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Contemporary restoration and management of sagebrush-dominated (Artemisia spp.) ecosystems across the intermountain west of the United States increasingly involves the removal of expanding conifer, particularly juniper (Juniperus spp.) and pinyon pine (Pinus edulis, P. monophylla). The impetus behind much of this management has been the demonstrated population benefits of sagebrush restoration via conifer removal to greater sage-grouse (Centrocercus urophasianus), a species of conservation concern. One of the challenges with scaling up from a focal-species approach to a community-level perspective, however, is balancing the habitat requirements of different species, some of which may overlap with sage-grouse and others which may have competing habitat needs. Here, we use a systematic conservation planning approach to compute spatial optimizations which prioritize areas for conifer removal across the sage-grouse range while incorporating woodland and sagebrush songbirds into decision-making. Three of the songbirds considered here, Brewer’s sparrow (Spizella breweri), green-tailed towhee (Pipilo chlorurus), and sage thrasher (Poocetes gramineus), are sagebrush-obligates, while another is a woodland-obligate, the pinyon jay (Gymnorhinus cyanocephalus). We find that the inclusion of sagebrush-obligates expands the model-selected area of consideration for conifer management, likely because habitat overlap between sagebrush-obligates is imperfect. The inclusion of pinyon jay, a woodland-obligate, resulted in substantial shifts in the distribution of model-selected priority areas for conifer removal – particularly away from pinyon jay strongholds in Nevada and east-central California. Finally, we compared the conifer optimizations created here with estimates of ongoing conifer removal efforts across the intermountain west and find that a small proportion (13-18%) of management efforts had occurred on areas predicted as being important for pinyon jay, suggesting that much of the ongoing work is already successfully avoiding critical pinyon jay habitat areas.

ADARs (adenosine deaminases acting on RNA) can be directed to sites in the transcriptome by complementary guide strands allowing for the correction of disease-causing mutations at the RNA level. However, ADARs show bias against editing adenosines with a guanosine 5′ nearest neighbor (5′-GA sites), limiting the scope of this approach. Earlier studies suggested this effect arises from a clash in the RNA minor groove involving the 2-amino group of the guanosine adjacent to an editing site. Here we show that nucleosides capable of pairing with guanosine in a syn conformation enhance editing for 5′-GA sites. We describe the crystal structure of a fragment of human ADAR2 bound to RNA bearing a G:G pair adjacent to an editing site. The two guanosines form a Gsyn:Ganti pair solving the steric problem by flipping the 2-amino group of the guanosine adjacent to the editing site into the major groove. Also, duplexes with 2′-deoxyadenosine and 3-deaza-2′-deoxyadenosine displayed increased editing efficiency, suggesting the formation of a Gsyn:AH+anti pair. This was supported by X-ray crystallography of an ADAR complex with RNA bearing a G:3-deaza dA pair. This study shows how non-Watson–Crick pairing in duplex RNA can facilitate ADAR editing enabling the design of next generation guide strands for therapeutic RNA editing.

Introduction Axillary surgery has been de-escalated in invasive breast carcinoma and may be omitted in certain age groups according to the Choosing Wisely initiative. Invasion can be found in 10-20% of patients with ductal carcinoma in-situ (DCIS). Therefore, Sentinel lymph node biopsy (SLNB) is indicated to rule out nodal metastasis. Our purpose was to study the risk factors and outcome of positive SLNB. Methods A retrospective analysis was performed on a series of 67 cases of patients who underwent mastectomy with SLNB for DCIS at Beaumont Hospital, Ireland, Royal College of Surgeons in Ireland, between 2015 and 2021. We evaluated their clinical, histopathological characteristics and regional recurrence. Results Only one invasive component was identified out of 67 cases (1.5%). Eight patients (11.9%) had positive SLN, six with isolated tumour cells, one micro-metastasis and one macro-metastasis. The three patients who proceeded for axillary lymph node dissection (ALND) presented with palpable lump, nipple discharge and through family history screening; however, all additional nodes retrieved were negative. All three patients had >5 cm high/intermediate grade disease. They were ER receptor positive and HER-2 negative. Regional recurrence was not reported in any. Conclusion This study identified a low rate of positive SLNB in DCIS and microinvasion on final histopathology. Factors which may increase the risk of positive SLNB are large tumours, palpable lump or nipple discharge. Our results indicate that ALND can be safely omitted in DCIS with positive SLNB but may be considered in high-risk patients.

