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Introduction: Work-related asthma accounts for ≥25% of asthma in working-age populations, though the relationship between work exposures and symptoms is frequently missed, leading to poor health and employment outcomes. We hypothesised that inhalable exposures at work are associated with poor asthma control in severe asthma (SA)., Methods: We searched the Birmingham (UK) Regional NHS SA Service clinical database (n=1453 records; 1 March 2004 to 1 March 2021) and undertook a cross-sectional study using baseline data collected at diagnosis. We included all employed patients aged 16-64 with documented current occupation (n=504), and collected socio-demographic, general health and asthma-specific data, including Asthma Control Questionnaire 7 (ACQ7) score. The Occupational Asthma Specific Job-Exposure Matrix (OAsJEM) was employed to determine the likelihood of exposure to respiratory sensitisers, irritants, cleaning agents and detergents; associations between exposures and ACQ7 were investigated using binary and multinomial regression., Results: Frequently reported occupations were care assistants (7%) and nurses (6%); 197/504 (39%) patients were exposed to an asthmagen, including respiratory sensitisers (30%), airway irritants (38%) and cleaning products/disinfectants (29%). ACQ7 score was available for 372/504 (74%) patients, of whom 14% had adequate control (ACQ7=0-1.5). After adjustment for major confounders there were no significant associations between inhaled asthmagens and ACQ7 score (either as binary or multinomial outcomes)., Conclusion: JEM-determined workplace exposures to inhaled asthmagens are not associated with asthma control in SA; 29-39% of patients may have current exposure to workplace asthmagens. Routine collection of lifetime occupational data including current job role and level of exposure, in the national asthma registry, would give further insights into this relationship., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: PICOBOO is a randomised, adaptive trial evaluating the immunogenicity, reactogenicity, and safety of COVID-19 booster strategies. We report data for second boosters among individuals 50-<70 years old primed with AZD1222 (50-<70y-AZD1222) until Day 84., Methods: Contributed equally as first authors.Immunocompetent adults who received any first booster >three months prior were eligible. Participants were randomly allocated to BNT162b2, mRNA-1273 or NVX-CoV2373 1:1:1. The concentrations of ancestral anti-spike immunoglobulin was summarised as the geometric mean concentrations (GMC). Reactogenicity and safety outcomes were captured. Additional analyses including neutralising antibodies were performed on a subset. ACTRN12622000238774., Results: Between Mar 2022-Aug 2023, 743 participants were recruited and had D28 samples; 155 belonged to the 50-<70y-AZD1222 stratum. The mean adjusted GMCs (95% credible intervals) were 20,690 (17,555-23,883), 23,867 (20,144-27,604) and 8,654 (7,267-9,962) U/mL at D28 following boosting with BNT162b2, mRNA-1273 and NVX-CoV2372, respectively, and 10,976 (8,826-13,196), 15,779 (12,512-19,070) and 6,559 (5 220-7 937) U/mL by D84. IgG against Omicron BA.5 was 2.7-2.9 times lower than the ancestral strain. Limited neutralisation against Omicron subvariants was found following all vaccines. Severe reactogenicity events were <4%., Conclusions: All vaccines were immunogenic with more rapid waning after mRNA vaccines. These data support boosting with vaccines with greater specificity for circulating Omicron subvariants., Competing Interests: Declaration of Competing Interest KF and TS are members of the Australian Technical Advisory Group on Immunisation (ATAGI) which advises the government on vaccine policy; their involvement as investigators on this trial has been declared to ATAGI. MP is involved in an ovarian cancer clinical trial that received funding from AstraZeneca. MP was involved in performing immunological assays on biological specimens obtained from participants in this trial, but was not involved in participant recruitment, data collection or the analysis of results. SNF leads the UK National Institute for Health and Care Research funded trial of third and fourth dose COVID-19 boosters. SNF acts on behalf of University Hospital Southampton NHS Foundation Trust, UK as an Investigator and/or providing consultative advice on clinical trials and studies of vaccines funded or sponsored by vaccine manufacturers including Moderna, Sanofi, Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Medimmune, Merck and Valneva vaccines and antimicrobials. UW is an investigator on clinical trials of vaccines funded or sponsored by vaccine manufactures including Moderna, Sanofi, Pfizer, Merck and GlaxoSmithKline. PR also reports acting on behalf of University of Western Australia, as an Investigator and/or providing consultative advice on clinical trials and studies of vaccines funded or sponsored by vaccine manufacturers including Moderna, Sanofi, Janssen, Pfizer, AstraZeneca, GlaxoSmithKline, Novavax, Seqirus, Merck and Clover Biopharmaceutical vaccines. They receive no personal financial payment for this work. The other authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Response times and their distributions serve as a powerful lens into cognitive processes. We present a novel statistical methodology called Stratified Distributional Analysis (SDA) to quantitatively assess how key determinants of response times (word frequency and length) shape their distributions. Taking advantage of the availability of millions of lexical decision response times in the English Lexicon Project and the British Lexicon Project, we made important advances into the theoretical issue of linking response times and word frequency by analysing RT distributions as a function of word frequency and word length. We tested these distributions against the lognormal, Wald, and Gamma distributions and three measures of word occurrence (word form frequencies obtained from subtitles and contextual diversity as operationalized as discourse contextual diversity and user contextual diversity). We found that the RT distributions were best described by a lnorm distribution across both megastudies when word occurrence was quantified by a contextual diversity measure. The link between the lnorm distribution and its generative process highlights the power of SDA in elucidating mechanisms that govern the generation of RTs through the fitting of probability distributions. Using a hierarchical Bayesian framework, SDA yielded posterior distributions for the distributional parameters at the single-participant level, enabling probabilistic predictions of response times as a function of word frequency and word length, which has the potential to serve as a diagnostic tool to uncover idiosyncratic features of word processing. Crucially, while we applied our parsimonious methodology to lexical decision response times, it is applicable to a variety of tasks such as word-naming and eye-tracking data.

