Evaluation and application of American College of Radiology Thyroid Imaging Reporting and Data System for improved malignancy detection in paediatric thyroid nodules.

OBJECTIVE: The American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) is a widely used method for the management of adult thyroid nodules. However, its use in paediatric patients is controversial because adult fine needle aspiration biopsy (FNAB) recommendations may lead to delayed diagnoses of cancer in children. The objectives of this study were to evaluate the performance of TI-RADS in paediatric thyroid nodules and to tailor FNAB recommendations for children. METHODS: Consecutive surgically resected paediatric thyroid nodules from two tertiary care centres between 2003 and 2021 were reviewed. Ultrasounds were blindly scored by radiologists according to TI-RADS. Management recommendations based on TI-RADS were evaluated. Various modelling methodologies were used to determine the optimal cutoff for FNAB in children. RESULTS: Of the 96 patients, 79 (82%) were female and the median age at surgery was 16.1 years. Fifty (52%) nodules were malignant on surgical pathology. The area under the receiver operating characteristic curve of TI-RADS for predicting malignancy was 0.78. Adult TI-RADS recommendations would have resulted in 4% of cancerous nodules being lost to follow-up. Modifications to TI-RADS (FNAB of all TR3 nodules ≥1.5 cm, FNAB of TR4 and TR5 nodules ≥0.5 cm, surveillance of nodules ≥1 cm, consider surgery for nodules >4 cm) reduced this missed malignancy rate to 0%. CONCLUSIONS: TI-RADS can risk-stratify paediatric thyroid nodules. However, the system requires modifications to reduce the missed malignancy rate in paediatric thyroid nodules. Our data suggest that lower size thresholds for FNAB are warranted in children.

A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Effect of Rurality in Head and Neck Cancer: A Scoping Review.

OBJECTIVES: This scoping review sought to evaluate the current literature regarding the following outcomes in relation to rurality: stage at diagnosis, clinical characteristics, treatment characteristics, and survival outcomes of head and neck cancer (HNC). DATA SOURCES: A literature search was performed using PubMed (MEDLINE), Science Direct, EMBASE, SCOPUS, and Web of Science databases. REVIEW METHODS: A 20-year study cutoff from the initial search was used to increase the comparability of the studies regarding population and standards of clinical care. These searches were designed to capture all primary studies reporting HNC incidence, presenting characteristics, treatments, and treatment outcomes. Two reviewers independently screened abstracts, selected articles for exclusion, extracted data, and appraised studies. Critical appraisal was done according to the Joanna Briggs Institute Quality Assessment Tool for Cohort Studies. FINDINGS: Twenty eligible original articles were included. Stage at diagnosis, clinical characteristics, treatment characteristics, and survival outcomes were measured. Our review indicates that although this relationship is unclear, there may be variations in treatment choice for laryngeal cancer based on geographic location and rural residency status. The studies assessing HNC outcomes related to stage at diagnosis, clinical characteristics, treatment characteristics, and overall survival demonstrated conflicting findings, indicating a need for further research examining HNC outcomes with a focus on rurality as the main exposure. CONCLUSIONS: The relationship between HNC and rural-urban status remains unclear. More studies are needed, along with a consistent metric for measuring rurality and recruitment of comparable populations from both rural and urban areas. Laryngoscope, 2024.

Priority effects transcend scales and disciplines in biology.

Although primarily studied through the lens of community ecology, phenomena consistent with priority effects appear to be widespread across many different scenarios spanning a broad range of spatial, temporal, and biological scales. However, communication between these research fields is inconsistent and has resulted in a fragmented co-citation landscape, likely due to the diversity of terms used to refer to priority effects across these fields. We review these related terms, and the biological contexts in which they are used, to facilitate greater cross-disciplinary cohesion in research on priority effects. In breaking down these semantic barriers, we aim to provide a framework to better understand the conditions and mechanisms of priority effects, and their consequences across spatial and temporal scales.

Understanding barriers to reducing antimicrobials on Australian dairy farms: A qualitative analysis.

