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.

Bilateral accessory flexor indicis muscle: A case study.

Muscular variations within the upper extremities are common and widely documented. They can have a range of implications including nerve compression and misdiagnosis but are often silent. Our report herein describes a bilateral accessory muscle found in the forearm during routine cadaveric dissection. The muscle originates from the medial epicondyle of the humerus between the origins of the flexor digitorum superficialis and flexor carpi radialis muscles. The muscle is digastric, with the distal belly existing as the first lumbrical and the proximal serving as a supernumerary flexor. This functionally atavistic variation could prove clinically relevant for the purposes of donor muscle or tendon tissue as well as surgical complications and compressive neuropathies.

Esophageal Stent Migration Diagnosed With Point-of-Care Ultrasound.

This unique case depicts the first published report of a physician using point-of-care ultrasound to diagnose an esophageal stent migration. Discussed in this article are the sonographic findings that clinicians should be familiar with when evaluating patients with abdominal pain or chest pain who have a history of an esophageal stent. When coupled with a high index of suspicion, ultrasound can be one of the most portable, readily available, low-cost, and minimally invasive techniques for making a rapid diagnosis of esophageal stent migration.

A Principle-Based Approach to Visual Identification Systems for Hospitalized People with Dementia.

A large proportion of hospital inpatients are affected by cognitive impairment, posing challenges in the provision of their care in busy, fast-paced acute wards. Signs and symbols, known as visual identifiers, are employed in many U.K. hospitals with the intention of helping healthcare professionals identify and respond to the needs of these patients. Although widely considered useful, these tools are used inconsistently, have not been subject to full evaluation, and attract criticism for acting as a shorthand for a routinized response. In order for visual identifiers to be used effectively in acute care settings, thorough consideration must be given to the ethical and legal issues that are engaged in this context, and their potential benefits and harms must be weighed and balanced. This paper proposes a set of legal and ethical principles that can be used to guide the implementation of visual identifiers. Together, these principles provide a framework applicable in the design and implementation phases to systematically identify relevant considerations arising from the use of these tools. We outline some tensions that arise between principles and conclude that selecting a preferred moral framework could help to guide decision-making, as does clarity around the purpose and objectives of the identifier.

A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. No direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs in patients commencing T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinicopathological information, prior treatment, the presence or absence of central nervous system (CNS) disease, outcomes and treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Twenty-nine female patients, with a median age of 52 years (interquartile range 44-62 years), were identified; the prevalence of BM was 41%. Median number of lines of prior therapy was 2 (range 2-6). At a median follow-up of 13.8 months, median progression-free survival (PFS) for the overall population was 13.9 months [95% confidence interval (CI) 12.4 months-not estimable (NE)], 16.1 months (95% CI 15.1 months-NE) for active BMs and 12.4 months (95% CI 8.3 months-NE) for progressive extracranial disease alone. The 12-month overall survival (OS) rate was 74% (95% CI 59% to 95%) in the overall population, and 83% (95% CI 58% to 100%) and 66% (95% CI 45% to 96%) for active BMs and extracranial disease only, respectively. Most common TEAEs were fatigue, alopecia, and constipation. In nine patients (31%, including two deaths), pneumonitis occurred. CONCLUSION: In this real-world population, we demonstrate T-DXd to be effective in patients with active BMs and those with progressive extracranial disease alone. PFS and OS were numerically longer in those with active BMs. These data demonstrate that patients with active BM treated with T-DXd have at least comparable outcomes to those with extracranial disease alone. The high rate of pneumonitis warrants further consideration.

Utilizing speech analysis to differentiate progressive supranuclear palsy from Parkinson's disease.

