Return of genetic research results in 21,532 individuals with autism.

PURPOSE: The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK (SPARKforAutism.org): a large recontactable cohort of people with autism in the United States. We also describe the process to return these clinically confirmed genetic findings. METHODS: We present results from microarray genotyping and exome sequencing (ES) of 21,532 individuals with autism and 17,785 of their parents. We returned LP and P (American College of Medical genetics (ACMG) criteria) copy number variants (CNVs), chromosomal aneuploidies, and variants in genes with strong evidence of association with autism and intellectual disability. RESULTS: We identified 1903 'returnable' LP/P variants in 1861 individuals with autism (8.6%). 89.5% of these variants were not known to participants. The diagnostic genetic result was returned to 589 participants (53% of those contacted). Features associated with a higher probability of having a returnable result include cognitive and medically complex features, being female, being White (versus non-White) and being diagnosed more than 20 years ago. We also find results among autistics across the spectrum, as well as in transmitting parents with neuropsychiatric features but no autism diagnosis. CONCLUSION: SPARK offers an opportunity to assess returnable results among autistic people who have not been ascertained clinically. SPARK also provides practical experience returning genetic results for a behavioral condition at a large scale.

Novel Mediastinoscope-Assisted Minimally Invasive Esophagectomy for Esophageal Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Minimally invasive surgery is an expanding field of surgery that has replaced many open surgical techniques. Surgery remains a cornerstone in the treatment of esophageal cancer, yet it is still associated with significant morbidity and technical difficulties. Mediastinoscope-assisted esophagectomy is a promising technique that aims to decrease the surgical burden and enhance recovery. METHODS: PubMed, MEDLINE, and EMBASE databases were searched for publications on mediastinoscope-assisted esophagectomies for esophageal cancer. The primary endpoint was a postoperative anastomotic leak, while secondary endpoints were assessment of harvested lymph nodes (LNs), blood loss, chyle leak, hospital length of stay (LOS), operative (OR) time, pneumonia, wound infection, mortality, and microscopic positive margin (R1). The pooled event rate (PER) and pooled mean were calculated for binary and continuous outcomes respectively. RESULTS: Twenty-six out of the 2274 searched studies were included. The pooled event rate (PER) for anastomotic leak was 0.145 (0.1144; 0.1828). The PERs for chyle leak, recurrent laryngeal nerve injury/hoarseness, postoperative pneumonia, wound infection, early mortality, postoperative morbidity, and microscopically positive (R1) resection margins were 0.027, 0.185, 0.09, 0.083, 0.020, 0.378, and 0.037 respectively. The pooled means for blood loss, hospital stay, operative time, number of total harvested LNs, and number of harvested thoracic LNs were 159.209, 15.187, 311.116, 23.379, and 15.458 respectively. CONCLUSIONS: Mediastinoscopic esophagectomy is a promising minimally invasive technique, avoiding thoracotomy, patient repositioning, and lung manipulation; thus allowing for shorter surgery, decreased blood loss, and decreased postoperative morbidity. It can also be reliable in terms of oncological safety and LN dissection.

Telling a different story: Historiography, ethics, and possibility for nursing.

With this paper, I will interrogate some of the implications of nursing's dominant historiography, the history written by and about nursing, and its implications for nursing ethics as a praxis, invoking feminist philosopher Donna Haraway's mantra that 'it matters what stories make worlds, what worlds make stories.' First, I will describe what I have come to understand as the nursing imaginary, a shared consciousness constructed both by nurses from within and by those outside the discipline from without. This imaginary is fashioned in part by the histories nursing produces about the discipline, our historical ontology, which is demonstrative of our disciplinary values and the ethics we practice today. I assert that how we choose to constitute ourselves as a discipline is itself an ethical endeavour, bound up with how we choose to be and what we allow as knowledge in nursing. To animate this discussion, I will outline the received historiography of nursing and dwell in the possibilities of thinking about Kaiserswerth, the training school that prepared Nightingale for her exploits in Crimea and beyond. I will briefly consider the normative values that arise from this received history and consider the possibilities that these normative values foreclose upon. I then shift the frame and ask what might be possible if we centred Kaiserswerth's contested legacy as a training school for formerly incarcerated women, letting go of the sanitary and sanitised visions of nursing as Victorian angels in the hospital. Much energy over the past 250 years has been invested in the professionalisation and legitimation of nursing, predicated (at least in our shared imaginary) on the interventions of Florence Nightingale, but this is one possibility of many. I conclude with a speculative dream of the terrain opens up for nursing if we shed this politics and ethos of respectability and professionalism and instead embrace community, abolition and mutual aid as organising values for the discipline.