INTRODUCTION: Reducing antibiotic use in production animal systems is one strategy which may help to limit the development of antimicrobial resistance. To reduce antimicrobial use in food-producing animals, it is important to first understand how antibiotics are used on farm and what barriers exist to decreasing their use. In dairy production systems, mastitis is one of the most common reasons for administering antimicrobials. Therefore, it is important to understand the motivations and behaviours of dairy farmers in relation to the diagnosis, treatment and prevention of mastitis. MATERIALS AND METHODS: In this study, we interviewed a sample of dairy farmers and dairy industry professionals from the major dairying regions of eastern Australia regarding their current practices used to diagnose, treat, and control subclinical and clinical mastitis. Inductive thematic analysis was used to code interview transcripts and identify the recurrent themes. RESULTS: Four overarching themes were identified: (1) the challenges associated with the detection and diagnosis of clinical mastitis, including with laboratory culture, (2) the motivations behind treatment decisions for different cases, (3) decisions around dry cow therapy and the role of herd recording, and (4) concerns regarding the development of antimicrobial resistance. DISCUSSION: This study identifies several challenges which may limit the ability of Australian dairy farmers to reduce antimicrobial use on farm, such as the need for rapid and reliable diagnostic tests capable of identifying the pathogenic causes of mastitis and the difficulties associated with conducting herd recording for the implementation of selective dry cow therapy. Industry professionals were concerned that farmers were not using individual cow records to aid in treatment decisions, which could result in unnecessary antimicrobial use. The results of this study can act as the basis for future research aimed at assessing these issues across the broader Australian dairy industry.

Topsoil porosity prediction across habitats at large scales using environmental variables.

Soil porosity and its reciprocal bulk density are important environmental state variables that enable modelers to represent hydraulic function and carbon storage. Biotic effects and their 'dynamic' influence on such state variables remain largely unknown for larger scales and may result in important, yet poorly quantified environmental feedbacks. Existing representation of hydraulic function is often invariant to environmental change and may be poor in some systems, particularly non-arable soils. Here we assess predictors of total porosity across two comprehensive national topsoil (0-15 cm) data sets, covering the full range of soil organic matter (SOM) and habitats (n = 1385 & n = 2570), using generalized additive mixed models and machine learning. Novel aspects of this work include the testing of metrics on aggregate size and livestock density alongside a range of different particle size distribution metrics. We demonstrate that porosity trends in Great Britain are dominated by biotic metrics, soil carbon and land use. Incorporating these variables into porosity prediction improves performance, paving the way for new dynamic calculation of porosity using surrogate measures with remote sensing, which may help improve prediction in data sparse regions of the world. Moreover, dynamic calculation of porosity could support representation of feedbacks in environmental and Earth System Models. Representing the hydrological feedbacks from changes in structural porosity also requires data and models at appropriate spatial scales to capture conditions leading to near-saturated soil conditions. Classification. Environmental Sciences.

Inflammatory Rhabdomyoblastic Tumor of the Posterior Pharyngeal Wall.

This case report describes a healthy man in his 40s who presented with a 1-year history of snoring, sleep apnea, dysphonia, and dysphagia owing to a large mass of the posterior pharynx and was diagnosed with an inflammatory rhabdomyoblastic tumor.

Reaching adults who smoke cigarettes in rural Appalachia: Rationale, design & analysis plan for a mixed-methods study disseminating pharmacy-delivered cessation treatment.