Per- and Polyfluorinated alkyl substances (PFAS) are a broad class of synthetic compounds that have fluorine substituted for hydrogen in several or all locations and are globally categorized as PFCs (perfluorochemicals; commonly called fluorinated chemicals). These compounds have unique chemical and physical properties that enable their use in non-stick surfaces, fire-fighting efforts, and as slick coatings. However, recent concerns over the health effects of such compounds, specifically perfluorooctanoic acid and perfluorooctane sulfonic acid (PFOA, PFOS; PFOA/S), have led to increased attention and research by the global community into degradation methods. In this study, soil samples from PFAS-contamination sites were cultured and screened for microbes with PFOA/S degradation potential, which led to the identification of Delftia acidovorans. It was found that D. acidovorans isolated from PFAS-contaminated soils was capable of growth in minimal media with PFOA as a sole carbon resource, and an observable fluoride concentration increase was observed when cells were exposed to PFOA. This suggests potential activity of a dehalogenase enzyme that may be of use in PFOA or PFAS microbial remediation efforts. Several associated haloacid dehalogenases have been identified in the D. acidovorans genome and have been engineered for expression in Escherichia coli for rapid production and purification. These enzymes have shown potential for enzymatic defluorination, a significant step in biological degradation and removal of PFOA/S from the environment. We hypothesize that bioremediation of PFAS using naturally occurring microbial degradation pathways may represent a novel approach to remove PFAS contamination.

Background Health disparities for children with intellectual disabilities can be challenging to measure due to many other factors that can impact health and healthcare use. The aim of the current study was to use longitudinal cohort data to compare children with intellectual disability (ID) in Ireland between 2006 and 2014 on healthcare utilisation and unmet need, at ages 9 and 13, using a propensity score matching (PSM) approach. Methods Using data from the Growing up in Ireland study, PSM was used to identify an appropriate control sample to compare with a sample of children with ID (n = 124). Participants were matched on variables that are known to influence healthcare utilisation to reduce the impact of confounding variables between groups so that differences between the groups can be estimated. Logistic regression was used to estimate effects at ages 9 and 13. Results Children with ID were no more likely to have visited a general practitioner or emergency department in the past 12 months than children without ID. They did have a greater likelihood of visiting a doctor in a hospital in the past 12 months and of having an overnight stay in hospital by age 9. Primary caregivers of children with ID were more likely to report unmet health needs at ages 9 and 13. Conclusions This approach is a novel means of comparing healthcare use in this population by balancing the impact of other factors that may result in inequities, to which children with ID may be more vulnerable.

Adenosine deaminases that act on RNA (ADARs) can be directed to predetermined sites in transcriptomes by forming duplex structures with exogenously delivered guide RNAs (gRNAs). They can then catalyze the hydrolytic deamination of adenosine to inosine in double stranded RNA, which is read as guanosine during translation. High resolution structures of ADAR2-RNA complexes revealed a unique conformation for the nucleotide in the guide strand base paired to the editing site's 5' nearest neighbor (-1 position). Here we describe the effect of 16 different nucleoside analogs at this position in a gRNA that targets a 5'-UA̲-3' site. We found that several analogs increase editing efficiency for both catalytically active human ADARs. In particular, 2'-deoxynebularine (dN) increased the ADAR1 and ADAR2 in vitro deamination rates when at the -1 position of gRNAs targeting the human MECP2 W104X site, the mouse IDUA W392X site, and a site in the 3'-UTR of human ACTB. Furthermore, a locked nucleic acid (LNA) modification at the -1 position was found to eliminate editing. When placed -1 to a bystander editing site in the MECP2 W104X sequence, bystander editing was eliminated while maintaining on-target editing. In vitro trends for four -1 nucleoside analogs were validated by directed editing of the MECP2 W104X site expressed on a reporter transcript in human cells. This work demonstrates the importance of the -1 position of the gRNA to ADAR editing and discloses nucleoside analogs for this site that modulate ADAR editing efficiency.

