This study aimed to investigate the impact of transitioning from work from home (WFH) to office work on workers’ musculoskeletal disorder symptoms (MSDs) and mental health among full-time Taiwanese employees who experienced both work modes during the COVID-19 pandemic. An anonymous self-report questionnaire was administered to 502 participants between June and November 2022. Participants’ characteristics, work-related behaviors, sitting posture, and changes in these factors during the transition from WFH to office work were collected. MSDs were assessed using the Nordic Musculoskeletal Questionnaire (NMQ), and mental health was evaluated by a 5-item Brief Symptom Rating Scale (BSRS-5). Participants’ ergonomic work environment was also assessed while WFH. Analyses were conducted using chi-square, McNemar, paired-t tests, and logistic regression. The transition from WHF to office work was associated with significant increases in MSDs (22.51% reported an increase in MSD scores) and mental health scores (7.02 to 8.75), indicating worsening in these areas. Participants who remained the same or increased BSRS-5 scores had a significantly higher risk of experiencing worsened MSDs compared to those in the Improved group (aORs = 15.666 and 8.596, respectively, both p < 0.001). Participants who shifted to a more tense sitting posture had a significantly higher likelihood of worsening MSD scores upon returning to the office compared with the Improved group (aOR = 7.914, p = 0.011). Furthermore, participants with poor ergonomic working environments during remote work had a significantly higher risk of worsening MSD scores rather than improvement after returning to the office (aORs = 2.750, p = 0.018). This study found that workers’ musculoskeletal disorder status deteriorated when they transitioned from remote work back to office-based work. Our findings suggest that this worsening of MSDs is significantly linked to a decline in mental health during the transition. The online version contains supplementary material available at 10.1186/s12889-026-26957-6.
An approach to rapid simulation of time-averaged wall shear stress (TAWSS) on 3D geometries created from 3D Quantitative Coronary Angiography (3D-QCA) methodology has been developed, which enables rapid computational fluid dynamic (CFD) shear stress simulation. We compared TAWSS estimated from 3D-QCA-CFD with optical coherence tomography (OCT)-based CFD simulations in coronary arteries. 15 normal and 5 stenotic coronary arteries in instrumented minipigs were studied. 3D arterial geometries were reconstructed from 3D-QCA and OCT using common centrelines and matched axial positions. Identical boundary conditions were used for both methods through directly measured vessel-specific inlet blood velocities. TAWSS was calculated for axially matched segments (n = 80 for normal arteries; n = 160 for stenotic arteries) and in 3 mm/60° sectors. Mean TAWSS simulation times for 3D-QCA and OCT-based CFD were 17.8 min and ~ 1.5 h respectively. There were significant but numerically small differences in TAWSS for normal arteries (-0.21 ± 0.64 Pa [95%CI -1.04,1.46], p < 0.001), and no significant difference for stenotic arteries (-0.39 ± 3.04 Pa [95%CI -6.35, 5.56], p = 0.25). Axial TAWSS profiles along vessel lengths were similar between the two methods. There is a trend of underestimation by 3D-QCA at higher values of TAWSS compared with OCT, due to differences in geometry dimensions. Similar spatial distributions of TAWSS in both normal and stenotic arteries were observed from co-registered TAWSS maps. This study suggests that 3D-QCA-based TAWSS is feasible in both normal and stenotic arteries and that further clinical evaluation of rapid TAWSS from 3D-QCA is warranted, which may facilitate clinical adoption of TAWSS assessment.
Changes in regulations related to medication for opioid use disorder (MOUD) have expanded access to MOUD in primary care. However, there has been concern that primary care practices are unwilling or unable to treat patients with OUD. To describe the practices and patients enrolled in the Patient-Centered Outcomes Research Institute (PCORI)-funded HOMER (Comparing Home, Office, and Telehealth Induction for Medication Enhanced Recovery) research study who delivered MOUD as part of routine primary care practice. A total of 79 practices from 25 states expressed interest in participation. Sixty-two practices signed up for HOMER. Practices were typical of US primary care, accepting a variety of payers, including commercial insurance, Medicaid, Medicare, and uninsured patients, and caring for patients of across a spectrum of adult ages, races and ethnicity, education, and income. The majority had health insurance (82%). Most patients reported using prescription opioids (59%), while 41% reported other opioid use. Greater than 40% of participating patients reported no prior medication treatment for OUD. The finding that nearly half of patients had no prior treatment supports the importance of primary care as a crucial component of MOUD. Practices in HOMER were similar to practices across the country. Patients enrolled were typical of family practice patients. Policies that support primary care MOUD may improve access to patients.