Background: The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and it is recommended in many guidelines, but this is based on limited evidence. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leukocidins (eg, Panton-Valentine leukocidin, toxic shock syndrome toxin 1, exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question., Methods and Analysis: The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multicenter adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality rates. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either 5 days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard-of-care antibiotics. Most participants with SAB (within 72 hours of index blood culture and with no contraindications) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol, and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and Panton-Valentine leukocidin-positive isolate., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Primary secretory carcinoma (SC) of the thyroid gland is a rare neoplasm, characterized by the presence of oncogenic ETV6::NTRK3 fusions, which are amenable to tropomyosin receptor kinase (TRK) inhibitor therapy. Despite its morphologic, immunophenotypic, and genetic similarities to SC of the salivary and mammary glands, diagnostic pitfalls may arise in differentiating from papillary thyroid carcinoma due to overlapping features such as papillary growth, nuclear irregularity, and variable expression of PAX8. Tumor misclassification may lead to delayed consideration of molecular testing and targeted therapy. A total of 13 cases of thyroid SC have been documented in the literature, indicating a tendency for advanced clinical presentation followed by a protracted clinical course, with most patients surviving until the end of the study period despite some experiencing recurrences. However, tumor-related mortality occurred in around 30% of cases, with the overall survival ranging from days to years, underscoring the variability in tumor behavior and the need for further research efforts. Among documented cases of thyroid SC, prognostic factors established for salivary SC have shown broad distributions, including a mitotic activity ranging from < 1 to 10 per 10 high-power fields and variable presence of necrosis, awaiting additional case experience to better elucidate their relevance in thyroid SC. We hereby present a 61-year-old female patient with widely metastatic thyroid SC treated with larotrectinib and provide an updated review of the literature on the molecular pathogenesis and clinicopathologic characteristics of this rare entity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: There is a recognized unmet need for clinical trials to provide evidence-informed care for infants, children and adolescents. This Special Communication outlines the capacity of 3 distinct trial design strategies, sequential, parallel, and a unified adult-pediatric bayesian adaptive design, to incorporate children into clinical trials and transform this current state of evidence inequity. A unified adult-pediatric whole-of-life clinical trial is demonstrated through the Staphylococcus aureus Network Adaptive Platform (SNAP) trial., Observations: Bayesian methods provide a framework for synthesizing data in the form of a probability model that can be used in the design and analysis of a clinical trial. Three trial design strategies are compared: (1) a sequential adult-pediatric bayesian approach that involves a separate, deferred pediatric trial that incorporates existing adult trial data into the analysis model to potentially reduce the pediatric trial sample size; (2) a parallel adult-pediatric bayesian trial whereby separate pediatric enrollment occurs in a parallel trial, running alongside an adult randomized clinical trial; and (3) a unified adult-pediatric bayesian adaptive design that supports the enrollment of both children and adults simultaneously in a whole-of-life bayesian adaptive randomized clinical trial. The SNAP trial whole-of-life design uses a bayesian hierarchical model that allows information sharing (also known as borrowing) between trial age groups by linking intervention effects of children and adults, thereby improving inference in both groups., Conclusion and Relevance: Bayesian hierarchical models may provide more precision for estimates of safety and efficacy of treatments in trials with heterogenous populations compared to traditional methods of analysis. They facilitate the inclusion of children in clinical trials and a shift from children deemed therapeutic orphans to the vision of no child left behind in clinical trials to ensure evidence for clinical practice exists across the life course. The SNAP trial provides an example of a bayesian adaptive whole-of-life inclusion design that enhances trial population inclusivity and diversity overall, as well as generalizability and translation of findings into clinical practice.

The CNO cycle is one of the most important nuclear energy sources in stars. At temperatures of hydrostatic H-burning (20  MK

Achieving a controlled release of several active pharmaceutical ingredients (APIs) remains a challenge for improving their therapeutic effects and reduced their side effects. In the current work, stimulable Drug Delivery Systems (DDS) based on supramolecular hydrogels were designed by combining two APIs featuring anticancer activities, namely the doxorubicin and phenazine 14. In vitro studies revealed promising physicochemical properties for all the investigated API loaded gels. Fluorinated GlycoNucleoLipid (GNF) based supramolecular gels remain stable in the presence of either doxorubicin (Doxo) or phenazine 14 (Phe) as anticancer drugs. Noteworthy, the stiffness of the GNF-based supramolecular gels was enhanced in the presence of both APIs while maintaining their thixotropic properties. We demonstrated that the storage modulus (G') of the GNF gels was increased from 1.3 kPa to 9.3 kPa upon loading of both APIs within the same gels. With a low mechanical stimulation (within the LVR), a passive diffusion out of gels was observed for Dox whereas Phe remained trapped in the GNF gels over several hours. Also, in this work we showed that mechanical stress triggered the release of both Phe and Doxo at different rates., (© 2024. Controlled Release Society.)

The nuclear two-photon or double-gamma (2γ) decay is a second-order electromagnetic process whereby a nucleus in an excited state emits two gamma rays simultaneously. To be able to directly measure the 2γ decay rate in the low-energy regime below the electron-positron pair-creation threshold, we combined the isochronous mode of a storage ring with Schottky resonant cavities. The newly developed technique can be applied to isomers with excitation energies down to ∼100  keV and half-lives as short as ∼10  ms. The half-life for the 2γ decay of the first-excited 0^{+} state in bare ^{72}Ge ions was determined to be 23.9(6) ms, which strongly deviates from expectations.

Charter school policy represents two simultaneous forms of accountability, in which schools are accountable to both parents and authorizers. This study of a K-8 charter renewal decision interrogates these accountability relationships and the role of race and power in privileging the interests of particular stakeholders over others. Using counternarrative methodology and qualitative interviews and observations, we draw on critical race theory and new managerialism to make sense of the competing accounts surrounding a non-renewal process. We find four areas of tension, in which district officials subscribe to new managerialist authorizing styles that leave little room for participation from the Black and low-income school community. We conclude with recommendations for how districts can partner with communities to work toward frameworks of accountability that value the goals of multiple stakeholder groups., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: A multicenter, double-blinded randomized controlled trial comparing isolated Bankart repair (NO REMP) to Bankart repair with remplissage (REMP) reported benefits of remplissage in reducing recurrent instability at 2 years postoperative. The ongoing benefits beyond this time point are yet to be explored., Purpose: To (1) compare medium-term (3 to 9 years) outcomes of these previously randomized patients undergoing isolated Bankart repair (NO REMP) or Bankart repair with remplissage (REMP) to manage recurrent anterior glenohumeral instability; (2) examine the failure rate, overall recurrent instability, and reoperation rate., Study Design: Randomized controlled trial; Level of evidence, 1., Methods: Recruitment and randomization for the original randomized trial occurred between 2011 and 2017. Patients ≥14 years diagnosed with recurrent traumatic anterior shoulder instability with an engaging Hill-Sachs defect of any size were included. Those with a glenoid defect >15% were excluded. In 2020, participants were contacted by telephone and asked standardized questions regarding ensuing instances of subluxation, dislocation, or reoperation on their study shoulder. "Failure" was defined as a redislocation, and "overall recurrent instability" was described as a redislocation or ≥2 subluxations. Descriptive statistics, relative risk, and Kaplan-Meier survival curve analyses were performed., Results: A total of 108 participants were randomized, of whom 50 in the NO REMP group and 52 in the REMP group were included in the analyses in the original study. The mean number of months from surgery to the final follow-up was 49.3 and 53.8 months for the NO REMP and REMP groups, respectively. Failure rates were 22% (11/50) in the NO REMP group versus 8% (4/52) in the REMP group. Rates of overall recurrent instability were 30% (15/50) in the NO REMP group versus 10% (5/52) in the REMP group. Survival curves were significantly different, favoring REMP in both scenarios., Conclusion: For the treatment of traumatic recurrent anterior shoulder instability with a Hill-Sachs lesion and subcritical glenoid bone loss (<15%), a significantly lower rate of overall postoperative recurrent instability was observed with arthroscopic Bankart repair and remplissage than with isolated Bankart repair at a medium-term follow-up (mean of 4 years). Patients who did not receive a remplissage experienced a failure (redislocated) earlier and had a higher rate of revision/reoperation than those who received a concomitant remplissage., Registration: NCT01324531 (ClinicalTrials.gov identifier)., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: The Pan Am Clinic Foundation is supported by Conmed, Arthrex, Ossur, Smith & Nephew, Stryker, and Zimmer Biomet. J.M.W. has received consulting fees from Smither & Nephew and Stryker. P.B.M. has received consulting fees from Conmed and Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Background: The COVID-19 pandemic has dramatically altered the way of life in the United States, which may be linked to self-injurious behaviors., Methods: We conducted a secondary analysis of data from the Fall 2020 Cohort of the Healthy Minds Survey, a non-probability sample of students enrolled at one of 28 universities across the United States. Participants completed an online survey during the COVID-19 pandemic (September-December, 2020)., Results: Nearly a quarter of the sample (n = 6999) reported engaging in non-suicidal self-injury (NSSI), 12.41% (n = 3819) reported suicidal ideation, 4.98% (n = 1531) reported making a suicide plan, and 1.09% (n = 334) reported a suicide attempt over the past 12 months. When accounting for all COVID-19 factors in the same model, COVID-19 related concern, COVID-19 related discrimination, financial distress, and infection were significantly associated with NSSI, suicidal ideation, and suicide plan; caregiving was significantly associated with lower odds of engaging in non-suicidal self-injury. None of the factors were associated with suicide attempt., Conclusions: This study showed that various COVID-19 factors were related to SIB. Interventions may consider multiple dimensions of COVID-19 and their specific impacts.

