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Abstract Permafrost thaw poses diverse risks to Arctic environments and livelihoods. Understanding the effects of permafrost thaw is vital for informed policymaking and adaptation efforts. Here, we present the consolidated findings of a risk analysis spanning four study regions: Longyearbyen (Svalbard, Norway), the Avannaata municipality (Greenland), the Beaufort Sea region and the Mackenzie River Delta (Canada) and the Bulunskiy District of the Sakha Republic (Russia). Local stakeholders’ and scientists’ perceptions shaped our understanding of the risks as dynamic, socionatural phenomena involving physical processes, key hazards, and societal consequences. Through an inter- and transdisciplinary risk analysis based on multidirectional knowledge exchanges and thematic network analysis, we identified five key hazards of permafrost thaw. These include infrastructure failure, disruption of mobility and supplies, decreased water quality, challenges for food security, and exposure to diseases and contaminants. The study’s novelty resides in the comparative approach spanning different disciplines, environmental and societal contexts, and the transdisciplinary synthesis considering various risk perceptions.

Background: Rupture of the long head of the distal bifid biceps tendon is a rare injury, for which surgical anatomical repair should be considered in active patients. The aim of this study was to review our patients who benefited from the EndoButton technique via a single anterior approach, comparing the clinical outcomes with the contralateral uninjured side and assessing their quality of life. Our hypothesis was that an “anatomical” insertion, through an anterior approach, by reinserting the 2 distinct tendons on the radial tuberosity, would restore the supination ability of the forearm more effectively than flexion strength. Methods: This study included 25 patients who underwent surgery between June 2015 and January 2021. All patients underwent distal biceps reattachment using an endo-osseous fixation technique with the same device. Each patient completed a quality-of-life questionnaire and participated in biomechanical performance tests. Results: We observed a significant 14% reduction in strength during flexion on the operated side compared to the healthy side. However, no significant differences in strength were found for supination, extension, and pronation between the operated and nonoperated limbs in these same patients. In terms of endurance, flexion on the operated side tended to exhibit greater endurance than on the healthy side, while endurance in supination appeared similar between the operated and healthy sides. This finding held irrespective of whether the operated limb was dominant or nondominant. We also discovered a strong correlation between the time elapsed since surgery and differences in strength during both flexion and supination. Conclusion: The ultimate goal is to achieve an anatomical surgical repair to restore all functions and maximize patient outcomes. As demonstrated, we have obtained good clinical results with EndoButton repair and a single anterior approach. The results in terms of strength and endurance are similar to those reported in the literature, and all our patients are satisfied. No postoperative complications were found.

BACKGROUND: Type 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers). METHODS: This epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre- vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7). RESULTS: The median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions. CONCLUSION: Differentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function.

Background Glioblastoma is a highly infiltrative, currently incurable brain cancer. To date, translation of novel therapies for glioblastoma from the laboratory into clinical trials has relied heavily on in vitro cell culture and murine (subcutaneous and orthotopic) xenograft models using cells derived from the main bulk of patient tumours. However, it is the residual cells left-behind after surgery that are responsible for disease progression and death in the clinic. A lack of substantial improvements in patient survival for decades suggests commonly used murine xenograft models, a key step before clinical trials, do not reflect the biology of residual disease in patients. Methods To address this, we have developed the ‘Sheffield Protocol’ to generate ex vivo models that reflect both resected, and post-surgical residual disease from the same patient. The protocol leverages parallel derivation of inherently treatment-resistant glioblastoma stem cells (GSCs) from ‘core’ and distant ‘edge’ regions through careful macrodissection of a large en bloc specimen, such as from a partial lobectomy for tumour, followed by tissue dissociation and propagation in serum-free media. Opportunistic en bloc specimen use can liberate the most distant infiltrative cells feasibly accessible from living patients. Results We provide an example illustrating that resected and residual disease models represent spatially divergent tumour subpopulations harbouring distinct transcriptomic and cancer stem cell marker expression profiles. We also introduce the ‘Sheffield Living Biobank’ of glioma models (SLB) that incorporates over 150 GSC lines from 60+ patients, including 44+ resected and residual models, which are available for academic use via MTA. Conclusions These models provide a novel tool to reduce animal xenograft usage by improving candidate drug triage in early preclinical studies and directly replacing animal studies for some therapies that are post-Phase 1+ clinical trial for other cancers/conditions to, ultimately, deliver more effective treatments for post-surgical residual disease in glioblastoma.

