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Background: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking. Materials and Methods: This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code. Results: Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed.A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58–0.85]; P = 4 ×10−4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 - 0.93]; P = 0.005).Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

Abstract The increasing availability of ultrabright Light Sources is facilitating the study of smaller crystals at faster timescales but with an increased risk of severe X-ray damage, leading to developments in multi-crystal methods such as serial crystallography (SX). SX studies on crystals with small unit cells are challenging as very few reflections are recorded in a single data image, making it difficult to determine the orientation matrix for each crystal and thus preventing the combination of the data from all crystals for structure solution. We herein present a Small-Rotative Fixed-Target Serial Synchrotron Crystallography (SR-FT-SSX) methodology, in which rotation of the serial target through a small diffraction angle $$(\varphi )$$ ( φ ) at each crystal delivers high-quality data, facilitating ab initio unit cell determination and atomic-scale structure solution. The method is benchmarked using microcrystals of the small-molecule photoswitch sodium nitroprusside dihydrate, obtaining complete data to d min = 0.6 Å by combining just 66 partial datasets selected against rigorous quality criteria.

Nephroblastoma or Wilms’ tumor (WT) is the most common pediatric renal malignancy but rare in adults. Treatment protocols for adults are typically extrapolated from pediatric guidelines, but there are no standard guidelines for adults due to the rarity of the disease. However, next-generation sequencing has led to new therapeutic options for adult WT patients. We present the first case to our knowledge of a recurrent adult WT treated with dual BRAF/MEK–targeted therapy, which showed initial robust clinical response and was well tolerated.

Summary: In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12high) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2highSAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis.

Objective: The effects of Coronavirus disease 2019 (COVID-19) infection and altered processes of care on nonelective coronary artery bypass grafting (CABG) outcomes remain unknown. We hypothesized that patients with COVID-19 infection would have longer hospital lengths of stay and greater mortality compared with COVID-negative patients, but that these outcomes would not differ between COVID-negative and pre-COVID controls. Methods: The National COVID Cohort Collaborative 2020-2022 was queried for adult patients undergoing CABG. Patients were divided into COVID-negative, COVID-active, and COVID-convalescent groups. Pre-COVID control patients were drawn from the National Surgical Quality Improvement Program database. Adjusted analysis of the 3 COVID groups was performed via generalized linear models. Results: A total of 17,293 patients underwent nonelective CABG, including 16,252 COVID-negative, 127 COVID-active, 367 COVID-convalescent, and 2254 pre-COVID patients. Compared to pre-COVID patients, COVID-negative patients had no difference in mortality, whereas COVID-active patients experienced increased mortality. Mortality and pneumonia were higher in COVID-active patients compared to COVID-negative and COVID-convalescent patients. Adjusted analysis demonstrated that COVID-active patients had higher in-hospital mortality, 30- and 90-day mortality, and pneumonia compared to COVID-negative patients. COVID-convalescent patients had a shorter length of stay but a higher rate of renal impairment. Conclusions: Traditional care processes were altered during the COVID-19 pandemic. Our data show that nonelective CABG in patients with active COVID-19 is associated with significantly increased rates of mortality and pneumonia. The equivalent mortality in COVID-negative and pre-COVID patients suggests that pandemic-associated changes in processes of care did not impact CABG outcomes. Additional research into optimal timing of CABG after COVID infection is warranted.

Abstract Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some patients develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie disease progression depending on joint location. Here, we identify joint-specific changes in RA synovium and synovial fibroblasts (SF) between knee and hand joints. We show that the long non-coding RNA HOTAIR, which is only expressed in knee SF, regulates more than 50% of this site-specific gene expression in SF. HOTAIR is downregulated after stimulation with pro-inflammatory cytokines and is expressed at lower levels in knee samples from patients with RA, compared with osteoarthritis. Knockdown of HOTAIR in knee SF increases PI-Akt signalling and IL-6 production, but reduces Wnt signalling. Silencing HOTAIR inhibits the migratory function of SF, decreases SF-mediated osteoclastogenesis, and increases the recruitment of B cells by SF. We propose that HOTAIR is an important epigenetic factor in joint-specific gene expression in RA.