Purpose: Nirmatrelvir/ritonavir is one of few options for outpatient treatment of COVID-19, but its use has been limited in transplant recipients due to significant drug interactions with immunosuppressants. Tacrolimus toxicity is possible when the drug is coadministered with nirmatrelvir/ritonavir and may require urgent reduction of tacrolimus levels. This case series describes the use of phenytoin for enzyme induction in 5 adult solid organ transplant recipients with supratherapeutic tacrolimus levels resulting from coadministration with nirmatrelvir/ritonavir., Summary: Solid organ transplant recipients are at high risk for complications related to COVID-19. Outpatient treatment options are limited, and therapeutic drug monitoring is complex in patients requiring quarantine. The 5 solid organ transplant recipients described herein were initiated on nirmatrelvir/ritonavir in the outpatient setting and subsequently presented with supratherapeutic tacrolimus concentrations greater than 59 ng/mL and developed signs and symptoms of tacrolimus toxicity. In all patients, nirmatrelvir/ritonavir and tacrolimus were discontinued, and oral phenytoin (200-400 mg/day) was given for 2 to 4 days. Tacrolimus was resumed once tacrolimus levels decreased to appropriate levels., Conclusion: These observations demonstrate that metabolism induction using phenytoin may be a useful strategy in the setting of supratherapeutic tacrolimus levels resulting from concomitant administration with nirmatrelvir/ritonavir., (© American Society of Health-System Pharmacists 2024. 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.)

Robotic surgery is increasingly utilized in hepatopancreatobiliary (HPB) surgery, but the learning curve is a substantial obstacle hindering implementation. Comprehensive robotic training can help to surmount this obstacle; however, despite the expansion of robotic training into residency and fellowship programs, limited data are available about how this translates into successful incorporation in faculty practice. All operations performed during the first three years of practice of a surgical oncologist at a tertiary care academic institution were retrospectively reviewed. The surgeon underwent comprehensive robotic training during residency and fellowship. 137 HPB operations were performed during the initial three years of practice. Over 80% were performed robotically each year across a spectrum of HPB procedures with a 6% conversion rate. Median operative time, a metric for operative proficiency and evaluation for a learning curve, was similar throughout the study period for each major operation and below several reported optimized operative time benchmarks. The major complications, defined as a Clavien-Dindo of 3 or more, were similar across the experience and comparable to published series. Comprehensive robotic training in residency and fellowship as well as a dedicated, well-trained operative team allows for early attainment of optimized outcomes in a new HPB robotic practice., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background: Clinical trials and real world studies demonstrated benefit of mepolizumab treatment in severe asthma but data on its effectiveness beyond 2 years remain limited. Herein, we provide mepolizumab treatment evaluation up to 4 years., Methods: we studied all patients initiated on mepolizumab in our center from June 2017 to August 2018. Clinical outcomes data were retrieved from the local dendrite systems registry. Comparison analyses and logistic regression were conducted to explore longevity and predictors of response to mepolizumab treatment., Results: a total of 66 patients initiated on mepolizumab with a median follow-up of 45.8 (42.4,48.1) months were included in the study [mean age 50.3 years (range 18-79), females 50 (73%) ]. At 20.7 months of treatment, 42 patients (63.6%) had positive response, 13 (19.7%) negative response, and 11 (16.7%) discontinued due to other factors. At 45.8 months, 35 (53%) patients were still on mepolizumab, 21 (31.8%) switched to a different biologic, and 10 (15.2%) discontinued biologics. Two deaths were recorded during the study period.The median blood eosinophil was reduced from 0.43x10 9 /L (0.27, 0.75) to 0.04 (0.0, 0.1) ( p  < 0.00001)]. The median annual exacerbations were reduced from 6.0 (4,8) to 1.0 (0.0,3.0) ( p  < 0.00001), and mOCS use was reduced from59% to 29%, p  = 0.001. The mean asthma control questionnaire-6 (ACQ6) improved from 3.1 ± 1.7 to 2.1 ± 1.3 ( p  < 0.00001)., Conclusions: mepolizumab clinical benefit was sustained over 4 years. However, approximately half of the cohort discontinued the treatment prompting the need for further research into the treatment response longevity.

This randomized controlled trial tested the Family Assessment and Feedback Intervention (FAFI), a new intervention to enhance family engagement with emotional and behavioral health services. The FAFI is a guided conversation with families about results of their multidimensional assessment that is set in the context of motivational enhancement. It differs from other assessment-with-feedback interventions by extending the focus of assessment beyond the target child to parents and the family environment, addressing parental emotional and behavioral problems and competencies, spanning a broad range of children's and parents' strengths and difficulties, and being generalizable to many settings and practitioners. Participants were 81 families in primary care pediatrics. The FAFI was associated with a significant increase in parental mental health literacy and with an increase in parental attitudinal engagement with health supports and services that closely approached statistical significance (p = .052), while controlling for children's age and gender and family socioeconomic status., (© 2024. The Author(s).)

