Development and preliminary testing of the psychosocial adjustment to hereditary diseases scale

Background: The presence of Lynch syndrome (LS) can bring a lifetime of uncertainty to an entire family as members adjust to living with a high lifetime cancer risk. The research base on how individuals and families adjust to genetic-linked diseases following predictive genetic testing has increased our understanding of short-term impacts but gaps continue to exist in knowledge of important factors that facilitate or impede long-term adjustment. The failure of existing scales to detect psychosocial adjustment challenges in this population has led researchers to question the adequate sensitivity of these instruments. Furthermore, we have limited insight into the role of the family in promoting adjustment. Methods: The purpose of this study was to develop and initially validate the Psychosocial Adjustment to Hereditary Diseases (PAHD) scale. This scale consists of two subscales, the Burden of Knowing (BK) and Family Connectedness (FC). Items for the two subscales were generated from a qualitative data base and tested in a sample of 243 participants from families with LS. Results: The Multitrait/Multi-Item Analysis Program-Revised (MAP-R) was used to evaluate the psychometric properties of the PAHD. The findings support the convergent and discriminant validity of the subscales. Construct validity was confirmed by factor analysis and Cronbach’s alpha supported a strong internal consistency for BK (0.83) and FC (0.84). Conclusion: Preliminary testing suggests that the PAHD is a psychometrically sound scale capable of assessing psychosocial adjustment. We conclude that the PAHD may be a valuable monitoring tool to identify individuals and families who may require therapeutic interventions

Rapid range expansion in the Great Plains narrow-mouthed toad (Gastrophryne olivacea) and a revised taxonomy for North American microhylids

We investigated genetic variation within the Great Plains narrow-mouthed toad, Gastrophryne olivacea, across its geographic range in the United States and Mexico. An analysis of mitochondrial DNA (mtDNA) from 105 frogs revealed remarkably low levels of genetic diversity in individuals inhabiting the central United States and northern Mexico. We found that this widespread matrilineal lineage is divergent (ca. 2% in mtDNA) from haplotypes that originate from the western United States and western coast of Mexico. Using a dataset that included all five species of Gastrophryne and both species of the closely related genus Hypopachus, we investigated the phylogenetic placement of G. olivacea. This analysis recovered strong support that G. olivacea, the tropically distributed G. elegans, and the temperately distributed G. carolinensisconstitute a monophyletic assemblage. However, the placement of G. pictiventris and G. usta render Gastrophryne paraphyletic with respect to Hypopachus. To complement our mitochondrial analysis, we examined a small fragment of nuclear DNA and recovered consistent patterns. In light of our findings we recommend (1) the resurrection of the nomen G. mazatlanensis Taylor (1943) for the disjunct western clade of G. olivaceaand (2) the tentative placement of G. pictiventris and G. usta in Hypopachus. To explore possible scenarios leading to low levels of genetic diversity in G. olivacea, we used mismatch distributions and Bayesian Skyline plots to examine historic population expansion and demography. Collectively these analyses suggest that G. olivacea rapidly expanded in effective population size and geographic range during the late Pleistocene or early Holocene. This hypothesis is consistent with fossil data from northern localities and contemporary observations that suggest ongoing northern expansion. Given our findings, we suspect that the rapid range expansion of G. olivacea may have been facilitated by ecological associations with open habitats and seasonal water bodies

Specific Etiologies Associated With the Multiple Organ Dysfunction Syndrome in Children: Part 2

To describe a number of conditions and therapies associated with multiple organ dysfunction syndrome (MODS) presented as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development MODS Workshop (March 26–27, 2015). In addition, the relationship between burn injuries and MODS is also included although it was not discussed at the Workshop

Sodium/Hydrogen Exchanger Gene Defect in Slow-Wave Epilepsy Mutant Mice

AbstractThe “housekeeping” sodium/hydrogen exchanger, NHE1, mediates the electroneutral 1:1 exchange of Na+ and H+ across the plasma membrane. NHE1 is ubiquitous and is studied extensively for regulation of pH i, cell volume, and response to growth factors. We describe a spontaneous mouse mutant, s low-w ave e pilepsy, (swe), with a neurological syndrome including ataxia and a unique epilepsy phenotype consisting of 3/sec absence and tonic-clonic seizures. swe was fine-mapped on Chromosome 4 and identified as a null allele of Nhe1. Mutants show selective neuronal death in the cerebellum and brainstem but otherwise are healthy. This first example of a disease-causing mutation in an Nhe gene provides a new tool for studying the delicate balance of neuroexcitability and cell survival within the CNS

