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Hiroshi Nakase,1,2 Shinji Sakuma,3 Takumi Fukuchi,4 Takuya Yoshino,1,5 Kohta Mohri,3 Kohei Miyata,3,6 Hironori Kumagai,6 Ken-Ichiro Hiwatari,6 Kazufumi Tsubaki,6 Tetsuya Ikejima,6 Etsuo Tobita,6 Meiying Zhu,7 Kevin J Wilson,7 Kay Washington,8 John C Gore,7,9–13 Wellington Pham7,9–12,14 1Division of Endoscopy, Kyoto University Hospital, Kyoto, Japan; 2Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan; 3Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan; 4Gastroenterology and Hepatology, Osakafu Saiseikai Nakatsu Hospital, Osaka, Japan; 5Division of Inflammatory Bowel Disease, Digestive Disease Center, Kitano Hospital, Osaka, Japan; 6Advanced Materials R&D Laboratory, ADEKA Corp., Tokyo, Japan; 7Department of Radiology, Vanderbilt University Institute of Imaging Science, 8Division of Gastrointestinal and Hepatic Pathology, Vanderbilt School of Medicine, 9Department of Radiology and Radiological Sciences, 10Department of Biomedical Engineering, 11Vanderbilt Ingram Cancer Center, Vanderbilt School of Medicine, 12Vanderbilt Brain Institute, 13Molecular Physiology and Biophysics, 14Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA Abstract: The Thomsen–Friedenreich (TF) antigen represents a prognostic biomarker of colorectal carcinoma. Here, using a nanobeacon, the surface of which was fabricated with peanut agglutinin as TF-binding molecules, we demonstrate that the nanobeacon is able to detect TF antigen in frozen and freshly biopsied polyps using fluorescence microscopy. Our results provide important clues about how to detect aberrant colonic tissues in the most timely fashion. Given the versatile application method for this topical nanobeacon, the protocol used in this work is amenable to clinical colonoscopy. Moreover, the prospects of clinical translation of this technology are evident. Keywords: TF antigen, fluorescence colonoscopy, nanobeacon, colorectal cancer

Background: Binary diagnostic tests are commonly used in medicine to answer a question about a patient's clinical status, most commonly, do they or do they not have some disease. Recent advances in statistical methodologies for performing inferential statistics to compare commonly used test metrics for two diagnostic tests have not yet been implemented in a robust statistical package., Methods: Up-to-date statistical methods to compare the test metrics achieved by two binary diagnostic tests are implemented in the new R package testCompareR. The output and efficiency of testCompareR is compared to the only other available package which performs this function, DTComPair, as well as an open-source program, compbdt, using a motivating example., Results: testCompareR achieves similar results to DTComPair using statistical methods with improved coverage and asymptotic performance. Further, testCompareR is faster than the currently available package and requires fewer pre-processing steps in order to produce accurate results., Conclusions: testCompareR provides a new tool to compare the test metrics for two binary diagnostic tests compared with the gold standard. This tool allows flexible inputs, which minimises the need for data pre-processing, and operates in very few steps, so that it is easy to use even for those less experienced with R. testCompareR achieves results comparable to those computed by DTComPair, using optimised statistical methods and with improved computational efficiency., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Wilson KJ et al.)