The 2S albumins Ara h 2 and Ara h 6 have been shown to be the most important source of allergenicity in peanut. Several isoforms of these allergens have been described. Using extraction and liquid chromatography we isolated proteins with homology to Ara h 2 and characterized hitherto unknown Ara h 2 proteoforms with additional post-translational cleavage. High-resolution mass spectrometry located the cleavage site on the non-structured loop of Ara h 2 while far UV CD spectroscopy showed a comparable structure to Ara h 2. The cleaved forms of Ara h 2 were present in genotypes of peanut commonly consumed. Importantly, we revealed that newly identified Ara h 2 cleaved proteoforms showed comparable IgE-binding using sera from 28 peanut-sensitized individuals, possessed almost the same IgE binding potency and are likely similarly allergenic as intact Ara h 2. This makes these newly identified forms relevant proteoforms of peanut allergen Ara h 2., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Koppelman Stef reports a relationship with DBV Technologies that includes: consulting or advisory. Marianne van Hage reports a relationship with Thermo Fisher Scientific ImmunoDiagnostics Division that includes: speaking and lecture fees. Marianne van Hage reports a relationship with AstraZeneca AB that includes: speaking and lecture fees. If there are other authors, they 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 B.V. All rights reserved.)

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The addition of epinephrine in irrigation fluid and the intravenous or local administration of tranexamic acid have independently been reported to decrease bleeding, thereby improving surgeons' visualization during arthroscopic shoulder procedures. No study has compared the effect of intravenous tranexamic acid, epinephrine in the irrigation fluid, or the combination of both tranexamic acid and epinephrine on visual clarity during shoulder arthroscopy with a placebo group. We hypothesized that intravenous tranexamic acid is more effective than epinephrine mixed in the irrigation fluid in improving visualization during shoulder arthroscopy, with no additive effect when both are used., Methods: Patients aged ≥18 years undergoing shoulder arthroscopy were randomized into one of 4 study arms: (1) saline irrigation fluid (placebo); (2) epinephrine (0.33 mL of 1:1000 per liter) mixed in irrigation fluid (EPI); (3) 1 g intravenous tranexamic acid (TXA); and (4) epinephrine and tranexamic acid combined (TXA + EPI). Visualization was rated intraoperatively on a scale from 0, indicating poor clarity, to 3, indicating excellent clarity, every 15 minutes and overall. The primary outcome measure was the overall rating of visualization. A stepwise linear regression was performed using visualization as the dependent variable and independent variables including presence or absence of epinephrine and tranexamic acid, surgery duration, complexity, mean arterial pressure, increase in pump pressure, and volume of irrigation fluid., Results: One hundred twenty-eight patients (mean age 56 years) were randomized. Mean visual clarity for the placebo, TXA, EPI, and TXA + EPI groups were 2.0 (±0.6), 2.0 (±0.6), 2.6 (±0.5), and 2.7 (±0.5), respectively (P < .001). The presence or absence of epinephrine was the most significant predictor of visual clarity (P < .001). Tranexamic acid presence or absence had no effect. No adverse events were recorded in any of the groups., Conclusion: Intravenous tranexamic acid is not an effective alternative to epinephrine in irrigation fluid to improve visualization during routine arthroscopic shoulder surgeries, and there is no additive effect when both are used., (Copyright © 2023 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Assessing competency across domains of knowledge, skills, and behavior is critical to ensure that graduating orthopaedic residents possess the requisite skills and attributes to enter independent orthopaedic practice. Of the domains, knowledge is most easily assessed. In addition to the AAOS Orthopaedic In-Training Examination ® , which provides a yearly gauge of residents' orthopaedic knowledge relative to their peers, there are several online platforms such as Orthobullets, the American Academy of Orthopaedic Surgeons ResStudy program, and the Journal of Bone and Joint Surgery Clinical Classroom that offer online learning resources and question banks. Clinical skills are best assessed through a combination of observation tools, including live or video assessments, 360° evaluations, and objective structured clinical examinations. Surgical skills can be evaluated in two domains: live surgical cases or simulations. The American Board of Orthopaedic Surgery is attempting to standardize live surgical evaluations through the use of the O-P tool. Although most available models feature only arthroscopic procedures, surgical simulators provide for opportunity to objectively evaluate resident performance. Behavior and professionalism has traditionally been the most challenging domain to assess. The American Board of Orthopaedic Surgery's Behavior Assessment Tool has demonstrated success in pilot testing and is being introduced as the standard for measuring behavior and professionalism in orthopaedic training. Although no single assessment tool can accurately gauge a resident's overall performance, a combination of readily available tools should be used to assess competence across domains.

Background: Femoral fragility fractures in older adults can result in devastating loss of physical function and independence. Skeletal muscle atrophy likely contributes to disability. The purpose of this study was to characterize the change in skeletal muscle mass, investigate the relationship with malnutrition and physical function, and identify risk factors for skeletal muscle loss., Methods: Adults ≥65 years of age who were treated with operative fixation of an isolated femoral fragility fracture were enrolled in this multicenter, prospective observational study. Skeletal muscle mass was assessed within 72 hours of admission using multifrequency bioelectrical impedance analysis, which was repeated at 6 weeks, 3 months, and 6 months. Sarcopenia was defined by sex-specific cutoffs for the appendicular skeletal muscle mass index. The Mini Nutritional Assessment was used to measure nutritional status at the time of injury. Physical function was measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function domain. Linear mixed models were used to evaluate changes in skeletal muscle mass and PROMIS Physical Function scores over time and to evaluate factors associated with skeletal muscle mass changes., Results: Ninety participants (74% female) with a mean age of 77.6 ± 9.0 years were enrolled. At the time of injury, 30 (33%) were sarcopenic and 44 (49%) were at risk for malnutrition or had malnutrition. Older age was associated with lower skeletal muscle mass (age of ≥75 versus <75 years: least squares mean [and standard error], -3.3 ± 1.6 kg; p = 0.042). From the time of injury to 6 weeks, participants lost an average of 2.4 kg (9%) of skeletal muscle mass (95% confidence interval [CI] = ‒3.0 to ‒1.8 kg; p < 0.001). This early loss did not recover by 6 months (1.8 kg persistent loss compared with baseline [95% CI = ‒2.5 to ‒1.1 kg]; p < 0.001). Participants with normal nutritional status lost more skeletal muscle mass from baseline to 6 weeks after injury compared with those with malnutrition (1.3 kg more loss [standard error, 0.6 kg]; p = 0.036). A 1-kg decrease in skeletal muscle mass was associated with an 8-point decrease in the PROMIS Physical Function (model parameter estimate, 0.12 [standard error, 0.04]; p = 0.002)., Conclusions: We found that older adults with femoral fragility fractures lost substantial skeletal muscle mass and physical function. Participants with adequate baseline nutrition actually lost more muscle mass than those who were malnourished, indicating that future investigations of interventions to prevent muscle loss should focus on older adults regardless of nutritional status., Level of Evidence: Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H709 )., (Copyright © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