Nursing for the Chthulucene: Abolition, affirmation, antifascism.

Critical posthumanism as a philosophical, antifascist nonhierarchical imagination for nursing offers a liberatory passageway forward amidst environmental collapse, an epic pandemic, global authoritarianism, extreme health and wealth disparities, over-reliance on technology and empirics, and unjust societal systems based in whiteness. Drawing upon philosophical and theoretical works from Black and Indigenous scholars, Haraway's idea of the Chthulucene, Deleuze and Guattari's rhizomatic thought, and Kaba's abolitionist organizing among others, we as activist nurse scholars continue the speculative discussion outlined in prior papers. Here we further imagine how we can engage a radical philosophical mission of care for all beings human and non, walking and working alongside the people and communities nurses accompany, connected as we are on this dystopian celestial orb. Discussion is centred on critical analyses of traditional justice framing in nursing, and on the praxis possibilities found within rhizomatic thought, making kin, and just episteme while knitting filaments of nursing theory and history, humming song lyrics from collective memory, and critically dismantling received wisdoms to stumble toward a more emancipatory present future.

What nursing chooses not to know: Practices of epistemic silence/silencing.

Drawing from a keynote panel held at the hybrid 25th International Philosophy of Nursing Conference, this discussion paper examines the question of epistemic silence in nursing from five different perspectives. Contributors include US-based scholar Claire Valderama-Wallace, who meditated on ecosystems of settler colonial logics of nursing; American scholar Lucinda Canty discussed the epistemic silencing of nurses of colour; Canadian scholar Amelie Perron interrogated the use of disobedience and parrhesia in and for nursing; Canada-based scholar Ismalia De Sousa considered what nursing protects in its silences; and Australian scholar Janice Gullick spoke to trans invisibility in nursing.

Implementation of preemptive DNA sequence-based pharmacogenomics testing across a large academic medical center: The Mayo-Baylor RIGHT 10K Study.

PURPOSE: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping. METHODS: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 and HLA, affecting 21 drug-gene pairs, were deposited preemptively in the Mayo electronic health record. RESULTS: For the 13 pharmacogenes of interest, the genomes of 79% of participants carried clinically actionable variants in 3 or more genes, and DNA sequencing identified an average of 3.3 additional conservatively predicted deleterious variants that would not have been evident using genotyping. CONCLUSION: Implementation of preemptive rather than reactive and sequence-based rather than genotype-based PGx prescribing revealed nearly universal patient applicability and required integrated institution-wide resources to fully realize individualized drug therapy and to show more efficient use of health care resources.

Reduced representation sequencing to understand the evolutionary history of Torrey pine (Pinus torreyana parry) with implications for rare species conservation.

Understanding the contribution of neutral and adaptive evolutionary processes to population differentiation is often necessary for better informed management and conservation of rare species. In this study, we focused on Pinus torreyana Parry (Torrey pine), one of the world's rarest pines, endemic to one island and one mainland population in California. Small population size, low genetic diversity, and susceptibility to abiotic and biotic stresses suggest Torrey pine may benefit from interpopulation genetic rescue to preserve the species' evolutionary potential. We leveraged reduced representation sequencing to tease apart the respective contributions of stochastic and deterministic evolutionary processes to population differentiation. We applied these data to model spatial and temporal demographic changes in effective population sizes and genetic connectivity, to identify loci possibly under selection, and evaluate genetic rescue as a potential conservation strategy. Overall, we observed exceedingly low standing variation within both Torrey pine populations, reflecting consistently low effective population sizes across time, and limited genetic differentiation, suggesting maintenance of gene flow between populations following divergence. However, genome scans identified more than 2000 candidate SNPs potentially under divergent selection. Combined with previous observations indicating population phenotypic differentiation, this indicates natural selection has probably contributed to the evolution of population genetic differences. Thus, while reduced genetic diversity, small effective population size, and genetic connectivity between populations suggest genetic rescue could mitigate the adverse effects of rarity, evidence for adaptive differentiation suggests genetic mixing could disrupt adaptation. Further work evaluating the fitness consequences of inter-population admixture is necessary to empirically evaluate the trade-offs associated with genetic rescue in Torrey pine.