Brief of Corporate Law Professors as Amici Curie in Support of Respondents

The Supreme Court has looked to the rights of corporate shareholders in determining the rights of union members and non-members to control political spending, and vice versa. The Court sometimes assumes that if shareholders disapprove of corporate political expression, they can easily sell their shares or exercise control over corporate spending. This assumption is mistaken. Because of how capital is saved and invested, most individual shareholders cannot obtain full information about corporate political activities, even after the fact, nor can they prevent their savings from being used to speak in ways with which they disagree. Individual shareholders have no “opt out” rights or practical ability to avoid subsidizing corporate political expression with which they disagree. Nor do individuals have the practical option to refrain from putting their savings into equity investments, as doing so would impose damaging economic penalties and ignore conventional financial guidance for individual investors

A probabilistic analysis of argument cogency

This paper offers a probabilistic treatment of the conditions for argument cogency as endorsed in informal logic: acceptability, relevance, and sufficiency. Treating a natural language argument as a reason-claim-complex, our analysis identifies content features of defeasible argument on which the RSA conditions depend, namely: change in the commitment to the reason, the reason’s sensitivity and selectivity to the claim, one’s prior commitment to the claim, and the contextually determined thresholds of acceptability for reasons and for claims. Results contrast with, and may indeed serve to correct, the informal understanding and applications of the RSA criteria concerning their conceptual dependence, their function as update-thresholds, and their status as obligatory rather than permissive norms, but also show how these formal and informal normative approachs can in fact align

Integrating services for HIV and multidrug-resistant tuberculosis: A global cross-sectional survey among ART clinics in low- and middle-income countries.

Tuberculosis (TB) is the leading cause of death among PLHIV and multidrug-resistant-TB (MDR-TB) is associated with high mortality. We examined the management for adult PLHIV coinfected with MDR-TB at ART clinics in lower income countries. Between 2019 and 2020, we conducted a cross-sectional survey at 29 ART clinics in high TB burden countries within the global IeDEA network. We used structured questionnaires to collect clinic-level data on the TB and HIV services and the availability of diagnostic tools and treatment for MDR-TB. Of 29 ART clinics, 25 (86%) were in urban areas and 19 (66%) were tertiary care clinics. Integrated HIV-TB services were reported at 25 (86%) ART clinics for pan-susceptible TB, and 14 (48%) clinics reported full MDR-TB services on-site, i.e. drug susceptibility testing [DST] and MDR-TB treatment. Some form of DST was available on-site at 22 (76%) clinics, while the remainder referred testing off-site. On-site DST for second-line drugs was available at 9 (31%) clinics. MDR-TB treatment was delivered on-site at 15 (52%) clinics, with 10 individualizing treatment based on DST results and five using standardized regimens alone. Bedaquiline was routinely available at 5 (17%) clinics and delamanid at 3 (10%) clinics. Although most ART clinics reported having integrated HIV and TB services, few had fully integrated MDR-TB services. There is a continued need for increased access to diagnostic and treatment options for MDR-TB patients and better integration of MDR-TB services into the HIV care continuum

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Supreme Court Amicus Brief of 19 Corporate Law Professors, Friedrichs v. California Teachers Association, No. 14-915

The Supreme Court has looked to the rights of corporate shareholders in determining the rights of union members and non-members to control political spending, and vice versa. The Court sometimes assumes that if shareholders disapprove of corporate political expression, they can easily sell their shares or exercise control over corporate spending. This assumption is mistaken. Because of how capital is saved and invested, most individual shareholders cannot obtain full information about corporate political activities, even after the fact, nor can they prevent their savings from being used to speak in ways with which they disagree. Individual shareholders have no “opt out” rights or practical ability to avoid subsidizing corporate political expression with which they disagree. Nor do individuals have the practical option to refrain from putting their savings into equity investments, as doing so would impose damaging economic penalties and ignore conventional financial guidance for individual investors