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Understanding the overlap of symptoms between oppositional defiant disorder (ODD) and obsessivecompulsive disorder (OCD) experienced by youth is pertinent for accurate diagnosis. A quantitative, retrospective, cross-sectional design format was used to assess the relationship between ODD and OCD in addition to evaluating the difference in ODD severity and symptoms based on OCD severity. Symptoms and severity ratings of ODD and OCD were collected from youth diagnosed with ODD (N = 179). Fisher's exact test and a Wilcoxon signed-rank test were performed. There were significant relationships between frustration related to obsessions and compulsions and the ODD symptoms of annoyance and anger. Results suggested that OCD severity predicted an increase in scores for ODD severity and symptoms.

In vitro gametogenesis (IVG), the reconstitution of germ cell development in vitro, is an emerging stem cell-based technology with profound implications for reproductive science. Despite researchers' long-term goals for future clinical applications, little is currently known about the views of IVG held by the stakeholders potentially most affected by its introduction in humans. We conducted focus groups and interviews with 80 individuals with lived experience of infertility and/or LGBTQ+ family formation in the US, two intersecting groups of potential IVG users. Respondents expressed hope that IVG would lead to higher reproductive success than current assisted reproductive technology (ART), alleviate suffering associated with ART use, and promote greater social inclusion, while expressing concerns predominantly framed in terms of equity and safety. These findings underscore the importance of sustained engagement with stakeholders with relevant experience to anticipate the implications of IVG for research and clinical translation.

Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C12FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C12FDG+ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C12FDG+ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C12FDG+ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C12FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.

ObjectiveOur objective was to gauge adherence to nationally endorsed protocols in implementation of pulse oximetry (POx) screening for critical congenital heart disease (CCHD) in infants after mandate by all states and to assess associated characteristics.Study designBetween March and October 2019, an online questionnaire was administered to nurse supervisors who oversee personnel conducting POx screening. The questionnaire used eight questions regarding performance and interpretation of screening protocols to measure policy consistency, which is adherence to nationally endorsed protocols for POx screening developed by professional medical societies. Multilevel linear regression models evaluated associations between policy consistency and characteristics of hospitals and individuals, state of hospital location, early versus late mandate adopters, and state reporting requirements.ResultsResponses from 189 nurse supervisors spanning 38 states were analyzed. Only 17% received maximum points indicating full policy consistency, and 24% selected all four options for potential hypoxia that require a repeat screen. Notably, 33% did not recognize ≤90% SpO2 as an immediate failed screen and 31% responded that an infant with SpO2 of 89% in one extremity will be rescreened by nurses in an hour rather than receiving an immediate physician referral. Lower policy consistency was associated with lack of state reporting mandates (beta = -1.23 p = 0.01) and early adoption by states (beta = -1.01, p

Castellaniella species have been isolated from a variety of mixed-waste environments including the nitrate and multiple metal-contaminated subsurface at the Oak Ridge Reservation (ORR). Previous studies examining microbial community composition and nitrate removal at ORR during biostimulation efforts reported increased abundances of members of the Castellaniella genus concurrent with increased denitrification rates. Thus, we asked how genomic and abiotic factors control the Castellaniella biogeography at the site to understand how these factors may influence nitrate transformation in an anthropogenically impacted setting. We report the isolation and characterization of several Castellaniella strains from the ORR subsurface. Five of these isolates match at 100% identity (at the 16S rRNA gene V4 region) to two Castellaniella amplicon sequence variants (ASVs), ASV1 and ASV2, that have persisted in the ORR subsurface for at least 2 decades. However, ASV2 has consistently higher relative abundance in samples taken from the site and was also the dominant blooming denitrifier population during a prior biostimulation effort. We found that the ASV2 representative strain has greater resistance to mixed metal stress than the ASV1 representative strains. We attribute this resistance, in part, to the large number of unique heavy metal resistance genes identified on a genomic island in the ASV2 representative genome. Additionally, we suggest that the relatively lower fitness of ASV1 may be connected to the loss of the nitrous oxide reductase (nos) operon (and associated nitrous oxide reductase activity) due to the insertion at this genomic locus of a mobile genetic element carrying copper resistance genes. This study demonstrates the value of integrating genomic, environmental, and phenotypic data to characterize the biogeography of key microorganisms in contaminated sites.