Novel acyl pyrazoles and acyl triazoles have been prepared by means of the oxidative amidation of aldehydes in the presence of the requisite azole. Yields range from modest to good in both cases, and some limitations of the substrate scope have been discovered. Acyl pyrazoles were prepared by treatment of a mixture of aldehyde and pyrazole with an oxoammonium salt bearing the nitrate anion. In the case of acyl triazoles, the oxidative functionalization was performed using sodium persulfate as a terminal oxidant in the presence of a catalytic quantity of a nitroxide.

Despite past geo-political turbulence, Nepal has made significant progress in societal and economic initiatives, particularly in relation to social determinants of health. These improvements, however, belie the suffering of those with life-limiting disease due to pain, stigma, social and financial distress, consequent upon low patient, caregiver and health professional awareness of the need for, and availability of, appropriate care and support. Two Worlds Cancer Collaboration (INCTR-Canada) has been working with partners in Nepal to build capacity for palliative care by: (a) organizational and administrative support – establishing the Nepal Association of Palliative Care (NAPCare), and the creation of the Nepal Strategy for Palliative Care, approved by government in 2017; (b) “twinning” between 2 hospital palliative care units in Nepal and the Nanaimo Hospice and Victoria Hospice, BC, Canada; (c) sustainable growth of palliative care according to WHO foundational measures, implementing facility-based clinical programs, and home-based care aligned with the cultural, social, and economic environment of Nepal; (d) training of health professionals in adult and paediatricpalliative carethrough interactive on-line “distance learning” (Extension of Community Healthcare Outcomes, ECHO);(e) leveraging palliative care training and expertise across the government health system, and (f) local and international support to build a newfacility for Hospice Nepal to provide more support for more patients in a rural ambience on the outskirts of Kathmandu. Palliative care needs to become standard-of-care, providing peace, comfort and dignity for adults and children. Working collaboratively with partners in Nepal, the collective vision is a capable professional Nepali community leading palliative care services for all in need, wherever in need.

Plant community response to climate change will be influenced by individual plant responses that emerge from competition for limiting resources that fluctuate through time and vary across space. Projecting these responses requires an approach that integrates environmental conditions and species interactions that result from future climatic variability. Dryland plant communities are being substantially affected by climate change because their structure and function are closely tied to precipitation and temperature, yet impacts vary substantially due to environmental heterogeneity, especially in topographically complex regions. Here, we quantified the effects of climate change on big sagebrush (Artemisia tridentata Nutt.) plant communities that span 76 million ha in the western United States. We used an individual-based plant simulation model that represents intra- and inter-specific competition for water availability, which is represented by a process-based soil water balance model. For dominant plant functional types, we quantified changes in biomass and characterized agreement among 52 future climate scenarios. We then used a multivariate matching algorithm to generate fine-scale interpolated surfaces of functional type biomass for our study area. Results suggest geographically divergent responses of big sagebrush to climate change (changes in biomass of -20% to +27%), declines in perennial C3 grass and perennial forb biomass in most sites, and widespread, consistent, and sometimes large increases in perennial C4 grasses. The largest declines in big sagebrush, perennial C3 grass and perennial forb biomass were simulated in warm, dry sites. In contrast, we simulated no change or increases in functional type biomass in cold, moist sites. There was high agreement among climate scenarios on climate change impacts to functional type biomass, except for big sagebrush. Collectively, these results suggest divergent responses to warming in moisture-limited versus temperature-limited sites and potential shifts in the relative importance of some of the dominant functional types that result from competition for limiting resources.