Adaptational lag to temperature in valley oak (Quercus lobata) can be mitigated by genome-informed assisted gene flow.

Climate change over the next century is predicted to cause widespread maladaptation in natural systems. This prediction, as well as many sustainable management and conservation practices, assumes that species are adapted to their current climate. However, this assumption is rarely tested. Using a large-scale common garden experiment combined with genome-wide sequencing, we found that valley oak (Quercus lobata), a foundational tree species in California ecosystems, showed a signature of adaptational lag to temperature, with fastest growth rates occurring at cooler temperatures than populations are currently experiencing. Future warming under realistic emissions scenarios was predicted to lead to further maladaptation to temperature and reduction in growth rates for valley oak. We then identified genotypes predicted to grow relatively fast under warmer temperatures and demonstrated that selecting seed sources based on their genotype has the potential to mitigate predicted negative consequences of future climate warming on growth rates in valley oak. These results illustrate that the belief of local adaptation underlying many management and conservation practices, such as using local seed sources for restoration, may not hold for some species. If contemporary adaptational lag is commonplace, we will need new approaches to help alleviate predicted negative consequences of climate warming on natural systems. We present one such approach, "genome-informed assisted gene flow," which optimally matches individuals to future climates based on genotype-phenotype-environment associations.

Skeptical Health Mavens May Limit COVID-19 Vaccine Diffusion: Using the Innovation Diffusion Cycle to Interpret Results of a Cross-sectional Survey among People Who are Socially Vulnerable.

We sought to identify barriers to COVID-19 vaccine uptake among persons who are socially vulnerable in light of the natural cycle of innovation diffusion. Widespread adoption of a health innovation requires a cadre of opinion leaders to build on successes experienced by early adopters. One type of opinion leader in healthcare are health mavens: members of a community who maintain up-to-date health knowledge and share their knowledge others. We surveyed 139 persons who are socially vulnerable regarding their COVID-19 vaccination intention, and evaluated their responses based on psychological traits captured by two scales: innovativeness and health mavenism. Health mavenism was not strongly correlated with COVID-19 vaccine intention. Health mavens often relied on their own healthcare providers (n = 46) and health agency websites (n = 42) for vaccine information. Those who relied on their faith leaders (n = 4) reported a lower likelihood of getting vaccinated (31.5% vs. 76.0%, p < .05). The observed lack of support by health mavens represents a critical barrier to COVID-19 vaccine uptake; targeting campaigns to health mavens may increase COVID-19 vaccine uptake in socially vulnerable communities.

SNPs in a Large Genomic Scaffold Are Strongly Associated with Cr1R, Major Gene for Resistance to White Pine Blister Rust in Range-Wide Samples of Sugar Pine (Pinus lambertiana).

Sugar pine, Pinus lambertiana Douglas, is a keystone species of montane forests from Baja California to southern Oregon. Like other North American white pines, populations of sugar pine have been greatly reduced by the disease white pine blister rust (WPBR) caused by a fungal pathogen, Cronartium ribicola, that was introduced into North America early in the twentieth century. Major gene resistance to WPBR segregating in natural populations has been documented in sugar pine. Indeed, the dominant resistance gene in this species, Cr1, was genetically mapped, although not precisely. Genomic single nucleotide polymorphisms (SNPs) placed in a large scaffold were reported to be associated with the allele for this major gene resistance (Cr1R). Forest restoration efforts often include sugar pine seed derived from the rare resistant individuals (typically Cr1R/Cr1r) identified through an expensive 2-year phenotypic testing program. To validate and geographically characterize the variation in this association and investigate its potential to expedite genetic improvement in forest restoration, we developed a simple PCR-based, diploid genotyping of DNA from needle tissue. By applying this to range-wide samples of susceptible and resistant (Cr1R) trees, we show that the SNPs exhibit a strong, though not complete, association with Cr1R. Paralleling earlier studies of the geographic distribution of Cr1R and the inferred demographic history of sugar pine, the resistance-associated SNPs are marginally more common in southern populations, as is the frequency of Cr1R. Although the strength of the association of the SNPs with Cr1R and thus, their predictive value, also varies with geography, the potential value of this new tool in quickly and efficiently identifying candidate WPBR-resistant seed trees is clear.