INTRODUCTION: Distinguishing Parkinson's disease (PD) from Progressive supranuclear palsy (PSP) at early disease stages is important for clinical trial enrollment and clinical care/prognostication. METHODS: We recruited 21 participants with PSP(n = 11) or PD(n = 10) with reliable caregivers. Standardized passage reading, counting, and sustained phonation were recorded on the BioDigit Home tablet (BioSensics LLC, Newton, MA USA), and speech features from the assessments were analyzed using the BioDigit Speech platform (BioSensics LLC, Newton, MA USA). An independent t-test was performed to compare each speech feature between PSP and PD participants. We also performed Spearman's correlations to evaluate associations between speech measures and clinical scores (e.g., PSP rating scales and MoCA). In addition, the model's performance in classifying PSP and PD was evaluated using Rainbow passage reading analysis. RESULTS: During Rainbow passage reading, PSP participants had a significantly slower articulation rate (2.45(0.49) vs 3.60(0.47) words/minute), lower speech-to-pause ratio (2.33(1.08) vs 3.67(1.18)), intelligibility dynamic time warping (DTW, 0.26(0.19) vs 0.53(0.26)), and similarity DTW (0.43(0.27) vs 0.67(0.13)) compared to PD participants. PSP participants also had longer pause times (17.24(5.47) vs 8.45(3.13) sec) and longer total signal times (52.44(6.67) vs (36.67(6.73) sec) when reading the passage. In terms of the phonation 'a', PSP participants showed a significant higher spectral entropy, spectral centroid, and spectral spread compared to PD participants and no differences were found for phonation 'e'. PD participants had more accurate reverse number counts than PSP participants (14.89(3.86) vs 7.36(4.67)). PSP Rating Scale (PSPRS) dysarthria (r = 0.79, p = 0.004) and bulbar item scores (r = 0.803, p = 0.005) were positively correlated with articulation rate in reverse number counts. Correct reverse number counts were positively correlated with total Montreal Cognitive Assessment scores (r = 0.703, p = 0.016). Machine learning models using passage reading-derived measures obtained an AUC of 0.93, and the sensitivity/specificity in correctly classifying PSP and PD participants were 0.95 and 0.90, respectively. CONCLUSION: Our study demonstrates the feasibility of differentiating PSP from PD using a digital health technology platform. Further multi-center studies are needed to expand and validate our initial findings.

The role of outpatient needle arthroscopy in the diagnosis and management of musculoskeletal complaints: A systematic review of the Arthrex NanoScope.

BACKGROUND: The aim was to review the literature regarding needle arthroscopy using the Arthrex NanoScope system and evaluate: (1) the diagnostic indications, utility, and efficacy compared to conventional methods, and (2) the therapeutic indications, safety, and reported outcomes. METHODS: Searches of three databases (MEDLINE, Embase and PubMed) were conducted in November 2021 using MeSH terms: 'needle arthroscopy', 'human', 'in office arthroscopy', 'needle arthroscope', 'nanoscopic', 'surgery', 'nanoscope' and 'percutaneous arthroscopy'. The included studies were catalogued, quality-assessed using Methodological Index for Non-Randomised Studies (MINORS), and analysed using the Cochrane data collection templates for randomised control trials (RCT) and non-randomised control trials (non-RCT). The majority of studies were non-numerical and were examined using qualitative analysis. RESULTS: The search yielded 314 studies, 22 of which were included for analysis. MINORS assessment was applicable to four studies. Mean MINORS was 10.7/16 with the most frequent limitations being lack of unbiased endpoint or sample size calculation. The level of evidence ranged from level IV-V. Diagnostic and therapeutic indications were described in relation to the: knee (n = 10); shoulder (n = 6); foot/ankle (n = 3); elbow (n = 2), and miscellaneous (n = 1). CONCLUSIONS: Needle arthroscopy can augment the diagnostic process in patients presenting with musculoskeletal complaints, and may provide benefits in terms of diagnostic accuracy, cost efficiency, timeliness of investigation, and a visually impactful patient-centred consultation. Therapeutic interventions are reported by a small number of pioneer groups who report some benefits over conventional arthroscopy. The available literature remains small and of low quality, and more evidence is needed with regards to patient selection, efficacy, safety, and cost. LEVEL OF EVIDENCE: Level V (based on the weakest study included in the Systematic Review).

Moving orthopaedic procedures out of the operating theatre:Outpatient needle arthroscopy can reduce cost & waste, and increase inpatient capacity compared to conventional knee arthroscopy.