Serotherapeutic agents facilitate engraftment and prevent graft-versus-host disease (GVHD) following hematopoietic stem cell transplant. Anti-thymocyte globulin is generally added to conditioning chemotherapy for matched related donor transplant (MRD-HCT) for sickle cell disease (SCD). Alemtuzumab, however, is appealing due to its broad lymphocyte killing that may achieve very low rejection and GVHD rates. To assess the impact of alemtuzumab in MRD-HCT for SCD, we retrospectively reviewed transplant-related outcomes and markers of immunity in 38 consecutive patients at Texas Children’s Hospital having received myeloablative conditioning with alemtuzumab. Median follow-up was 4.8 years (range: 0.2–17). All patients engrafted. Donor chimerism was mixed in 47.1% of patients at ≥2-years. Donor chimerism

Health equity research has identified fundamental social causes of health, many of which disproportionately affect Black Americans, such as early life socioeconomic conditions, neighborhood disadvantage, and racial discrimination. However, the role of life course factors in premature mortality among Black Americans has not been tested extensively in prospective samples into later adulthood. To better understand how social factors at various life stages impact mortality, this study examines the effect of life course poverty, neighborhood disadvantage, and discrimination on mortality and factors that may buffer their effect (i.e., education, social integration) among the Woodlawn cohort (N = 1242), a community cohort of urban Black Americans followed since 1966. Taking a life course perspective, we analyze mortality data for deaths through age 58 years old, as well as data collected at ages 6, 16, 32, and 42. At age 58, 204 (16.4%) of the original cohort have died, with ages of death ranging from 9 to 58.98 (mean = 42.9). Cox proportional hazard models adjusting for confounders show statistically significant differences in mortality risk based on timing and persistence of poverty; those who were never poor or poor only in early life had lower mortality risk at ages 43-58 than those who were persistently poor from childhood to adulthood. Education beyond high school and high social integration were shown to reduce the risk of mortality more for those who did not experience poverty early in their life course. Findings have implications for the timing and content of mortality prevention efforts that span the full life course.

The hydrolytic deamination of adenosine-to-inosine (A-to-I) by RNA editing is a widespread post-transcriptional modification catalyzed by the adenosine deaminase acting on RNA (ADAR) family of proteins. ADAR-mediated RNA editing modulates cellular pathways involved in innate immunity, RNA splicing, RNA interference, and protein recoding, and has been investigated as a strategy for therapeutic intervention of genetic disorders. Despite advances in basic and translational research, the mechanisms regulating RNA editing are poorly understood. Though several trans-acting regulators of editing have been shown to modulate ADAR protein expression, previous studies have not identified factors that modulate ADAR catalytic activity. Here, we show that RNA editing increases upon intracellular acidification, and that these effects are predominantly explained by both enhanced ADAR base-flipping and deamination rate at acidic pH. We also show that the extent of RNA editing increases with the reduction in pH associated with conditions of cellular hypoxia., Graphical Abstract Graphical AbstractIntracellular acidification drives protonation of a conserved glutamate in the ADAR deaminase domain, which in turn enhances base-flipping and increases the extent of RNA editing.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. Early detection and appropriate treatment and management of COPD can lower morbidity and perhaps mortality. Clinicians in the primary care setting provide the majority of COPD care and are pivotal in the diagnosis and management of COPD. In this review, we provide an overview of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 report, with a focus on the management of COPD in the primary care setting. We discuss the pathophysiology of COPD; describe COPD risk factors, signs, and symptoms that may facilitate earlier diagnosis of COPD; and reinforce the importance of spirometry use in establishing the diagnosis of COPD. Disease monitoring, as well as a review of the 2020 GOLD treatment recommendations, is also discussed. Patients and families are important partners in COPD management; therefore, we outline simple steps that may assist them in caring for those affected by COPD. Finally, we discuss nonpharmacological treatment options for COPD, COPD monitoring tools that may aid in the evaluation of disease progression and response to therapy, and the importance of developing a COPD action plan on an individualized basis.