INTRODUCTION: Unlike other U.S. geographical regions, cigarette smoking prevalence remains stagnant in rural Appalachia. One avenue for reaching rural residents with evidence-based smoking cessation treatments could be utilizing community pharmacists. This paper describes the design, rationale, and analysis plan for a mixed-method study that will determine combinations of cessation treatment components that can be integrated within community pharmacies in rural Appalachia. The aim is to quantify the individual and synergistic effects of five highly disseminable and sustainable cessation components in a factorial experiment. METHODS: This sequential, mixed-method research design, based on the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework, will use a randomized controlled trial with a 25 fully crossed factorial design (32 treatment combinations) to test, alone and in combination, the most effective evidence-based cessation components: (1) QuitAid (yes vs. no) (2) tobacco quit line (yes vs. no) (3) SmokefreeTXT (yes vs. no) (4) combination NRT lozenge + NRT patch (vs. NRT patch alone), and (5) eight weeks of NRT (vs. standard four weeks). RESULTS: Logistic regression will model abstinence at six-months, including indicators for the five treatment factors and all two-way interactions between the treatment factors. Demographic and smoking history variables will be considered to assess potential effect modification. Poisson regression will model quit attempts and percent of adherence to treatment components as secondary outcomes. CONCLUSION: This study will provide foundational evidence on how community pharmacies in medically underserved, rural regions can be leveraged to increase utilization of existing evidence-based tobacco cessation resources for treating tobacco dependence. CLINICAL TRIALS: NCT05660525.

We care but we're not carers: perceptions and experiences of social prescribing in a UK national community organisation.

AIMS: (1) To explore how social prescribing referrals impact experiences of existing members of a voluntary and community-based organisation and (2) to describe the processes and relationships associated with joining community and voluntary organisations. METHODS: Online survey and qualitative interviews with members of Men's Sheds, a global volunteer-led initiative to address loneliness and social isolation in men. 93 self-selecting Shed members (average age 67 years, 93% male) from across England and Scotland took part in the survey about demographics, joining the Shed, and free-text questions about experiences in the Shed. From the survey participants, 21 Shed members were purposively sampled and interviewed to explore the impact of social prescribing and referrals on the Sheds. RESULTS: Participating in the Men's Shed was often associated with a significant change in personal circumstances, and Sheds provided a unique social support space, particularly valuable for men. Key factors around experiences of social prescribing and referral mechanisms were identified. We developed three themes: the experience of joining a Shed, success factors and risks of social prescribing, and 'we care but we're not carers'. CONCLUSIONS: The results show that Men's Sheds are a caring organisation, but their members are not trained as professional carers, and men come to the Shed for their own personal reasons. They are concerned about the potential additional responsibilities associated with formal referrals. They encourage the development of relationships and local-level understanding of the essence of Sheds to enable social prescribing. As models of social prescribing grow nationally and internationally, collaboratively working with voluntary and community organisations to develop a mutually beneficial approach is essential for the effectiveness and sustainability of social prescribing in community health.

A novel STRN3::PRKD1 fusion in a cribriform adenocarcinoma of salivary gland with high-grade transformation.

Cribriform adenocarcinoma of salivary gland (CASG) is a rare form of salivary gland neoplasm that mostly arises from minor salivary glands. We report a case of CASG with high-grade transformation harboring a novel STRN3::PRKD1 fusion. A 59-year-old male presented with a palatal mass. Morphologically, the tumor consisted of two components: solid high-grade and glandular low-grade areas. The solid high-grade area comprised solid nests of high-grade carcinoma with central necrosis arranged in lobules delineated with prominent stromal septa. The glandular low-grade area comprised of cribriform and microcystic architecture in a hyalinized and hypocellular stroma. Immunophenotypically, the tumor was positive for S100 but negative for p40 and actin. However, due to the high-grade component, tissue was sent for salivary gland NGS fusion panel analysis to confirm the diagnosis. The current case illustrates high-grade transformation in CASG. Furthermore, identification of a STRN3::PRKD1 fusion expands the genetic spectrum of CASG.

The structural components of the Azotobacter vinelandii iron-only nitrogenase, AnfDKG, form a protein complex within the plant mitochondrial matrix.