BackgroundOur preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib.Patients and methodsThis multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR).ResultsFifty-one patients received ramucirumab and olaparib. The RP2D was olaparib 300 mg twice daily with ramucirumab 8 mg/kg. In evaluable patients at the RP2D the ORR was 6/43 (14%) (95% CI 4.7-25.6). The median progression-free survival (PFS) was 2.8 months (95% CI 2.3-4.2) and median overall survival (OS) was 7.3 months (95% CI 5.7-13.0). Non-statistically significant improvements in PFS and OS were observed for patients with tumours with mutations in HRD genes.ConclusionsOlaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric cancer in a heavily pre-treated patient population.

Mobile genetic elements (MGEs) like plasmids, viruses, and transposable elements can provide fitness benefits to their hosts for survival in the presence of environmental stressors. Heavy metal resistance genes (HMRGs) are frequently observed on MGEs, suggesting that MGEs may be an important driver of adaptive evolution in environments contaminated with heavy metals. Here, we report the meta-mobilome of the heavy metal-contaminated regions of the Oak Ridge Reservation subsurface. This meta-mobilome was compared with one derived from samples collected from unimpacted regions of the Oak Ridge Reservation subsurface. We assembled 1615 unique circularized DNA elements that we propose to be MGEs. The circular elements from the highly contaminated subsurface were enriched in HMRG clusters relative to those from the nearby unimpacted regions. Additionally, we found that these HMRGs were associated with Gamma and Betaproteobacteria hosts in the contaminated subsurface and potentially facilitate the persistence and dominance of these taxa in this region. Finally, the HMRGs were associated with conjugative elements, suggesting their potential for future lateral transfer. We demonstrate how our understanding of MGE ecology, evolution, and function can be enhanced through the genomic context provided by completed MGE assemblies.

Precision prevention embraces personalized prevention but includes broader factors such as social determinants of health to improve cardiovascular health. The quality, quantity, precision, and diversity of data relatable to individuals and communities continue to expand. New analytical methods can be applied to these data to create tools to attribute risk, which may allow a better understanding of cardiovascular health disparities. Interventions using these analytic tools should be evaluated to establish feasibility and efficacy for addressing cardiovascular disease disparities in diverse individuals and communities. Training in these approaches is important to create the next generation of scientists and practitioners in precision prevention. This state-of-the-art review is based on a workshop convened to identify current gaps in knowledge and methods used in precision prevention intervention research, discuss opportunities to expand trials of implementation science to close the health equity gaps, and expand the education and training of a diverse precision prevention workforce.

International literature has recognised the importance of education research with Pacific learners. In an Australian context, the early years learning framework for Australia and the Australian curriculum emphasise that education sectors should work towards cultivating respect for cultural diversity and to develop intercultural understanding and intercultural capabilities. As such, the call to better understand the cultural complexities that underpins Pacific learners and their interactions with educational processes remains pertinent. This scoping review offers an important synthesis of empirical research on the educational successes and challenges of Pacific learners in Australian educational settings from 2010 to 2021. While this study offers critical insights for teacher education and research, the findings also revealed paucities in education research with Pacific learners. Thereby, propositions for future and ongoing education research with Pacific learners in Australia are offered in this article.

Environmental contamination constrains microbial communities impacting diversity and total metabolic activity. The former S-3 Ponds contamination site at Oak Ridge Reservation (ORR), TN, has elevated concentrations of nitric acid and multiple metals from decades of processing nuclear material. To determine the nature of the metal contamination in the sediment, a three-step sequential chemical extraction (BCR) was performed on sediment segments from a core located upgradient (EB271, non-contaminated) and one downgradient (EB106, contaminated) of the S-3 Ponds. The resulting exchangeable, reducing, and oxidizing fractions were analyzed for 18 different elements. Comparison of the two cores revealed changes in operational speciation for several elements caused by the contamination. Those present from the S-3 Ponds, including Al, U, Co, Cu, Ni, and Cd, were not only elevated in concentration in the EB106 core but were also operationally more available with increased mobility in the acidic environment. Other elements, including Mg, Ca, P, V, As, and Mo, were less operationally available in EB106 having decreased concentrations in the exchangeable fraction. The bioavailability of essential macro nutrients Mg, Ca, and P from the two types of sediment was determined using three metal-tolerant bacteria previously isolated from ORR. Mg and Ca were available from both sediments for all three strains; however, P was not bioavailable from either sediment for any strain. The decreased operational speciation of P in contaminated ORR sediment may increase the dependence of the microbial community on other pools of P or select for microorganisms with increased P scavenging capabilities. Hence, the microbial community at the former S-3 Ponds contamination site may be constrained not only by increased toxic metal concentrations but also by the availability of essential elements, including P.

