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Abstract Genetic and environmental variation are key contributors during organism development, but the influence of minor perturbations or noise is difficult to assess. This study focuses on the stochastic variation in allele-specific expression that persists through cell divisions in the nine-banded armadillo (Dasypus novemcinctus). We investigated the blood transcriptome of five wild monozygotic quadruplets over time to explore the influence of developmental stochasticity on gene expression. We identify an enduring signal of autosomal allelic variability that distinguishes individuals within a quadruplet despite their genetic similarity. This stochastic allelic variation, akin to X-inactivation but broader, provides insight into non-genetic influences on phenotype. The presence of stochastically canalized allelic signatures represents a novel axis for characterizing organismal variability, complementing traditional approaches based on genetic and environmental factors. We also developed a model to explain the inconsistent penetrance associated with these stochastically canalized allelic expressions. By elucidating mechanisms underlying the persistence of allele-specific expression, we enhance understanding of development’s role in shaping organismal diversity.

Abstract Background Dose-limiting toxicities significantly impact the benefit/risk profile of many drugs. Whole genome sequencing (WGS) in patients receiving drugs with dose-limiting toxicities can identify therapeutic hypotheses to prevent these toxicities. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting neurological toxicity of chemotherapies with no effective approach for prevention. Methods We conducted a genetic study of time-to-first peripheral neuropathy event using 30× germline WGS data from whole blood samples from 4900 European-ancestry cancer patients in 14 randomized controlled trials. A substantial number of patients in these trials received taxane and platinum-based chemotherapies as part of their treatment regimen, either standard of care or in combination with the PD-L1 inhibitor atezolizumab. The trials spanned several cancers including renal cell carcinoma, triple negative breast cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, ovarian cancer, and melanoma. Results We identified a locus consisting of low-frequency variants in intron 13 of GRID2 associated with time-to-onset of first peripheral neuropathy (PN) indexed by rs17020773 (p = 2.03 × 10−8, all patients, p = 6.36 × 10−9, taxane treated). Gene-level burden analysis identified rare coding variants associated with increased PN risk in the C-terminus of GPR68 (p = 1.59 × 10−6, all patients, p = 3.47 × 10−8, taxane treated), a pH-sensitive G-protein coupled receptor (GPCR). The variants driving this signal were found to alter predicted arrestin binding motifs in the C-terminus of GPR68. Analysis of snRNA-seq from human dorsal root ganglia (DRG) indicated that expression of GPR68 was highest in mechano-thermo-sensitive nociceptors. Conclusions Our genetic study provides insight into the impact of low-frequency and rare coding genetic variation on PN risk and suggests that further study of GPR68 in sensory neurons may yield a therapeutic hypothesis for prevention of CIPN.

Single cell RNA-sequencing analysis poses challenges in replication due to technical biases and analytic variability among bioinformatics pipelines. Here, Crow et al develop MetaNeighbor for measuring cell-type replication across datasets, and use it to identify marker genes for neuron subtypes with evidence of replication.

Chronic pain is a common and devastating condition that induces well-characterized changes in neurons and microglia. One major unanswered question is why these changes should persist long after the precipitating injury has healed. Here, we suggest that some of the longer-lasting consequences of nerve injury may be hidden in the epigenome. Cell sorting and sequencing techniques were used to characterize the spinal cord immune response in a mouse model of chronic neuropathic pain. Infiltration of peripheral myeloid cells was found to be absent, and RNA sequencing (RNA-seq) of central microglia revealed transient gene expression changes in response to nerve ligation. Conversely, examination of microglial enhancers revealed persistent, post-injury alterations in close proximity to transcriptionally regulated genes. Enhancers are regions of open chromatin that define a cell’s transcription factor binding profile. We hypothesize that changes at enhancers may constitute a mechanism by which painful experiences are recorded at a molecular level.

Research has indicated that an increasing number of college students work at least part-time, which is particularly true of community college students (Velez et al., 2018). Although balancing school and work is a challenge, adding parenthood creates a major opportunity for conflict for the 22% of undergraduate students who are also parents, nearly half of whom attend community college (Cruse et al., 2019). For the present research, we investigated the differences between working student parents and working students on academic and work-related variables. We surveyed 145 working students, with 30.30% parents, at a Midwest community college and assessed grade point average, family-school conflict, school-family conflict, continuance commitment, job involvement, job performance, and organizational citizenship behaviors. Using independent-groups t tests, we found significantly higher family-school conflict, t(143) = 3.36, p = .001, d = 0.60, school-family conflict, t(143) = 4.81, p < .001, d = 0.92, and continuance commitment, t(143) = 2.41, p = .017, d = 0.43 for working student parents compared to working students. However, analysis of covariance results demonstrated there was no longer a statistical difference in continuance commitment when controlling for age, F(1, 142) = 0.14, p = .706, X² = .001. These results signal both a burden for working student parents and a vital opportunity for employers and colleges to intervene. [ABSTRACT FROM AUTHOR]