BackgroundUnderstanding genetic underpinnings of immune-mediated inflammatory diseases is crucial to improve treatments. Single-cell RNA sequencing (scRNA-seq) identifies cell states expanded in disease, but often overlooks genetic causality due to cost and small genotyping cohorts. Conversely, large genome-wide association studies (GWAS) are commonly accessible.MethodsWe present a 3-step robust benchmarking analysis of integrating GWAS and scRNA-seq to identify genetically relevant cell states and genes in inflammatory diseases. First, we applied and compared the results of three recent algorithms, based on pathways (scGWAS), single-cell disease scores (scDRS), or both (scPagwas), according to accuracy/sensitivity and interpretability. While previous studies focused on coarse cell types, we used disease-specific, fine-grained single-cell atlases (183,742 and 228,211 cells) and GWAS data (Ns of 97,173 and 45,975) for rheumatoid arthritis (RA) and ulcerative colitis (UC). Second, given the lack of scRNA-seq for many diseases with GWAS, we further tested the tools’ resolution limits by differentiating between similar diseases with only one fine-grained scRNA-seq atlas. Lastly, we provide a novel evaluation of noncoding SNP incorporation methods by testing which enabled the highest sensitivity/accuracy of known cell-state calls.ResultsWe first found that single-cell based tools scDRS and scPagwas called superior numbers of supported cell states that were overlooked by scGWAS. While scGWAS and scPagwas were advantageous for gene exploration, scDRS effectively accounted for batch effect and captured cellular heterogeneity of disease-relevance without single-cell genotyping. For noncoding SNP integration, we found a key trade-off between statistical power and confidence with positional (e.g. MAGMA) and non-positional approaches (e.g. chromatin-interaction, eQTL). Even when directly incorporating noncoding SNPs through 5’ scRNA-seq measures of regulatory elements, non disease-specific atlases gave misleading results by not containing disease-tissue specific transcriptomic patterns. Despite this criticality of tissue-specific scRNA-seq, we showed that scDRS enabled deconvolution of two similar diseases with a single fine-grained scRNA-seq atlas and separate GWAS. Indeed, we identified supported and novel genetic-phenotype linkages separating RA and ankylosing spondylitis, and UC and crohn’s disease. Overall, while noting evolving single-cell technologies, our study provides key findings for integrating expanding fine-grained scRNA-seq, GWAS, and noncoding SNP resources to unravel the complexities of inflammatory diseases.

BackgroundOxylipins are inflammatory biomarkers derived from omega-3 and-6 fatty acids implicated in inflammatory diseases but have not been studied in a genome-wide association study (GWAS). The aim of this study was to identify genetic loci associated with oxylipins and oxylipin profiles to identify biologic pathways and therapeutic targets for oxylipins.MethodsWe conducted a GWAS of plasma oxylipins in 316 participants in the Diabetes Autoimmunity Study in the Young (DAISY). DNA samples were genotyped using the TEDDY-T1D Exome array, and additional variants were imputed using the Trans-Omics for Precision Medicine (TOPMed) multi-ancestry reference panel. Principal components analysis of 36 plasma oxylipins was used to capture oxylipin profiles. PC1 represented linoleic acid (LA)- and alpha-linolenic acid (ALA)-related oxylipins, and PC2 represented arachidonic acid (ARA)-related oxylipins. Oxylipin PC1, PC2, and the top five loading oxylipins from each PC were used as outcomes in the GWAS (genome-wide significance: p

Oxylipins, pro-inflammatory and pro-resolving lipid mediators, are associated with the risk of type 1 diabetes (T1D) and may be influenced by diet. This study aimed to develop a nutrient pattern related to oxylipin profiles and test their associations with the risk of T1D among youth. The nutrient patterns were developed with a reduced rank regression in a nested case-control study (n = 335) within the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal cohort of children at risk of T1D. The oxylipin profiles (adjusted for genetic predictors) were the response variables. The nutrient patterns were tested in the case-control study (n = 69 T1D cases, 69 controls), then validated in the DAISY cohort using a joint Cox proportional hazards model (n = 1933, including 81 T1D cases). The first nutrient pattern (NP1) was characterized by low beta cryptoxanthin, flavanone, vitamin C, total sugars and iron, and high lycopene, anthocyanidins, linoleic acid and sodium. After adjusting for T1D family history, the HLA genotype, sex and race/ethnicity, NP1 was associated with a lower risk of T1D in the nested case-control study (OR: 0.44, p = 0.0126). NP1 was not associated with the risk of T1D (HR: 0.54, p-value = 0.1829) in the full DAISY cohort. Future studies are needed to confirm the nested case-control findings and investigate the modifiable factors for oxylipins.

BackgroundHTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors.Patients and methodsWe recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification.ResultsWe found that systemic IL-6 was positively correlated with both age (r = 0.50, p

BackgroundThere has been renewed focus on advancing inclusivity within organized medicine to reduce health disparities and achieve health equity by addressing the deleterious effects of implicit bias in healthcare and clinical outcomes. It is well documented that negative implicit attitudes and stereotypes perpetuate inequity in healthcare. The aim of this study is to investigate implicit bias training in postgraduate physician assistant (PA) and nurse practitioner (NP) education; describe delivery of content to trainees; and detail program directors' attitudes toward this type of training. Although there is research examining implicit bias training in physician residency education, there are no published studies on implicit bias training in postgraduate PA and NP postgraduate residency/fellowship programs.MethodA non-experimental, descriptive study was designed to obtain information via survey from members of the Association of Postgraduate Physician Assistant Programs (APPAP).ResultsThe response rate was 41%. The majority of respondents (76%) felt that PA and NP postgraduate programs should include implicit bias instruction. Educational strategies used by PA and joint PA/NP postgraduate programs or their sponsoring institution to deliver implicit bias content to trainees include: implicit bias training modules (50%), facilitated group discussions (36%), invited speaker on implicit bias (33%), case studies on implicit bias (16%), and implicit association test (10%); however, 30% of postgraduate programs do not provide implicit bias training to PA and/or NP trainees. Barriers to implementing implicit bias training expressed by some postgraduate programs include: uncertainty in how to incorporate implicit bias training (16%); lack of strategic alignment with training program or sponsoring institution (13%); time constraints (10%); financial constraints (6%); lack of access to content experts (6%); and unfamiliarity with evidence supporting implicit bias training (6%).ConclusionThe present study sheds some light on the current state of implicit bias training in PA and joint PA/NP postgraduate residency/fellowship programs. While the majority of programs offer some sort of implicit bias training, there is a need to standardize this training in PA and joint PA/NP postgraduate education curricula using an actionable framework.

Following publication of the original article [1], the author informed us that the response rate was incorrectly reported. The updated rate is given below and the changes have been highlighted in bold typeface as follows: Abstract Results: Twenty-three out of 73 postgraduate programs (31.5%) responded to the survey. The study reported that applicant PAs and nurse practitioners (NPs) are largely selected on the basis of several factors. Results Seventy-three postgraduate programs were invited to participate, and 23 programs completed the entire survey. The overall response rate was 31.5%. Limitations Third, this study includes a low response rate of (31.5%), which may have contributed to response bias. The original article has been corrected.

BackgroundType 1 diabetes (T1D) is preceded by a heterogenous pre-clinical phase, islet autoimmunity (IA). We aimed to identify pre vs. post-IA seroconversion (SV) changes in DNAm that differed across three IA progression phenotypes, those who lose autoantibodies (reverters), progress to clinical T1D (progressors), or maintain autoantibody levels (maintainers).MethodsThis epigenome-wide association study (EWAS) included longitudinal DNAm measurements in blood (Illumina 450K and EPIC) from participants in Diabetes Autoimmunity Study in the Young (DAISY) who developed IA, one or more islet autoantibodies on at least two consecutive visits. We compared reverters - individuals who sero-reverted, negative for all autoantibodies on at least two consecutive visits and did not develop T1D (n=41); maintainers - continued to test positive for autoantibodies but did not develop T1D (n=60); progressors - developed clinical T1D (n=42). DNAm data were measured before (pre-SV visit) and after IA (post-SV visit). Linear mixed models were used to test for differences in pre- vs post-SV changes in DNAm across the three groups. Linear mixed models were also used to test for group differences in average DNAm. Cell proportions, age, and sex were adjusted for in all models. Median follow-up across all participants was 15.5 yrs. (interquartile range (IQR): 10.8-18.7).ResultsThe median age at the pre-SV visit was 2.2 yrs. (IQR: 0.8-5.3) in progressors, compared to 6.0 yrs. (IQR: 1.3-8.4) in reverters, and 5.7 yrs. (IQR: 1.4-9.7) in maintainers. Median time between the visits was similar in reverters 1.4 yrs. (IQR: 1-1.9), maintainers 1.3 yrs. (IQR: 1.0-2.0), and progressors 1.8 yrs. (IQR: 1.0-2.0). Changes in DNAm, pre- vs post-SV, differed across the groups at one site (cg16066195) and 11 regions. Average DNAm (mean of pre- and post-SV) differed across 22 regions.ConclusionDifferentially changing DNAm regions were located in genomic areas related to beta cell function, immune cell differentiation, and immune cell function.