Objectives: To perform a systematic review of published academic literature related to lost, mislabeled, and mishandled surgical and clinical pathology specimens during the preanalytical stage., Methods: The authors used Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines to search PubMed, MEDLINE, Web of Science, and Scopus for relevant articles published from January 1, 1990, to May 1, 2023., Results: The authors screened 1313 articles and identified 44 peer-reviewed, English-language articles published between 1990 and 2021 for inclusion in the final systematic review. Most articles (n = 36) reported results from US-based facilities. Articles primarily focused on general clinical and general surgical pathology. Analysis of the articles revealed that articles reported a range of methodological approaches, including incident reports, implementation analyses, case studies, and commentary recommendations. Most articles focused on mislabeling errors (61.3%) and missing or lost specimens (18.2%), while several articles combined specimen errors (20.5%). Several implementation studies (22.7%) reported using multiple interventions to mitigate errors. Implementation efforts reported between 70% and 100% reduction in pathology errors., Conclusions: The review highlights the limited research on the topic, with an average of 2 articles per year discussing lost, mislabeled, or mishandled specimens. Intervention studies addressed The Joint Commission's patient safety goals for laboratory practice. More research is needed about error incidents and reporting in non-Western countries to gain a more global perspective on the topic., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Researchers choose different methods of making giant unilamellar vesicles to satisfy different constraints of their experimental designs. A challenge that arises when researchers use a variety of methods is that each method may produce vesicles with a different average lipid ratio, even if all experiments use lipids from a common stock mixture. Here, we use mass spectrometry to investigate ratios of lipids in vesicle solutions made by five common methods: electroformation on indium tin oxide slides, electroformation on platinum wires, gentle hydration, emulsion transfer, and extrusion. We made vesicles from either five-component or binary mixtures of lipids chosen to span a wide range of physical properties: di(18:1)PC, di(16:0)PC, di(18:1)PG, di(12:0)PE, and cholesterol. For a mixture of all five of these lipids, ITO electroformation, Pt electroformation, gentle hydration, and extrusion methods result in only minor shifts in lipid ratios (≤5 mol %) relative to a common stock solution. In contrast, emulsion transfer results in ∼80% less cholesterol than expected from the stock solution, which is counterbalanced by a surprising overabundance of saturated PC-lipid relative to all other phospholipids. Experiments using binary mixtures of saturated and unsaturated PC-lipids and cholesterol largely support results from the five-component mixture. In general, our results imply that experiments that increment lipid ratios in small steps will produce data that are highly sensitive to the technique used and to sample-to-sample variations. For example, sample-to-sample variations are ∼±2 mol % for five-component vesicles produced by a single technique. In contrast, experiments that explore larger increments in lipid ratio or that seek to explain general trends and new phenomena will be less sensitive to sample-to-sample variation and the method used., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Despite longstanding excitement and progress toward understanding liquid-liquid phase separation in natural and artificial membranes, fundamental questions have persisted about which molecules are required for this phenomenon. Except in extraordinary circumstances, the smallest number of components that has produced large-scale, liquid-liquid phase separation in bilayers has stubbornly remained at three: a sterol, a phospholipid with ordered chains, and a phospholipid with disordered chains. This requirement of three components is puzzling because only two components are required for liquid-liquid phase separation in lipid monolayers, which resemble half of a bilayer. Inspired by reports that sterols interact closely with lipids with ordered chains, we tested whether phase separation would occur in bilayers in which a sterol and lipid were replaced by a single, joined sterol-lipid. By evaluating a panel of sterol-lipids, some of which are present in bacteria, we found a minimal bilayer of only two components (PChemsPC and diPhyPC) that robustly demixes into micron-scale, liquid phases. It suggests an additional role for sterol-lipids in nature, and it reveals a membrane in which tie-lines (and, therefore, the lipid composition of each phase) are straightforward to determine and will be consistent across multiple laboratories., Competing Interests: Competing interests statement:The authors declare no competing interest.

At the intersection of drug policy, the opioid crisis, and fragmented care systems, persons with opioid use disorder (OUD) in the United States are significantly vulnerable to contact with the criminal legal system (CLS). In CLS settings, provision of evidence-based treatment for OUD is variable and often secondary to punitive approaches. Linkage facilitation at every touch point along the CLS Sequential Intercept Model has potential to redirect persons with OUD into recovery-oriented systems of care, increase evidence-based OUD treatment connections, and therefore reduce CLS re-exposure risk. Research in this area is still nascent. Thus, this narrative review explores the state of the science on linkage facilitation across the varied CLS contexts, including general barriers, facilitators, and opportunities for using linkage facilitation for OUD treatment and related services. Following the CLS Sequential Intercept Model, the specific CLS contexts examined include community services, police encounters, the courts (pre- and post-disposition), incarceration (pre-trial detention, jail, and prison), reentry (from jails, prisons, and unified systems), and community supervision (probation and parole). Examples of innovative linkage facilitation interventions are drawn from the Justice Community Opioid Innovation Network (JCOIN). Areas for future research and policy change are highlighted to advance the science of linkage facilitation for OUD services in the CLS., (© 2024. The Author(s).)