Objectives To evaluate the effectiveness of COVID-19 vaccinations (initial and booster) during pre-Delta, Delta and Omicron dominant periods among pregnant people via (1) COVID-19 incident and severe infections among pregnant people who were vaccinated versus unvaccinated and (2) post-COVID-19 vaccination breakthrough infections and severe infections among vaccinated females who were pregnant versus non-pregnant.Design Retrospective cohort study using nationally sampled electronic health records data from the National COVID Cohort Collaborative, 10 December 2020 –7 June 2022.Participants Cohort 1 included pregnant people (15–55 years) and cohort 2 included vaccinated females of reproductive age (15–55 years).Exposures (1) COVID-19 vaccination and (2) pregnancy.Main outcome measures Adjusted HRs (aHRs) for COVID-19 incident or breakthrough infections and severe infections (ie, COVID-19 infections with related hospitalisations).Results In cohort 1, 301 107 pregnant people were included. Compared with unvaccinated pregnant people, the aHRs for pregnant people with initial vaccinations during pregnancy of incident COVID-19 were 0.77 (95% CI 0.62 to 0.96) and 0.88 (95% CI 0.73 to 1.07) and aHRs of severe COVID-19 infections were 0.65 (95% CI 0.47 to 0.90) and 0.79 (95% CI 0.51 to 1.21) during the Delta and Omicron periods, respectively. Compared with pregnant people with full initial vaccinations, the aHR of incident COVID-19 for pregnant people with booster vaccinations was 0.64 (95% CI 0.58 to 0.71) during the Omicron period. In cohort 2, 934 337 vaccinated people were included. Compared with vaccinated non-pregnant females, the aHRs of severe COVID-19 infections for people with initial vaccinations during pregnancy was 2.71 (95% CI 1.31 to 5.60) during the Omicron periods.Conclusions Pregnant people with initial and booster vaccinations during pregnancy had a lower risk of incident and severe COVID-19 infections compared with unvaccinated pregnant people across the pandemic stages. However, vaccinated pregnant people still had a higher risk of severe infections compared with non-pregnant females.

High levels of loneliness are associated with poorer outcomes for physical and mental health and a large body of research has examined how using social media sites such as Facebook is associated with loneliness. Time spent on Facebook tends to be associated with higher levels of loneliness, whereas a larger number of Facebook Friends and more active use of Facebook tends to be associated with lower levels of loneliness. However, whilst the network size and structure of ‘offline’ networks have been associated with loneliness, how the network structure on Facebook is associated with loneliness is still unclear. In this study, participants used the Getnet app to directly extract information on network size (number of Facebook Friends), density, number of clusters in the network, and average path length from their Facebook networks, and completed the 20-item UCLA Loneliness questionnaire. In total, 107 participants (36 men, 71 women, Mage = 20.6, SDage = 2.7) took part in the study. Participants with a larger network size reported significantly lower feelings of loneliness. In contrast, network density, number of clusters, and average path length were not significantly related to loneliness. These results suggest that whilst having a larger Facebook network is related to feelings of social connection to others, the structure of the Facebook network may be a less important determinant of loneliness than other factors such as active or passive use of Facebook and individual characteristics of Facebook users.

Abstract The development of a generic drug product involves demonstrating that there is no significant difference in the rate and extent to which the active ingredient becomes available at the site of action, relative to the reference listed drug product. This remains challenging for many locally acting topical dermatological products because measuring the concentration of the active ingredient at the site of action in the skin may not be straightforward, and, in most instances, there are no established relationships between skin and plasma pharmacokinetic profiles. In recent years, the Office of Generic Drugs of the US Food and Drug Administration (FDA) established scientific research programs with the goal of enhancing patient access to high quality, affordable topical dermatological generics. A key strategy of these research programs was to leverage modeling and simulation methodologies that accelerate the development of these generics by facilitating alternative bioequivalence approaches for dermatological drug products. This report summarizes relevant insights and discussions from a 2021 FDA public workshop titled “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches,” which illustrated how mechanistic modeling and simulation approaches can be utilized (and have been used) to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA.