The regulation of seal and whale hunting in Kalaallit Nunaat (Greenland) belongs to the Naalakkersuisut (National Government), which is notably informed by the work of the Scientific Committee (SC) of the North Atlantic Marine Mammal Commission (NAMMCO). Since 2004, quotas were set in Kalaallit Nunaat to regulate hunting practices and promote ecologically sustainable harvesting. In South East Greenland, the SC's recommendations for the closure of the narwhal (Monodon monoceros or qialuar) hunt since 2019 has met both national disagreement and local resistance due to a desire to preserve the long-standing relation with narwhals organised around hunting, which is strongly intertwined within place-based communities’ experiences. The situation requires further attention to deploy an informed dialogue in the light of both available literature and local narratives capturing knowledge and values which are underrepresented within scientific discussions, as are social sciences. Grounded in repetitive and long-standing research fieldwork in Ittoqqortoormiit, and extensive qualitative data collection from 2019 to 2023, the article shows that community members express strong attachment and concern towards narwhal hunting together with the social, economic and cultural importance of mattak (narwhal skin). Local narratives also suggest that the resistance against limitations on narwhal hunting is not to be understood only as a conservatism that aims to preserve traditional hunting practices or about sustaining economic incomes for hunters, but in a significant way as protest against epistemic injustices, resulting from a feeling of being systematically unheard, distrusted and uninvolved in decision-making processes. Together with the expression of concern and attachment for narwhal hunting, the tensions between scientific knowledge and local value and knowledge were reiterated while shared concern for the preservation of the species is affirmed. We show that legitimacy and credibility of the scientific evidence and species management are contested. Ultimately, we ascertain the situation of epistemic injustices and raise the need to shift towards decolonial practices to open the possibility for the emergence of a fair and respectful dialogue that would support narwhal preservation, through securing hunters' material living conditions, community food security, and ensuring consideration and respect is given to individual and collective immaterial dimensions associated with narwhal.

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997–2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.

Objective/Research Question: The urgency to replace retiring community college leaders has been a topic of research and discussion for the past two decades. Concurrently, expansive definitions of leadership and collaborative approaches to leading have emerged. The central research question for this study was: How do sitting community college leaders define leadership? The sub-questions included: Do definitions of leadership differ by gender? Do definitions of leadership differ by position? Methods: Coding of survey data from approximately 770 sitting leaders occurred based on responses to the prompt: How do you define leadership? Descriptive statistical analysis occurred based on demographics and on position related to the coded responses. Results: This study found three prevalent ways of defining leadership: leader-focused (leader's abilities mentioned); other-focused (leader included others, collaboration mentioned); institution-focused (leader focused on institutional needs/mission). About half of both women and men used leader-focused definitions, with slightly more men than women in the tallies. More women than men used other-focused definitions, whereas men used definitions more institutionally focused compared to women (not statistically significant). Leader-focused definitions were also most prevalent by position, with mid-level leaders using this definition slightly more than top-level leaders. Top-level leaders used a combination of institution-focused definitions more so than mid-level leaders, however (not statistically significant). Conclusions: A shift to more other-focused ways of leading is emerging. Those in mid-level positions hold onto leader-focused definitions of leadership, and this points to the need to reconceptualize mid-level leadership and ideas of leading that include others and connect to institutional missions and initiatives. The complex nature of today's organizations requires broader conceptions of leadership.