In dead biological tissues such as human hair, the ability of antioxidants to minimise autoxidation is determined by their chemical reactions with reactive oxygen species. In order to improve our understanding of factors determining such antioxidant properties, the mechanistic chemistry of four phenolic antioxidants found in tea and rosemary extracts (epicatechin, epigallocatechin gallate, rosmarinic and carnosic acids) has been investigated. The degradation of N -acetyl alanine by photochemically generated hydroxyl radicals was used as a model system. A relatively high concentration of the antioxidants (0.1 equivalent with respect to the substrate) tested the ability of the antioxidants to intercept both initiating hydroxyl radicals (preventive action) and propagating peroxyl radicals (chain-breaking action). LC-MS data showed the formation of hydroxylated derivatives, quinones and hydroperoxides of the antioxidants. The structure of the assignment was aided by deuterium exchange experiments. Tea polyphenolics (epicatechin and epigallocatechin gallate) outperformed the rosemary compounds in preventing substrate degradation and were particularly effective in capturing the initiating radicals. Carnosic acid was suggested to act mostly as a chain-breaking antioxidant. All of the antioxidants except for rosmarinic acid generated hydroperoxides which was tentatively ascribed to the insufficient lability of the benzylic C-H bond of rosmarinic acid.

Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of the MAPT mutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the three MAPT mutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs, SNHG8 was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer's disease brains. We show that SNHG8 interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tau in vitro is sufficient to reduce SNHG8 expression and induce stress granule formation. Rescuing SNHG8 expression leads to reduced stress granule formation and reduced TIA1 levels in immortalized cells and in MAPT mutant neurons, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies., (© 2023. The Author(s).)

Background: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients., Protocol: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care)., Discussion: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Publication 137 of the International Commission on Radiological Protection (ICRP) describes a biokinetic model for radon used to derive dose coefficients for occupational intake of radon isotopes. The model depicts transfer of inhaled or ingested radon to blood, exchange of radon between blood and tissues, and gradual loss of radon from the body based on physical laws governing transfer of a non-reactive and soluble gas between materials. This paper describes an age- and sex-specific variation of that model developed for use in an upcoming ICRP series of reports on environmental intake of radionuclides by members of the public titled 'Dose Coefficients for Intakes of Radionuclides by Members of the Public'. The proposed model modifies the model structure and transfer coefficients presented in Publication 137 to allow more realistic dosimetric treatment of bone marrow and breast and expands the model to address pre-adult ages, based on the physical principles used in the development of the model of Publication 137 together with anatomical and physiological changes occurring during human development., (© 2023 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Background: House dust mite (HDM) is the most common sensitising allergen in asthma. Ethnic minority groups (EMGs) in the UK are more likely to live in deprived conditionings with a greater exposure to HDM and other aero-allergens., Aim: To compare the ethnicity-based patterns of sensitisation to aero-allergens and the impact of ethnicity on clinical outcomes in patients with difficult-to-treat asthma (DTA)., Methods: Data of patients with DTA were extracted from the registry of the Birmingham Regional Severe Asthma Service (BRSAS), which have a catchment population of 7.3million from Central England. Patients from White and EMG backgrounds were compared in terms of the prevalence of atopy, total serum immunoglobulin E (IgE), specific serum IgE (ssIgE) and asthma related clinical outcomes. Logistic regression analysis was conducted to explore ethnicity-based risk factors for HDM sensitisation., Results: A total of 1272 patients [White 1016 (79.9%), EMG 256 (20.1%) EMG] with a median age of 51 years (range 16-97) were included in the analysis. Patients from EMG were more likely (64%) to reside in the worst scale of index of multiple deprivation (IMD) than the White patients (25.5%), p < 0.0001. Positive HDM sensitisation was more prevalent in the EMG than in the White group [142/216 (66%) versus 375/842 (45%), p < 0.0001]. The median HDM ssIgE level was higher in the EMG than in the White group [3.0 KUA/L (IQR 0.06, 11.5) versus 0.1 (0.01, 3.0), p < 0.000001]. The odds ratio for positive sensitisation to HDM conveyed by the EMG status was 2.61 (95%CI, 1.8-3.8), p < 0.0001. Compared to the White group, the EMG had higher median total serum IgE [326 KU/L (115, 971) versus 114 (29.8, 434.8), p < 0.000001], higher blood eosinophil count (0.36 × 10 9 (0.18, 0.62) versus 0.23 (0.1,0.47), p < 0.000001), were marginally more atopic (79.2% vs. 75.6%, p = 0.098) and were less likely to being on maintenance oral corticosteroids (22% vs. 39.7%, p < 0.0001)., Conclusion: In this DTA cohort, positive HDM sensitisation was greater amongst the EMG than the White patients. The EMG status was a significant risk factor for HDM sensitisation., (© 2023 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

This randomized controlled trial tested the Vermont Family Based Approach (VFBA) in primary care pediatrics. The VFBA is a model of healthcare delivery that shifts the focus from the individual to the family, emphasizes emotional and behavioral health, and uses evidence-based health promotion/prevention along with the treatment of emotional and behavioral problems. Participants were 81 families of 3-15-year-olds. For children, the VFBA was associated with greater reductions than the Control condition on the Child Behavior Checklist Emotionally Reactive, Withdrawn, Sleep Problems, Aggressive Behavior and Total Problems scales. For parents, the VFBA was associated with greater reductions than the Control condition on the Adult Self-Report Anxious/Depressed, Rule-Breaking Behavior, Internalizing Problems and Total Problems scales. The VFBA was also associated with greater improvement than the Control condition in the parents' health-related quality of life, as indicated by all scales of the Medical Outcomes Study Health Survey., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: The youth unemployment rate in Australia is more than double the national average. Policies and programs to address barriers and improve youth engagement in education and employment are essential to achieve many of the United Nations' Sustainable Development Goals (SDGs). The aim of this mixed-methods study was to evaluate the OzHarvest Nourish Program, a free, hospitality-focused pathway to support employment and engagement for young people aged 16-25 years., Study Design: Mixed-methods study., Methods: An online survey, workshop and semi-structured interviews with staff, volunteers, participants, and broader stakeholders were conducted using a qualitative, exploratory approach. Ethics approval was granted by the Griffith University Human Research Ethics Committee (#2022/492)., Results: Five key themes were identified from interview data and a logic model was developed. Participants described significant benefits of participation, including improved food security, self-efficacy, and communication skills, reduced social isolation, and greater hope for the future., Conclusions: The Nourish Program is a transformative service that is improving wellbeing outcomes for program participants. Additional resourcing, including adequate funding, may be required to maximise program impact and support sustainability., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: OzHarvest staff (Nourish Program Manager Belinda Woollett and Nourish Projects Coordinator Dan Baynes) were involved in this research, though they did not influence the evaluation outcomes of this research., (© 2023 Published by Elsevier Ltd on behalf of The Royal Society for Public Health.)