Maximizing the Potential of Mini-Grants to Promote Policy, Systems, and Environmental Changes: Outcomes and Challenges.

PURPOSE AND OBJECTIVES: This article describes the implementation and evaluation of a chronic disease mini-grant initiative, coordinated by a state health department in collaboration with multiple stakeholders. Braided funding from federal and state sources was used to build and implement the initiative. INTERVENTION APPROACH: Mini-grants, facilitated by five different facilitating organizations, were funded to promote implementation of policy, systems, and environmental (PSE) changes at the local level. Grant recipients represented a variety of sectors, including education, government, and nonprofit organizations. EVALUATION METHODS: Primary (surveys) and secondary (final reports) data documented achievement of PSE changes. RESULTS: A total of $196,369 was dispersed to 65 organizations; 126 PSE changes in the areas of physical activity, nutrition, and tobacco were reported. Challenges in implementing and evaluating mini-grants were identified, including the heterogeneity of the sectors/settings involved and associated variability of proposed activities, time lines, measurement, and evaluation activities. COVID-19 (coronavirus disease 2019) also disrupted the plans for many projects. IMPLICATIONS FOR PUBLIC HEALTH: The success of this initiative can be attributed to four main elements: (1) the use of intermediary organizations to facilitate the mini-grants; (2) a participatory evaluation process, combined with early and ongoing communication among all stakeholders; (3) a braided funding strategy; and (4) a multisector approach that engaged both traditional and nontraditional public health organizations. The processes and outcomes, including challenges, can inform other state health departments' efforts in braiding funding and engaging intermediary organizations to expand the reach of PSE changes at the local level.

A radical imagination for nursing: Generative insurrection, creative resistance.

In the crucible of the pandemic, it has never before been clearer that, to ensure the relevance and even the survival of the discipline, nursing must cultivate a radical imagination. In the paper that follows, I trace the imperative for conjuring a radical imagination for nursing. In this fever dream for nursing futures, built on speculative visions of what could be, I draw on anarchist, abolitionist, posthuman, Black feminist, new materialist and other big ideas to plant seeds of generative insurrection and creative resistance. In thinking through a radical imagination, I unpack the significance of reparatory history for nursing, a discipline founded on normative whiteness. From there, I consider what it would take to shift the capitalist frame of healthcare to one of mutual aid, which requires the deep work of abolition. With a radical imagination that breaks down the enclosures that contain us through reparatory history, mutual aid and abolition, kinship becomes urgently possible.

Landscape genomics of Quercus lobata reveals genes involved in local climate adaptation at multiple spatial scales.

Understanding how the environment shapes genetic variation provides critical insight about the evolution of local adaptation in natural populations. At multiple spatial scales and multiple geographic contexts within a single species, such information could address a number of fundamental questions about the scale of local adaptation and whether or not the same loci are involved at different spatial scales or geographic contexts. We used landscape genomic approaches from three local elevational transects and rangewide sampling to (a) identify genetic variation underlying local adaptation to environmental gradients in the California endemic oak, Quercus lobata; (b) examine whether putatively adaptive SNPs show signatures of selection at multiple spatial scales; and (c) map putatively adaptive variation to assess the scale and pattern of local adaptation. Of over 10 k single-nucleotide polymorphisms (SNPs) generated with genotyping-by-sequencing, we found signatures of natural selection by climate or local environment at over 600 SNPs (536 loci), some at multiple spatial scales across multiple analyses. Candidate SNPs identified with gene-environment tests (LFMM) at the rangewide scale also showed elevated associations with climate variables compared to the background at both rangewide and elevational transect scales with gradient forest analysis. Some loci overlap with those detected in other oak species, raising the question of whether the same loci might be involved in local climate adaptation in different congeneric species that inhabit different geographic contexts. Mapping landscape patterns of adaptive versus background genetic variation identified regions of marked local adaptation and suggests nonlinear association of candidate SNPs and environmental variables. Taken together, our results offer robust evidence for novel candidate genes for local climate adaptation at multiple spatial scales.