Abstract Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is ‘at-risk’ for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA. Tetramer studies show increased abundance of T cells recognizing citrullinated (cit) epitopes in At-Risk participants, including expansion of T cells reactive to citrullinated cartilage intermediate layer protein I (cit-CILP); these T cells have Th1, Th17, and T stem cell memory-like phenotypes. Antibody-antigen array analyses show that antibodies targeting cit-clusterin, cit-fibrinogen and cit-histone H4 are elevated in At-Risk and Early RA participants, with the highest levels of antibodies detected in those with Early RA. These findings indicate that an ACPA positive at-risk state is associated with multifaceted immune dysregulation that may represent a potential opportunity for targeted intervention.

IntroductionThe development of postgraduate programs for physician assistants (PAs) began in 1973 and by 2020 there were approximately 72 programs spread across a broad range of medical and surgical disciplines. PA Post-graduate education programs are voluntary and available to American licensed PAs. Therefore, an assessment of the characteristics of PA post-graduate fellowships and residencies programs was initiated.MethodA non-experimental, descriptive research study was designed to obtain information on the characteristics of PA postgraduate education programs in the US. The source of information was from surveyed members of the Association of Postgraduate Physician Assistant Programs (APPAP). Questions were drawn from consensus discussions. Directors of postgraduate programs that were operational in 2020 were eligible to participate.ResultsSeventy-two postgraduate program directors were invited to the survey and 34 program directors replied. These programs are geographically distributed across the US in 13 states. The respondents represent a wide range of medicine: surgery, emergency medicine, critical care, orthopaedics, hospitalist, psychiatry, oncology, primary care, pediatrics, and cardiology. Most programs are associated with an academic medical center and some institutions have more than one postgraduate specialty track. The curriculum includes bedside teaching, lectures, mentorship, assigned reading, procedures, simulation, and conferences. An average program length is 12 months and awards a certificate. Stipends for PA fellows are $50,000-80,000 (2020 dollars) and benefits include paid time off, health and liability insurance. About half of the programs bill for the services rendered by the PA. Over 90% of graduates are employed within 2 months of completing a PA postgraduate training program.ConclusionA trend is underway in American medicine to include PAs in postgraduate education. PA postgraduate training occurs across a broad spectrum of medical and surgical areas, as well as diverse institutions and organizations overseeing these programs. Most PA postgraduate programs are in teaching hospitals where the PA resident or PA fellow also serves as a house officer alongside a categorical resident. This study sets the stage for more granular economic and social research on this growing phenomenon in American medicine.

BackgroundThis study aims to investigate the admission criteria used by physician assistant postgraduate education programs in selecting licensed PA applicants for postgraduate training in the United States. To our knowledge, there have been no previously published reports on selection criteria and/or other factors influencing postgraduate PA admission decisions.MethodA non-experimental, descriptive research study was designed to obtain information from members of the Association of Postgraduate Physician Assistant Programs (APPAP).ResultsTwenty-three out of 73 postgraduate programs (35%) responded to the survey. The study reported that applicant PAs and NPs are largely selected on the basis of several factors. The most heavily weighted factor is the interview itself; other selection criteria perceived to be extremely/very important included board certification/eligibility, letters of recommendation, advanced degree, and personal essay. Survey data suggest that publications, undergraduate transcripts, and class rankings are not considered to be of high importance in applicant selection. The number of PA applicants applying to each postgraduate training program averages around 26 and total number of enrollees is about 3.6 per program. Additionally, some programs reported furloughing of trainees (temporary suspension of didactic and clinical training) during the pandemic, whereas the vast majority of postgraduate PA programs remained operational and some even experienced an increase in application volume. The total cost of training a PA resident or fellow in postgraduate programs is currently $93,000 whereas the average cost of training a categorical physician resident is estimated at $150,000 per year when considering both salary and benefits.ConclusionsThis novel study examined criteria and other factors used by postgraduate PA programs in selecting candidates for admission. Results can be used by postgraduate programs to improve or modify current selection criteria to enhance the quality of trainee selection. Further research is needed to examine correlations between applicant attributes, selection criteria, and trainee success in completing postgraduate training.

