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Human neutrophil-derived extracellular vesicles induce renal endothelial inflammation in critical illness: an ex vivo investigation
No full textBackground
Circulating neutrophil-derived extracellular vesicles (NEVs) may contribute to the pathophysiology of acute kidney injury by causing glomerular endothelial inflammation.
Methods
NEVs were first isolated from ex vivo, lipopolysaccharide stimulation of whole blood taken from healthy volunteers (median age [interquartile range {IQR}]: 32 [26–42] yr; 47% female), and also from plasma of COVID-19 patients with acute respiratory distress syndrome (median age [IQR]: 59 [52–66] yr; 45% female). NEVs were incubated for 4 h in a co-culture of peripheral blood mononuclear cells and either human umbilical vein endothelial cells or renal glomerular endothelial cells. Enzyme-linked immunoassays (tumour necrosis factor-alpha [TNF]) and flow cytometry (median fluorescence intensity [MFI]) were used to quantify cell-specific markers of inflammation/activation, in the presence/absence of pharmacological inhibitors.
Results
NEVs were internalised by monocytes, leading to their activation via the p38 mitogen-activated protein kinase pathway and increased release of TNF (median [IQR]: 676 [474–1731] pg ml−1 after NEV internalisation, compared with controls (27 [18–29] pg ml−1, P=0.003). This proinflammatory response increased cell adhesion molecule expression (E-selectin) on human umbilical vein endothelial cells (median MFI [IQR]; NEVs: 4120 [3671–4858] vs untreated: 1438 [1252–1708], P=0.008) and human renal glomerular endothelial cells (median MFI [IQR]; NEVs: 2960 [2471–4991] vs untreated: 931 [881–1181], P=0.003). NEVs contained substantial amounts of matrix metalloproteinase-8 and -9, inhibitors of which (doxycycline, MMP-8 inhibitor or MMP-9 inhibitor) prevented endothelial cell inflammation.
Conclusions
Circulating NEVs may contribute to acute kidney injury through renal endothelial inflammation in a monocyte-dependent fashion in patients with acute respiratory distress syndrome
The case for optimal investment in combating HIV, tuberculosis, and malaria: a global modelling study
No full textBackground:
The Sustainable Development Goals (SDGs) include ending the epidemics of HIV, tuberculosis, and malaria by 2030. With 5 years remaining to meet this goal, and with the Global Fund to Fight AIDS, Tuberculosis and Malaria seeking funding for programmes in 2027–29, establishing what can be achieved through continued investment in combatting these diseases is crucial. We aimed to estimate the potential for impact by analysing the funding landscape and epidemiological situations of these three diseases, the costs of key programmes, and the extent of possible future progress in the countries eligible for Global Fund support.
Method:
In this modelling study, we developed estimates of the financial resources needed in Global Fund-supported countries to combat HIV, tuberculosis, and malaria from the global plans produced by UNAIDS, the Stop TB Partnership, and WHO. Estimates of available resources in the coming years were obtained by assuming that national expenditure on the three diseases would grow in line with general governmental expenditures, that the Global Fund would contribute an additional 140·6 billion in 2027–29. We calculated that 69·7 billion), the Global Fund (23·6 billion). Optimal use of these available resources could save 23 million lives and avert 400 million cases and new infections during 2027–29. The trajectory of the combined mortality rate for all diseases was projected to approach that needed to reach the SDG for 2030 (with a difference between the target in 2030 and the projection at the end of 2029 of between 1·5% and 15·5% of the normalised aggregated mortality rate), inequality in life expectancy between countries would be 7% lower by 2029, and 189 million fewer hospital days and 572 million fewer outpatient visits would be needed in 2027–29, saving 1·00 invested, there could be up to 3·50 in direct economic benefits.
Interpretation:
Continued investments to combat HIV, tuberculosis, and malaria could yield enormous health gains and a high return on investment. Realising these benefits will require continued growth in national expenditure and a broad maintenance of external financing for these diseases, including a successful replenishment of the Global Fund in 2025
Healthcare utilisation among low-income individuals affected by violence in Rio de Janeiro, Brazil: a retrospective cohort study
No full textBackground
Violence is associated with adverse health outcomes and affects healthcare utilisation, but there is limited robust evidence on this relationship in the context of violence in urban environments. This study examines subsequent patterns of healthcare utilisation by individuals who accessed healthcare as a result of experiencing violence in Rio de Janeiro, Brazil.
Methods
A retrospective cohort analysis was conducted on 529,219 low-income individuals from January 2010 to December 2016. Electronic medical records were screened for ICD-10 and primary care codes, and clinical free text identifying individuals who used healthcare due to violence. Control individuals (who did not use healthcare due to violence) were identified via coarsened exact matching. Logistic panel regression assessed the association between healthcare use due to violence and subsequent healthcare utilisation.