The muscle-tendon junction (MTJ) is a specialised interface between muscle and tendon and transmits muscle-generated force to the tendon. The MTJ is particularly vulnerable to injuries compared to muscle and tendon and becomes more injury prone with age. Despite its clinical importance, the mechanisms driving MTJ ageing and age-related functional deterioration remain poorly understood. In this study, young (3-month-old) and old (23-month-old) male mice were used to provide the first comprehensive three-dimensional characterisation of age-related structural and cellular changes at the mouse Achilles MTJ. This was achieved using the high-resolution imaging techniques, micro-computed tomography (µCT) and confocal microscopy. µCT analysis revealed a 27% reduction in muscle fibre diameter with age, accompanied by a trend toward increased MTJ surface area and a 19% reduction in pennation angle, which may indicate diminished force generation capacity. Confocal imaging showed a 49% reduction in endothelial cell volume (VWF-labelled) in the old mouse muscle-tendon unit, suggesting a loss of vascularity. In situ hybridisation demonstrated increased expression of senescence markers p16 and p21 in endothelial and MTJ-specific cells, with MTJ-specific cells showing the greatest accumulation of p16 and p21 (270% and 310% increases, respectively) with age, and immunofluorescence also showed increased expression of p21. These findings suggest that vascular and MTJ-specific cells are particularly susceptible to ageing and may collectively contribute to the age-related functional decline of the MTJ. Understanding these mechanisms may help to develop targeted therapeutic strategies to preserve or restore MTJ integrity and function in ageing populations.
The E3 ubiquitin ligase HUWE1 modifies a diverse network of substrate proteins by ubiquitination, through which it regulates various intracellular processes and contributes to both oncogenic and tumour suppressor mechanisms in different cancer contexts. Here, by analysing human lung adenocarcinoma (LUAD) patient samples, we reveal that HUWE1 protein expression is commonly upregulated in LUAD tumours compared to normal adjacent lung tissue and that this increase is associated with tumour stage. Using multiple, independent murine models of LUAD initiation and growth, we identify that Huwe1 is essential for mutant Kras-induced lung tumour development and reveal a novel, p53-independent requirement for Huwe1 in LUAD. Mechanistically, we demonstrate induction of senescence following HUWE1 depletion - characterised by impaired proliferation, an atypical cell cycle distribution, emergence of morphologically abnormal enlarged cells, increased β-galactosidase activity, and transcriptional reprogramming associated with inflammatory senescence-associated secretory phenotype (SASP) signalling and NFκB activation. Together, these data highlight a crucial role for HUWE1 in mutant Kras-induced LUAD tumorigenesis and in the continued growth and proliferation of established LUAD cells, confirming HUWE1 as a rational therapeutic target for LUAD.
