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Osteoblast-derived extracellular vesicles (EVs) have demonstrated therapeutic utility for bone repair as transporters of key biomolecules capable of accelerating biomineralisation and tissue repair. The clinical translation of these biologically derived nanoparticles, however remains limited due to scalability, heterogeneity and standardisation issues. Herein we investigate the generation of nanovesicles (NVs) from mineralising osteoblasts by extrusion directly compared against natural EV counterparts from the same parental cells. Mineralising osteoblast-derived EVs (MO-EVs) were isolated via ultracentrifugation from cell culture media. The parental osteoblasts were then processed via serial extrusion to <200 nm. EVs and NVs were characterised by comparing their size, concentration and morphology. The presence of tetraspanin markers was detected by Single Particle Interferometric Reflectance Imaging Sensor (SP-IRIS). Osteoblasts viability and metabolic activity was assessed after both EV and NV-treatment before comparing their mineralising potency via alizarin red staining. EVs and NVs exhibited similar diameters of approximately 100 nm with a vesicular morphology. EVs were found to be richer in proteins and exhibited a significantly more negative ζ-potential compared to NVs. SP-IRIS analysis confirmed the presence of CD9, CD63 and CD81 in EVs. At both 1 and 10 μg/mL, EVs and NVs reduced the metabolic activity of osteoblasts, however, this was not associated with any cytotoxic effects. The biomineralisation study performed using osteoblasts showed that only EVs significantly increased mineral deposition (p < 0.05) compared to untreated control. In this study, we have established for the first time the biofabrication of cell-derived nanovesicles as a promising alternative to extracellular vesicles derived from mineralising osteoblasts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The neutron time-of-flight (nToF) diagnostic technique has a lengthy history in Inertial Confinement Fusion (ICF) and High Energy Density (HED) Science experiments. Its initial utility resulted from the simple relationship between the full width half maximum of the fusion peak signal in a distant detector and the burn averaged conditions of an ideal plasma producing the flux [Lehner and Pohl, Z. Phys. 207, 83-104 (1967)]. More recent precision measurements [Gatu-Johnson et al., Phys. Rev. E 94(8), 021202 (2016)] and theoretical studies [Munro, Nucl. Fusion 56, 035001 (2016)] have shown the spectrum to be more subtle and complicated, driving the desire for an absolute calibration of the spectrum to disambiguate plasma dynamics from the conditions producing thermonuclear reactions. In experiments where the neutron production history is not well measured, but the neutron signal is preceded by a concomitant flux of photons, the spectrum can be in situ calibrated using a set of collinear detectors to obtain a true "time-of-flight" measurement. This article presents the motivation and overview of this technique along with estimates of the experimental precision needed to make useful measurements in existing and future nToF systems such as the pulsed power Z-machine located in Albuquerque, NM, at Sandia National Laboratories., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