Introduction: The Orthopaedic Trauma Association (OTA) has maintained an accreditation process of orthopaedic trauma fellowships with various requirements including an annually reviewed list of qualifying trauma cases in the form of American Medical Association Current Procedural Terminology (CPT) codes. The correlation between these established and monitored CPTs and the actual practices of orthopaedic trauma surgeons has not been studied., Methods: American Board of Orthopaedic Surgery part II case logs (trauma subspecialty) (2012 to 2018) were compared with OTA fellowship case logs (2015 to 2019). Case logs from 447 surgeons and 166 trauma fellowship programs were compared. Four CPT code categories were defined: complex trauma (OTA required CPT codes, excluding Accreditation Council for Graduate Medical Education [ACGME] orthopaedic residency requirements), general trauma (ACGME residency required trauma codes), general orthopaedics (nontrauma ACGME residency requirements), and others (codes not included in residency or trauma fellowship requirements)., Results: OTA fellows performed a higher median percentage of complex trauma compared with American Board of Orthopaedic Surgery candidates (34% vs. 21%, P < 0.001): Both cohorts performed a similar percentage of general trauma (23%). OTA fellows performed more general orthopaedics (40% vs. 1%, P < 0.001). Several OTA required codes were performed infrequently (0 to 3 during board collection) by most surgeons, and several procedures are being performed that are not included in current CPT code requirements., Discussion: Early-career traumatologists are performing orthopaedic trauma procedures they were trained on during residency and fellowship, with varying complexity. Trauma fellows perform a higher percentage of complex trauma compared with early-career trauma surgeons. Continued surveillance is necessary such that educational improvements can be made to maximize the quality of trauma fellowship education., Level of Evidence: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence., (Copyright © 2023 by the American Academy of Orthopaedic Surgeons.)

Introduction: Video otoscopy plays an important role in improving access to ear health services. This study investigated the clinician-rated quality of video otoscopy recordings and still images, and compared their suitability for asynchronous diagnosis of middle-ear disease., Methods: Two hundred and eighty video otoscopy image-recording pairs were collected from 150 children (aged six months to 15 years) by an ear, nose, and throat (ENT) specialist, audiologists, and trained research assistants, and independently rated by an audiologist and ENT surgeon. On a five-point scale, clinicians rated the cerumen amount, field of view, quality, focus, light, and gave an overall rating, and asked whether they could make an accurate diagnosis for both still images and recordings., Results: More video otoscopy recordings were rated as 'good' or 'excellent' compared to still images across all domains. The mean difference between the two otoscopic procedures ratings was significant across almost all domains ( p  < 0.05), except 'cerumen amount'. The suitability to make a diagnosis significantly improved when using recordings (p<0.05). Younger participant age was found to have a significant, negative impact on the ratings across all domains ( p  < 0.03). The role of the tester conducting video otoscopy did not have a significant impact on the ratings., Discussion: Video otoscopy recordings were found to provide clearer views of the tympanic membrane and increase the ability to make diagnoses, compared to still images, for both audiologists and ENT surgeons. Research assistants with limited practice were able to obtain video otoscopy images and recordings that were comparable to the ones obtained by clinicians.

While defective α-synuclein homeostasis is central to Parkinson's pathogenesis, fundamental questions about its degradation remain unresolved. We have developed a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of α-synuclein and identified lysine residues 45, 58, and 60 as critical ubiquitination sites for its degradation. This is mediated by NBR1 binding and entry into endosomes in a process that involves ESCRT I-III for subsequent lysosomal degradation. Autophagy or the autophagic chaperone Hsc70 is dispensable for this pathway. Antibodies against diglycine-modified α-synuclein peptides confirmed that endogenous α-synuclein is similarly ubiquitinated in the brain and targeted to lysosomes in primary and iPSC-derived neurons. Ubiquitinated α-synuclein was detected in Lewy bodies and cellular models of aggregation, suggesting that it may be entrapped with endo/lysosomes in inclusions. Our data elucidate the intracellular trafficking of de novo ubiquitinated α-synuclein and provide tools for investigating the rapidly turned-over fraction of this disease-causing protein.

Background: Previous research highlights the need for effective lifestyle interventions for men. Hockey Fans in Training (Hockey FIT) was developed as a pragmatic healthy lifestyle program tailored to men with overweight or obesity. This paper overviews the rationale, program details, and design of a recently completed cluster randomized controlled trial (RCT) of Hockey FIT. Participant engagement and baseline characteristics are also described., Methods: The RCT evaluated the effectiveness, cost-effectiveness, and implementation of Hockey FIT. Forty-two sites in Canada and the United States were randomized to either the Hockey FIT intervention group or wait-list control group. Participants were men, aged 35-65 years, with a body mass index (BMI) ≥27 kg/m 2 . Hockey FIT is a group-based, off-ice, in-person healthy lifestyle program, including both a 3-month active phase and a 9-month minimally-supported phase. Outcomes were assessed at baseline, 3, and 12 months. The primary outcome was weight loss at 12 months., Results: The design of the cluster RCT incorporates evaluations of participant health outcomes, program implementation, and broader healthcare system impact. In the RCT, 1397 participants were assessed for eligibility and 997 were enrolled. Most participants heard about the program through social media or hockey team emails. Participants averaged 49 years of age, had BMI values of 35.3 kg/m 2 , were predominately white, and had varying levels of education., Conclusion: The intended audience for Hockey FIT was recruited successfully, however, targeted recruitment to better engage diverse populations is warranted. This paper affords a useful outline for evaluating future lifestyle interventions tailored to men. This trial was registered on August 17, 2018 with ClinicalTrials.gov (identifier: NCT03636282)., 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 Elsevier Inc. All rights reserved.)