Abstract Background Dosimetry after radiopharmaceutical therapy with 177Lu (177Lu-RPT) relies on quantitative SPECT/CT imaging, for which suitable reconstruction protocols are required. In this study, we characterized for the first time the quantitative performance of a ring-shaped CZT-based camera using two different reconstruction algorithms: an ordered subset expectation maximization (OSEM) and a block sequential regularized expectation maximization (BSREM) combined with noise reduction regularization. This study lays the foundations for the definition of a reconstruction protocol enabling accurate dosimetry for patients treated with 177Lu-RPT. Methods A series of 177Lu-filled phantoms were acquired on a StarGuide™ (GE HealthCare), with energy and scatter windows centred at 208 (± 6%) keV and 185 (± 5%) keV, respectively. Images were reconstructed with the manufacturer implementations of OSEM (GE-OSEM) and BSREM (Q.Clear) algorithms, and various combinations of iterations and subsets. Additionally, the manufacturer-recommended Q.Clear-based reconstruction protocol was evaluated. Quantification accuracy, measured as the difference between the SPECT-based and the radionuclide calibrator-based activity, and noise were evaluated in a large cylinder. Recovery coefficients (RCs) and spatial resolution were assessed in a NEMA IEC phantom with sphere inserts. The reconstruction protocols considered suitable for clinical applications were tested on a cohort of patients treated with [177Lu]Lu-PSMA-I&T. Results The accuracy of the activity from the cylinder, although affected by septal penetration, was

Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk. These pairs included five DNAm probes mediated by histidine (a metabolite known to affect T1D risk), one probe (cg01604946) mediated by phostidyl choline p-32:0 or o-32:1, and one probe (cg00390143) mediated by sphingomyelin d34:2. The top 100 DNAm probes were over-represented in six reactome pathways at the FDR

Aims/hypothesisOxylipins are lipid mediators derived from polyunsaturated fatty acids. Some oxylipins are proinflammatory (e.g. those derived from arachidonic acid [ARA]), others are pro-resolving of inflammation (e.g. those derived from α-linolenic acid [ALA], docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) and others may be both (e.g. those derived from linoleic acid [LA]). The goal of this study was to examine whether oxylipins are associated with incident type 1 diabetes.MethodsWe conducted a nested case-control analysis in the Diabetes Autoimmunity Study in the Young (DAISY), a prospective cohort study of children at risk of type 1 diabetes. Plasma levels of 14 ARA-derived oxylipins, ten LA-derived oxylipins, six ALA-derived oxylipins, four DHA-derived oxylipins and two EPA-related oxylipins were measured by ultra-HPLC-MS/MS at multiple timepoints related to autoantibody seroconversion in 72 type 1 diabetes cases and 71 control participants, which were frequency matched on age at autoantibody seroconversion (of the case), ethnicity and sample availability. Linear mixed models were used to obtain an age-adjusted mean of each oxylipin prior to type 1 diabetes. Age-adjusted mean oxylipins were tested for association with type 1 diabetes using logistic regression, adjusting for the high risk HLA genotype HLA-DR3/4,DQB1*0302. We also performed principal component analysis of the oxylipins and tested principal components (PCs) for association with type 1 diabetes. Finally, to investigate potential critical timepoints, we examined the association of oxylipins measured before and after autoantibody seroconversion (of the cases) using PCs of the oxylipins at those visits.ResultsThe ARA-related oxylipin 5-HETE was associated with increased type 1 diabetes risk. Five LA-related oxylipins, two ALA-related oxylipins and one DHA-related oxylipin were associated with decreased type 1 diabetes risk. A profile of elevated LA- and ALA-related oxylipins (PC1) was associated with decreased type 1 diabetes risk (OR 0.61; 95% CI 0.40, 0.94). A profile of elevated ARA-related oxylipins (PC2) was associated with increased diabetes risk (OR 1.53; 95% CI 1.03, 2.29). A critical timepoint analysis showed type 1 diabetes was associated with a high ARA-related oxylipin profile at post-autoantibody-seroconversion but not pre-seroconversion.Conclusions/interpretationThe protective association of higher LA- and ALA-related oxylipins demonstrates the importance of both inflammation promotion and resolution in type 1 diabetes. Proinflammatory ARA-related oxylipins may play an important role once the autoimmune process has begun.