College students often engage in multiple health-related behaviors simultaneously which can lead to negative outcomes and further risky behaviors. During the COVID-19 pandemic, college students reported decreased condom use, increased solitary cannabis use, and increased alcohol consumption. This current study aimed to (1) identify profiles of health-related behaviors (i.e., alcohol consumption, cannabis use, and sexual behaviors), and (2) determine if these profiles would differ in engagement and perceived effectiveness of COVID-19 preventative measures. Participants were 273 college students from a large Northeastern U.S. public university who completed surveys about health-related behaviors during the 2021 academic year. We used a latent profile analysis to identify distinct subgroups of college students based on their engagement in health-related behaviors. Based on fit indices a three-profile solution showed the best fit: low (N = 196), moderate (N = 54), and high (N = 23). Two one-way ANOVAs examined whether profile membership predicted engagement and perceived effectiveness of COVID-19 safety measures. Participants in the low health-related behaviors profile engaged in preventative measures more than students in the other two profiles. However, profile membership did not predict perceived effectiveness of preventative behaviors. Taken together, our results indicate that college students reporting lower levels of health-related behaviors engage in more preventative measures during a pandemic. Understanding distinct health-related behaviors profiles among college students, and their links with COVID-preventative health-related behaviors, can inform prevention strategies., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities., Competing Interests: Declaration of interests E.T., E.C., K.R., J. Button, A.M., M.B., J.A., A.W., M.A., T.K., A.C., S.S.A., D.L.P., and R.J.T. were employees of and stockholders in Illumina, Inc. at the time of this investigation. V.R. is a stockholder in Illumina, Inc. J.O. is a stockholder in Illumina, Inc. and employee of C2N Diagnostics. J. Belmont and T.W. are stockholders in Illumina, Inc. and were compensated as research advisors through Genetics & Genomics Services Inc. C.S. was compensated as a consultant through Genetics & Genomics Services Inc. for statistical analysis. K.M. is an employee of Ambry Genetics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Many college students "mature out" of heavy drinking when they graduate. Yet, those who go onto graduate education report engaging in problematic drinking patterns. Drinking motives are one factor that uniquely predicts problematic drinking patterns in college students. Evidence suggests that these unique associations also generalize to individuals' post-college, specifically between drinking motives and specific alcohol-related consequences. However, no research to date has examined the association between drinking motives and alcohol-related consequences in graduate students. The current study aimed to examine the unique associations between drinking motives, and drinks per week and specific alcohol-related consequences. Participants included 330 graduate students from various universities in the United States, recruited through social media. The majority of participants were White (71.3%), 54.9% female identifying, with a mean age of 26. Results revealed that conformity motives were positively associated with drinks per week, self-control consequences, self-care consequences, risky consequences, academic/occupational consequences, and blackout consequences. Social motives were negatively associated with interpersonal consequences and academic/occupational consequences. Enhancement motives were negatively associated with drinks per week, and positively associated with academic/occupational consequences. However, coping motivation was not associated with any of the outcomes. These findings highlight the need to further understand how drinking motives influence specific types of alcohol-related consequences as these associations change post-college. Results can be used to better inform future prevention and interventions for this population., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Cell adhesion to the extracellular matrix (ECM) is required for normal cell cycle progression and accurate cell division. However, how cell adhesion to the wide range of ECM proteins found in human tissues influences the cell cycle is not fully understood. The composition and physical properties of the ECM can have profound effects on cell proliferation but can also promote cell cycle exit and quiescence. Furthermore, during tumor development and progression, changes in the ECM can drive both cancer cell proliferation and dormancy. Cell-matrix adhesion is primarily sensed via integrin-associated adhesion complexes, which in turn are regulated by the cell cycle machinery. In particular, cyclin-dependent kinase 1 (CDK1) has been shown to play a crucial role in regulating adhesion complexes during interphase and entry into mitosis. These reciprocal links between cell cycle progression and cell-matrix interactions are now being identified., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Recurrent deletions involving 17q12 are associated with a variety of clinical phenotypes, including congenital abnormalities of the kidney and urinary tract (CAKUT), maturity onset diabetes of the young, type 5, and neurodevelopmental disorders. Structural and/or functional renal disease is the most common phenotypic feature, although the prenatal renal phenotypes and the postnatal correlates have not been well characterized., Method: We reviewed pre- and postnatal medical records of 26 cases with prenatally or postnatally identified 17q12/HNF1B microdeletions (by chromosomal microarray or targeted gene sequencing), obtained through a multicenter collaboration. We specifically evaluated 17 of these cases (65%) with reported prenatal renal ultrasound findings., Results: Heterogeneous prenatal renal phenotypes were noted, most commonly renal cysts (41%, n = 7/17) and echogenic kidneys (41%), although nonspecific dysplasia, enlarged kidneys, hydronephrosis, pelvic kidney with hydroureter, and lower urinary tract obstruction were also reported. Postnatally, most individuals developed renal cysts (73%, 11/15 live births), and there were no cases of end-stage renal disease during childhood or the follow-up period., Conclusion: Our findings demonstrate that copy number variant analysis to assess for 17q12 microdeletion should be considered for a variety of prenatally detected renal anomalies. It is important to distinguish 17q12 microdeletion from other etiologies of CAKUT as the prognosis for renal function and presence of associated findings are distinct and may influence pregnancy and postnatal management., (© 2023 John Wiley & Sons Ltd.)