Abstract Background Breaking bad news is one of the most difficult aspects of communication in medicine. The objective of this study was to assess the relevance of a novel active learning course on breaking bad news for fifth-year students. Methods Students were divided into two groups: Group 1, the intervention group, participated in a multidisciplinary formative discussion workshop on breaking bad news with videos, discussions with a pluri-professional team, and concluding with the development of a guide on good practice in breaking bad news through collective intelligence; Group 2, the control group, received no additional training besides conventional university course. The relevance of discussion-group-based active training was assessed in a summative objective structured clinical examination (OSCE) station particularly through the students’ communication skills. Results Thirty-one students were included: 17 in Group 1 and 14 in Group 2. The mean (range) score in the OSCE was significantly higher in Group 1 than in Group 2 (10.49 out of 15 (7; 13) vs. 7.80 (4.75; 12.5), respectively; p = 0.0007). The proportion of students assessed by the evaluator to have received additional training in breaking bad news was 88.2% (15 of the 17) in Group 1 and 21.4% (3 of the 14) in Group 2 (p = 0.001). The intergroup differences in the Rosenberg Self-Esteem Scale and Jefferson Scale of Empathy scores were not significant, and both scores were not correlated with the students’ self-assessed score for success in the OSCE. Conclusion Compared to the conventional course, this new active learning method for breaking bad news was associated with a significantly higher score in a summative OSCE. A longer-term validation study is needed to confirm these exploratory data.

Abstract Background Spinal muscular atrophy type 1 (SMA1) is the most severe and early form of SMA, a genetic disease with motor neuron degeneration. Onasemnogene abeparvovec gene transfer therapy (GT) has changed the natural history of SMA1, but real-world data are scarce. Methods A French national expert committee identified 95 newly diagnosed treatment-naive SMA1 patients between June 2019 and June 2022. We prospectively report on children treated with GT as the first and only therapy who had more than one-year of follow-up. Results Forty-six SMA1 patients received GT. Twelve patients received other treatments. Patients with respiratory insufficiency were oriented toward palliative care after discussion with families. Twenty-nine of the treated patients with more than 12 months of follow-up were included in the follow-up analysis. Among them, 17 had 24 months of follow-up. The mean age at treatment was 7.5 (2.1–12.5) months. Twenty-two patients had two SMN2 copies, and seven had three copies. One infant died in the month following GT due to severe thrombotic microangiopathy, and another died due to respiratory distress. Among the 17 patients with 24 months of follow-up, 90% required spinal bracing (15/17), three patients required nocturnal noninvasive ventilation, and two needed gastrostomy. Concerning motor milestones at the 24-month follow-up, all patients held their head, 15/17 sat for 30 s unassisted, and 12/17 stood with aid. Motor scores (CHOPINTEND and HINE-2) and thoracic circumference significantly improved in all patients. Conclusions Our study shows favorable motor outcomes and preserved respiratory and feeding functions in treatment-naive SMA1 infants treated by GT as the first and only therapy before respiratory and bulbar dysfunctions occurred. Nevertheless, almost all patients developed spinal deformities.

Abstract The neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species. The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors and the emergence of indirect neurogenesis during brain evolution. The molecular pathways that control these biological processes and are disrupted in neurological disorders remain largely unknown. Here we show that the transcription factors BRN1 and BRN2 have an evolutionary conserved function in neocortical progenitors to control their proliferative capacity and the switch from direct to indirect neurogenesis. Functional studies in mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution.

Abstract Background The main aim of this study was to build an item bank for assessing the care quality of multi-professional healthcare centers (MPHCC) from the perspective of patients with multimorbidity. This study was part of the QUALSOPRIM (QUALité des SOins PRIMaires; primary healthcare quality) research project to create a psychometrically robust self-administered questionnaire to assess healthcare quality. Methods First, twelve experts built an item bank using data from a previous qualitative work and a systematic literature review. Second, the validity of each item was assessed in a sample of patients. Adult patients with multimorbidity were recruited from six French MPHCC. Items were assessed based on ceiling effects, the level of missing or neutral responses and patient feedback. Patient feedback was recorded after the item bank completion. Based on results, items were validated, improved, or removed during expert meetings. In case of disagreement the Delphi method was used to reach consensus. Results The study sample included 209 outpatients. The most frequent medical conditions were cardiovascular risk factors, cardiovascular diseases and rheumatological conditions. In total, a bank of 109 items classified in nine domains was built. The validity assessment led to the removal of 34 items. Retained items explored a variety of topics related to care quality: availability, accessibility, premises’ layout and building, technical care, expertise, organization, relationships with caregivers and communication, involvement and personal relationships. Conclusions This study allowed cross-validation of a bank of 75 items, leading to a complete picture of the patient perception of care quality items. Overall, patients were generally satisfied with their care at the MPHCC. Nonetheless, there were still numerous items on subjects for which patients’ satisfaction could be improved.