Professional development of scientists is enhanced by training students in responsible conduct of research earlier in their careers. One aspect of responsible conduct of research is authorship ethics, which concerns granting of credit to those who make intellectual contributions to the research. The activity discussed in this article emphasizes how authorship ethics can be integrated with Course-based Undergraduate Research Experience (CURE) and includes an adaption that could also be used for independent research students. The activity allows students to reflect upon inequalities and problems seen in scientific authorship, including gender bias, failure to credit effort (ghostwriters), and inclusion of authors that did not meaningfully contribute to the work (honorary/gift authorship). Themes seen in student reflections on how they could demonstrate ethics in authorship included: determining authorship by contribution, appropriate attributions on curriculum vitas (CV) and posters, different credit levels, understanding authorship criteria, and tracking contributions. Themes seen in student reflections on the importance of authorship were proper authorship credit distribution, authorship impacting career opportunities, and accountability in research. In the activity, students also created attributions for a poster to be presented from their research. We found that most students were able to create attributions that were correctly formatted, included the same authors, and positioned authors in the same order as other group members, matching what was presented on the finalized poster. We found that students' reflection on authorship and this professionalization of their activities in their CURE led to modest increases in their view of themselves as scientists., Competing Interests: The authors declare no conflict of interest.

Despite longstanding excitement and progress toward understanding liquid-liquid phase separation in natural and artificial membranes, fundamental questions have persisted about which molecules are required for this phenomenon. Except in extraordinary circumstances, the smallest number of components that has produced large-scale, liquid-liquid phase separation in bilayers has stubbornly remained at three: a sterol, a phospholipid with ordered chains, and a phospholipid with disordered chains. This requirement of three components is puzzling because only two components are required for liquid-liquid phase separation in lipid monolayers, which resemble half of a bilayer. Inspired by reports that sterols interact closely with lipids with ordered chains, we tested whether phase separation would occur in bilayers in which a sterol and lipid were replaced by a single, joined sterol-lipid. By evaluating a panel of sterol-lipids, some of which are found in bacteria, we discovered a minimal bilayer of only two components (PChemsPC and diPhyPC) that robustly demixes into micron-scale, liquid phases. It suggests a new role for sterol-lipids in nature, and it reveals a membrane in which tie-lines (and, therefore, the lipid composition of each phase) are straightforward to determine and will be consistent across multiple laboratories., Significance Statement: A wide diversity of bilayer membranes, from those with hundreds of lipids (e.g., vacuoles of living yeast cells) to those with very few (e.g., artificial vesicles) phase separate into micron-scale liquid domains. The number of components required for liquid-liquid phase separation has been perplexing: only two should be necessary, but more are required except in extraordinary circumstances. What minimal set of molecular characteristics leads to liquid-liquid phase separation in bilayer membranes? This question inspired us to search for single, joined "sterol-lipid" molecules to replace both a sterol and a phospholipid in membranes undergoing liquid-liquid phase separation. By producing phase-separating membranes with only two components, we mitigate experimental challenges in determining tie-lines and in maintaining constant chemical potentials of lipids.

Background: Disparities in birth outcomes continue to exist in the United States, particularly for low-income, publicly insured women. Doula support has been shown to be a cost-effective intervention in predominantly middle-to-upper income White populations, and across all publicly insured women at the state level. This analysis extends previous studies by providing an estimate of benefits that incorporates variations in averted outcomes by race and ethnicity in the context of one region in Texas. The objectives of this study were to determine (1) whether the financial value of benefits provided by doula support exceeds the costs of delivering it; (2) whether the cost-benefit ratio differs by race and ethnicity; and (3) how different doula reimbursement levels affect the cost-benefit results with respect to pregnant people covered by Medicaid in central Texas., Methods: We conducted a forward-looking cost-benefit analysis using secondary data carried out over a short-term time horizon taking a public payer perspective. We focused on a narrow set of health outcomes (preterm delivery and cesarean delivery) that was relatively straightforward to monetize. The current, usual care state was used as the comparison condition., Results: Providing pregnant people covered by Texas Medicaid with access to doulas during their pregnancies was cost-beneficial (benefit-to-cost ratio: 1.15) in the base model, and 65.7% of the time in probabilistic sensitivity analyses covering a feasible range of parameters. The intervention is most cost-beneficial for Black women. Reimbursing doulas at $869 per client or more yielded costs that were greater than benefits, holding other parameters constant., Conclusions: Expanding Medicaid pregnancy-related coverage to include doula services would be cost-beneficial and improve health equity in Texas., (© 2023 Wiley Periodicals LLC.)