A long-held goal of synthetic biology has been the transfer of a bacterial nitrogen-fixation pathway into plants to reduce the use of chemical fertiliser on crops such as rice, wheat and maize. There are three classes of bacterial nitrogenase, named after their metal requirements, containing either a MoFe-, VFe- or FeFe-cofactor, that converts N2 gas to ammonia. Relative to the Mo-nitrogenase the Fe-nitrogenase is not as efficient for catalysis but has less complex genetic and metallocluster requirements, features that may be preferable for engineering into crops. Here we report the successful targeting of bacterial Fe-nitrogenase proteins, AnfD, AnfK, AnfG and AnfH, to plant mitochondria. When expressed as a single protein AnfD was mostly insoluble in plant mitochondria, but coexpression of AnfD with AnfK improved its solubility. Using affinity-based purification of mitochondrially expressed AnfK or AnfG we were able to demonstrate a strong interaction of AnfD with AnfK and a weaker interaction of AnfG with AnfDK. This work establishes that the structural components of the Fe-nitrogenase can be engineered into plant mitochondria and form a complex, which will be a requirement for function. This report outlines the first use of Fe-nitrogenase proteins within a plant as a preliminary step towards engineering an alternative nitrogenase into crops.

Adjuvant radiotherapy mitigates impact of perineural invasion on oncologic outcomes in early-stage oral cavity squamous cell carcinoma. A multi-institutional analysis of 557 patients.

OBJECTIVES: Understand the prognostic impact of perineural invasion (PNI) in early-stage oral cavity squamous cell carcinoma (OCSCC). Assess the influence of adjuvant radiotherapy on outcomes of patients with PNI-positive early-stage OCSCC. MATERIALS AND METHODS: Retrospective seven-institution cohort study including patients with pathologic T1-2 N0-1 OCSCC who underwent primary surgery with negative margins. Outcomes included disease-free survival (DFS) and locoregional control (LRC). Cox proportional hazards models were used to evaluate oncologic outcomes. Interaction terms were introduced to assess relationships between PNI and adjuvant radiotherapy. RESULTS: Among 557 patients (mean (SD) age 61.0 (13.9), 47.2% female, 66.6% pathologic T1, 93.5% pathologic N0), 93 had PNI-positive tumors, among which 87.1% underwent neck dissection and 39.6% received radiotherapy. On multivariable analysis, PNI was associated with lower DFS and LRC. Adjuvant radiotherapy was not associated with improved outcomes on multivariable analysis of the entire cohort. However, among patients with PNI-positive tumors, adjuvant radiotherapy significantly decreased hazard for DFS. CONCLUSION: Among patients with low-risk, early-stage OCSCC, PNI was associated with worse DFS and LRC. In patients with PNI-positive tumors, adjuvant radiotherapy lowered hazard for DFS on multivariable analysis. These data support using adjuvant radiotherapy for patients with early-stage OCSCC with PNI.

How to use natural history collections to resurrect information on historical parasite abundances.

Many of the most contentious questions that concern the ecology of helminths could be resolved with data on helminth abundance over the past few decades or centuries, but unfortunately these data are rare. A new sub-discipline - the historical ecology of parasitism - is resurrecting long-term data on the abundance of parasites, an advancement facilitated by the use of biological natural history collections. Because the world's museums hold billions of suitable specimens collected over more than a century, these potential parasitological datasets are broad in scope and finely resolved in taxonomic, temporal and spatial dimensions. Here, we set out best practices for the extraction of parasitological information from natural history collections, including how to conceive of a project, how to select specimens, how to engage curators and receive permission for proposed projects, standard operating protocols for dissections and how to manage data. Our hope is that other helminthologists will use this paper as a reference to expand their own research programmes along the dimension of time.

The effects of dexamethasone administration on physiological, behavioral, and production parameters in dairy cows after a difficult calving.