Abstract More than half of the world’s rivers dry up periodically, but our understanding of the biological communities in dry riverbeds remains limited. Specifically, the roles of dispersal, environmental filtering and biotic interactions in driving biodiversity in dry rivers are poorly understood. Here, we conduct a large-scale coordinated survey of patterns and drivers of biodiversity in dry riverbeds. We focus on eight major taxa, including microorganisms, invertebrates and plants: Algae, Archaea, Bacteria, Fungi, Protozoa, Arthropods, Nematodes and Streptophyta. We use environmental DNA metabarcoding to assess biodiversity in dry sediments collected over a 1-year period from 84 non-perennial rivers across 19 countries on four continents. Both direct factors, such as nutrient and carbon availability, and indirect factors such as climate influence the local biodiversity of most taxa. Limited resource availability and prolonged dry phases favor oligotrophic microbial taxa. Co-variation among taxa, particularly Bacteria, Fungi, Algae and Protozoa, explain more spatial variation in community composition than dispersal or environmental gradients. This finding suggests that biotic interactions or unmeasured ecological and evolutionary factors may strongly influence communities during dry phases, altering biodiversity responses to global changes.

Abstract Rehabilitation technologies offer promising opportunities for interventions for patients with motor disabilities. However, their use in routine care remains limited due to their high cost and persistent doubts about their cost-effectiveness. Providing solid evidence of the economic efficiency of rehabilitation technologies would help dispel these doubts in order to better take advantage of these technologies. In this context, this systematic review aimed to examine the cost-effectiveness of rehabilitation interventions based on the use of digital technologies. In total, 660 articles published between 2011 and 2021 were identified, of which eleven studies met all the inclusion criteria. Of these eleven studies, seven proved to be cost-effective, while four were not. Four studies used cost-utility analyses (CUAs) and seven used cost-minimization analyses (CMAs). The majority (ten studies) focused on the rehabilitation of the upper and/or lower limbs after a stroke, while only one study examined the rehabilitation of the lower limbs after knee arthroplasty. Regarding the evaluated devices, seven studies analyzed the cost-effectiveness of robotic rehabilitation and four analyzed rehabilitation with virtual reality.The assessment of the quality of the included studies using the CHEERS (Consolidated Health Economic Evaluation Reporting Standards) suggested that the quality was related to the economic analysis method: all studies that adopted a cost-utility analysis obtained a high quality score (above 80%), while the quality scores of the cost-minimization analyses were average, with the highest score obtained by a CMA being 72%. The average quality score of all the articles was 75%, ranging between 52 and 100. Of the four studies with a considering score, two concluded that there was equivalence between the intervention and conventional care in terms of cost-effectiveness, one concluded that the intervention dominated, while the last one concluded that usual care dominated. This suggests that even considering the quality of the included studies, rehabilitation interventions based on digital technologies remain cost-effective, they improved health outcomes and quality of life for patients with motor disorders while also allowing cost savings.

PURPOSE: Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS: A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS: Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation (P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION: Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

BackgroundTreatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies.MethodsThis multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided.ResultsAmong 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P

Research development in higher education is a service-delivery system. In any service field, when choosing appropriate services, practitioners should reach for 'evidence-based practices.' Limited empirical research has addressed the preferences of research faculty regarding research support services. In this project, we sought to provide research development professionals with critical knowledge related to decision making and strategic utilization of resources and in choosing client-centered grant-related services for faculty. The specific research question or objective of this study was to answer, "What factors are perceived by faculty to be barriers or facilitators to grants activity based on extant literature?" This systematic literature review on faculty perceptions of barriers and facilitators to grant activity used an eight-step systematic literature review methodology. The findings describe the characteristics, methodological attributes, and the methodological quality of the articles. Additionally, the integration of the findings revealed eight main factors that faculty perceived to be important for facilitating or hindering grant activity. Three main emerging factors or core categories appeared to be most important across all barriers or facilitators to faculty grant activity. Research development professionals need to be able to provide evidence-based and client-centered research support services. This review provides the factors that faculty view as being most important to grant activity and recommendations for management. Implementing effective client-centered research support services is critical for the success of faculty grant activity.

Abstract Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8–10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.