PURPOSE:In response to limited physician adoption of various healthcare initiatives, we sought to propose and assess a novel approach to policy development where one first characterizes diverse physician groups' common interests, using a medical student and constructivist grounded theory. METHODS:In 6 months, a medical student completed 36 semi-structured interviews with interventional radiologists, gynecologists, and vascular surgeons that were systematically analyzed according to constructivist grounded theory to identifying common themes. Common drivers of clinical decision making and professional values across 3 distinct specialty groups were derived from physicians' descriptions of their clinical decision making, stories, and concerns. RESULTS:Common drivers of clinical decision making included patient preference/benefit, experience, reimbursement, busyness/volume, and referral networks. Common values included honesty, trustworthiness, loyalty, humble service, compassion and perseverance, and practical wisdom. Although personal gains were perceived as important interests, such values were easily sacrificed for the good of patients or other non-financial interests. This balance was largely dependent on the incentives and security provided by physicians' environments. CONCLUSIONS:Using a medical student interviewer and constructivist grounded theory is a feasible means of collecting rich qualitative data to guide policy development. Healthcare administrators and medical educators should consider incorporating this methodology early in policy development to anticipate how value differences between physician groups will influence their acceptance of policies and other broad healthcare initiatives.

The Iambic-Trochaic Law (Bolton, 1894; Hayes, 1995; Woodrow, 1909) asserts that listeners associate greater intensity with group beginnings (a loud-first preference) and greater duration with group endings (a long-last preference). Hayes (1987; 1995) posits a natural connection between the prominences referred to in the ITL and the locations of stressed syllables in feet. However, not all lengthening in final positions originates with stressed syllables, and greater duration may also be associated with stress in nonfinal (trochaic) positions. The research described here challenged the notion that presumptive long-last effects necessarily reflect stress-related duration patterns, and investigated the general hypothesis that the robustness of long-last effects should vary depending on the strength of the association between final positions and increased duration, whatever its source. Two ITL studies were conducted in which native speakers of Spanish and of English grouped streams of rhythmically alternating syllables in which vowel intensity and/or duration levels were varied. These languages were chosen because while they are prosodically similar, increased duration on constituent-final syllables is both more common and more salient in English than Spanish. Outcomes revealed robust loud-first effects in both language groups. Long-last effects were significantly weaker in the Spanish group when vowel duration was varied singly. However, long-last effects were present and comparable in both language groups when intensity and duration were covaried. Intensity was a more robust predictor of responses than duration. A primary conclusion was that whether or not humans’ rhythmic grouping preferences have an innate component, duration-based grouping preferences, at least, and the magnitude of intensity-based effects are shaped by listeners’ backgrounds.

RSV is a common illness among young children that causes significant morbidity and health care costs.Routinely collected health administrative data can be used to track disease incidence, explore risk factors and conduct health services research. Due to potential for misclassification bias, the accuracy of data-elements should be validated prior to use. The objectives of this study were to validate an algorithm to accurately identify pediatric cases of hospitalized respiratory syncytial virus (RSV) from within Ontario's health administrative data, estimate annual incidence of hospitalization due to RSV and report the prevalence of major risk factors within hospitalized patients.A retrospective chart review was performed to establish a reference-standard cohort of children from the Ottawa region admitted to the Children's Hospital of Eastern Ontario (CHEO) for RSV-related disease in 2010 and 2011. Chart review data was linked to Ontario's administrative data and used to evaluate the diagnostic accuracy of algorithms of RSV-related ICD-10 codes within provincial hospitalization and emergency department databases. Age- and sex-standardized incidence was calculated over time, with trends in incidence assessed using Poisson regression.From a total of 1411 admissions, chart review identified 327 children hospitalized for laboratory confirmed RSV-related disease. Following linkage to administrative data and restriction to first admissions, there were 289 RSV patients in the reference-standard cohort. The best algorithm, based on hospitalization data, resulted in sensitivity 97.9% (95%CI: 95.5-99.2%), specificity 99.6% (95%CI: 98.2-99.8%), PPV 96.9% (95%CI: 94.2-98.6%), NPV 99.4% (95%CI: 99.4-99.9%). Incidence of hospitalized RSV in Ontario from 2005-2012 was 10.2 per 1000 children under 1 year and 4.8 per 1000 children aged 1 to 3 years. During the surveillance period, there was no identifiable increasing or decreasing linear trend in the incidence of hospitalized RSV, hospital length of stay and PICU admission rates. Among the Ontario RSV cohort, 16.3% had one or more major risk factors, with a decreasing trend observed over time.Children hospitalized for RSV-related disease can be accurately identified within population-based health administrative data. RSV is a major public health concern and incidence has not changed over time, suggesting a lack of progress in prevention.

Este trabalho visa a demonstrar um processo de mudança fonológica incomum e suas implicações para uma teoria de mudança lingüística como aquela proposta por Labov (1994). Concretamente, o artigo descreve a mudança diacrônica que se deu no Sirionó e no Bïa-yë, duas línguas Tupí-Guaraní faladas na região oriental da Bolívia. Em Bïa-yë as vogais *ɨ, *i, e suas contrapartes nasais, * ɨ̃ e * ĩ do Proto-Tupí, fundiram-se nas vogais / i / e / ĩ /, respetivamente. Em Sirionó, porém, a anteriorização das proto-vogais * ɨ̃ e *ɨmotivou o recuo das vogais *i, * ĩ ou seja, essas vogais intercambiram suas posições originárias.