Introduction: This article proposes a taxonomy of linkage facilitation services used to help persons with opioid use disorder access treatment and recovery resources. Linkage facilitation may be especially valuable for persons receiving medication for opioid use disorder (MOUD) given the considerable barriers to treatment access and initiation that have been identified. The science of linkage facilitation currently lacks both consistent communication about linkage facilitation practices and a conceptual framework for guiding research., Methods: To address this gap, this article presents a taxonomy derived from expert consensus that organizes the array of practitioners, goals, and activities associated with linkage services for OUD and related needs. Expert panelists first independently reviewed research reports and policy guidelines summarizing the science and practice of linkage facilitation for substance use disorders generally and OUD specifically, then met several times to vet the conceptual scheme and content of the taxonomy until they reached a final consensus., Results: The derived taxonomy contains eight domains: facilitator identity, facilitator lived experience, linkage client, facilitator-client relationship, linkage activity, linkage method, linkage connectivity, and linkage goal. For each domain, the article defines basic domain categories, highlights research and practice themes in substance use and OUD care, and introduces innovations in linkage facilitation being tested in one of two NIDA-funded research networks: Justice Community Opioid Innovation Network (JCOIN) or Consortium on Addiction Recovery Science (CoARS)., Conclusions: To accelerate consistent application of this taxonomy to diverse research and practice settings, the article concludes by naming several considerations for linkage facilitation workforce training and implementation., Competing Interests: Declaration of competing interest This work was jointly supported by the Justice Community Opioid Innovation (JCOIN) Network and the Consortium on Addiction Recovery Science (CoARS) (CoARS: 3R24DA051946-01S1: PI: Hogue), both of which are funded by the National Institute on Drug Abuse (NIDA) through the National Institute of Health Helping to End Addiction Long-term (HEAL) Initiative. Additionally, Dr. Drazdowski's activities were supported by NIDA (K23DA048161); Dr. Satcher's activities were supported by NIDA (R25DA037190) and the Health Resources and Services Administration (T32HP32520)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

One of the biggest challenges in utilizing non-commercial forest biomass is its widely distributed nature. The best solution to the biomass problem, to avoid expensive and carbon-intensive processing (chipping) and transportation costs, is to process it onsite. However, conventional burn piles have destructive impacts on forest soil and provide no benefits other than fuel reduction. Converting forest slash to biochar onsite has many ecological advantages over the current practice of slash disposal by incineration in burn piles, including reduced soil heating and particulate emissions, along with multiple benefits of the biochar to forest soil health and water holding capacity when left in place. Making biochar onsite in the woods is a way to return a pyrogenic carbon component to forest soils that has been missing due to the recent history of fire suppression. Biochar is also a leading method of carbon removal and sequestration for climate change mitigation. In this study, we document a method for making biochar using a portable biochar kiln. This low-cost method utilizes hand crews equipped with water for quenching kilns before the biochar burns to ash. Simple techniques for quantifying and characterizing the biochar produced are incorporated into the method for the purpose of measuring impact and qualifying for carbon removal certificates to help pay for the cost of the work. We describe the CM002 Component Methodology that provides standardized procedures for the quantification of GHG benefits during three stages of the process: waste biomass sourcing, biochar production, and biochar soil application. The CM002 Methodology is based on international best practices, including the most recent VCS methodology VM0044 Standards and EBC C-Sink Artisan Standards. Reliable quantification methods utilizing appropriate safety factors are the first essential step toward eligibility for carbon removal finance.

Students often see college courses as the presentation of disconnected facts, especially in the life sciences. Student-created Structure Mechanism/Relationship Function (SMRF) models were analyzed to understand students' abilities to make connections between genotype, phenotype, and evolution. Students were divided into two sections; one section received instructions that included a specific gene as an example related to larger issues like human disease or the environment. The other section was only given generic examples, like gene X and phenotype Y. Coding of exam models and a comprehensive (extensive) model reveled students were able to make links and work within and between biological scales of organization. Modeling provided a way to show and allow students to practice and demonstrate the ability to build step-by-step causal relationships that link ideas together. We also observed a small differing with students receiving the specific prompt performing better than students receiving generic prompt at the point in the semester where linking across many biological scales was required to be successful., (© 2023 International Union of Biochemistry and Molecular Biology.)