BACKGROUND: Needle arthroscopy (NA) is an emerging technique that could streamline pathways, facilitate timely care, and reduce service burden. The primary aim was to assess the practical and economic viability of an outpatient NA service. Secondary aims were to assess the relative costs and benefits compared to a conventional arthroscopy (CA) service. METHODS: This service feasibility study was conducted between 2021-2022 in a high-volume national treatment centre. A NA pathway was established for patients with chronic soft tissue pathology or early degenerative knee disease. The pathway was evaluated in terms of: i) cost; ii) efficiency, and iii) waste production, and an assessment was conducted of the patient-related and service-related effects. RESULTS: The cost of the NA pathway was £1555.20 per patient, compared to £2,351.53 for CA. Time to management was 45 days for NA versus 180 days for CA. The NA pathway involved two hospital attendances, whereas CA required a minimum of three. NA cases produced 1.4 kg of non-recyclable waste compared to 5.0 kg produced by CA. For every two cases managed by NA instead of CA, capacity for one additional obligate-inpatient procedure was created. CONCLUSIONS: The NA pathway offers a technically and economically viable approach for the management of refractory knee symptoms in the context of chronic soft tissue or early degenerative disease. NA placed less demand on hospital resources, produced two-thirds less non-recyclable waste, and is amenable to a one-stop clinic approach. Clinical studies focused on objective and patient-reported outcome measures are required to assess clinical efficacy.

Giant valley-Zeeman coupling in the surface layer of an intercalated transition metal dichalcogenide.

Spin-valley locking is ubiquitous among transition metal dichalcogenides with local or global inversion asymmetry, in turn stabilizing properties such as Ising superconductivity, and opening routes towards 'valleytronics'. The underlying valley-spin splitting is set by spin-orbit coupling but can be tuned via the application of external magnetic fields or through proximity coupling. However, only modest changes have been realized to date. Here, we investigate the electronic structure of the V-intercalated transition metal dichalcogenide V1/3NbS2 using microscopic-area spatially resolved and angle-resolved photoemission spectroscopy. Our measurements and corresponding density functional theory calculations reveal that the bulk magnetic order induces a giant valley-selective Ising coupling exceeding 50 meV in the surface NbS2 layer, equivalent to application of a ~250 T magnetic field. This energy scale is of comparable magnitude to the intrinsic spin-orbit splittings, and indicates how coupling of local magnetic moments to itinerant states of a transition metal dichalcogenide monolayer provides a powerful route to controlling their valley-spin splittings.

The reach and benefits of a digital intervention to improve physical activity in people with a musculoskeletal condition delivered during the COVID-19 pandemic in the UK.

AIM: To evaluate a digital intervention to improve physical activity in people in the UK with a musculoskeletal condition delivered during movement restrictions brought about because of the COVID-19 pandemic. METHOD: Service evaluation data collected from 26,041 participants over 5 months was assessed against national datasets to understand the reach and representativeness of the digital physical activity intervention. Measures to restrict the movement and interaction of people were in place during these 5 months. Cross-sectional data from 2752 participants across different stages of the 12-week programme assessed levels of physical activity and the components of behaviour as defined by the COM-B model (Capability, Opportunity, Motivation = Behaviour). Regression analysis investigated the relationship between programme stage and physical activity and the components of behaviour. RESULTS: In comparison to the UK population of people with a musculoskeletal condition, the intervention participants were over-represented by females, White, and inactive people. A cross-sectional analysis suggested that the number of participants regularly active increased by programme stage. Scores for the behavioural components of automatic and reflective motivation, physical and psychological capability, and physical opportunity were also improved by programme stage. CONCLUSION: The service evaluation suggests that the digital intervention, designed to improve physical activity in people with a musculoskeletal condition, could be beneficial during measures to restrict movement to slow the spread of infectious disease in those who are already motivated to become or stay active.

Surgeon educator perspectives of implementing a national undergraduate curriculum in otolaryngology.

OBJECTIVE: The General Medical Council will be implementing a national medical licensing assessment for all UK medical students by 2024-25. Surgeon educator perceptions on a national undergraduate curriculum in otolaryngology were reviewed accordingly. METHOD: A mixed methods study was undertaken within a UK school of surgery assessing ENT surgeon educators. Perspectives on teaching content, quality and student experience were assessed with degree of agreement assessed (Likert scoring). Associated qualitative focus group sessions underwent detailed thematic analysis according to grounded theory. RESULTS: A response rate of 50 per cent was achieved involving 21 participants working across 14 hospitals. These showed strong agreement that implementation of a national curriculum would improve the standard of teaching delivered at a personal, institutional and national level. Further themes were identified relating to the personal, institutional and specialty related factors influencing practical delivery. CONCLUSION: A series of practical recommendations are made to potentially assist the implementation of a national ENT curriculum.