Tree expansion among historic grassland and shrubland systems is a global phenomenon, which results in dramatic influences on ecosystem processes and wildlife populations. In the western US, pinyon-juniper woodlands have expanded by as much as six-fold among sagebrush steppe landscapes since the late nineteenth century, with demonstrated negative impacts to the behavior, demography, and population dynamics of species that rely on intact sagebrush rangelands. Notably, greater sage-grouse (Centrocercus urophasianus) are unable to tolerate even low conifer cover, which can result in population declines and local extirpation. Removing expanding conifer cover has been demonstrated to increase sage grouse population growth rates and sagebrush-obligate songbird abundance. However, advances in restoring sagebrush habitats have been met with concern about unintended impacts to species that rely on conifer woodlands, notably the pinyon jay (Gymnorhinus cyanocephalus) whose population declines are distinctive among birds breeding in pinyon-juniper woodlands. We modeled indices to abundance in relation to multi-scale habitat features for nine songbirds reliant on both sagebrush and pinyon-juniper woodlands for breeding. Findings demonstrate that targeted sage grouse habitat restoration under the Sage Grouse Initiative is not at odds with protection of pinyon jay populations. Rather, conifer management has largely occurred in the northern sagebrush ecosystem where models suggest that past cuts likely benefit Brewer’s sparrow and sage thrasher while avoiding pinyon jay habitat. Extending our spatial modeling further south beyond the sagebrush biome could better equip conservationists with more comprehensive decision-support, particularly where pinyon jays face additional pressures of drought-induced tree mortality.

The high incidence of error reports received by the US Food and Drug Administration (FDA) involving 2-component vaccines led to collaboration between the United States Pharmacopeia (USP) and the Institute for Safe Medication Practices (ISMP). This collaborating group sought to further understand errors associated with all 2-component vaccines (i.e. vaccine components provided by the manufacturer in physically separate containers) and to provide safe practice strategies for storing, preparing, dispensing, and administering these vaccines as intended. Fourteen available 2-component vaccines were identified. The ISMP National Vaccine Errors Reporting Program (VERP) and the FDA Vaccine Adverse Event Reporting System (VAERS) were searched from the initiation of each respective reporting system through December 31, 2019. The three vaccines with the most reported reconstitution errors in the VERP and VAERS are Menveo® (meningococcal), Pentacel® (DTaP, Polio, Haemophilus influenzae type b), and ActHIB® [H. influenzae type b (Hib)]. Manufacturers should design labeling and packaging of vaccines to provide ease of storage and fail-safe preparation to prevent 2-component vaccine errors. Implementing risk reduction strategies, such as training healthcare professionals and affixing storage bin labels, remind healthcare professionals to mix the 2-components and facilitate appropriate administration.

Non-fibrillar β-amyloid (Aβ) oligomers are considered as major neurotoxic species in the pathology of Alzheimer’s disease (AD). The presence of Aβ oligomers were shown to cause membrane disruptions in a broad range of model systems. However, the molecular basis of such disruption process remains unknown. We previously demonstrated that membrane-incorporated 40-residue Aβ (Aβ(40)) oligomers could form co-aggregates with phospholipids. This process occurred more rapidly than the fibrillization of Aβ(40) and led to more severe membrane disruption. The present study probes the time-dependent changes in lipid dynamics, bilayer structures and peptide-lipid interactions along the time course of the oligomer-induced membrane disruption, using the solid-state NMR spectroscopy. Our results suggest the presence of certain intermediate states with phospholipid molecules entering the C-terminal hydrogen-bonding networks of the Aβ(40) oligomeric cores. This work provides insights on the molecular mechanisms of Aβ(40)-oligomer-induced membrane disruption.

Sugar oxime ether surfactants are a new class of surfactants produced by the reaction of a sugar with a hydrophobic alkoxyamine, producing an oxime ether linkage. We examined nine examples of this class of surfactants. The sugars used were maltose, sucrose, and glyceraldehyde; the alkoxyamines were decyloxyamine, dodecyloxya mine, and adamantyloxyamine. For the resulting surfactants we determined their thermal stability, melting point, water solubility, effect on surface tension, and critical micelle concentration. We found that all the compounds tested were thermally stable and decreased substantially the surface tension of water.