Permafrost degradation in peatlands is altering vegetation and soil properties and impacting net carbon storage. We studied four adjacent sites in Alaska with varied permafrost regimes, including a black spruce forest on a peat plateau with permafrost, two collapse scar bogs of different ages formed following thermokarst, and a rich fen without permafrost. Measurements included year-round eddy covariance estimates of net carbon dioxide (CO 2 ), mid-April to October methane (CH 4 ) emissions, and environmental variables. From 2011 to 2022, annual rainfall was above the historical average, snow water equivalent increased, and snow-season duration shortened due to later snow return. Seasonally thawed active layer depths also increased. During this period, all ecosystems acted as slight annual sources of CO 2 (13-59 g C m -2  year -1 ) and stronger sources of CH 4 (11-14 g CH 4  m -2 from ~April to October). The interannual variability of net ecosystem exchange was high, approximately ±100 g C m -2  year -1 , or twice what has been previously reported across other boreal sites. Net CO 2 release was positively related to increased summer rainfall and winter snow water equivalent and later snow return. Controls over CH 4 emissions were related to increased soil moisture and inundation status. The dominant emitter of carbon was the rich fen, which, in addition to being a source of CO 2 , was also the largest CH 4 emitter. These results suggest that the future carbon-source strength of boreal lowlands in Interior Alaska may be determined by the area occupied by minerotrophic fens, which are expected to become more abundant as permafrost thaw increases hydrologic connectivity. Since our measurements occur within close proximity of each other (≤1 km 2 ), this study also has implications for the spatial scale and data used in benchmarking carbon cycle models and emphasizes the necessity of long-term measurements to identify carbon cycle process changes in a warming climate., (Global Change Biology© 2024 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Regulatory T (T reg ) cell modulation of adaptive immunity and tissue homeostasis is well described; however, less is known about T reg cell-mediated regulation of the innate immune response. Here we show that deletion of ST2, the receptor for interleukin (IL)-33, on T reg cells increased granulocyte influx into the lung and increased cytokine production by innate lymphoid and γδ T cells without alteration of adaptive immunity to influenza. IL-33 induced high levels of the interleukin-1 receptor antagonist (IL-1Ra) in ST2 + T reg cells and deletion of IL-1Ra in T reg cells increased granulocyte influx into the lung. T reg cell-specific deletion of ST2 or IL-1Ra improved survival to influenza, which was dependent on IL-1. Adventitial fibroblasts in the lung expressed high levels of the IL-1 receptor and their chemokine production was suppressed by T reg cell-produced IL-1Ra. Thus, we define a new pathway where IL-33-induced IL-1Ra production by tissue T reg cells suppresses IL-1-mediated innate immune responses to respiratory viral infection., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Student-athletes are one subgroup of college students in the USA at risk for dating violence and sexual risk behaviors. Despite this, research on student-athletes' dating behaviors is limited; existing research pertains primarily to the National Collegiate Athletic Association (NCAA) Division I athletes and focuses on male student-athletes as perpetrators of dating and sexual violence. While some existing programs aim to reduce dating violence and promote healthy relationships, these programs are education based, and not tailored to the specific strengths and challenges of student-athletes. We therefore designed Supporting Prevention in Relationships for Teams (SPoRT), a novel, four-session prevention intervention for Division III student-athletes of all genders to reduce dating violence and sexual risk behavior by targeting knowledge and skills identified in pilot research, incorporating psychoeducation with techniques from cognitive-behavioral therapy, mindfulness, bystander intervention, and normative feedback., Methods: This study represents stage 1 of the National Institutes of Health (NIH) Stage Model for Behavioral Intervention Development, evaluating the feasibility and acceptability of SPoRT. We describe the development, content, and proposed delivery methods for SPoRT and evaluated the feasibility and acceptability of the program using a mixed-methods approach. Thirty college student-athletes (12 men, 18 women) completed questionnaires and participated in focus groups to provide feedback on the program's length, timing, group size and dynamics, content, and suggestions for making the SPoRT prevention intervention more feasible and acceptable., Results: Our recruitment procedures were successful, and participants rated the program as feasible in terms of delivery methods and logistics. Participants liked that SPoRT was developed based on pilot data collected from student-athletes, brief, and skills based and tailored to athletic team needs. SPoRT was perceived as appropriate and relevant to student-athlete needs in terms of dating violence and sexual risk prevention knowledge and skills. Most participants (63%) rated the program as "excellent" and said they would recommend it to others., Conclusions: We found SPoRT to be both feasible and acceptable in terms of content and delivery. Suggested modifications will be incorporated into the SPoRT healthy relationships prevention intervention to be tested in an NIH Stage 1 efficacy trial., (© 2023. The Author(s).)

Real-world data encompass data primarily captured for the provision or operation of services, for example, electronic health records for direct care purposes, but which may have secondary uses for informing research or commissioning. Public benefit is potentially forfeited by the underutilisation of real-world data for secondary uses, in part due to risk aversion when faced with the prospect of navigating necessary and important data governance processes. Such processes can be perceived as complex, daunting, time-consuming and exposing organisations to risk. By providing an overview description and discussion around the role of six key legal and information governance frameworks and their role regarding responsible data access, linkage and sharing, our intention is to make data governance a less daunting prospect and reduce the perception that it is a barrier to secondary uses, thus enabling public benefit., Competing Interests: Competing interests: MCJ, TS, SMM, AM and MF report no other funding other from the NIHR, during the conduct of the study. No other disclosures were reported., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Emerging evidence suggests that women living with HIV (WLWH) may experience higher rates of anxiety than men living with HIV and women living without HIV. To date, relatively little knowledge exists on valid anxiety screening and diagnostic tools and how they are used among WLWH, specifically WLWH of reproductive age. Thus, the purpose of this scoping review was to describe what is known in the published literature about anxiety among WLWH and the tools used to measure and screen for anxiety in clinical and research contexts. The Arksey and O'Malley methodological framework was used to guide a scoping review of published articles in PsycINFO, Scopus, Sociological Abstracts, and PubMed databases. Twenty-one measures of anxiety were used across the 52 articles identified in the search. Most measures used were self-report. Inconsistencies in standardized screening tools and cutoff scores were observed across studies. Further, measures to assess anxiety varied among studies focused on WLWH. Based on the results from this review, there is a need for consistent, valid measures of anxiety to advance research and clinical practice to support the well-being of WLWH., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population., (© 2023 Wiley Periodicals LLC.)