Abstract On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled “Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches.” The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop.

Abstract Introduction Research driven by real‐world clinical data is increasingly vital to enabling learning health systems, but integrating such data from across disparate health systems is challenging. As part of the NCATS National COVID Cohort Collaborative (N3C), the N3C Data Enclave was established as a centralized repository of deidentified and harmonized COVID‐19 patient data from institutions across the US. However, making this data most useful for research requires linking it with information such as mortality data, images, and viral variants. The objective of this project was to establish privacy‐preserving record linkage (PPRL) methods to ensure that patient‐level EHR data remains secure and private when governance‐approved linkages with other datasets occur. Methods Separate agreements and approval processes govern N3C data contribution and data access. The Linkage Honest Broker (LHB), an independent neutral party (the Regenstrief Institute), ensures data linkages are robust and secure by adding an extra layer of separation between protected health information and clinical data. The LHB's PPRL methods (including algorithms, processes, and governance) match patient records using “deidentified tokens,” which are hashed combinations of identifier fields that define a match across data repositories without using patients' clear‐text identifiers. Results These methods enable three linkage functions: Deduplication, Linking Multiple Datasets, and Cohort Discovery. To date, two external repositories have been cross‐linked. As of March 1, 2023, 43 sites have signed the LHB Agreement; 35 sites have sent tokens generated for 9 528 998 patients. In this initial cohort, the LHB identified 135 037 matches and 68 596 duplicates. Conclusion This large‐scale linkage study using deidentified datasets of varying characteristics established secure methods for protecting the privacy of N3C patient data when linked for research purposes. This technology has potential for use with registries for other diseases and conditions.

Abstract In contrast to long-term relationships, far less is known about the temporal evolution of transient relationships, although these constitute a substantial fraction of people’s communication networks. Previous literature suggests that ratings of relationship emotional intensity decay gradually until the relationship ends. Using mobile phone data from three countries (US, UK, and Italy), we demonstrate that the volume of communication between ego and its transient alters does not display such a systematic decay, instead showing a lack of any dominant trends. This means that the communication volume of egos to groups of similar transient alters is stable. We show that alters with longer lifetimes in ego’s network receive more calls, with the lifetime of the relationship being predictable from call volume within the first few weeks of first contact. This is observed across all three countries, which include samples of egos at different life stages. The relation between early call volume and lifetime is consistent with the suggestion that individuals initially engage with a new alter so as to evaluate their potential as a tie in terms of homophily.

Abstract Background There are a range of treatment options for osteoarthritis (OA) of the knee and hip, each with a unique profile of risks and benefits. Patient decision aids can help incorporate patient preferences in treatment decision‐making. The aim of this study was to develop and test the utility of a patient decision aid for OA that was developed using a multicriteria decision analytic framework. Methods People contemplating treatment for OA who had accessed the website myjointpain.org.au were invited to participate in the study by using the online patient decision aid. Two forms of the patient decision aid were created: A shorter form and a longer form, which allowed greater customization that was offered to respondents after they had completed the shorter form. Respondents also completed questions asking about their experience using the patient decision aid. Results A total of 625 self‐selected respondents completed the short‐form and 180 completed the long‐form. Across both forms, serious side effects, pain and function were rated as the most important treatment outcomes. Most respondents (64%) who completed the longer form reported that using the tool was a positive experience, 38% reported that using the tool had changed their mind and 48% said that using the tool would improve the quality of their decision‐making. Conclusions Overall, the findings suggest that this patient decision aid may be of use to a substantial number of people in facilitating appropriate treatment decision‐making. Patient or Public Contribution Service users of myjointpain.org.au were involved through their participation in the study, and their feedback will guide the development of future iterations of the tool.

A fundamental question of any new relationship is, will it last? Transient relationships, recently defined by the authors, are an ideal type of social tie to explore this question: these relationships are characterized by distinguishable starting and ending temporal points, linking the question of tie longevity to relationship finite lifetime. In this study, we use mobile phone data sets from the UK and Italy to analyse the weekly allocation of time invested in maintaining transient relationships. We find that more relationships are created during weekdays, with a greater proportion of them receiving more contact during these days of the week in the long term. The smaller group of relationships that receive more phone calls during the weekend tend to remain active for more time. We uncover a sorting process by which some ties are moved from weekdays to weekends and vice versa, mostly in the first half of the relationship. This process also carries more information about the ultimate lifetime of a tie than the part of the week when the relationship started, which suggests an early evaluation period that leads to a decision on how to allocate time to different types of transient ties.