Developing A Conceptual Framework for Early Intervention Vocational Rehabilitation for People Following Spinal Cord Injury.

PURPOSE: Early intervention vocational rehabilitation (EIVR) can improve return to work (RTW) outcomes for people with spinal cord injury (SCI). However, mechanisms explaining how and why EIVR works are not well understood. This study aims to develop a conceptual framework describing key mechanisms of EIVR intervention effect following SCI. METHODS: We synthesised data from a realist literature review with data from interviews of people with SCI (n = 30), a survey of people with SCI who had received EIVR (n = 37), a focus group of EIVR providers and a focus group of community vocational providers. We first synthesised the literature review and interviews to develop an initial programme theory describing the contexts in which mechanisms are activated to produce EIVR outcomes. Then we used data from the survey and focus groups to further refine the EIVR programme theory. Finally, a conceptual framework was developed to support knowledge dissemination. RESULTS: By ensuring consistent messaging across the multi-disciplinary team, EIVR programmes establish and maintain hope that work is possible following injury. Conversations about work allow individuals to determine the priority of work following injury. These conversations can also improve self-efficacy by providing individualized support to envisage pathways toward RTW goals and maintain worker identity. The synthesised study findings highlight the contexts and resources required to trigger activation of these mechanisms. CONCLUSIONS: EIVR key mechanisms of effect are not specific to SCI as a health condition, therefore enabling this framework to be applied to other populations who face similar impairments and return to work barriers.

A GeoHealth Call to Action: Moving Beyond Identifying Environmental Injustices to Co-Creating Solutions.

As marginalized communities continue to bear disproportionate impacts from environmental hazards, we urgently call for researchers and institutions to elevate the principles of Environmental Justice. The American Geophysical Union (AGU) GeoHealth section supports members' engagement in health-related community-engaged and community-led transdisciplinary research. We highlight intersectional research that provides examples and actions for both individuals and organizations on community science and trust building, removing barriers created by scientific agency priorities and career expectations, and opportunities in education and policy. Justice does not start or end at one meeting; this is ongoing work that is active, evolving, and an ethical responsibility of AGU's membership.

The extreme yet transient nature of glacial erosion.

Ice can sculpt extraordinary landscapes, yet the efficacy of, and controls governing, glacial erosion on geological timescales remain poorly understood and contended, particularly across Polar continental shields. Here, we assimilate geophysical data with modelling of the Eurasian Ice Sheet - the third largest Quaternary ice mass that spanned 49°N to 82°N - to decipher its erosional footprint during the entire last ~100 ka glacial cycle. Our results demonstrate extreme spatial and temporal heterogeneity in subglacial erosion, with rates ranging from 0 to 5 mm a-1 and a net volume equating to ~130,000 km3 of bedrock excavated to depths of ~190 m. A hierarchy of environmental controls ostensibly underpins this complex signature: lithology, topography and climate, though it is basal thermodynamics that ultimately regulates erosion, which can be variously protective, pervasive, or, highly selective. Our analysis highlights the remarkable yet fickle nature of glacial erosion - critically modulated by transient ice-sheet dynamics - with its capacity to impart a profound but piecemeal geological legacy across mid- and high latitudes.

Probing the self-assembly and anti-glioblastoma efficacy of a cinnamoyl-capped dipeptide hydrogelator.

Herein, we introduce the first diphenylalanine dipeptide hydrogelator capped with the cinnamoyl functional group (Cin-L-F-L-F). We evaluate the effects of the cinnamoyl moiety on molecular self-assembly events and resultant physical properties of the hydrogel formed. In addition, we report our preliminary results of this dipeptide's cytotoxicity against glioblastoma (GBM) cancer cells.

Identification of a branchial cleft anomaly via handheld point-of-care ultrasound.