Given the paucity of comparative efficacy data and the difference in cost between andexanet-alfa and prothrombin complex concentrates (PCC), debates continue regarding optimal cost-effective therapy for patients who present with major bleeding associated with oral factor Xa inhibitors. Available literature comparing the cost-effectiveness of the reversal agents is limited, and the large difference in price between therapy options has led many health systems to exclude andexanet-alfa from their formularies. To evaluate the clinical outcomes and cost of PCC compared to andexanet-alfa for patients with factor Xa inhibitor associated bleeds. We performed a quasi-experimental, single health system study of patients treated with PCC or andexanet-alfa from March 2014 to April 2021. Deterioration-free discharge, thrombotic events, length of stay, discharge disposition, and cost were reported. 170 patients were included in the PCC group and 170 patients were included in the andexanet-alfa group. Deterioration-free discharge was achieved in 66.5% of PCC-treated patients compared to 69.4% in the andexanet alfa-treated patients. 31.8% of PCC-treated patients were discharged home compared to 30.6% in the andexanet alfa-treated patients. The cost per deterioration-free discharge was $20,773.62 versus $5230.32 in the andexanet alfa and 4 F-PCC group, respectively. Among patients that experienced a bleed while taking a factor Xa inhibitor, there was no difference in clinical outcomes for patients treated with andexanet-alfa compared to PCC. Although there was no difference in the clinical outcomes, there was a significant difference in cost with andexanet-alfa costing approximately four times as much as PCC per deterioration-free discharge., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Endosomal Sorting Complex Required for Transport (ESCRT) proteins can be transiently recruited to the plasma membrane for membrane repair and formation of extracellular vesicles. Here, we discovered micrometer-sized worm-shaped ESCRT structures that stably persist for multiple hours at the plasma membrane of macrophages, dendritic cells, and fibroblasts. These structures surround clusters of integrins and known cargoes of extracellular vesicles. The ESCRT structures are tightly connected to the cellular support and are left behind by the cells together with surrounding patches of membrane. The phospholipid composition is altered at the position of the ESCRT structures, and the actin cytoskeleton is locally degraded, which are hallmarks of membrane damage and extracellular vesicle formation. Disruption of actin polymerization increased the formation of the ESCRT structures and cell adhesion. The ESCRT structures were also present at plasma membrane contact sites with membrane-disrupting silica crystals. We propose that the ESCRT proteins are recruited to adhesion-induced membrane tears to induce extracellular shedding of the damaged membrane., (© 2023 Stempels et al.)

College women are at an elevated risk for sexual victimization (SV) and secondary physical and psychological consequences. While some women experience negative outcomes such as posttraumatic stress disorder (PTSD), others experience reduced or complete absence of distress following SV. The variation in outcomes may be associated with the victim's level of intoxication, which may in turn affect their processing of and coping with the event. We examined the effects of SV severity on PTSD via coping and intoxication using a moderated mediation analysis among female college students ( N  = 375). Results demonstrate that coping mediates the association between SV severity and PTSD symptomology; however, intoxication did not moderate these associations. Results suggest that regardless of intoxication, SV severity influences various coping styles and plays an important role in a victim's adjustment post-victimization.

This study investigated the impact of gastro-intestinal fluid volume and bile salt (BS) concentration on the dissolution of carbamazepine (CBZ) immediate release (IR) 100 mg tablets and to integrate these in vitro biorelevant dissolution profiles into physiologically based pharmacokinetic modelling (PBPK) in pediatric and adult populations to determine the biopredictive dissolution profile. Dissolution profiles of CBZ IR tablets (100 mg) were generated in 50-900 mL biorelevant adult fasted state simulated gastric and intestinal fluid (Ad-FaSSGF and Ad-FaSSIF), also in three alternative compositions of biorelevant pediatric FaSSGF and FaSSIF medias at 200 mL. This study found that CBZ dissolution was poorly sensitive to changes in the composition of the biorelevant media, where dissimilar dissolution (F2 = 46.2) was only observed when the BS concentration was changed from 3000 to 89 μM (Ad-FaSSIF vs Ped-FaSSIF 50% 14 BS). PBPK modeling demonstrated the most predictive dissolution volume and media composition to forecast the PK was 500 mL of Ad-FaSSGF/Ad-FaSSIF media for adults and 200 mL Ped-FaSSGF/FaSSIF media for pediatrics. A virtual bioequivalence simulation was conducted by using Ad-FaSSGF and/or Ad-FaSSIF 500 mL or Ped-FaSSGF and/or Ped-FaSSIF 200 mL dissolution data for CBZ 100 mg (reference and generic test) IR product. The CBZ PBPK models showed bioequivalence of the product. This study demonstrates that the integration of biorelevant dissolution data can predict the PK profile of a poorly soluble drug in both populations. Further work using more pediatric drug products is needed to verify biorelevant dissolution data to predict the in vivo performance in pediatrics., (© 2023. The Author(s).)