Abstract Physiologically‐based pharmacokinetic models combine knowledge about physiology, drug product properties, such as physicochemical parameters, absorption, distribution, metabolism, excretion characteristics, formulation attributes, and trial design or dosing regimen to mechanistically simulate drug pharmacokinetics (PK). The current work describes the development of a multiphase, multilayer mechanistic dermal absorption (MPML MechDermA) model within the Simcyp Simulator capable of simulating uptake and permeation of drugs through human skin following application of drug products to the skin. The model was designed to account for formulation characteristics as well as body site‐ and sex‐ population variability to predict local and systemic bioavailability. The present report outlines the structure and assumptions of the MPML MechDermA model and includes results from simulations comparing absorption at multiple body sites for two compounds, caffeine and benzoic acid, formulated as solutions. Finally, a model of the Feldene (piroxicam) topical gel, 0.5% was developed and assessed for its ability to predict both plasma and local skin concentrations when compared to in vivo PK data.

Introduction Evidence has shown that throughout their undergraduate years, many nursing and midwifery students obtain paid employment in a wide variety of clinical and non-clinical positions. Across Australia, inconsistencies exist in the models of clinical employment available to these student groups. Previous Australian studies have described the employment of undergraduate nursing and midwifery students in regulated and unregulated clinical roles. No studies have reported on the various regulated roles available to both student nurses and midwives in Australia. The purpose of this scoping review is to identify and synthesize evidence related to nursing and/or midwifery students employed in regulated and unregulated clinical roles in Australia. Methods This scoping review utilized published recommendations for data screening, abstraction, and synthesis. One of the authors, a librarian, undertook systematic searches in CINAHL Complete (1937–present), Emcare on Ovid (1995–present), Scopus (1969–present), and Ovid MEDLINE(R) (including Epub Ahead of Print, In-Process, and In-Data-Review & Other Non-Indexed Citations, 1946–present). The initial searches were completed in April 2019 and repeated in March 2021 and May 2022 to identify any new literature. Manual searching of reference lists in the included papers was also undertaken, together with selected organizational websites. The extracted data included the lead author, date, title, study design, study sample and location, and key findings. Results From the 53 items retrieved, 23 peer-reviewed studies met the inclusion criteria and were included in the review. All items were published between 2011 and 2022. Only four of the studies focused upon student midwives. Undergraduate nursing and midwifery students in Australia obtain paid employment in a variety of regulated and unregulated clinical roles. Conclusion The literature reported here demonstrates that there are differing models, nomenclature, educational requirements, and pay scales in place for student employment in clinical roles across Australian states and territories.

Abstract Background Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. Results Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. Conclusions Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.

IntroductionChildhood adversity is pervasive and linked to numerous disadvantages in adulthood, including physical health problems, mental illness, and substance use disorders. Initial sensitivity to the rewarding effects of alcohol predicts the risk of developing an alcohol use disorder, and may be linked to developmental stress. The opioid peptide β-endorphin (β-E) regulates the stress response and is also implicated in the risk for excessive alcohol consumption.MethodsWe explored the influence of β-E in an animal model of early life adversity using controlled maternal separation by evaluating changes in locomotor activity, anxiety-like behavior, and the initial rewarding effects of alcohol in a single exposure conditioned place preference paradigm in control C57BL/6J and β-E deficient β-E +/+ 0.129S2-Pomc tm1Low/J; β-E −/− mice. Maternal separation (MS) occurred for 3 h each day from post-natal days (PND) 5–18 in approximately half the subjects.ResultsMaternal interactions increased following the separation protocol equally in both genotypes. MS and control subjects were tested as adolescents (PND 26–32) or adults (PND 58–72); the effects of MS were generally more pronounced in older subjects. Adults were more active than adolescents in the open field, and MS decreased activity in adolescent mice but increased it in adults. The increase in adult activity as a result of early life stress depended on both β-E and sex. β-E also influenced the effect of maternal separation on anxiety-like behavior in the Elevated Plus Maze. MS promoted rewarding effects of alcohol in male β-E deficient mice of either age, but had no effect in other groups.DiscussionTaken together, these results suggest that the effects of MS develop over time and are β-E and sex dependent and may aid understanding of how individual differences influence the impact of adverse childhood experiences.