Aim of the study: Branchial anomalies result from incomplete obliteration of the branchial arch structures during embryogenesis. Second branchial arch anomalies are commonly found on the lower third of the neck, with an opening at the anterior border of the sternocleidomastoid muscle, and may drain secretions or purulent material. This case demonstrates the use of handheld point-of-care ultrasound to aid in the diagnosis of a branchial anomaly. Case description: The patient presented with a "hole" in the neck with intermittent drainage from the site. A 2 mm defect in the skin was noted anterior to the sternocleidomastoid muscle. A handheld ultrasound system was used to identify a well-defined, hypoechoic, cyst-like structure. Given the history, physical findings, and point-of-care ultrasound imaging, the diagnosis of a second branchial cleft sinus was made. Conclusions: The use of point-of-care ultrasound and knowledge of the sonographic characteristics of these lesions can assist the physician in the diagnosis of branchial arch anomalies.

Bacteroidales species in the human gut are a reservoir of antibiotic resistance genes regulated by invertible promoters.

Antibiotic-resistance genes (ARGs) regulated by invertible promoters can mitigate the fitness cost of maintaining ARGs in the absence of antibiotics and could potentially prolong the persistence of ARGs in bacterial populations. However, the origin, prevalence, and distribution of these ARGs regulated by invertible promoters remains poorly understood. Here, we sought to assess the threat posed by ARGs regulated by invertible promoters by systematically searching for ARGs regulated by invertible promoters in the human gut microbiome and examining their origin, prevalence, and distribution. Through metagenomic assembly of 2227 human gut metagenomes and genomic analysis of the Unified Human Gastrointestinal Genome (UHGG) collection, we identified ARGs regulated by invertible promoters and categorized them into three classes based on the invertase-regulating phase variation. In the human gut microbiome, ARGs regulated by invertible promoters are exclusively found in Bacteroidales species. Through genomic analysis, we observed that ARGs regulated by invertible promoters have convergently originated from ARG insertions into glycan-synthesis loci that were regulated by invertible promoters at least three times. Moreover, all three classes of invertible promoters regulating ARGs are located within integrative conjugative elements (ICEs). Therefore, horizontal transfer via ICEs could explain the wide taxonomic distribution of ARGs regulated by invertible promoters. Overall, these findings reveal that glycan-synthesis loci regulated by invertible promoters in Bacteroidales species are an important hotspot for the emergence of clinically-relevant ARGs regulated by invertible promoters.

Impact of the utilization of 500 mL IV bags on crystalloid resuscitation volumes administered to trauma patients.

INTRODUCTION: Administering large volumes of crystalloids to trauma patients has been shown to exacerbate metabolic complications of hemorrhage including dilutional coagulopathy and worsening acidosis The aim of this study was to evaluate crystalloid administration volumes in trauma patients after replacing 1 L IV containers with 500 mL IV containers in the emergency department trauma resuscitation bay. MATERIALS AND METHODS: This was a single-center, IRB-approved, retrospective cohort evaluation of adult trauma patients conducted at an 864-bed community tertiary referral center located in the southeastern United States. Patterns of crystalloid administration were examined before and after the trauma resuscitation bay began to exclusively stock 500 mL IV containers. The primary outcome was mean total crystalloid volume infused from time of injury to hospital admission. Secondary outcomes included mean total crystalloid volume infused prior to administration of blood products, proportion of patients who received less than 2 L total of crystalloids, time to initiation of blood products, and mortality in both the emergency department and in-hospital. RESULTS: Patient characteristics were largely similar between both groups including age, mechanism of injury, and Injury Severity Score. For the primary outcome, the mean total crystalloid volume infused from time of injury to hospital administration, patients in the 500 mL IV fluid container group were administered 555 mL less crystalloid when compared to the 1 L IV fluid container group, 1048 mL vs 1603 mL (p < 0.01; 95% CI 406 mL - 704 mL), respectively. After conversion to the 500 mL IV container bags, there was a 27.5% increase in the proportion of patients receiving less than 2 L of crystalloid, 90.5% vs 63.0% in the 500 mL IV fluid container and 1 L IV fluid container groups, respectively (p < 0.01). CONCLUSIONS: Due to reduced mortality, expanding literature and guidelines clearly support minimizing IV crystalloid resuscitation. Institutions must now work to minimize use of IV crystalloids to hemorrhaging trauma patients and a simple solution of using smaller IV fluid bags was shown to improve adherence to this practice.