Arthropods require periodic molting (ecdysis) for growth. While the neuroendocrine orchestration of ecdysis is well characterized in insects, it remains comparatively poorly understood in crustaceans. In insects, ecdysis-triggering hormone (ETH) from epitracheal cells and eclosion hormone (EH) from the brain initiate and coordinate ecdysis. ETH triggers pre-ecdysis behaviors, while EH amplifies ETH release and promotes neuropeptide secretion of crustacean cardioactive peptide (CCAP), myoinhibitory peptide (MIP) for exuviation. Definitive evidence for functional ETH and EH in crustaceans is lacking. Here, we investigate ETH and EH in the crab Carcinus maenas by functionally characterizing the ETH receptor, comprehensively mapping transcript and peptide localization of ETH and EH, and quantifying ETH neurohormone and transcript throughout the molt cycle. We identified a single CamETH GPCR with high specificity for arthropod ETHs, signaling via calcium and cAMP. ETHR mRNA is expressed in multiple tissues, but ETH is restricted to the central nervous system (CNS) with a complex neuroarchitecture in pericardial organs, adjacent to the branchiocardiac veins. EH is limited to CNS, notably in the eyestalk ganglia. Of note, complex EH immunopositive fibers in the abdominal ganglion, adjacent to CCAP/allatostatin-C (AST-C)/bursicon cells, represent a novel putative neurohemal site. Measurements of ETH mRNA and peptide through the molt cycle showed that transcription peaks in late premolt, while peptide is released during active ecdysis, later than observed in insects. While crustacean and insect ecdysis share neuroendocrine components, reflecting common ancestry, there is clear divergence in terms of functionality. We propose a new crustacean ecdysis cascade: ETH released from pericardial organs may stimulate EH to initiate CCAP/AST-C and bursicon release from adjacent neurons.
Pancreatic ductal adenocarcinomas (PDACs) are highly lethal and aggressive with oncogenic KRAS being the main oncogenic driver of the disease. PDACs have been extensively profiled at advanced stages, and in advanced disease the tumor microenvironment is a major determinant that critically shapes patient outcomes. Since the molecular events occurring prior to invasive growth remain poorly understood, we aimed to investigate changes in the precancerous epithelium and its surrounding niche. We acquired time-resolved, single-cell transcriptomic (scRNAseq), and accessible-chromatin data from human pluripotent stem cell-derived pancreatic duct-like organoids (PDLO) inducibly expressing KRASG12D and from various niche cells. Analysis of the pure epithelium already revealed key signatures of matrix remodeling and inflammation-related signaling upon few days of KRASG12D expression. Machine learning captured KRASG12D-dependent transcriptomic classifiers with high prediction accuracy and niche preparatory relevance. Various co-culture approaches followed by scRNAseq and functional validation, including T-cell microfluidics, demonstrated that the KRASG12D-induced PDLO-secretome activates pancreatic stellate cells (PaSCs) and protects precancerous organoids from T cell infiltration. Additional, in silico approaches reconstructed a virtual pancreatic (pre)cancerous space to profile cell–cell interactions between PDLOs and niche cells. TNFα emerged as a top-ranked ligand and was functionally validated to mediate T-cell shielding and PaSC activation. Cyst fluid from 80 prospectively sampled Intraductal Papillary Mucinous Neoplasm (IPMNs) –well-known cystic PDAC precursor lesions– showed a stepwise TNFα rise across LGD (low-grade), HGD (high-grade), and IC (invasive cancer). Our study reveals that oncogenic KRAS orchestrates niche-preparatory programs that precede PDAC formation and highlight a T cell exclusion program governed by epithelial-derived TNFα. The online version contains supplementary material available at 10.1186/s12943-025-02541-1.
Sclerostin regulates bone formation via Wnt/β-catenin signaling inhibition and contributes to intestinal epithelial homeostasis. Circulating sclerostin levels are reduced in axial spondyloarthritis (axSpA) and correlate with structural damage. LRP5, a receptor inhibited by sclerostin, also controls bone formation by regulating gut-derived serotonin synthesis, indicating a hormonal link between the intestine and bone. We hypothesized that gut dysbiosis-dependent downregulation of sclerostin alters intestinal serotonin production, contributing to disease-specific gut-bone signaling in axSpA. We quantified sclerostin and the serotonin-synthesizing enzyme TPH1 by qRT-PCR, and assessed serotonin protein levels by immunohistochemistry in ileal biopsies from treatment-naïve axSpA patients (n = 25) and healthy controls (n = 20), alongside measurement of circulating serotonin in peripheral blood platelets. We evaluated TPH1 expression in BON-1 cells following sclerostin and WNT3a treatment. Findings were validated in HLA-B27 transgenic rats, SKG mice, and Sost⁻/⁻ mice. Serotonin receptor expression in spinal entheseal cells was analyzed by RT-PCR, and LPS-induced HTR2B modulation was examined. In healthy controls, sclerostin modulated TPH1 expression and serotonin synthesis in enterochromaffin cells. In axSpA patients, intestinal sclerostin downregulation coincided with increased numbers of serotonin-positive enterochromaffin cells and elevated platelet serotonin levels. Broad-spectrum antibiotics restored intestinal sclerostin expression and normalized serotonin production in HLA-B27 transgenic rats. Sost⁻/⁻ mice exhibited increased intestinal Tph1 expression, while SKG mice showed reduced sclerostin and elevated Tph1 following curdlan-induced colitis-an effect dependent on the presence of intestinal microbiota. Human spinal entheses expressed HTR1B, HTR2A, and HTR2B, with LPS selectively inducing HTR2B expression. We identify a gut microbiota-dependent sclerostin-serotonin axis that regulates serotonin production and may contribute to gut-bone pathology in axSpA. These findings reveal novel mechanisms linking gut dysbiosis to bone disease and suggest potential therapeutic targets within the gut-bone-immune axis.