Objectives: This review aimed to provide an overview of the prevalence of undernutrition in children under 5 years old in refugee camps according to the different indicators. In addition, we aimed to evaluate the quality and quantity of relevant epidemiological data available., Design: We used a systematic review of prevalence study design to achieve the above aims. We sought eligible observational studies through database searching of OVID Medline, CAB Global Health, Scopus and PubMed; citation chasing; and grey literature searching., Setting: The setting of interest was refugee camps across the globe., Participants: Participants in the studies included in the review were children under 5 years old., Primary and Secondary Outcome Measures: Outcome measures of interest were the prevalence of wasting, global acute malnutrition, stunting and underweight., Results: The review included 33 cross-sectional studies in 86 sites and a total of 36 750 participants. Overall, the quality of the studies was moderate to high, but some reports lacked clarity around data collection or outcome definitions. The results showed a wide variation in prevalence estimates across the different indicators and between different refugee camps. The median prevalence estimates of global acute malnutrition based on weight-for-height z-score, stunting and underweight were 7.1%, 23.8% and 16.7%, respectively. Using weight-for-height z-score identified a higher prevalence of acute malnutrition than using mid-upper arm circumference in the majority of studies., Conclusions: Acute malnutrition remains a public health problem in many refugee camps, but chronic malnutrition has a high prevalence in more locations. Research and policy must, therefore, focus not only on nutrition but also on the wider determinants of both acute and chronic undernutrition. The difference in prevalence of global acute malnutrition depending on the measure used has implications for screening and diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity in vivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Reassessing the confluence model of men's risk for sexual aggression-the confluence model of sexual aggression has been widely used to study men's risk for perpetrating sexual violence. Over time, researchers have attempted to expand this model to improve its predictive utility. Unfortunately, this work has continued to produce similar results with only slight improvements in prediction at best. One explanation for the inability to enhance the model could be due to changes in the dating landscape and shifts in beliefs about gender roles. Therefore, the current study aims to reassess the confluence model using a more contemporary construct, hostile sexism, in an effort to improve the predictive utility of the confluence model of sexual aggression. Participants were 258 college men recruited from a medium-sized public university in the northeastern United States, using an online participant pool of students who volunteered to participate as part of a requirement for a psychology course. Structural equation modeling using mean- and variance-adjusted weighted least squares estimation indicated that the confluence of hostile sexism and impersonal sex appears to be a better predictor of sexual aggression in comparison to the confluence of hostile masculinity and impersonal sex. The results suggest that replacing hostile masculinity with hostile sexism may produce a model that is better able to predict men's risk for perpetrating sexual aggression. These results can provide insight for future iterations of the confluence model, which may include hostile sexism as a core construct. Attitudes that stem from hostile sexism may be a beneficial target for future interventions designed to decrease the frequency of perpetration.

Models of sexuality have evolved substantially in the past several decades through the inclusion of new aspects which were previously overlooked. Components such as romantic attraction and behavior have also traditionally been included in models of sexuality. However, romantic and sexual orientations do not coincide for all individuals. A population for which this is true and one that has developed a robust language for discussing romantic orientation is the asexual community. The current study aimed to explore romantic and sexual orientation through patterns found within the factors of attraction, behavior, and identity in the asexual community. The current sample composed of individuals who identified as asexual (N = 306, M age  = 27.1) was 61% female, 13% non-binary, and 10% self-described or used multiple labels. Within this sample, aspects of sexual and romantic orientations and experiences were measured, including fluidity, the quantity and type of self-identified labels, desire for romance or sex, and the role of contextual influences on these experiences. These aspects were used as the primary characteristics to construct participant profiles, both complete profiles and factor specific (attraction, behavior, identity). t-distributed stochastic neighbor embedding (tSNE) was used to find patterns of similarity between individual participant profiles. Overall, it appeared that attraction was the factor most closely associated with overall experiences; however, substantial variability existed between participants. These findings provide a mechanism for better understanding of some nuances of romantic and sexual orientation and may be a useful first step toward future inquiry and hypothesis generation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this Review Article, we discuss a range of soft x-ray power diagnostics at inertial confinement fusion (ICF) and pulsed-power fusion facilities. This Review Article describes current hardware and analysis approaches and covers the following methods: x-ray diode arrays, bolometers, transmission grating spectrometers, and associated crystal spectrometers. These systems are fundamental for the diagnosis of ICF experiments, providing a wide range of critical parameters for the evaluation of fusion performance.