We present an optimized dissociation protocol for preparing high-quality skin cell suspensions for in-depth single-cell RNA-sequencing (scRNA-seq) analysis of fresh and cultured human skin. Our protocol enabled the isolation of a consistently high number of highly viable skin cells from small freshly dissociated punch skin biopsies, which we use for scRNA-seq studies. We recapitulated not only the main cell populations of existing single-cell skin atlases, but also identified rare cell populations, such as mast cells. Furthermore, we effectively isolated highly viable single cells from ex vivo cultured skin biopsy fragments and generated a global single-cell map of the explanted human skin. The quality metrics of the generated scRNA-seq datasets were comparable between freshly dissociated and cultured skin. Overall, by enabling efficient cell isolation and comprehensive cell mapping, our skin dissociation-scRNA-seq workflow can greatly facilitate scRNA-seq discoveries across diverse human skin pathologies and ex vivo skin explant experimentations.

Background High levels of loneliness are associated with negative health outcomes and there are several different types of interventions targeted at reducing feelings of loneliness. It is therefore important to accurately measure loneliness. A key unresolved debate in the conceptualisation and measurement of loneliness is whether it has a unidimensional or multidimensional structure. The aim of this study was to examine the dimensional structure of the widely used UCLA Loneliness Scale and establish whether this factorial structure is equivalent in men and women. Methods and sample Two online UK-based samples were recruited using Prolific. The participants in Study 1 were 492 adults, selected to be nationally representative by age and gender, whilst the participants in Study 2 were 290 older adults aged over 64. In both studies, participants completed the UCLA Loneliness Scale (Version 3) as part of a larger project. Results In both studies, the best fitting model was one with three factors corresponding to ‘Isolation,’ ‘Relational Connectedness,’ and ‘Collective Connectedness.’ A unidimensional single factor model was a substantially worse fit in both studies. In both studies, there were no meaningful differences between men and women in any of the three factors, suggesting measurement invariance across genders. Conclusion These results are consistent with previous research in supporting a multidimensional, three factor structure to the UCLA scale, rather than a unidimensional structure. Further, the measurement invariance across genders suggests that the UCLA scale can be used to compare levels of loneliness across men and women. Overall the results suggest that loneliness has different facets and thus future research should consider treating the UCLA loneliness scale as a multidimensional scale, or using other scales which are designed to measure the different aspects of loneliness.

Current carbon pricing and trading mechanisms, despite their efficacy in reducing GHG emissions from industry, will not be sufficient to achieve Net Zero targets. Current mechanisms that redress emissions are largely economic disincentives, in effect financial penalties for emitters. In order to attain Net Zero futures, financial incentives for activities that sequester carbon from the atmosphere are needed. Herein, we present the environmental and economic co-benefits of soil re-carbonization and justify support for soil carbon remuneration. With increasing momentum to develop green economies, and projected increases in carbon price, growth in the global carbon market is inevitable. The establishment of a soil-based carbon economy, within this emerging financial space, has the potential to deliver a paradigm shift that will accelerate climate change mitigation, and concurrently realize net gains for soil health and the delivery of soil ecosystem services. Pivotal to the emergence of a global soil carbon economy will be a consensus on certification instruments used for long-term soil carbon storage, and the development of robust institutional agreements and processes to facilitate soil carbon trading.

Summary: This protocol describes the peptidomic analysis of organoid lysates, FACS-purified cell populations, and 2D culture secretions by liquid chromatography mass spectrometry (LC-MS). Currently, most peptides are quantified by ELISA, limiting the peptides that can be studied. However, an LC-MS-based approach allows more peptides to be monitored. Our group has previously used LC-MS for tissue peptidomics and secretion of enteroendocrine peptides from primary culture. Now, we extend the use to organoid models.For complete details on the use and execution of this protocol, please refer to Goldspink et al. (2020).

Nuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies have indicated that the regulation and function of nuclear RNAi-mediated heterochromatin are highly complex. Our knowledge of histone modifications and the corresponding histonemodifying enzymes involved in the system remains limited. In this study, we show that the heterochromatin mark, H3K23me3, is induced by nuclear RNAi at both exogenous and endogenous targets in C. elegans. In addition, dsRNA-induced H3K23me3 can persist for multiple generations after the dsRNA exposure has stopped. We demonstrate that the histone methyltransferase SET-32, methylates H3K23 in vitro. Both set-32 and the germline nuclear RNAi Argonaute, hrde-1, are required for nuclear RNAi-induced H3K23me3 in vivo. Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.

Abstract The structure of egocentric networks reflects the way people balance their need for strong, emotionally intense relationships and a diversity of weaker ties. Egocentric network structure can be quantified with ’social signatures’, which describe how people distribute their communication effort across the members (alters) of their personal networks. Social signatures based on call data have indicated that people mostly communicate with a few close alters; they also have persistent, distinct signatures. To examine if these results hold for other channels of communication, here we compare social signatures built from call and text message data, and develop a way of constructing mixed social signatures using both channels. We observe that all types of signatures display persistent individual differences that remain stable despite the turnover in individual alters. We also show that call, text, and mixed signatures resemble one another both at the population level and at the level of individuals. The consistency of social signatures across individuals for different channels of communication is surprising because the choice of channel appears to be alter-specific with no clear overall pattern, and ego networks constructed from calls and texts overlap only partially in terms of alters. These results demonstrate individuals vary in how they allocate their communication effort across their personal networks and this variation is persistent over time and across different channels of communication.

As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic.

Background: Atrial fibrillation (AF) is associated with cardiac fibrosis, which can now be measured noninvasively using T1-mapping with cardiac magnetic resonance imaging (CMRI). This study aimed to assess the impact of AF on ventricular T1 at the time of CMRI. Methods: Subjects with AF scheduled for AF ablation underwent CMRI with standard electrocardiography gating and breath-hold protocols on a 1.5 T scanner with post-contrast ventricular T1 recorded from 6 regions of interest at the mid-ventricle. Baseline demographic, clinical, and imaging characteristics were examined using univariate and multivariable linear regression modeling for an association with myocardial T1. Results: One hundred fifty-seven patients were studied (32% women; median age, 61 years [interquartile range {IQR}, 55–67], 50% persistent AF [episodes>7 days or requiring electrical or pharmacologic cardioversion], 30% in AF at the time of the CMRI). The median global T1 was 404 ms (IQR, 381–428). AF at the time of CMRI was associated with a 4.4% shorter T1 (p=0.000) compared to sinus rhythm when adjusted for age, sex, persistent AF, body mass index, congestive heart failure, and renal dysfunction (estimated glomerular filtration rate

Background. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are commonly present with metastatic disease, and the liver is the most frequent metastatic site. Herein, we studied whether primary tumor site affects survival in patients with GEP-NETs and liver metastases (NELM). As a secondary endpoint, we studied whether extrahepatic disease and surgical resection impact survival in this patient population. Methods. Patients with NELM diagnosed from 2006 to 2014 were identified from the National Cancer Database. Kaplan-Meier curves and nested Cox proportional hazards were used to assess variables associated with survival. Results. 2947 patients with well- or moderately differentiated GEP-NETs and NELM met the inclusion criteria for this study. Patients with small bowel NETs survived the longest of all GEP-NETs with NELM (median not reached). Rectal and gastric NETs with NELM had the shortest survival (median 31 months). Patients with extrahepatic metastases who underwent any operation survived longer than those managed nonoperatively (median survival 38.7 months vs. 18.6 months, p=0.01). On multivariable analysis, operations on the primary tumor and distant metastatic site (HR 0.23-0.43 vs. no surgery), treatment at an academic/research hospital, Charlson comorbidity index of 0, no extrahepatic metastases, and younger age were associated with prolonged survival (p

Aortoduodenal syndrome is a rare clinical entity characterized by an upper gastrointestinal obstruction in association with an abdominal aortic aneurysm. The exact mechanism of obstruction is unknown. We present a case of aortoduodenal syndrome and discuss the interplay of the aneurysm and duodenum in the development of the duodenal obstruction.