In 2016, researchers warned that as medical education becomes increasingly dependent on video-recorded data, protocols must be developed before an international conflict forces the conversion. Four years later, SARS-CoV-2 forced medical societies to find social distancing options for certifying examinations (CE). Our objective was twofold: incorporate a communication protocol that impacts the video-capture process for each candidate in an established review course; and monitor results on the CE (2020-2024). A multi-institutional prospective cohort design was used to assess "virtual-presence" and "knowledge-base" of candidates pre and post intervention. Didactics from previous in-person courses were reengineered to include sessions on variables that affect professionalism on virtual platforms. Descriptive statistics were conducted comparing pre and post-test scores for each metric. All sessions were interactive. The final session was a simulation of the American Board of Surgery (ABS) (CE). Zoom Professional was selected as the video conferencing application to simulate the ABS CE. Settings were mixed: home, office, hotel rooms. The 136 candidates varied: general surgery, plastic, vascular, several fellowships, and eleven residents. Twenty-three volunteer faculty and 2 communication scientists were invited to participate. Use of technology versus live in-person interactions presented a challenge: direct eye contact was impossible, images were limited to a coronal view, and the activity of the social systems of the brain was reduced. The paired-samples t-test demonstrated a statistically significant improvement in virtual presence over 5 years. Knowledge bases varied more than in previous in-person courses. Pass rates were excellent for those who followed the virtual protocol. The protocol assisted those with hearing loss, hypochondriasis, soft voices and eye-contact avoidance behaviors. All candidates were initially unaware of shortcomings regarding their virtual presence. All received continuous constructive feedback. However, those who incorporated their virtual protocol were successful in their certifying examination and perhaps improved their virtual patient and colleague interactions.
Non-pharmaceutical interventions (NPIs) have been important for controlling SARS-CoV-2 transmission, particularly before and during initial vaccine rollout. During the pandemic, the US Centers for Disease Control and Prevention issued isolation and masking guidance in case of COVID-19-like illness, a positive SARS-CoV-2 test, or known exposure to SARS-CoV-2. However, the impact of this guidance on mitigating transmission in office workplaces is unclear. We used a network-based mathematical model to estimate the impact of this guidance on SARS-CoV-2 transmission among office workers and their communities. The model represented social contacts in the home, office, and community. We used data from the CorporateMix study to parametrize social contacts among office workers and calibrated the model to represent the COVID-19 epidemic in Georgia, USA from January 2021 through August 2022. In the reference scenario (58% adherence to guidance among office workers and the broader population), workplace transmission accounted for a small fraction of total infections. Reducing adherence among office workers to 0% increased workplace transmissions by 27.1% and increasing adherence to 75% reduced workplace transmission by 7.0%. Increasing adherence to 75% among office workers had minimal impact on symptomatic cases and deaths; increasing it among the broader population was more effective in reducing office worker cases and deaths. In our model, moderate adherence to recommended NPIs in workplaces was effective in reducing transmission, but increasing adherence had limited benefit given workplaces that have low contact intensity and hybrid work arrangements. These results underscore the public health benefits of community-wide adoption of recommended NPIs.