We consider the design of a two-arm superiority cluster randomized controlled trial (RCT) with a continuous outcome. We detail Bayesian inference for the analysis of the trial using a linear mixed-effects model. The treatment is compared to control using the posterior distribution for the treatment effect. We develop the form of the assurance to choose the sample size based on this analysis, and its evaluation using a two loop Monte Carlo sampling scheme. We assess the proposed approach, considering the effect of different forms of prior distribution, and the number of Monte Carlo samples needed in both loops for accurate determination of the assurance and sample size. Based on this assessment, we provide general advice on each of these choices. We apply the approach to the choice of sample size for a cluster RCT into poststroke incontinence, and compare the resulting sample size to that from assurance based on a Wald test for the treatment effect. The Bayesian approach to design and analysis developed in this article can offer advantages in terms of an increase in the robustness of the chosen sample size to parameter mis-specification and reduced sample sizes if prior information indicates the treatment effect is likely to be larger than the minimal clinically important difference., (© 2023 The Author. Statistics in Medicine published by John Wiley & Sons Ltd.)

Background: In a pandemic setting, it is critical to evaluate and deploy accurate diagnostic tests rapidly. This relies heavily on the sample size chosen to assess the test accuracy (e.g. sensitivity and specificity) during the diagnostic accuracy study. Too small a sample size will lead to imprecise estimates of the accuracy measures, whereas too large a sample size may delay the development process unnecessarily. This study considers use of a Bayesian method to guide sample size determination for diagnostic accuracy studies, with application to COVID-19 rapid viral detection tests. Specifically, we investigate whether utilising existing information (e.g. from preceding laboratory studies) within a Bayesian framework can reduce the required sample size, whilst maintaining test accuracy to the desired precision., Methods: The method presented is based on the Bayesian concept of assurance which, in this context, represents the unconditional probability that a diagnostic accuracy study yields sensitivity and/or specificity intervals with the desired precision. We conduct a simulation study to evaluate the performance of this approach in a variety of COVID-19 settings, and compare it to commonly used power-based methods. An accompanying interactive web application is available, which can be used by researchers to perform the sample size calculations., Results: Results show that the Bayesian assurance method can reduce the required sample size for COVID-19 diagnostic accuracy studies, compared to standard methods, by making better use of laboratory data, without loss of performance. Increasing the size of the laboratory study can further reduce the required sample size in the diagnostic accuracy study., Conclusions: The method considered in this paper is an important advancement for increasing the efficiency of the evidence development pathway. It has highlighted that the trade-off between lab study sample size and diagnostic accuracy study sample size should be carefully considered, since establishing an adequate lab sample size can bring longer-term gains. Although emphasis is on its use in the COVID-19 pandemic setting, where we envisage it will have the most impact, it can be usefully applied in other clinical areas., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Cerebral malaria (CM) continues to present a major health challenge, particularly in sub-Saharan Africa. CM is associated with a characteristic malarial retinopathy (MR) with diagnostic and prognostic significance. Advances in retinal imaging have allowed researchers to better characterize the changes seen in MR and to make inferences about the pathophysiology of the disease. The study aimed to explore the role of retinal imaging in diagnosis and prognostication in CM; establish insights into pathophysiology of CM from retinal imaging; establish future research directions., Methods: The literature was systematically reviewed using the African Index Medicus, MEDLINE, Scopus and Web of Science databases. A total of 35 full texts were included in the final analysis. The descriptive nature of the included studies and heterogeneity precluded meta-analysis., Results: Available research clearly shows retinal imaging is useful both as a clinical tool for the assessment of CM and as a scientific instrument to aid the understanding of the condition. Modalities which can be performed at the bedside, such as fundus photography and optical coherence tomography, are best positioned to take advantage of artificial intelligence-assisted image analysis, unlocking the clinical potential of retinal imaging for real-time diagnosis in low-resource environments where extensively trained clinicians may be few in number, and for guiding adjunctive therapies as they develop., Conclusions: Further research into retinal imaging technologies in CM is justified. In particular, co-ordinated interdisciplinary work shows promise in unpicking the pathophysiology of a complex disease., (© 2023. The Author(s).)