Nanobubbles have the potential to curtail the loss of oxygen during activated sludge aeration due to their extensive surface areas and lack of buoyance in solution. In this study, nanobubble aeration was explored as a novel approach to enhance aerobic activated sludge treatment and benchmarked against coarse bubble aeration at the lab scale. Nanobubble aerated activated sludge reactors achieved greater dissolved oxygen levels at faster rates. Higher soluble chemical oxygen demand removal by 10% was observed when compared to coarse bubble aeration with the same amount of air. The activated sludge produced compact sludge yielding easier waste sludge for subsequent sludge handling. The samples showed fewer filamentous bacteria with a lower relative abundance of floc forming Corynebacterium, Pseudomonas, and Zoogloea in the sludge. The microbiome of the nanobubble-treated activated sludge showed significant shifts in the abundance of community members at the genus level and significantly lower alpha and beta diversities.

Introduction Excessive daytime sleepiness (EDS) persists in some positive airway pressure (PAP)-treated patients with obstructive sleep apnoea (OSA). This study examined prevalence and severity of EDS in a real-world population with OSA to understand how EDS, PAP adherence, and patient satisfaction with care relate. Methods US-resident adults (self-reported clinician OSA diagnosis [1/1/2015-31/3/2020]) were surveyed (Epworth Sleepiness Scale [ESS], PAP usage, and patient satisfaction) in Evidation Health’s Achievement app. Self-reported PAP use was categorised: nonuse, nonadherent ( 10 defined EDS. In PAP users, a linear model tested whether PAP use and ESS score relate; logistic regression models tested how PAP use (nonadherence=0, adherence=1) and EDS impact satisfaction with healthcare providers (HCPs) and overall OSA care. Due to no adjustments for multiplicity, P-values are nominal. Results Of 2289 participants (50.3% female; mean±SD 44.8±11.1 years old; 42.5% ESS>10), 72% were satisfied with HCPs and 65% with OSA care. In the nonuse (n=700), nonadherent (n=153), intermediate (n=225), and highly adherent (n=1211) groups, 47%, 52%, 53%, and 36% had EDS, respectively. An additional h/night PAP use was associated with lower ESS scores (n=1589, β=–0.28; 95% confidence interval [CI]=–0.40, –0.16; P Discussion In this real-world study, EDS was prevalent among highly adherent PAP users. PAP adherence was associated with greater patient satisfaction with HCPs and overall care, whereas persistent EDS was associated with lower patient satisfaction with HCPs and overall OSA care.

While high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) leads to improved disease-free survival (DFS) for children and adults with relapsed/refractory Hodgkin lymphoma (HL), relapse remains the most frequent cause of mortality post-transplant. Rituximab has been successfully incorporated into regimens for other B-cell lymphomas, yet there have been limited studies of rituximab in HL patients. We hypothesized that adding rituximab to BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning would reduce relapse risk in HL patients post-transplant. Here, we retrospectively review the outcomes of patients with relapsed/refractory HL who received rituximab in addition to BEAM. The primary outcome was DFS. Our cohort included 96 patients with a median age of 28 years (range, 6-76). Majority of patients (57%) were diagnosed with advanced (Stage III-IV) disease, and 62% were PET negative pre-transplant. DFS was 91.5% at 1 year [95% CI 86-98%], and 78% at 3 years [95% CI 68-88%]. NRM was 0% and 3.5% at 1-year [95% CI 0-3%] and 3-years [95% CI 0-8.5%], respectively. 25% of patients developed delayed neutropenia, with 7% requiring infection-related hospitalizations, and one death. We have demonstrated excellent outcomes for patients receiving rituximab with BEAM conditioning for relapsed/refractory HL. Future comparative studies are needed to better determine whether rituximab augments outcomes post-transplant.