Results
2,038 individuals used healthcare due to violence. This group were 11% more likely (OR:1.11;95%CI:1.00–1.24;p < 0.05) to use PHC in the subsequent 1–3 months after initial healthcare use compared to those not using healthcare due to violence. They were 79% less likely (OR:0.21;95%CI:0.05–0.93;p < 0.05) to be Hospitalised at 7–12 months. Female users were 4.25 times (OR:4.25;95%CI:2.14–8.44;p < 0.001) and 2.57 times (OR:2.57;95%CI:1.20–5.53;p < 0.05) more likely to use PHC for poor pregnancy outcomes in the first 1–3 months and 7–12 months, respectively. PHC use for mental health increased by 50% (OR:1.50;95%CI:1.27–1.77;p < 0.005) in the subsequent 1–3 months after initial healthcare use.
Conclusions
Violence was associated with short-term increases in healthcare utilisation among low-income individuals in Rio de Janeiro, Brazil
Theory and modeling of large scale plasmapause surface waves
No full textThe plasmapause in Earth's magnetosphere represents the boundary between the plasma which co-rotates with the Earth (plasmasphere), and the more tenuous plasmatrough outside. The density change across the plasmapause can be large, changing by approximately 1–2 orders of magnitude depending on the prevailing conditions. This would suggest it to be a location where magnetohydrodynamic (MHD) surface waves can form, and indeed, this has been proposed in previous works to explain ultra-low frequency (ULF) wave observations around the plasmapause location. The main question is how such a large scale surface wave on the plasmapause would be excited. In this paper, we propose a model whereby surface waves at the plasmapause are driven by energy input from the magnetopause through solar wind driving. We derive an analytical form for the amplitude of these surface waves with this new driven boundary condition at the magnetopause. The excitation of these waves is then tested in several MHD simulations, where the model geometry, wavenumbers and temporal dependence of the magnetopause driver are varied. We establish that surface waves on the plasmapause can be excited by driving from the magnetopause, and that this still occurs with impulsive and continuous broadband driving. The azimuthal scale of the wave is a critical factor for this excitation, with longer azimuthal scales more favorable for driving larger amplitude surface waves. This mechanism provides new insight for how large scale and large amplitude ULF waves can access the inner magnetosphere, with potential implications for their interaction with radiation belt particles
An explicit direct method for transient stability analysis of multimachine power systems with nonzero transfer conductances
No full textWe propose an explicit analytical direct method for the transient stability analysis of multimachine power systems with nonzero transfer conductances (TCs). The proposed method addresses two issues. In the first issue, we study the transient stabilization of the entire power system through excitation control design. To this end, a globally well-defined Lyapunov function is constructed, and a locally well-defined dynamic passivity-based control law is proposed. The closed-loop equilibrium is therefore guaranteed to be locally asymptotically stable. In the second issue, we study the transient stability property of post-fault initial states. To this end, an optimization-based approach to calculate the critical level set of the proposed Lyapunov function is proposed. This allows to estimate an explicit region of attraction of the closed-loop equilibrium. Therefore, the transient stability property of a post-fault initial state can be directly assessed. A case study on the IEEE 10-machine 39-bus power system, to demonstrate the performance and effectiveness of the proposed direct method, is presented
Environmental lead risk in the 21st century
No full textLead has played a vital role in the technological development of human societies over centuries, but exposure to this toxic element following leakage into the environment poses significant risks to public health. This study assesses the contemporary environmental lead risk as global lead production and use are rapidly increasing driven largely by the rising demand for electrification. We show that the environmental lead exposure persists due to legacy contamination, ongoing coal usage, and insufficient protection of workforces during production, use, and recycling of lead-acid battery and other lead-containing products, particularly in low- and middle-income countries. We estimate that contemporary childhood lead exposure alone leads to an annual global economic loss exceeding $3.4 trillion (2021 US dollars adjusted for purchasing power parity), with pronounced disparities between high- and low- and middle-income countries. To prevent a large-scale resurgence in lead exposure, we identify four critical areas for policy intervention
Management of subglottic stenosis with the “Maddern procedure”: long term follow‐up outcomes
No full textObjective
Full-thickness resection and skin grafting of the laryngotracheal junction, the “Maddern Procedure,” can be used to treat patients with recalcitrant laryngotracheal stenosis. We report the long-term surgical outcomes of this procedure.
Methods
A consecutive series of 27 females with idiopathic, iatrogenic, or vasculitic subglottic stenosis who underwent the Maddern procedure between 2012 and 2023 were retrospectively reviewed. Airway outcome was assessed using the Modified Medical Research Council Dyspnea (mMRC) Scale. Secondary outcomes included voice, swallowing, mucus management, complications, and the need for subsequent airway surgery.
Results
Most patients had idiopathic subglottic stenosis (n = 20, 74.1%), followed by vasculitic (n = 4, 14.8%) and intubation-related (n = 3, 11.1%) etiologies. Patients had an average of 7.3 (SD 3.4) endoscopic procedures before undergoing the Maddern procedure. Mean pre-Maddern inter-treatment interval was 7.5 months (SD 3.4). The median follow-up was 6.6 years (interquartile range 0.75–11.3). The mMRC dyspnea scale improved from 2.7 (SD 0.73) to 0.52 (SD 0.85). The five-year recurrence-free rate was 63%. It differed between etiologies, ranging from 83% for idiopathic stenosis to 67% for intubation-related and 0% for vasculitis-related stenoses. During the first 4 years after Maddern, 67% of patients reported daily cough and the need to use nebulizers regularly.