To monitor community-level consumption of 20 illicit drugs across urban areas of England using wastewater-based epidemiology (WBE) surveillance at high temporal resolution. This study was conducted over a 12-month period in 2022 sampling 24-hour composite wastewater samples at 15 wastewater treatment plants (WWTPs) covering catchment population equivalents ranging from ~100 000 to >1 million. Analysis was conducted using rapid liquid chromatography-tandem mass spectrometry methods. The sampled WWTPs collectively covered 21% of the national population. Primary data outcomes were the population-normalised daily loads (PNLs) entering the WWTP, estimated population-normalised consumption (both in mg/1000 people/day) and total mass (g/day) of 20 targeted illicit drugs and total mass in each catchment, quantified using suitable drug target residue markers in 1746 wastewater samples. Covariables included temporal indicators (e.g. public holidays, events) and regional factors. Presence, quantity and correlation of WBE-derived drug use data were used to infer drug use patterns. Of the 20 illicit drugs investigated, 18 were detected in at least one sample. Cocaine exhibited the highest average daily PNL (2770 ± 829 mg/1000 people/day), followed by heroin (382 ± 248), ketamine (287 ± 183), amphetamine (272 ± 268), 3,4-methylenedioxymethamphetamine (MDMA) (80 ± 57) and methamphetamine (60 ± 99) across 2022. When comparing PNLs to Sewage analysis CORe group-Europe (SCORE) and European Drugs Agency WBE data for 109 other WWTPs across Europe from March to May, 2022 cocaine and ketamine PNLs from sites in England were ranked statistically higher [cocaine: Wilcoxon rank-sum test statistic (W) = 971, adjusted P = 0.000115; ketamine: W = 264, adjusted P = 0.0000389]. Importantly, seven English WWTPs recorded higher mean ketamine PNLs than any other European site over the same period in 2022. Temporal spikes in drug consumption aligned with public holidays and major events. A notable decrease in cocaine use coincided with a 3.7-t UK seizure. Strong inter-drug correlations were observed across catchments, particularly for benzoylecgonine/ketamine and benzoylecgonine/cocaethylene. Extrapolation to generate a representative national average consumption estimate is not recommended, as the WWTPs studied were mostly classified as urban areas and found not to be representative of the entire population of England. Wastewater analysis revealed widespread and temporally variable illicit drug use across England in 2022, with ketamine use exceeding European levels at multiple sites. The findings highlight wastewater-based epidemiology's capacity to monitor drug use trends and identify community-level impacts of interventions and events.
Chronic inflammatory disease is responsible for huge and increasing global mortality and morbidity. Unregulated inflammatory cells, including neutrophils and macrophages, are major drivers of chronic inflammatory disease. Efferocytosis plays a critical role in inflammation resolution by removing effete inflammatory cells from tissues. Despite defective efferocytosis being critical in inflammatory disease progression there are no therapies to correct these defects in clinical use. Here, using experimental models of atherosclerosis and lung injury, we identify the ErbB family tyrosine kinase inhibitor (TKI), neratinib, as a putative efferocytosis-targeting therapy. In an experimental model of atherosclerosis and lung injury, two doses of neratinib significantly increased efferocytosis in the lungs of mice concomitant with a reduction in the proportion of lung neutrophils. Neratinib significantly increased human neutrophil apoptosis and efferocytosis of apoptotic neutrophils by monocyte-derived macrophages (MDMs). In addition to increased efferocytosis, neratinib treated macrophages demonstrated both increased phagocytosis and macropinocytosis. Neratinib increased MDM surface expression of the efferocytosis receptor MerTK independent of protein synthesis and transcription which correlated with elevated efferocytosis in MDMs and inhibitors of MerTK blocked neratinib-induced efferocytosis. Thus, we describe a novel role for neratinib in driving efferocytosis in multimorbidity and suggest that ErbB TKIs may have therapeutic potential in inflammatory disease by restoring macrophage function and promoting inflammation resolution.