Naphthoquinone (1,4-NQ) and its derivatives (NQs, juglone, plumbagin, 2-methoxy-1,4-NQ, and menadione) have a variety of therapeutic applications, many of which are attributed to redox cycling and the production of reactive oxygen species (ROS). We previously demonstrated that NQs also oxidize hydrogen sulfide (H 2 S) to reactive sulfur species (RSS), potentially conveying identical benefits. Here we use RSS-specific fluorophores, mass spectroscopy, EPR and UV-Vis spectrometry, and oxygen-sensitive optodes to examine the effects of thiols and thiol-NQ adducts on H 2 S-NQ reactions. In the presence of glutathione (GSH) and cysteine (Cys), 1,4-NQ oxidizes H 2 S to both inorganic and organic hydroper-/hydropolysulfides (R 2 S n , R=H, Cys, GSH; n = 2-4) and organic sulfoxides (GS n OH, n = 1, 2). These reactions reduce NQs and consume oxygen via a semiquinone intermediate. NQs are also reduced as they form adducts with GSH, Cys, protein thiols, and amines. Thiol, but not amine, adducts may increase or decrease H 2 S oxidation in reactions that are both NQ- and thiol-specific. Amine adducts also inhibit the formation of thiol adducts. These results suggest that NQs may react with endogenous thiols, including GSH, Cys, and protein Cys, and that these adducts may affect both thiol reactions as well as RSS production from H 2 S.

Cerebral malaria (CM) remains a significant global health challenge with high morbidity and mortality. Malarial retinopathy has been shown to be diagnostically and prognostically significant in the assessment of CM. The major mechanism of death in paediatric CM is brain swelling. Long term morbidity is typically characterised by neurological and neurodevelopmental sequelae. Optical coherence tomography can be used to quantify papilloedema and macular ischaemia, identified as hyperreflectivity. Here we describe a protocol to test the hypotheses that quantification of optic nerve head swelling using optical coherence tomography can identify severe brain swelling in CM, and that quantification of hyperreflectivity in the macula predicts neurodevelopmental outcomes post-recovery. Additionally, our protocol includes the development of a novel, low-cost, handheld optical coherence tomography machine and artificial intelligence tools to assist in image analysis., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Wilson KJ et al.)

Substance use disorders (SUD) are prevalent among justice-involved youth (JIY) and are a robust predictor of re-offending. Only a fraction of JIY with substance use problems receive treatment. This paper describes the impacts of system-level efforts to improve identification and referral to treatment on recidivism of JIY. A cluster randomized trial involving 20 county juvenile justice agency sites across 5 states was used to implement an organizational intervention (Core vs Enhanced) to juvenile justice staff and community-based treatment providers, working with 18,698 JIY from March 2014 to August 2017. Recidivism rates over four study time periods were examined. Logistic regression was used to predict recidivism as a function of site, need for SUD services, level of supervision, time, organizational intervention, and time x intervention interaction terms. Results indicated that Enhanced sites showed decreased levels of recidivism compared to Core-only sites, where it increased over time. Additionally, need for SU services, level of supervision, and site were significant predictors of reoffending. Findings suggest the potential value of facilitation of juvenile justice agency efforts to increasing identification of and referral to SUD services of JIY in need of such services for reducing further contact with the legal system., (© 2023. The Author(s).)

The relaxin/insulin-like family peptide receptor 2 (RXFP2) belongs to the family of class A G-protein coupled receptors (GPCRs) and it is the only known target for the insulin-like factor 3 peptide (INSL3). The importance of this ligand-receptor pair in the development of the gubernacular ligament during the transabdominal phase of testicular descent is well established. More recently, RXFP2 has been implicated in maintaining healthy bone formation. In this report, we describe the discovery of a small molecule series of RXFP2 agonists. These compounds are highly potent, efficacious, and selective RXFP2 allosteric agonists that induce gubernacular invagination in mouse embryos, increase mineralization activity in human osteoblasts in vitro, and improve bone trabecular parameters in adult mice. The described RXFP2 agonists are orally bioavailable and display favorable pharmacokinetic properties, which allow for future evaluation of the therapeutic benefits of modulating RXFP2 activation in disease models., (© 2022. The Author(s).)

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced expression of the survival motor neuron (SMN) protein. Current disease-modifying therapies increase SMN levels and dramatically improve survival and motor function of SMA patients. Nevertheless, current treatments are not cures and autopsy data suggest that SMN induction is variable. Our group and others have shown that combinatorial approaches that target different modalities can improve outcomes in rodent models of SMA. Here we explore if slowing SMN protein degradation and correcting SMN splicing defects could synergistically increase SMN production and improve the SMA phenotype in model mice. We show that co-administering ML372, which inhibits SMN ubiquitination, with an SMN-modifying antisense oligonucleotide (ASO) increases SMN production in SMA cells and model mice. In addition, we observed improved spinal cord, neuromuscular junction and muscle pathology when ML372 and the ASO were administered in combination. Importantly, the combinatorial approach resulted in increased motor function and extended survival of SMA mice. Our results demonstrate that a combination of treatment modalities synergistically increases SMN levels and improves pathophysiology of SMA model mice over individual treatment., (Published by Oxford University Press 2022.)