COVID-19 Transmission, Current Treatment, and Future Therapeutic Strategies.

At the stroke of the New Year 2020, COVID-19, a zoonotic disease that would turn into a global pandemic, was identified in the Chinese city of Wuhan. Although unique in its transmission and virulence, COVID-19 is similar to zoonotic diseases, including other SARS variants (e.g., SARS-CoV) and MERS, in exhibiting severe flu-like symptoms and acute respiratory distress. Even at the molecular level, many parallels have been identified between SARS and COVID-19 so much so that the COVID-19 virus has been named SARS-CoV-2. These similarities have provided several opportunities to treat COVID-19 patients using clinical approaches that were proven to be effective against SARS. Importantly, the identification of similarities in how SARS-CoV and SARS-CoV-2 access the host, replicate, and trigger life-threatening pathological conditions have revealed opportunities to repurpose drugs that were proven to be effective against SARS. In this article, we first provided an overview of COVID-19 etiology vis-à-vis other zoonotic diseases, particularly SARS and MERS. Then, we summarized the characteristics of droplets/aerosols emitted by COVID-19 patients and how they aid in the transmission of the virus among people. Moreover, we discussed the molecular mechanisms that enable SARS-CoV-2 to access the host and become more contagious than other betacoronaviruses such as SARS-CoV. Further, we outlined various approaches that are currently being employed to diagnose and symptomatically treat COVID-19 in the clinic. Finally, we reviewed various approaches and technologies employed to develop vaccines against COVID-19 and summarized the attempts to repurpose various classes of drugs and novel therapeutic approaches.

Estimating the minimum important difference in the DEMQOL instrument in people with dementia.

PURPOSE: The Dementia-Related Quality of Life (DEMQOL) measure and the DEMQOL-Utility Score (DEMQOL-U) are validated tools for measuring quality of life (QOL) in people with dementia. What score changes translate to a clinically significant impact on patients' lives was unknown. This study establishes the minimal important differences (MID) for these two instruments. METHODS: Anchor-based and distribution-based methods were used to estimate the MID scores from patients enrolled in a randomised controlled trial. For the anchor-based method, the global QOL (Q29) item from the DEMQOL was chosen as the anchor for DEMQOL and both Q29 and EQ-5D for DEMQOL-U. A one category difference in Q29, and a 0.07 point difference in EQ-5D score, were used to classify improvement and deterioration, and the MID scores were calculated for each category. These results were compared with scores obtained by the distribution-based methods. RESULTS: A total of 490 people with dementia had baseline DEMQOL data, of these 386 had 8-month data, and 344 had 12-month DEMQOL data. The absolute change in DEMQOL for a combined 1-point increase or decrease in the Q29 anchor was 5.2 at 8 months and 6.0 at 12 months. For the DEMQOL-U, the average absolute change at 8 and 12 months was 0.032 and 0.046 for the Q29 anchor and 0.020 and 0.024 for EQ-5D anchor. CONCLUSION: We present MID scores for the DEMQOL and DEMQOL-U instruments obtained from a large cohort of patients with dementia. An anchored-based estimate of the MID for the DEMQOL is around 5 to 6 points; and 0.02 to 0.05 points for the DEMQOL-U. The results of this study can guide clinicians and researchers in the interpretation of these instruments comparisons between groups or within groups of people with dementia. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: ISRCTN17993825 on 11th October 2016.

Assessing fidelity of a community based psychosocial intervention for people with mild dementia within a large randomised controlled trial.