Tumour-associated macrophages are highly abundant in the tumour microenvironment, and their levels influence tumour progression and therapy response. Tracking macrophages by positron-emission tomography (PET) can yield critical information on the dynamics of macrophage infiltration, particularly in diseases such as breast cancer, in which tumour-associated macrophages are significant in the evolution of the tumour microenvironment. Two complementary PET imaging methods were used to track macrophages. The first method used a novel [89Zr]Zr-labelled antibody that targets the murine F4/80 receptor, which is located on the cell surface of in situ macrophages. [89Zr]Zr-DFO-anti-F4/80 and a non-specific [89Zr]Zr-labelled control antibody were developed and characterised for their specificity. The second method involved directly labelling mouse-derived macrophages with [89Zr]Zr-oxine, and the effect of [89Zr]Zr-radiolabelling on macrophage viability and phenotype was evaluated. Using PET imaging and ex vivo tissue counting, the in vivo biodistribution of [89Zr]Zr-DFO-anti-F4/80 and [89Zr]Zr-labelled murine macrophages was quantified in female BALB/c mice bearing syngeneic, orthotopic 4T1 breast cancer tumours. [89Zr]Zr-DFO-anti-F4/80 showed target-specific uptake in vitro. At a dose of 100 μg DFO-anti-F4/80 per mouse, [89Zr]Zr-DFO-anti-F4/80 enabled visualization of tumour-resident macrophages by PET/CT with high contrast. This was not observed for non-specific [89Zr]Zr-DFO-IgG2b. PET/CT imaging showed that intravenously administered [89Zr]Zr-labelled M0 macrophages migrated to the liver and spleen, with a proportion of macrophages trafficking to the tumour. [89Zr]Zr-oxine labelling did not affect macrophage viability nor phenotype, even at an absorbed radiation dose of 3.31 Gy. For the first time, we have applied and compared two complementary PET/CT imaging strategies to quantify the infiltration of macrophages in an orthotopic, syngeneic murine model of breast cancer. First, PET/CT imaging using an “indirect” cell tracking approach with a new [89Zr]Zr-DFO-anti-F4/80 antibody radiotracer showed that resident tumour-associated macrophages are abundant in this syngeneic breast cancer model. Second, PET/CT imaging using [89Zr]Zr-labelled M0 macrophages showed that macrophages in the blood pool migrate to the tumour, within 24 h. These tools have utility in quantifying macrophage distribution and migration in cancer, particularly in the context of new and existing therapies in which macrophage populations are perturbed. The online version contains supplementary material available at 10.1007/s00259-025-07752-8.
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Inflammation affects cardiac remodelling following myocardial infarction (MI), and can be imaged using Positron Emission Tomography (PET) targeting the 18 kDa translocator protein (TSPO). We utilised a rat reperfusion MI model to assess whether longitudinal [18F]LW223 could accurately measure macrophage-driven inflammation using outcome measures amenable to clinical translation, in addition to assessing the prognostic potential of [18F]LW223 for cardiac dysfunction. Adult male Sprague-Dawley rats underwent coronary artery ligation and reperfusion to induce MI. [18F]LW223 PET/Computed Tomography was performed longitudinally on day 2, 7, 14 and 28 post-MI. On day 28, cardiac function was assessed by ultrasound. Naïve and sham rat controls were compared to the MI cohort. A separate cohort of rats were produced for histological validation and proteomic analysis. [18F]LW223 standard uptake value corrected for myocardial blood flow (SUVMBF) was highest within the MI cohort and localised to the infarct. This peaked at day 2 and remained elevated versus naïve and sham controls out to day 28. These patterns were validated by histology, revealing that the majority of TSPO expressing cells within the infarct at day 2 were also CD68+ (55.2%). Proteomics confirmed upregulation of several proinflammatory processes at day 2, and a commonality in upregulated inflammatory response proteins at both day 2 and day 28, indicting ongoing inflammation. Infarct [18F]LW223 uptake at day 2 correlated with infarct size (p = 0.0016, R2 = 0.73) and cardiac dysfunction at day 28 (p = 0.0020, R2 = 0.82). [18F]LW223 identifies a persistent and predominantly macrophage-driven inflammatory response with early [18F]LW223 infarct binding associated with later cardiac dysfunction.