The development of a new diagnostic test ideally follows a sequence of stages which, among other aims, evaluate technical performance. This includes an analytical validity study, a diagnostic accuracy study, and an interventional clinical utility study. In this article, we propose a novel Bayesian approach to sample size determination for the diagnostic accuracy study, which takes advantage of information available from the analytical validity stage. We utilize assurance to calculate the required sample size based on the target width of a posterior probability interval and can choose to use or disregard the data from the analytical validity study when subsequently inferring measures of test accuracy. Sensitivity analyses are performed to assess the robustness of the proposed sample size to the choice of prior, and prior-data conflict is evaluated by comparing the data to the prior predictive distributions. We illustrate the proposed approach using a motivating real-life application involving a diagnostic test for ventilator associated pneumonia. Finally, we compare the properties of the approach against commonly used alternatives. The results show that, when suitable prior information is available, the assurance-based approach can reduce the required sample size when compared to alternative approaches., (© 2022 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Objectives: To explore the lived (narrative) experience of obesity and/or diabetes mellitus within focus groups consisting of individuals and community support persons residing in Genesee County, Michigan., Design: Qualitative study, using Community-Based Participatory Research (CBPR) methodology to design and conduct focus group interviews., Sample: Nineteen participants from faith-based organizations (FBOs) in Genesee County (74.5% Caucasian, 3.0% Hispanic American)., Measurements: Semi-structured narrative focus group interviews, using thematic coding and qualitative analysis software (Otter.com)., Results: Participants from diverse FBOs revealed barriers that prevent them from reaching their weight goals and preventing or controlling diabetes. A shared theme included the concern that providers do not actively inquire about patient concerns at appointments, and they fail to offer practical strategies beyond pharmaceutical interventions., Conclusion: Focus group interviews with community residents revealed issues and barriers patients and their support persons face in health care experiences. Utilizing CBPR (methodology) is an opportunity for advanced practice nurses (health care professionals) to co-create strategies and interventions with the community that can assist them in successfully reaching their weight loss and diabetes prevention goals., (© 2021 Wiley Periodicals LLC.)

Background: Acute increases of ≥20% + 2 ng/mL (20 + 2 rule) over basal serum tryptase (BST) is the recommended threshold supporting a clinical diagnosis of anaphylaxis. Prospective studies have demonstrated high sensitivity for this algorithm after parenteral exposure, but specificity has not been evaluated., Objective: We sought to define a serum tryptase change that distinguishes baseline variability from anaphylaxis on the basis of intraindividual variation in BST., Methods: Ninety-three total subjects with atopy (n = 62) or hereditary α-tryptasemia (HαT) (n = 31) and ≥2 BST measurements were identified. Sequential BST variability measurements were modeled and threshold ratios that optimized sensitivity and/or specificity determined. Models were tested in 22 individuals with physician-diagnosed anaphylaxis and validated in independent cohorts of individuals with HαT (n = 33), indolent systemic mastocytosis (ISM) (n = 52), and ISM + HαT (n = 12). Mature tryptase levels were measured in HαT (n = 19) and ISM (n = 20). An online application was developed for clinical use., Results: As a result of BST variability, 9.7% (9/93) of primary cohort patients, and 18% (6/33) of HαT, 30% (16/53) of ISM, and 25% (3/12) of ISM + HαT patients from validation cohorts met the 20 + 2 rule despite absent immediate hypersensitivity symptoms; mature tryptase was noncontributory among individuals with HαT or ISM at baseline. A ratio of acute tryptase/BST exceeding 1.685 provided the optimized diagnostic rule for jointly maximizing sensitivity and specificity. Statistically significant improvement in specificity relative to the 20 + 2 rule was observed among individuals with elevated BST caused by HαT and ISM., Conclusions: Using an acute tryptase/BST ratio of 1.685 improves specificity of measured changes among individuals with HαT and ISM while maintaining high sensitivity for confirmation of anaphylaxis., (Published by Elsevier Inc.)