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Soybean (Glycine max) is a major crop that contributes more than half of global oilseed production. Much research has been directed towards improvement of the fatty acid profile of soybean seeds through marker assisted breeding. Recently published soybean pangenomes, based on thousands of soybean lines, provide an opportunity to identify new alleles that may be involved in fatty acid biosynthesis. In this study, we identify fatty acid biosynthesis genes in soybean pangenomes based on sequence identity with known genes and examine their sequence diversity across diverse soybean collections. We find three possible instances of a gene missing in wild soybean, including FAD8 and FAD2-2D, which may be involved in oleic and linoleic acid desaturation, respectively, although we recommend follow-up research to verify the absence of these genes. More than half of the 53 fatty acid biosynthesis genes identified contained missense variants, including one linked with a previously identified QTL for oil quality. These variants were present in multiple studies based on either short read mappings or alignment of reference grade genomes. Missense variants were found in previously characterized genes including FAD2-1A and FAD2-1B, both of which are involved in desaturation of oleic acid, as well as uncharacterized candidate fatty acid biosynthesis genes. We find that the frequency of missense alleles in fatty acid biosynthesis genes has been reduced significantly more than the global average frequency of missense mutations during domestication, and missense variation in some genes is near absent in modern cultivars. This could be due to the selection for fatty acid profiles in seed, though future work should be conducted towards understanding the phenotypic impacts of these variants., (© 2023 The Authors. The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Posttraumatic osteoarthritis (PTOA) is a subset of osteoarthritis that occurs after joint injury and is associated with degradation of articular cartilage and subchondral bone. As compared with primary osteoarthritis, PTOA occurs in a time window initiated by a traumatic event resulting in damage to layers of joint structure and alterations in joint shape. As techniques in open reduction and internal fixation continue to mature, our success in preventing posttraumatic osteoarthritis has not kept pace. Advances in research in the subchondral bone, inflammatory response, and joint mechanics continue to open our understanding of this posttraumatic process. In addition, there are possibilities emerging as biological agents to therapeutically alter the progression of PTOA., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: Healthcare-associated infections can be acquired via transmission of pathogens within the healthcare setting. Often, patients are assumed to have short duration (< 90 days) of transmissibility with bacterial pathogens after developing a clinical infection. This assumption may wrongly exclude patients as sources of transmission when they have persistent bacterial carriage. We studied patients with persistent carriage and associated transmission using whole genome sequencing surveillance., Methods: Patient culture positive isolates for select bacterial pathogens between 11/2016 and 11/2019 were collected if the patient was housed in the hospital for ≥3 days or had a recent healthcare exposure in the prior 30 days. Isolates were considered genetically related with ≤15 SNPs for all organisms except C. difficile (≤2 SNPs). Patients with serial isolates separated by >100 days were examined for other patients with related isolates and epidemiological commonalities between the first and last culture dates., Results: There were 779 related isolates from 369 unique patients (range 2-11 isolates/patient). The mean time from first to last culture date was 81.9 days (median 33 days, range 1-899 days) (Figure 1). 77 patients had isolates that were related to another patient of which 18 (23%) patients had >100 days between their first and last isolate (median 216, range 103-899). Of these, 9 (50%) patients had epidemiological links with another patient between their first and last isolate culture dates. The median time from exposure to positive culture date of the exposed patient was 14 days (mean 34, range 2-115). An example of potential transmission is shown in Figure 2.Days between the first and last related isolates within the same patientExample of patient with persistent carriage of K. pneumoniae and evidence of transmission to another patient., Conclusion: Some patients had persistent carriage with the same strain for over two years and appear to be a potential source of ongoing transmission to other patients. WGS surveillance, in addition to detecting outbreaks, can identify patients with persistent colonization as potential a transmission source. Healthcare outbreak investigations should include patients with persistent carriage as potential sources based upon temporal restrictions., Disclosures: Graham Snyder, MD, SM , Infectious Diseases Connect: Advisor/Consultant Daria Van Tyne, PhD , Century Therapeutics, Inc: Advisor/Consultant., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Increases in life expectancy, the availability of sexual performance enhancing medication, and changes in sexual partnering suggest that sexually transmitted infections (STIs) among older persons could be on the rise, yet there have been relatively few studies examining STIs in this demographic. Our systematic review aimed to further characterize the incidence and prevalence of chlamydia, gonorrhea, and syphilis, along with associated risk factors among older adults (45 years or older) in the United States., Methods: We searched five electronic databases (PubMed, Embase, Cinahl, Web of Science, and Global Health) for data published from inception to January 2021. The retrieved articles were screened based on eligibility criteria, and subsequent review of relevant article bibliographies was conducted., Results: Of 4748 articles identified, 23 studies met our inclusion criteria and one additional article was identified through bibliography review. Of the 23 included articles, only 3 (11.5%) were focused exclusively on evaluating STIs in an older population. We found prevalence to be the following ranges: syphilis (0-18%), chlamydia (0-14.2%) and gonorrhea (0-15%). Few studies specifically investigated risk factors in this demographic., Conclusions: The understudied burden of STIs in the older adult population substantiates the need to recognize issues surrounding sexuality in this demographic.

Community involvement engages, empowers, and mobilises people to achieve their shared goals by addressing structural inequalities in the social and built environment. Through this review, we summarised published information on models, frameworks, and/or processes of community organising used in the context of health initiatives or interventions and documented the outcomes following their use. A systematic scoping review was conducted in three databases with no restrictions on the date of publication, country, or written language. Out of 5044 studies, 38 met the inclusion criteria and were included in the review. The targeted health outcomes explored by the studies were diverse and included sub-domains such as the promotion of a healthy lifestyle, sexual and reproductive health, access to healthcare and equity, and substance abuse and chronic disease management. The outcomes of most initiatives or interventions were promising, with positive changes reported for the target populations. A wide variation was noted in the models, frameworks, or processes of community organising utilised in these studies. We concluded that variation implies that no single model, framework, or process seems to have predominance over others in implementing community organising as a vehicle of positive social change within the health domain. The review also highlighted the need for a more standardised approach to the implementation and evaluation of these initiatives. We recommend that it is essential to foster public and non-governmental sector partnerships to promote community-driven health promotion efforts for a more sustainable approach to these initiatives.

Background: Cystic fibrosis (CF) is a rare, inherited, life-limiting condition predominantly affecting the lungs, for which there is no cure. The disease is characterized by recurrent pulmonary exacerbations (PEx), which are thought to drive progressive lung damage. Management of these episodes is complex and generally involves multiple interventions targeting different aspects of disease. The emergence of innovative trials and use of Bayesian statistical methods has created renewed opportunities for studying heterogeneous populations in rare diseases. Here, we present the protocol for the BEAT CF PEx cohort, a prospective, multi-site, perpetual, platform enrolling adults and children with CF. The BEAT CF PEx cohort will be used to evaluate the comparative effectiveness of interventions for the treatment of PEx requiring intensive therapy (PERITs), with a primary focus on short-term improvements in lung function. This will be achieved through the conduct of cohort-nested studies, including adaptive clinical trials, within the BEAT CF PEx cohort. This protocol will outline key features of the BEAT CF PEx cohort, including the design, implementation, data collection and management, governance and analysis, and dissemination of results., Methods: This platform will be conducted across multiple sites, commencing with CF treatment centers in Australia. People of all ages with a clinical diagnosis of CF will be eligible to participate, except those who have previously received a lung transplant. Data including demographic and clinical information, treatment details, and outcomes (including safety, microbiology, and patient-reported outcome measures including quality of life scores) will be systematically collected and securely stored via a digital centralized trial management system (CTMS). The primary endpoint is the absolute change in the percentage predicted forced expiratory volume in 1 s (ppFEV 1 ) from the commencement of intensive therapy to 7 to 10 days afterwards., Discussion: The BEAT CF PEx cohort will report clinical, treatment, and outcome data for PEx among people with CF and is intended to serve as a core (master) protocol for future nested, interventional trials evaluating treatment(s) for these episodes. The protocols for nested sub-studies are beyond the scope of this document and will be reported separately., Trial Registration: ANZCTR BEAT CF Platform - ACTRN12621000638831. Registration date: Sept. 26, 2022., (© 2023. Crown.)