In mature trauma systems, most trauma deaths occur soon after injury yet studies often only include patients who survive to hospital admission. These studies exclude pre-hospital deaths and introduce substantial survival bias. Understanding trauma fatalities across all phases of care is essential to identify opportunities to further improve trauma outcomes. This retrospective cohort study analysed adult trauma fatalities attended by London's Air Ambulance from 1 January 2019 to 31 December 2020. Deaths were classified as pre-hospital if traumatic cardiac arrest occurred before hospital arrival. Timing of death was recorded as minutes from injury to arrest for pre-hospital cases and days from admission to death for in-hospital cases. A multidisciplinary panel determined the likely cause of death using clinical, radiological, and post-mortem findings. Among 3,089 adult trauma patients attended, 497 (16.1%) died. Most deaths (77.1%) occurred pre-hospital, with a median time from injury to traumatic cardiac arrest of 12 minutes (IQR 6-24). Haemorrhage and traumatic brain injury accounted for 81.9% of deaths overall, but their distribution differed markedly by phase of care: 96.2% of haemorrhage deaths occurred pre-hospital, whereas 84.2% of in-hospital deaths were due to traumatic brain injury. In addition, deaths from all other potentially reversible causes, and 95.1% of penetrating trauma deaths, occurred pre-hospital. In mature trauma systems, most trauma deaths now occur before arrival in hospital, with many due to potentially reversible causes. The greatest opportunities to improve trauma outcomes now lie in the pre-hospital phase of care. Serious injury is a major cause of death, especially in younger people. Although hospital trauma care has improved, most people who die after serious injury die before reaching hospital. This study examined when and why adult trauma patients died within a well-developed, organised urban trauma system. Most deaths occurred very soon after injury and usually before hospital admission, often due to severe bleeding or other conditions that can usually be treated if care is given quickly in hospital. In contrast, patients who reached hospital rarely died from these potentially treatable problems. These findings show that further reductions in trauma deaths are most likely to come from action before hospital arrival. This includes preventing violent injury, helping members of the public and first responders to control life-threatening bleeding, and ensuring access to life-saving treatments before hospital arrival, alongside rapid transport to hospital.
Hypertension is linked to endothelial dysfunction, but causality and direction is not entirely known. The aim was to study the cross-sectional associations between home, office, and central BP and microcirculatory peak oxygen saturation (OxyP). In the observational Swedish CArdioPulmonary bioImage Study (SCAPIS) Linköping subsample, office and home BP were measured using an oscillometric device and OxyP was measured in forearm skin after a 5-min occlusion of the brachial artery. A linear regression was fitted to evaluate the mean change in OxyP per SD increase in BP. A logistic regression was fitted to evaluate the associations between BP above the median and OxyP below the median. Of participants, 3,291 were included in the analyses. Per SD increase in systolic home BP, the adjusted mean (95% CI) difference in OxyP was -0.4 (-0.6 to -0.1%). In subgroup analyses, the association remained for women but not men, although the interaction by sex was not statistically significant. Also, in women but not in men, OxyP was lower in those with white coat hypertension vs. sustained normotension, i.e., mean (95% CI) 88.8 (88.2-89.4%) vs. 89.6 (89.3-90.0%), and in those with masked hypertension vs. sustained normotension, i.e., 87.5 (85.9-89.1%) vs. 89.6 (89.3-90.0%). Home BP, which better predicts cardiovascular disease than office BP, was inversely associated with OxyP. This correlation remained in subgroup analyses of women but not men, suggesting possible sex-dependent microcirculatory dysfunction or that masked hypertension could be a more important cardiovascular risk marker in women, despite its higher prevalence in men.