Dairy cows are predisposed to diseases during the postpartum period. Dystocia has been associated with increased risk for disease, which is likely the result of increased tissue trauma and stress during the prolonged parturition. To attenuate the inflammatory response seen in dystocic animals and improve well-being, we assessed the effects of a glucocorticoid, dexamethasone administered within 12 h after calving. Dystocia was defined as a difficult birth resulting in a prolonged calving (≥70 min after the amniotic sac appears) and was monitored through 3 video cameras in the close-up dry-cow pen. Cows meeting the dystocia definition were randomly assigned to receive a single intramuscular injection of either dexamethasone (DEX; 0.1 mg/kg of body weight; n = 43) or saline (CON, n = 44) within 12 h following a dystocic calving. Serum haptoglobin, blood ß-hydroxybutyrate (BHB) concentrations, body temperature, and several behaviors were measured for the first 7 d postpartum. Additionally, milk production and components for the first 120 d were recorded. Using a mixed model, the fixed effects of treatment, parity, calving assistance, and time, along with 2- and 3-way interactions, were analyzed with cow as a random effect. We observed that primiparous DEX cows had greater serum haptoglobin concentrations on d 3 and d 7 postpartum compared with primiparous CON cows. There was no difference between treatment groups for blood BHB concentrations and body temperature. Behavior was altered between treatments, with DEX cows having reduced activity for the first week postpartum, as well as less restlessness and increased lying times on some of the days following calving. Treatment interacted with time for milk yield, such that DEX cows produced 2.7 kg/d less milk than CON cows for the first month following calving. The administration of dexamethasone resulted in changes in behavioral measurements, which could suggest a reduction in discomfort; however, due to the reduction in milk yield for the first month following calving, DEX administration may not be applicable for typical farm use. Additional research is needed to investigate treatments for cows experiencing dystocia without detrimental effects on milk yield.

Healthcare Costs Before and After Diagnosis of Cancer of Unknown Primary Versus Ovarian Cancer in Australia.

BACKGROUND: Little is known about the healthcare resource usage and costs for patients with cancer of unknown primary (CUP). OBJECTIVE: The aim of this study was to describe and quantify healthcare resource use and costs in Australia, 6 months prior to and after a diagnosis of CUP, and compare to those of women with ovarian cancer. METHODS: Individual-level data combining baseline surveys, clinical records and Medicare Benefits Schedule (MBS) claim records were analysed for 149 patients with CUP and 480 patients with ovarian cancer from two prospective cohort studies. MBS data were aggregated for the period 6 months prior to diagnosis date and 6 months after diagnosis. Data included doctor consultations, pathology, diagnostics, therapeutic procedures, imaging, allied health and medicines. Generalised linear models were used to evaluate the cost differences between CUP and ovarian cancer using gamma family and log link functions. Models were adjusted for age, employment, marital status, surgery, chemotherapy and number of comorbidities. RESULTS: The mean healthcare costs in the 6 months prior to diagnosis of CUP were Australian (AU) $3903 versus AU$1327 for ovarian cancer (adjusted cost ratio 2.94, 95% confidence interval [CI] 2.08-4.15). Mean healthcare costs 6 months post-diagnosis were higher for patients with CUP versus ovarian cancer (AU$20,339 vs AU$13,819, adjusted cost ratio 1.47, 95% CI 1.13-1.92). Higher costs for patients with CUP were driven by imaging (AU$1937 vs AU$1387), procedures (AU$5403 vs AU$2702) and prescribed medicines for all conditions (AU$10,111 vs AU$6717). CONCLUSIONS: Pre-diagnosis costs for patients with CUP are nearly triple those for ovarian cancer. Six months after diagnosis, healthcare costs for CUP remained higher than for ovarian cancer due to imaging, procedures and medicines.

A Multi-institutional Analysis of Late Complications in Scapula, Fibula, and Osteocutaneous Radial Forearm Free Flaps.