BACKGROUND: Understanding intervention delivery as intended, particularly in complex interventions, should be underpinned by good quality fidelity assessment. We present the findings from a fidelity assessment embedded as part of a trial of a complex community-based psychosocial intervention, Journeying through Dementia (JtD). The intervention was designed to equip individuals with the knowledge and skills to successfully self-manage, maintain independence, and live well with dementia and involves both group and individual sessions. The methodological challenges of developing a conceptual framework for fidelity assessment and creating and applying purposely designed measures derived from this framework are discussed to inform future studies. METHODS: A conceptual fidelity framework was created out of core components of the intervention (including the intervention manual and training for delivery), associated trial protocols and pre-defined fidelity standards and criteria against which intervention delivery and receipt could be measured. Fidelity data collection tools were designed and piloted for reliability and usability. Data collection in four selected sites (fidelity sites) was via non-participatory observations of the group aspect of the intervention, attendance registers and interventionist (facilitator and supervisor) self-report. RESULTS: Interventionists from all four fidelity sites attended intervention training. The majority of group participants at the four sites (71%) received the therapeutic dose of 10 out of 16 sessions. Weekly group meeting attendance (including at 'out of venue' sessions) was excellent at 80%. Additionally, all but one individual session was attended by the participants who completed the intervention. It proved feasible to create tools derived from the fidelity framework to assess in-venue group aspects of this complex intervention. Results of fidelity assessment of the observed groups were good with substantial inter-rater reliability between researchers KAPPA 0.68 95% CI (0.58-0.78). Self-report by interventionists concurred with researcher assessments. CONCLUSIONS: There was good fidelity to training and delivery of the group aspect of the intervention at four sites. However, the methodological challenges of assessing all aspects of this complex intervention could not be overcome due to practicalities, assessment methods and ethical considerations. Questions remain regarding how we can assess fidelity in community-based complex interventions without impacting upon intervention or trial delivery. TRIAL REGISTRATION: ISRCTN17993825 .

8-Chloroadenosine Alters the Metabolic Profile and Downregulates Antioxidant and DNA Damage Repair Pathways in Macrophages.

The exposure of RNA and DNA nucleobases to the oxidant hypochlorous acid (HOCl) results in the generation of different stable chlorinated products. These chlorinated nucleobases are formed in vivo, particularly in chronic inflammatory pathologies, which are characterized by the overproduction of HOCl by myeloperoxidase. As such, chlorinated nucleosides are used as biomarkers of inflammation. However, these compounds have also attracted attention as potential chemotherapeutic agents with 8-chloro-adenosine (8ClA), for example, currently in clinical trials for the treatment of hematological cancers, including chronic lymphocytic leukemia. 8ClA has mainly RNA-directed effects in malignant cells, with exposure resulting in ATP depletion and apoptotic cell death. Whether 8ClA has significant reactivity with nonmalignant cells has not been widely studied. Here we show that prolonged incubation of J774A.1 macrophage-like cells with 8ClA results in the perturbation of cellular metabolism and apoptotic cell death. These effects are associated with an accumulation of 8-chloroadenosine triphosphate (8Cl-ATP), an effect not seen in experiments utilizing other chlorinated nucleosides. Exposure of the macrophages to 8ClA did not significantly change basal mitochondrial respiration or glycolysis but resulted in an increase in maximal mitochondrial respiration as well as spare respiratory capacity within these cells. Additionally, 8ClA exposure also altered the mRNA expression of a range of antioxidant and DNA damage repair genes in the macrophages in a manner consistent with a reduction in the capacity of the cells to cope with oxidative stress and repair DNA damage. Taken together, these results provide new insight into pathways by which the production of HOCl during chronic inflammation could perturb immune cell function and may also have implications for the use of 8ClA as a chemotherapeutic drug.

The case for "structural missingness:" A critical discourse of missed care.