Methionine-1 (M1)-linked ubiquitin chains, assembled by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, are critical regulators of inflammation and immune homoeostasis. Genetic loss or mutation of the LUBAC subunits HOIP and HOIL-1 or of OTULIN causes autoinflammatory syndromes accompanied by metabolic defects, including amylopectinosis, lipodystrophy, and fatty liver disease. Yet, it remains unclear how LUBAC and OTULIN control metabolic signalling. Here, we demonstrate that LUBAC and OTULIN dynamically regulate the energy-sensing kinase AMPK, a central sensor and switch for cellular and organismal energy balance. LUBAC's activity through the catalytic subunit HOIP is required for full AMPK activation in response to energetic stress, whereas OTULIN antagonises this response. LUBAC and OTULIN form a complex with AMPK, and LUBAC can directly ubiquitinate AMPKα and β subunits in cells and in vitro, establishing AMPK as a bona fide M1-linked ubiquitin substrate. Loss of LUBAC blunts AMPK activation, reduces bioenergetic adaptability, impairs autophagy, and sensitises cells to starvation-induced death, while Drosophila lacking Lubel - the fly orthologue of LUBAC - exhibit defective AMPK activation and reduced survival during starvation. Our findings identify M1-linked ubiquitination as a previously unrecognised regulatory layer controlling AMPK activation, metabolic adaptability, and the cellular response to energetic stress.
The poultry red mite, Dermanyssus gallinae, is a haematophagous ectoparasite causing significant economic losses in the commercial egg-laying sector. Blood meal digestion by D. gallinae is required for nutrient acquisition, with acidic lysosomal proteinases such as cathepsin L and cathepsin D playing a critical role in haemoglobin digestion. This study investigated the role of a cathepsin D-like aspartyl proteinase, Dg-CatD-1, in the haemoglobin digestion cascade. Haemoglobin processing was investigated by RNA interference (RNAi)-mediated silencing of Dg-CatD-1 and assessing the impact on haemoglobin digestion. RNAi-mediated knockdown of Dg-CatD-1 was achieved by feeding a target-specific double-stranded RNA (dsRNA) to D. gallinae in a blood meal. The minimum length and concentration of Dg-CatD-1 dsRNA for effective knockdown was determined. In addition, the effect of Dg-CatD-1 knockdown on mite digestive physiology, haemoglobin digestion, and egg-laying by adult female mites was assessed. Feeding Dg-CatD-1 dsRNAs via a blood meal to adult female D. gallinae mites resulted in a substantial knockdown of target gene expression. The minimum length and concentration of dsRNA required for effective Dg-CatD-1 knockdown were 25 base pairs (bp, at 200 ng/μl) (61% knockdown) and 25 ng/μl (at 485  bp) (42% knockdown), respectively. When Dg-CatD-1 dsRNA was delivered as a single feed it resulted in up to 91% reduction in Dg-CatD-1 expression, although no observable effect on blood digestion was observed. The phenotypic impact of Dg-CatD-1 knockdown was demonstrated following two consecutive rounds of Dg-CatD-1 dsRNA feeding where knockdown reduced the ability of mites to process and clear their blood meal relative to control non-specific dsRNA-fed mites. This work highlights the importance of Dg-CatD-1 as an essential enzyme in the haemoglobin digestion pathway of D. gallinae. These findings open avenues for the development of targeted control strategies aimed at disrupting the digestive processes of D. gallinae. Furthermore, this research suggests that reductions in gene expression via RNAi do not always lead to corresponding decreases in protein levels or observable phenotypes. Repeated exposure to dsRNA may be necessary to reveal phenotypic effects of gene knockdown.
Outcomes for pediatric acute myeloid leukemia (AML) have improved significantly in recent years. However, relapsed and refractory disease remains a significant problem. The chemotherapy burden experienced by these patients makes the translational development of non-genotoxic experimental therapies attractive. We previously reported that the anti-helminth drug mebendazole induces degradation of the transcription factor MYB and has potent anti-AML activity. In the present study, we use CRISPR drop-out screening to identify genes encoding the proapoptotic regulators BAK and NOXA as hits conferring resistance to mebendazole activity in AML cells. Conversely, targeting MCL1 with a BH3-mimetic significantly enhanced the anti-AML activity of mebendazole in both AML cell lines in vitro and pediatric patient-derived xenograft (PDX) AML cells ex vivo. Treatment of mice transplanted with THP-1 AML cells or aggressive infant PDX AML cells with this drug combination significantly impaired disease progression in vivo. Our data indicate that mebendazole-induced MYB degradation in combination with MCL1 targeting is a novel non-genotoxic therapeutic strategy for pediatric AML.