: a 10-year United States nationwide analysis.

Background: Patients with inflammatory bowel disease (IBD) and substance use disorder (SUD) may have worse clinical outcomes. However, data specific to the hospital admission and mortality rates among IBD patients with SUD are scarce. Our objective was to assess trends in admission, healthcare expenses, and mortality for IBD patients with SUD. Methods: We conducted a retrospective study using the National Inpatient Sample database to analyze SUD (alcohol, opioids, cocaine, and cannabis) among IBD hospitalizations from 2009 to 2019. Results: A total of 132,894 hospitalizations for IBD had a secondary diagnosis of SUD. Of these patients, 75,172 (57%) were men and 57,696 (43%) were women. The IBD-SUD cohort had a longer length of stay than the non-SUD cohort (P < 0.001). The mean inpatient charges for IBD hospitalizations with SUD increased from $48,699 ± $1374 in 2009 to $62,672 ± $1528 in 2019 (P < 0.001). We found a 159.5% increase in IBD hospitalizations with SUD. The hospitalization rate increased from 3492 per 100,000 IBD hospitalizations in 2009 to 9063 per 100,000 in 2019 (P < 0.001). In-hospital mortality for IBD hospitalizations with SUD increased by 129.6% (from 250 deaths per 100,000 IBD hospitalizations in 2009 to 574 deaths per 100,000 IBD hospitalizations in 2019) (P < 0.001). Conclusions: Over the last decade, there has been a rise in IBD hospitalizations with SUD. This has resulted in a longer length of stay, higher inpatient charges, and higher mortality rates. Identifying IBD patients potentially at risk for SUD by screening for anxiety, depression, pain, or other factors has become crucial.

Disease-associated inosine misincorporation into RNA hinders translation.

Failure to prevent accumulation of the non-canonical nucleotide inosine triphosphate (ITP) by inosine triphosphate pyrophosphatase (ITPase) during nucleotide synthesis results in misincorporation of inosine into RNA and can cause severe and fatal developmental anomalies in humans. While the biochemical activity of ITPase is well understood, the pathogenic basis of ITPase deficiency and the molecular and cellular consequences of ITP misincorporation into RNA remain cryptic. Here, we demonstrate that excess ITP in the nucleotide pool during in vitro transcription results in T7 polymerase-mediated inosine misincorporation in luciferase RNA. In vitro translation of inosine-containing luciferase RNA reduces resulting luciferase activity, which is only partly explained by reduced abundance of the luciferase protein produced. Using Oxford Nanopore Direct RNA sequencing, we reveal inosine misincorporation to be stochastic but biased largely towards misincorporation in place of guanosine, with evidence for misincorporation also in place of cytidine, adenosine and uridine. Inosine misincorporation into RNA is also detected in Itpa-null mouse embryonic heart tissue as an increase in relative variants compared with the wild type using Illumina RNA sequencing. By generating CRISPR/Cas9 rat H9c2 Itpa-null cardiomyoblast cells, we validate a translation defect in cells that accumulate inosine within endogenous RNA. Furthermore, we observe hindered cellular translation of transfected luciferase RNA containing misincorporated inosine in both wild-type and Itpa-null cells. We therefore conclude that inosine misincorporation into RNA perturbs translation, thus providing mechanistic insight linking ITPase deficiency, inosine accumulation and pathogenesis.

Health Insurance Status as a Predictor of Mode of Colon Cancer Detection but Not Stage at Diagnosis: Implications for Early Detection.

OBJECTIVE: For colon cancer patients, one goal of health insurance is to improve access to screening that leads to early detection, early-stage diagnosis, and polyp removal, all of which results in easier treatment and better outcomes. We examined associations among health insurance status, mode of detection (screen detection vs symptomatic presentation), and stage at diagnosis (early vs late) in a diverse sample of patients recently diagnosed with colon cancer from the Chicago metropolitan area. METHODS: Data came from the Colon Cancer Patterns of Care in Chicago study of racial and socioeconomic disparities in colon cancer screening, diagnosis, and care. We collected data from the medical records of non-Hispanic Black and non-Hispanic White patients aged ≥50 and diagnosed with colon cancer from October 2010 through January 2014 (N = 348). We used logistic regression with marginal standardization to model associations between health insurance status and study outcomes. RESULTS: After adjusting for age, race, sex, and socioeconomic status, being continuously insured 5 years before diagnosis and through diagnosis was associated with a 20 (95% CI, 8-33) percentage-point increase in prevalence of screen detection. Screen detection in turn was associated with a 15 (95% CI, 3-27) percentage-point increase in early-stage diagnosis; however, nearly half (47%; n = 54) of the 114 screen-detected patients were still diagnosed at late stage (stage 3 or 4). Health insurance status was not associated with earlier stage at diagnosis. CONCLUSIONS: For health insurance to effectively shift stage at diagnosis, stronger associations are needed between health insurance and screening-related detection; between screening-related detection and early stage at diagnosis; or both. Findings also highlight the need to better understand factors contributing to late-stage colon cancer diagnosis despite screen detection.

Approaches for Disseminating Environmental Research Findings to Navajo Communities.

We report the use of three different dissemination approaches for providing environmental research results back to Navajo communities from different research projects. The objectives of the dissemination are to provide the results to the community, have a dialogue about the results, and learn more about the environmental concerns of the community for potential future research projects. The first approach utilizes radio announcements and flyers provided to the community announcing dissemination meetings specific to the research projects. The second approach is more collaborative, working with a grassroots organization to organize report-back meetings, as well as one-on-one discussions of the research project. The third approach involves the development of a booklet for distribution to communities along with an oral presentation at the regularly scheduled monthly community meetings to discuss the information. Overall, the second and third approaches are more effective than the first approach in terms of dissemination to a larger number of community members, as well as increased dialogue between the researchers and the communities.

Assessing temperature-dependent competition between two invasive mosquito species.

Invasive mosquitoes are expanding their ranges into new geographic areas and interacting with resident mosquito species. Understanding how novel interactions can affect mosquito population dynamics is necessary to predict transmission risk at invasion fronts. Mosquito life-history traits are extremely sensitive to temperature, and this can lead to temperature-dependent competition between competing invasive mosquito species. We explored temperature-dependent competition between Aedes aegypti and Anopheles stephensi, two invasive mosquito species whose distributions overlap in India, the Middle East, and North Africa, where An. stephensi is currently expanding into the endemic range of Ae. aegypti. We followed mosquito cohorts raised at different intraspecific and interspecific densities across five temperatures (16-32°C) to measure traits relevant for population growth and to estimate species' per capita growth rates. We then used these growth rates to derive each species' competitive ability at each temperature. We find strong evidence for asymmetric competition at all temperatures, with Ae. aegypti emerging as the dominant competitor. This was primarily because of differences in larval survival and development times across all temperatures that resulted in a higher estimated intrinsic growth rate and competitive tolerance estimate for Ae. aegypti compared to An. stephensi. The spread of An. stephensi into the African continent could lead to urban transmission of malaria, an otherwise rural disease, increasing the human population at risk and complicating malaria elimination efforts. Competition has resulted in habitat segregation of other invasive mosquito species, and our results suggest that it may play a role in determining the distribution of An. stephensi across its invasive range.