Reversion of islet autoimmunity (IA) may point to mechanisms that prevent IA progression. We followed 199 individuals who developed IA during the Diabetes Autoimmunity Study in the Young. Untargeted metabolomics was performed in serum samples following IA. Cox proportional hazards models were used to test whether the metabolites (2,487) predicted IA reversion: two or more consecutive visits negative for all autoantibodies. We conducted a principal components analysis (PCA) of the top metabolites; |hazard ratio (HR) >1.25| and nominal P < 0.01. Phosphatidylcholine (16:0_18:1(9Z)) was the strongest individual metabolite (HR per 1 SD 2.16, false discovery rate (FDR)-adjusted P = 0.0037). Enrichment analysis identified four clusters (FDR P < 0.10) characterized by an overabundance of sphingomyelin (d40:0), phosphatidylcholine (16:0_18:1(9Z)), phosphatidylcholine (30:0), and l-decanoylcarnitine. Overall, 63 metabolites met the criteria for inclusion in the PCA. PC1 (HR 1.4, P < 0.0001), PC2 (HR 0.85, P = 0.0185), and PC4 (HR 1.28, P = 0.0103) were associated with IA reversion. Given the potential influence of diet on the metabolome, we investigated whether nutrients were correlated with PCs. We identified 20 nutrients that were correlated with the PCs (P < 0.05). Total sugar intake was the top nutrient. Overall, we identified an association between phosphatidylcholine, sphingomyelin, and carnitine levels and reversion of IA.

BackgroundOxylipins are formed from oxidation of omega-6 (n6) and omega-3 (n3) fatty acids (FAs). Evidence for inflammatory effects comes mostly from adults.MethodsOxylipins from n6 FA (27 n6-oxylipins) and n3 FA (12 n3-oxylipins) were measured through ultra-high-performance liquid chromatography-mass spectrometry (LC-MS/MS) in plasma from 111 children at risk of type 1 diabetes (age 1-17 years) studied longitudinally. Oxylipin precursor FAs (arachidonic acid, linoleic acid, alpha-linolenic acid, docosahexaenoic acid, eicosapentaenoic acid) were measured in red blood cell (RBC) membrane and plasma. Precursor FAs dietary intake was measured through food frequency questionnaire and environmental tobacco smoke (ETS) through questionnaires. Linear mixed models were used to test oxylipins with predictors.ResultsAge associated with 15 n6- and 6 n3-oxylipins; race/ethnicity associated with 3 n6- and 1 n3-oxylipins; sex associated with 2 n6-oxylipins. ETS associated with lipoxin-A4. Oxylipins associated with precursor FAs in plasma more often than RBC. RBC levels and dietary intake of precursor FAs more consistently associated with n3-oxylipins than with n6-oxylipins.ConclusionsIn healthy children, oxylipin levels change with age. Oxylipins associated with precursor FAs more often in plasma than RBC or diet, suggesting that inflammatory regulation leading to FA release into plasma may also be a determinant of oxylipin generation.ImpactThis is the first study to examine predictors of oxylipins in healthy children at risk of type 1 diabetes. In healthy children at risk of type 1 diabetes, many oxylipins change with age, and most oxylipins do not differ by sex or race/ethnicity. Environmental tobacco smoke exposure was associated with the presence of lipoxin A4. Omega-6- and omega-3-related oxylipin levels were consistently associated with their respective precursor fatty acid levels measured in the plasma. Proportionally more omega-3 compared to omega-6 oxylipins were associated with dietary intake and red blood cell membrane levels of the respective precursor fatty acid.

Orchards have a high potential for carbon sequestration. However, little research is available on the spatial variability at catchment scale and on the difference between the tree area and the lanes. We analyzed theik spatial variability of soil organic carbon stock, SOCstock at 90 cm depth in an 8-ha catchment in Southern Spain with olives on a vertic soil. Results showed higher soil organic carbon concentration, SOC, in the tree area as compared to the lane up to 60 cm depth, but its impact on SOCstock was negligible since it was compensated by the higher soil bulk density in the lane. SOC at different depths was correlated with that in the top 0–5 cm. The overall SOCstock of the orchard was 4.14 kg m−2, ranging between 1.8 and 6.0 kg m−2. This SOCstock is in the mid-lower range of values reported for olive orchards, measured at smaller scale, and similar to those other intensive field crops and agroforestry under comparable rainfall conditions. The spatial variability in SOCstock was correlated to several geomorphological variables: elevation, cumulative upstream area, topographic wetness index, sediment transport index, and tillage erosion. Differences in SOC and SOCstock are driven by the sediment redistribution downslope, mainly by tillage erosion, and higher soil water availability in lower areas allowing higher biomass production. These topographic indexes and the correlation between SOC in the topsoil and SOCstock up to 90 cm should be further explored in other typology of olive orchards for facilitating the mapping of SOCstock.