OBJECTIVES: (1) Evaluate the association of flap type with late complications in patients undergoing osseous head and neck reconstruction with the fibula free flap (FFF), osteocutaneous radial forearm free flap (OCRFFF), and scapula free flap (SFF). (2) Compare the prevalence of late complications based on minimum duration of follow-up. STUDY DESIGN: Retrospective cohort study. SETTING: Multiple academic medical centers. METHODS: Patients undergoing FFF, OCRFFF, or SFF with ≥6-month follow-up were stratified by type of flap performed. The association of flap type with late complications was analyzed via univariable and multivariable logistic regression, controlling for relevant clinical risk factors. Additionally, the frequency of late complications by minimum duration of follow-up was assessed. RESULTS: A total of 617 patients were analyzed: 312 (50.6%) FFF, 230 (37.3%) OCRFFFF, and 75 (12.2%) SFF. As compared with the SFF, the FFF (adjusted odds ratio [aOR], 3.05; 95% CI, 1.61-5.80) and OCRFFF (aOR, 2.17; 95% CI, 1.12-4.22) were independently associated with greater odds of overall late recipient site wound complications. The SFF was independently associated with the lowest odds of hardware exposure when compared with the FFF (aOR, 2.61; 95% CI, 1.27-5.41) and OCRFFF (aOR, 2.38; 95% CI, 1.11-5.12). The frequency of late complications rose as minimum duration of follow-up increased until plateauing at 36 months. CONCLUSIONS: This multi-institutional study suggests that the long-term complication profile of the SFF and OCRFFF compares favorably to the FFF. The SFF may be associated with the fewest overall late recipient site complications and hardware exposure, while the FFF may be associated with the most of these 3 options.

A retrospective observational study investigating safety netting documentation in the emergency department.

BACKGROUND: Safety netting is an important aspect of medical practice, especially for first contact clinicians. Adequate safety netting provision and documentation is vital for optimal patient care and medicolegal security. This is the first study to report safety netting documentation practices in the emergency department, a specialty with a variety of high-acuity presentations and which is particularly vulnerable to medicolegal issues. METHODS: A retrospective observational study was conducted at University Hospital Wales (UHW) Emergency Department (ED) in the months January-February and August 2023. Randomized paper notes review was performed for adult patients who were discharged from the ED without admission to hospital. Patient characteristics, time of consultation, grade of emergency medicine practitioner (EMP) and presence/level of safety netting documentation was recorded. The statistical software STATA was used to identify any associations between these factors on safety netting practices. RESULTS: A total of 500 notes were included. Safety netting advice was documented in 45% of consultations (n=224). This was 'basic' in 166 cases, 'general' in 32, 'specific' in 15 and both 'general and specific' in 11. Frequency of safety netting documentation was higher for ages < 65 years and consultations within working hours (09:00 - 17:00). CONCLUSION: This study shows that there is no 'universal' level of safety netting documentation amongst practicing EMPs. Although there is well-established guidance about when, what and how safety netting should be provided, there is little guidance in terms of documentation details. Further audit and quality improvement to embed safety netting documentation in ED clerking is required to further improve safety netting practices.

Regulation of B cell receptor signalling by Epstein-Barr virus nuclear antigens.

The cancer-associated Epstein-Barr virus (EBV) latently infects and immortalises B lymphocytes. EBV latent membrane protein 2A and EBV-encoded microRNAs are known to manipulate B cell receptor signalling to control cell growth and survival and suppress lytic replication. Here, we show that the EBV transcription factors EBNA2, 3A, 3B and 3C bind to genomic sites around multiple B cell receptor (BCR) pathway genes, regulate their expression and affect BCR signalling. EBNA2 regulates the majority of BCR pathway genes associated with binding sites, where EBNA3 proteins regulate only 42% of targets predicted by binding. Both EBNA2 and 3 proteins predominantly repress BCR pathway gene expression and target some common genes. EBNA2 and at least one EBNA3 protein repress the central BCR components CD79A and CD79B and the downstream genes BLNK, CD22, CD72, NFATC1, PIK3CG and RASGRP3. Studying repression of CD79B, we show that EBNA2 decreases transcription by disrupting binding of Early B cell Factor-1 to the CD79B promoter. Consistent with repression of BCR signalling, we demonstrate that EBNA2 and EBNA3 proteins suppress the basal or active BCR signalling that culminates in NFAT activation. Additionally, we show that EBNA2, EBNA3A and EBNA3C expression can result in reductions in the active serine 473 phosphorylated form of Akt in certain cell contexts, consistent with transcriptional repression of the PI3K-Akt BCR signalling arm. Overall, we identify EBNA2, EBNA3A and EBNA3C-mediated transcription control of BCR signalling as an additional strategy through which EBV may control the growth and survival of infected B cells and maintain viral latency.