The Z machine is a current driver producing up to 30 MA in 100 ns that utilizes a wide range of diagnostics to assess accelerator performance and target behavior conduct experiments that use the Z target as a source of radiation or high pressures. We review the existing suite of diagnostic systems, including their locations and primary configurations. The diagnostics are grouped in the following categories: pulsed power diagnostics, x-ray power and energy, x-ray spectroscopy, x-ray imaging (including backlighting, power flow, and velocimetry), and nuclear detectors (including neutron activation). We will also briefly summarize the primary imaging detectors we use at Z: image plates, x-ray and visible film, microchannel plates, and the ultrafast x-ray imager. The Z shot produces a harsh environment that interferes with diagnostic operation and data retrieval. We term these detrimental processes "threats" of which only partial quantifications and precise sources are known. We summarize the threats and describe techniques utilized in many of the systems to reduce noise and backgrounds.

Introduction: Technosphere insulin (TI) is an inhaled dry powder ultra-rapid-acting insulin. This report describes the results of the first study of TI in children with type 1 diabetes (T1D)., Methods: Pharmacokinetics (PK) of TI and the effect of TI on circulating glucose concentrations were evaluated in a single-arm study that enrolled children ages 8-17 years with T1D for more than 1 year, on a stable multiple daily insulin injection (MDI) regimen, and meeting pre-defined pulmonary function testing criteria (at least 70% predicted). To assess PK, subjects received an individualized single preprandial dose of TI (4-12 U, in 4-U increments) via oral inhalation, based on their usual meal-time subcutaneously injected rapid-acting insulin dose and meal content. Serum insulin and blood glucose were measured at - 30 to 250 min relative to dosing., Results: Twenty-seven children with T1D participated in this single-dose PK study. Mean subject age was 13.3 years (59% female; 81.5% White). Mean serum insulin C max (maximum concentration) was 77.3, 119.15, and 207.7 µU/mL for doses of 4, 8, and 12 U, respectively. T max occurred at 10.5, 13.9, and 14.6 min post-dose for 4, 8, and 12 U. Glucose lowering 30-60 min post-dose was consistent with the PK profile., Conclusion: Serum insulin rapidly increased post-dose and returned to baseline by 120 min. The data suggests the PK of TI in youth with T1D ages 8-17 years was similar to that seen in previous adult studies., Trial Registration: ClinicalTrials.gov identifier, NCT02527265., (© 2023. The Author(s).)

Wetlands cover a small portion of the world, but have disproportionate influence on global carbon (C) sequestration, carbon dioxide and methane emissions, and aquatic C fluxes. However, the underlying biogeochemical processes that affect wetland C pools and fluxes are complex and dynamic, making measurements of wetland C challenging. Over decades of research, many observational, experimental, and analytical approaches have been developed to understand and quantify pools and fluxes of wetland C. Sampling approaches range in their representation of wetland C from short to long timeframes and local to landscape spatial scales. This review summarizes common and cutting-edge methodological approaches for quantifying wetland C pools and fluxes. We first define each of the major C pools and fluxes and provide rationale for their importance to wetland C dynamics. For each approach, we clarify what component of wetland C is measured and its spatial and temporal representativeness and constraints. We describe practical considerations for each approach, such as where and when an approach is typically used, who can conduct the measurements (expertise, training requirements), and how approaches are conducted, including considerations on equipment complexity and costs. Finally, we review key covariates and ancillary measurements that enhance the interpretation of findings and facilitate model development. The protocols that we describe to measure soil, water, vegetation, and gases are also relevant for related disciplines such as ecology. Improved quality and consistency of data collection and reporting across studies will help reduce global uncertainties and develop management strategies to use wetlands as nature-based climate solutions., Supplementary Information: The online version contains supplementary material available at 10.1007/s13157-023-01722-2., Competing Interests: Competing InterestsThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Author(s) 2023.)

Neutron time-of-flight (nTOF) detectors have been used on Sandia National Laboratories' Z-Machine for inertial confinement fusion and magnetized liner fusion experiments to infer physics parameters including the apparent fuel-ion temperature, neutron yield, the magnetic-radius product (BR), and the liner rho-r. Single-paddle, dual-paddle, and co-axial scintillation nTOF detectors are used in axial lines-of-sight (LOS) and LOS that are 12° from the midplane. Detector fabrication, characterization, and calibration are discussed.

Juxtaphyseal fractures of the distal phalanges of upper extremity digits are most commonly of the Salter-Harris II variety and occur most commonly in the thumb. The diagnosis of this injury is essential as it may present as an open fracture with a nailbed injury ("Seymour fracture"). However, an intra-articular, epiphyseal fracture may also occur and mimic a mallet deformity or Seymour fracture. Prompt diagnosis is essential to rule out an open fracture and obtain anatomical alignment and stability to attempt to reduce complications such as physeal arrest. Here, we present a patient with a displaced Salter-Harris type III fracture of his thumb distal phalanx and review his management and early-term outcome. We present this case to bring attention to this rare and unique injury, review the available literature, and discuss management and outcomes.