Background: The need for coronavirus 2019 (COVID-19) vaccination in different age groups and populations is a subject of great uncertainty and an ongoing global debate. Critical knowledge gaps regarding COVID-19 vaccination include the duration of protection offered by different priming and booster vaccination regimens in different populations, including homologous or heterologous schedules; how vaccination impacts key elements of the immune system; how this is modified by prior or subsequent exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and future variants; and how immune responses correlate with protection against infection and disease, including antibodies and effector and T cell central memory., Methods: The Platform Trial In COVID-19 priming and BOOsting (PICOBOO) is a multi-site, multi-arm, Bayesian, adaptive, randomised controlled platform trial. PICOBOO will expeditiously generate and translate high-quality evidence of the immunogenicity, reactogenicity and cross-protection of different COVID-19 priming and booster vaccination strategies against SARS-CoV-2 and its variants/subvariants, specific to the Australian context. While the platform is designed to be vaccine agnostic, participants will be randomised to one of three vaccines at trial commencement, including Pfizer's Comirnaty, Moderna's Spikevax or Novavax's Nuvaxovid COVID-19 vaccine. The protocol structure specifying PICOBOO is modular and hierarchical. Here, we describe the Core Protocol, which outlines the trial processes applicable to all study participants included in the platform trial., Discussion: PICOBOO is the first adaptive platform trial evaluating different COVID-19 priming and booster vaccination strategies in Australia, and one of the few established internationally, that is designed to generate high-quality evidence to inform immunisation practice and policy. The modular, hierarchical protocol structure is intended to standardise outcomes, endpoints, data collection and other study processes for nested substudies included in the trial platform and to minimise duplication. It is anticipated that this flexible trial structure will enable investigators to respond with agility to new research questions as they arise, such as the utility of new vaccines (such as bivalent, or SARS-CoV-2 variant-specific vaccines) as they become available for use., Trial Registration: Australian and New Zealand Clinical Trials Registry ACTRN12622000238774. Registered on 10 February 2022., (© 2023. Crown.)

Background & Hypothesis: Psychotic disorders are inequitably distributed by race in the United States, although it is not known whether this is due to assessment biases or inequitable distributions of risk factors. Psychotic experiences are subclinical hallucinations and delusions used to study the etiology of psychosis, which are based on self-report and therefore not subject to potential clinician biases. In this study, we test whether the prevalence of psychotic experiences (PE) varies by race and if this variance is explained by socioenvironmental risk factors., Study Design: Data on demographics, PE, and socioenvironmental risk factors were collected through the National Survey of Poly-victimization and Mental Health, a national probability sample of US young adults. Logistic regression analyses were used to determine whether PE prevalence varied by race/ethnicity and, if so, whether this was attenuated with inclusion of indicators of income, education, urban/rural living, discrimination, and trauma exposure., Study Results: Black and Hispanic respondents reported PE at significantly greater rates than White or "other" ethnoracial groups, with hallucinations more commonly reported by Hispanic respondents. PE were significantly associated with police violence exposure, discrimination, adverse childhood experiences, and educational attainment. These factors statistically explained ethnoracial differences in the likelihood of overall PE occurrence and of nearly all PE subtypes., Conclusions: Previously observed racial differences in psychosis extend beyond clinical schizophrenia, and therefore, are unlikely to be explained entirely by clinician biases. Instead, racial disparities in PE appear to be driven by features of structural racism, trauma, and discrimination., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background/objective: Cavity shave margins (CSMs) decrease rate of positive margins and need for re-excision. Recurrence data following breast-conserving surgery (BCS) are not always available in large cancer registries. We sought to define our recurrence and survival data in BCS with routine excision of CSMs., Methods: A single institution, 10-year retrospective review of breast cancer patients who underwent BCS with routine CSMs was conducted. Cavity shave margin technique was standard. Cox proportional hazard analyses and the Kaplan-Meier method were used to estimate recurrence and survival., Results: Breast-conserving surgery with CSM was performed in 839 patients. Re-excision rate to achieve negative margins was 8.5%. Fifty-two patients (75%) underwent margin re-excision vs 18 patients (25%) underwent salvage mastectomy. Positive margin rate stratified by tumor histology was highest for invasive lobular carcinoma followed by mixed invasive ductal carcinoma (IDC) and ductal carcinoma in situ (DCIS), followed by pure DCIS and lowest for IDC. Length of follow-up was (4.7 ± 2.6, years). Overall recurrence rate (locoregional and systemic) was 4.3%: highest in patients with negative lumpectomy margin but positive CSM (L-S+ = 15%) followed by positive lumpectomy and CSMs (L+S+ = 14%), followed by patients with positive lumpectomy margin but negative CSMs (L+S- = 13%) and lowest for negative lumpectomy and CSM (L-S- = 5%), ( P = .0008). There was no difference in 5-year breast cancer-specific survival between the 4 subgroups: 96% for L-S-, 86.7% L-S+, 94.7% L+S+ and 90% L+S- ( P = .094)., Conclusions: Recurrence following BCS with CSMs can be stratified based on both lumpectomy and cavity shave margin positivity. Routine excision of CSMs allows identification of these patient subsets.

Aim: The suicide rate among college students is particularly high, with evidence that psychosis-like experiences (PLEs) put these individuals at greater risk. The current study explored whether there are differential relations between four subtypes of PLEs and three suicide outcomes., Methods: We analysed a large sample of college students from the Fall semester cohort of the 2020 Healthy Minds Study (HMS) (weighted N = 36727). PLEs and suicide outcomes were assessed using binary variables from the World Health Organization Composite International Diagnostic Interview., Results: Findings revealed that reporting any of the subtypes of PLEs was associated with greater odds of suicidal ideation (SI), a suicide plan (SP) and a suicide attempt (SA) (signficant a ORs ranging from 1.30 to 3.30). For college students who endorsed SI or a SP in the past year, experiencing delusional mood (aOR [95% CI] = 1.30 [1.02-1.65]), suspiciousness (aOR [95% CI] = 1.31 [1.00-1.71]) and hallucinatory experiences (aOR [95% CI] = 2.76 [2.05-3.71]) in their lifetime increased their odds of reporting a SA in the past year. There was also evidence of a dose-dependent relation between the number of PLEs endorsed and all three suicide outcomes., Conclusions: Certain subtypes of PLEs including delusional mood, suspiciousness and hallucinatory experiences may contribute to an elevated risk of suicide outcomes in college students. Moreover, the odds of reporting suicide outcomes were greater for individuals who endorsed a greater number of PLEs. It may be helpful to assess for indicated subtypes when determining suicide risk among college students and to be particularly mindful of those who report three or more PLEs., (© 2022 John Wiley & Sons Australia, Ltd.)