Stimulated by our conversations at the 2018 International Philosophy of Nursing Society Conference and our shared interests, the coauthors present an argument for augmenting the broader discussion of "missed care" with our synthesized concept called structural missingness. We take the problem of missed care to be largely grounded on a particular economic construction of the healthcare system within an era of what some are calling the Capitalocene, capturing the pervasive influence of capitalism on nature, humanity and the world order. Our perspective is that of the United States, however, extrapolations can be made to the social and healthcare systems in other countries. We are concerned with the underlying conditions that structurally reify inequality and ultimately undermine nursing practice. To situate the discussion, we briefly review existing literature on the contextualization of missed care. We understand contemporary circumstances of missed care as a function of the neoliberalization of healthcare, including the idea of nursing as a commodity. From this, we discuss the implications of missed care, which forms the basis of our critique. Synthesizing the term "structural missingness, we locate a moral imperative in the professional and disciplinary commitments of nursing to consider who and what have been left out. This moral imperative for the nursing profession, along with other social and health related professions, underscores our obligation to be involved in uncovering inequities and conceptualizing upstream solutions for structural missingness.

Seedling response to water stress in valley oak (Quercus lobata) is shaped by different gene networks across populations.

Drought is a major stress for plants, creating a strong selection pressure for traits that enable plant growth and survival in dry environments. Many drought responses are conserved species-wide responses, while others vary among populations distributed across heterogeneous environments. We tested how six populations of the widely distributed California valley oak (Quercus lobata) sampled from contrasting climates would differ in their response to soil drying relative to well-watered controls in a common environment by measuring ecophysiological traits in 93 individuals and gene expression (RNA-seq) in 42 individuals. Populations did not differ in their adjustment of turgor loss point during soil drying, suggesting a generalized species-wide response. Differential expression analysis identified 689 genes with a common response to treatment across populations and 470 genes with population-specific responses. Weighted gene co-expression network analysis (WGCNA) identified groups of genes with similar expression patterns that may be regulated together (gene modules). Several gene modules responded differently to water stress among populations, suggesting regional differences in gene network regulation. Populations from sites with a high mean annual temperature responded to the imposed water stress with significantly greater changes in gene module expression, indicating that these populations may be locally adapted to respond to drought. We propose that this variation among valley oak populations provides a mechanism for differential tolerance to the increasingly frequent and severe droughts in California.

A Role for Chlorinated Nucleosides in the Perturbation of Macrophage Function and Promotion of Inflammation.

During inflammation, myeloperoxidase released from activated phagocytes generates the highly reactive oxidant hypochlorous acid (HOCl). This oxidant plays an important role in the immune response but can also promote tissue damage and has been strongly linked with the development of numerous inflammatory diseases. HOCl reacts with cellular DNA forming chlorinated nucleobases, which induce strand breaks, mutations, and cross-links. Although it has been shown that chlorinated nucleosides are present within inflammatory pathologies and diseased tissue, whether or not these species are biomarkers formed as a byproduct of chronic inflammation or play a role in the disease progression has not been ascertained. In this study, we show that exposure of J774A.1 macrophage-like cells to chlorinated ribose and deoxyribose nucleosides results in the incorporation of 5-chloro-cytidine (5ClC), 8-chloro-adenosine (8ClA), and 8-chloro-guanosine (8ClG) into the cellular RNA and 5-chloro-deoxycytidine (5CldC) but not 8-chloro-deoxyguanosine (8CldG) or 8-chloro-deoxyadenosine (8CldA) into cellular DNA. Evidence was obtained for the clearance of 5ClC from the RNA, with a loss of 8ClA and 8ClG observed to a lesser extent, whereas an increase in the level of 5CldC in DNA was seen on further incubation of treated cells in the absence of chlorinated nucleosides. Importantly, exposure of the macrophages to chlorinated nucleosides, particularly 8ClG and 5ClC, resulted in the increased expression of interleukin-1ß, and other pro-inflammatory cytokines and chemokines. With 5ClC, this inflammatory response was associated with the increased nuclear translocation of the NF-κB subunit, p65, rather than inflammasome activation. This alteration in gene expression appeared to be unrelated to the extent of incorporation of the chlorinated nucleosides into RNA or DNA and was not associated with any significant changes in cell viability or proliferation. Taken together, these results highlight a potential biological role for chlorinated nucleosides to promote inflammatory disease, in addition to their utility as biomarkers.