Abstract: Little is known about the impact of prebriefing on students' experiences of learning with simulation. This mixed-methods study evaluated the impact of prebriefing activities on nursing students' satisfaction, confidence, and performance of nursing skills during a simulation. Findings revealed students who experienced a structured, more robust prebriefing had improved performance during the simulation and reported higher levels of confidence and satisfaction in learning compared to a group that experienced a standard prebriefing. Findings are significant to the profession, they support the incorporation of structured, reflective prebriefing activities in simulation-based experiences., Competing Interests: The authors have declared no conflict of interest., (Copyright © 2022 National League for Nursing.)

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development., (© 2022 Wiley Periodicals LLC.)

High-latitude peatlands are changing rapidly in response to climate change, including permafrost thaw. Here, we reconstruct hydrological conditions since the seventeenth century using testate amoeba data from 103 high-latitude peat archives. We show that 54% of the peatlands have been drying and 32% have been wetting over this period, illustrating the complex ecohydrological dynamics of high latitude peatlands and their highly uncertain responses to a warming climate., (© 2022. The Author(s).)

Objectives: The Centers for Medicare and Medicaid Services Severe Sepsis and Septic Shock Management Bundle (SEP-1) assesses antibiotic administration, lactate measurement, and blood culture collection within 3 h of severe sepsis onset. The impact of the SEP-1 3-hour bundle among patients with severe sepsis is not extensively described. This investigation aimed to describe the impact of 3-hour bundle compliance on 28-day in-hospital mortality in patients with severe sepsis., Study Design: This was a retrospective, propensity adjusted, nested case-control study assessing the impact of compliance with a 3-hour sepsis bundle among patients with severe sepsis., Setting: This study was conducted at a large, academic, tertiary care medical center in Detroit, Michigan from July 1, 2017 to December 31, 2019., Patients: Cases were defined as those suffering 28-day in-hospital mortality. Controls were defined as those surviving at or discharged by 28 days. Patients were separated based on 3-hour bundle compliance or noncompliance. Nested and overall cohorts were assessed. Severe sepsis time zero was manually validated. Patients with shock, requiring vasopressors within 8 h of time zero, or those not meeting SEP-1 inclusion criteria were excluded., Intervention: The primary outcome was the propensity adjusted odds of 28-day in-hospital mortality among 3-hour bundle compliant versus noncompliant patients. Secondary outcomes included mortality for individual bundle element compliance, progression to septic shock, and predictors of mortality according to logistic regression., Results: A total of 325 compliant and 325 noncompliant patients were included. The median Sequential Organ Failure Assessment (SOFA) score was three in each group. There was no difference in propensity adjusted odds of mortality among those compliant versus noncompliant with the 3-hour bundle (odds-ratio [OR] 1.039; 95% CI: 0.721-1.497; p = 0.838) or with individual bundle elements. SOFA score and female sex were predictors of mortality., Conclusions: Three-hour bundle compliance did not impact 28-day in-hospital mortality in patients with severe sepsis. Further research is needed to understand the impact of 3-hour bundle compliance on mortality in severe sepsis., (© 2022 Pharmacotherapy Publications, Inc.)

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis due to its aggressive progression, late detection and lack of druggable driver mutations, which often combine to result in unsuitability for surgical intervention. Together with activating mutations of the small GTPase KRas, which are found in over 90% of PDAC tumours, a contributory factor for PDAC tumour progression is formation of a rigid extracellular matrix (ECM) and associated desmoplasia. This response leads to aberrant integrin signalling, and accelerated proliferation and invasion. To identify the integrin adhesion systems that operate in PDAC, we analysed a range of pancreatic ductal epithelial cell models using 2D, 3D and organoid culture systems. Proteomic analysis of isolated integrin receptor complexes from human pancreatic ductal epithelial (HPDE) cells predominantly identified integrin α6β4 and hemidesmosome components, rather than classical focal adhesion components. Electron microscopy, together with immunofluorescence, confirmed the formation of hemidesmosomes by HPDE cells, both in 2D and 3D culture systems. Similar results were obtained for the human PDAC cell line, SUIT-2. Analysis of HPDE cell secreted proteins and cell-derived matrices (CDM) demonstrated that HPDE cells secrete a range of laminin subunits and form a hemidesmosome-specific, laminin 332-enriched ECM. Expression of mutant KRas (G12V) did not affect hemidesmosome composition or formation by HPDE cells. Cell-ECM contacts formed by mouse and human PDAC organoids were also assessed by electron microscopy. Organoids generated from both the PDAC KPC mouse model and human patient-derived PDAC tissue displayed features of acinar-ductal cell polarity, and hemidesmosomes were visible proximal to prominent basement membranes. Furthermore, electron microscopy identified hemidesmosomes in normal human pancreas. Depletion of integrin β4 reduced cell proliferation in both SUIT-2 and HPDE cells, reduced the number of SUIT-2 cells in S-phase, and induced G1 cell cycle arrest, suggesting a requirement for α6β4-mediated adhesion for cell cycle progression and growth. Taken together, these data suggest that laminin-binding adhesion mechanisms in general, and hemidesmosome-mediated adhesion in particular, may be under-appreciated in the context of PDAC. Proteomic data are available via ProteomeXchange with the identifiers PXD027803, PXD027823 and PXD027827., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