The purpose of this study was to examine the effect of perceived airfare fairness on domestic airline Patronage in Nigeria. The study population comprised seventy five thousand (75,000) passengers of registered and Operational Domestic Airlines operating within the Nigerian airspace and the sample size for the study constitute three hundred and eighty two (382) passengers of the airlines which was determined using the Krejice and Morgan (1970) table. Furthermore, three hundred and eighty-two (382) copies of structured questionnaire was distributed to airline passengers at the respective waiting lounges of the airports while three hundred and seventy-seven (377) were retrieved and used for the study. Anova statistic was used to test the hypotheses postulated in the study. The result of the analysis revealed that perceived airfare fairness does not significantly influence domestic airline patronage in Nigeria. We concluded that perceived airfare fairness does not significantly affect domestic airline patronage in the authors therefore suggests that the domestic airline service providers in Nigeria should endeavor to make their airfare to be be attractive on order to improve their level of patronage.

Proton beam therapy is a new form of radiotherapy. Little is known about patients’ experiences of proton beam therapy and less about parents’ experiences of children receiving treatment. Semi-structured interviews explored 10 parents’ experiences of travelling from the United Kingdom to the United States to have their children’s brain tumours treated with proton beam therapy. Thematic analysis uncovered themes of ‘adjusting to the PBT routine’, ‘finding benefit in the situation’ and ‘readjusting upon returning home’. Parents’ initial worries were elevated by travel, but they found benefit in their experiences, describing them positively. The periods before and after treatment were most difficult, illustrating a cycle from upset to calm, back to upset upon their return home.

Circadian rhythms are known to be important drivers of human activity and the recent availability of electronic records of human behaviour has provided fine-grained data of temporal patterns of activity on a large scale. Further, questionnaire studies have identified important individual differences in circadian rhythms, with people broadly categorised into morning-like or evening-like individuals. However, little is known about the social aspects of these circadian rhythms, or how they vary across individuals. In this study we use a unique 18-month dataset that combines mobile phone calls and questionnaire data to examine individual differences in the daily rhythms of mobile phone activity. We demonstrate clear individual differences in daily patterns of phone calls, and show that these individual differences are persistent despite a high degree of turnover in the individuals' social networks. Further, women's calls were longer than men's calls, especially during the evening and at night, and these calls were typically focused on a small number of emotionally intense relationships. These results demonstrate that individual differences in circadian rhythms are not just related to broad patterns of morningness and eveningness, but have a strong social component, in directing phone calls to specific individuals at specific times of day.

Three outbreaks of Ebola hemorrhagic fever have recently occurred in Gabon. Virus has been isolated from clinical materials from all three outbreaks, and nucleotide sequence analysis of the glycoprotein gene of the isolates and virus present in clinical samples has been carried out. These data indicate that each of the three outbreaks should be considered an independent emergence of a different Ebola virus of the Zaire subtype. As in earlier Ebola virus outbreaks, no genetic variability was detected between virus samples taken during an individual outbreak.

The theory of inclusive fitness has transformed our understanding of cooperation and altruism. However, the proximate psychological underpinnings of altruism are less well understood, and it has been argued that emotional closeness mediates the relationship between genetic relatedness and altruism. In this study, we use a real-life costly behaviour (travel time) to dissociate the effects of genetic relatedness from emotional closeness. Participants travelled further to see more closely related kin, as compared to more distantly related kin. For distantly related kin, the level of emotional closeness mediated this relationship--when emotional closeness was controlled for, there was no effect of genetic relatedness on travel time. However, participants were willing to travel further to visit parents, children and siblings as compared to more distantly related kin, even when emotional closeness was controlled for. This suggests that the mediating effect of emotional closeness on altruism varies with levels of genetic relatedness.