Conclusion
The Maddern procedure is an effective and durable option for patients with idiopathic subglottic stenosis. Careful screening of patients with presumed idiopathic subglottic stenosis for possible underlying auto-immune conditions remains important when considering patients for this procedure.
Level of Evidence
Level 4
Plasma folate dynamics in Plasmodium falciparum-infected African children treated with artemisinin combination therapy and single low-dose primaquine or placebo
No full textBackground
Adding single low-dose (0.25 mg/kg) primaquine (SLDPQ) to block Plasmodium falciparum transmission is now a WHO recommendation. Whether SLDPQ increases haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) patients, leading to increased folate demand and impaired haemoglobin (Hb) recovery is unknown. This study sought to answer this question.
Methods
This randomized, placebo-controlled trial measured serial plasma folate concentrations [Day (D) 0, 3, 7 and 28] in falciparum-infected Ugandan and Congolese children (6 months to 11 years), treated with age-dosed SLDPQ/placebo and artemether-lumefantrine/dihydroartemisinin-piperaquine. Genotyping defined G6PD (G6PD c.202T allele) status. Multiple linear and non-linear, mixed effects, cubic spline regression were fitted to identify factors significantly associated with plasma folate at baseline and over time, respectively.
Results
408 children (3 had missing D0 values) had ≥ 1 plasma folate value. Of these, 66 (16.2%) were G6PD-deficient, 51 (12.5%) heterozygous females, 283 normal and 8 unknown. Mean baseline folate concentrations were 10.83 [standard deviation (SD) 3.58, SLDPQ] vs 10.92 (SD 4.54, placebo) ng/ml, associated independently with baseline Hb [estimate: 0.52 ng/ml (95% CI: 0.26 to 0.79, p = 0.0001)] and baseline parasitaemia [estimate: − 0.18 ng/ml (− 0.32 to − 0.05, p = 0.007)]. For all patients, mean plasma folate concentration paralleled mean haemoglobin concentration with an initial mean fall of 1.65 ng/ml (p < 0.0001 vs. baseline), followed by a sustained rise achieving a mean D28 concentration of 11.04 (SD 4.45) ng/ml. Over time, only age (p = 0.0001), male sex (p = 0.017) and baseline parasitaemia (p = 0.029) were significantly associated with a reduced plasma folate.
Conclusion
SLDPQ and G6PD status did not compromise posttreatment plasma folate concentrations in young children with acute uncomplicated falciparum malaria, providing additional evidence of SLDPQ safety and supporting its use without G6PD testing.
Trial registration The trial is registered, reference number ISRCTN1159443
Mitigating the impact of motor impairment on self-administered digital tests: A longitudinal cohort study in stroke
No full textBackground
Cognitive impairments are prevalent in many neurological disorders and remain underdiagnosed and poorly studied longitudinally. Unsupervised remote cognitive testing is an accessible, scalable, and cost-effective solution. However it often fails to separate cognitive deficits from commonly co-occurring motor impairments. To address this gap, we present a computational framework that isolates cognitive ability from motor impairment in self-administered digital tasks.
Methods
Stroke was chosen as a representative neurological disorder, as patients frequently experience both motor and cognitive impairments. Our validation analyses spanned 18 computerised tasks that were completed longitudinally by a cohort of stroke survivors (N = 171) collected as part of the IC3 study between 2022 and 2024, covering a broad spectrum of cognitive and motor domains across multiple timepoints within the first two years post-stroke. IC3 study was registered under NCT05885295 and IRAS:299333. The computational model was applied on trial-level data to disentangle the contribution of motor and cognitive processes. Bayesian Principal Component Analysis (PCA) was applied to the resultant data for dimensionality reduction purposes, while mixed effects regression models and multivariate canonical correlation analyses were used to assess the model's clinical utility.
Findings
In patients with motor hand impairment, standard accuracy performance metrics were confounded in 10 tasks (p 0.05, FDR-corrected). Moreover, the Modelled Cognitive metrics correlated more strongly with clinical pen-and-paper scales (mean R2 = 0.65 vs 0.43) and functional outcomes (mean R2 = 0.16 vs 0.09). Brain-behaviour associations were stronger when using the Modelled Cognitive metrics, and revealed intuitive multivariate relationships with individual tasks.
Interpretation
We present converging evidence for the improved clinical utility and validity of the Modelled Cognitive metrics within neurological conditions characterised by co-occurring motor and cognitive deficits. Addressing the confounding effects of motor impairment improves the reliability and biological validity of self-administered digital assessments, potentially enhancing accessibility and supporting early detection and intervention across neurological disorders.
Funding
This research is funded by the UK Medical Research Council (MR/T001402/1). Infrastructure support was provided by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care