While influenza infection induces robust, long-lasting, antibody responses and protection, including the T follicular helper cells (T FH ) required to drive B cell germinal center (GC) responses, most influenza vaccines do not. We investigated the mechanisms that drive strong T FH responses during infection. Infection induces viral replication and antigen (Ag) presentation lasting through the CD4 effector phase, but Ag and pathogen recognition receptor signals are short-lived after vaccination. We analyzed the need for both infection and Ag presentation at the effector phase, using an in vivo sequential transfer model to time their availability. Differentiation of CD4 effectors into T FH and GC-T FH required that they recognize Ag locally in the site of T FH development, at the effector phase, but did not depend on specific Ag-presenting cells (APCs). In addition, concurrent signals from infection were necessary even when sufficient Ag was presented. Providing these signals with a second dose of live attenuated influenza vaccine at the effector phase drove T FH and GC-T FH development equivalent to live infection. The results suggest that vaccine approaches can induce strong T FH development that supports GC responses akin to infection, if they supply these effector phase signals at the right time and site. We suggest that these requirements create a checkpoint that ensures T FH only develop fully when infection is still ongoing, thereby avoiding unnecessary, potentially autoimmune, responses., Competing Interests: The authors declare no competing interest.

Objective: A growing literature supports mindfulness and acceptance-based interventions (MABIs) for depression prevention and treatment with individuals from dominant cultural groups, and MABIs have been theorized to be well suited to resonate with individuals from nondominant groups. The aim of the current meta-analysis was to determine whether this promise is realized in practice by evaluating the efficacy of MABIs for depression symptoms in Black Americans., Method: Thirty studies with an adequate proportion (>20%) of Black Americans were identified using previous reviews and electronic databases, yielding a total of 1,703 participants with an average proportion of 70% Black Americans. Data on moderators (i.e., geographic location, study design, and intervention protocol) and outcomes were extracted and analyzed using metaregression., Results: Results indicated a moderate effect of MABIs on symptom outcomes in the full sample g = 0.48. Effect sizes were similar in study subsets comprising majority (>50%; k = 19) g = 0.39, and predominantly (>90%; k = 10) g = 0.35, Black participants, with no significant moderating effect of racial composition. Effects were moderated by both sample and intervention level characteristics., Conclusions: The current findings support the conclusion that MABIs are efficacious to varying degrees for Black Americans; with stronger support for use in adult samples than youth samples. These results are promising, and further support efforts to expand research on evidence-based treatments (EBTs) to meet the specific mental health needs of Black Americans. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Diagnostic stewardship interventions can decrease unnecessary antimicrobial therapy and microbiology laboratory resources and costs. This retrospective cross-sectional study evaluated factors associated with inappropriate initial cerebrospinal fluid (CSF) testing in patients with suspected community-acquired meningitis or encephalitis. In 250 patients, 202 (80.8%) and 48 (19.2%) were suspected meningitis and encephalitis, respectively. 207 (82.8%) patients had inappropriate and 43 (17.2%) appropriate testing. Any inappropriate CSF test was greatest in the immunocompromised (IC) group (n = 54, 91.5%), followed by non-IC (n = 109, 80.1%) and HIV (n = 44, 80%). Ordering performed on the general ward was associated with inappropriate CSF test orders (adjOR 2.81, 95% CI [1.08-7.34]). Laboratory fee costs associated with excessive testing was close to $300,000 per year. A stepwise algorithm defining empiric and add on tests according to CSF parameters and patient characteristics could improve CSF test ordering in patients with suspected meningitis or encephalitis., Competing Interests: Declaration of competing interest The authors report no conflicts of interest relevant to this article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We have discovered that the determination of CD4 effector and memory fates after infection is regulated not only by initial signals from antigen and pathogen recognition, but also by a second round of such signals at a checkpoint during the effector response. Signals to effectors determine their subsequent fate, inducing further progression to tissue-restricted follicular helpers, cytotoxic CD4 effectors, and long-lived memory cells. The follicular helpers help the germinal center B-cell responses that give rise to high-affinity long-lived antibody responses and memory B cells that synergize with T-cell memory to provide robust long-lived protection. We postulate that inactivated vaccines do not provide extended signals from antigen and pathogen beyond a few days, and thus elicit ineffective CD4 T- and B-cell effector responses and memory. Defining the mechanisms that underlie effective responses should provide insights necessary to develop vaccine strategies that induce more effective and durable immunity., (Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved.)