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Diabetic Nephropathy: a Tangled Web to Unweave
Diabetic nephropathy (DN) is currently the leading cause of end-stage renal disease globally. Given the increasing incidence of diabetes, many experts hold the view that DN will eventually progress toward pandemic proportions. Whilst hyperglycaemia-induced vascular dysfunction is the primary initiating mechanism in DN, its progression is also driven by a heterogeneous set of pathological mechanisms, including oxidative stress, inflammation and fibrosis. Current treatment strategies for DN are targeted against the fundamental dysregulation of glycaemia and hypertension. Unfortunately, these standards of care can delay but do not prevent disease progression or the significant emotional, physical and financial costs associated with this disease. As such, there is a pressing need to develop novel therapeutics that are both effective and safe. Set against the genomic era, numerous potential target pathways in DN have been identified. However, the clinical translation of basic DN research has been met with a number of challenges. Moreover, the notion of DN as a purely vascular disease is outdated and it has become clear that DN is a multi-dimensional, multi-cellular condition. The review will highlight the current therapeutic approaches for DN and provide an insight into how the inherent complexity of DN is shaping the research pathways toward the development and clinical translation of novel therapeutic strategies.
Journal Article
A randomized trial of normothermic preservation in liver transplantation
Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here we show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.
Normothermic machine perfusion of the liver improved early graft function, demonstrated by reduced peak serum aspartate transaminase levels and early allograft dysfunction rates, and improved organ utilization and preservation times, although no differences were seen in graft or patient survival.
Journal Article
Reactive oxygen species signalling in the diabetic heart: emerging prospect for therapeutic targeting
Despite being first described 45 years ago, the existence of a distinct diabetic cardiomyopathy remains controversial. Nonetheless, it is widely accepted that the diabetic heart undergoes characteristic structural and functional changes in the absence of ischaemia and hypertension, which are independently linked to heart failure progression and are likely to underlie enhanced susceptibility to stress. A prominent feature is marked collagen accumulation linked with inflammation and extensive extracellular matrix changes, which appears to be the main factor underlying cardiac stiffness and subclinical diastolic dysfunction, estimated to occur in as many as 75% of optimally controlled diabetics. Whether this characteristic remodelling phenotype is primarily driven by microvascular dysfunction or alterations in cardiomyocyte metabolism remains unclear. Although hyperglycaemia regulates multiple pathways in the diabetic heart, increased reactive oxygen species (ROS) generation is thought to represent a central mechanism underlying associated adverse remodelling. Indeed, experimental and clinical diabetes are linked with oxidative stress which plays a key role in cardiomyopathy, while key processes underlying diabetic cardiac remodelling, such as inflammation, angiogenesis, cardiomyocyte hypertrophy and apoptosis, fibrosis and contractile dysfunction, are redox sensitive. This review will explore the relative contributions of the major ROS sources (dysfunctional nitric oxide synthase, mitochondria, xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidases) in the diabetic heart and the potential for therapeutic targeting of ROS signalling using novel pharmacological and non-pharmacological approaches to modify specific aspects of the remodelling phenotype in order to prevent and/or delay heart failure development and progression.
Journal Article
The High Latitude Ionospheric Response to the Major May 2024 Geomagnetic Storm: A Synoptic View
The high latitude ionospheric evolution of the May 10‐11, 2024, geomagnetic storm is investigated in terms of Total Electron Content and contextualized with Incoherent Scatter Radar and ionosonde observations. Substantial plasma lifting is observed within the initial Storm Enhanced Density plume with ionospheric peak heights increasing by 150–300 km, reaching levels of up to 630 km. Scintillation is observed within the cusp during the initial expansion phase of the storm, spreading across the auroral oval thereafter. Patch transport into the polar cap produces broad regions of scintillation that are rapidly cleared from the region after a strong Interplanetary Magnetic Field reversal at 2230UT. Strong heating and composition changes result in the complete absence of the F2‐layer on the eleventh, suffocating high latitude convection from dense plasma necessary for Tongue of Ionization and patch formation, ultimately resulting in a suppression of polar cap scintillation on the eleventh. Plain Language Summary The intense geomagnetic storm of May 2024 caused a plethora of different responses within the Earth's ionosphere. In the early phases of the storm, the auroral oval quickly expands to upper midlatitudes and induces strong variations in Global Navigation Satellite System (GNSS) phase measurements. Concurrently, midlatitude plasma is repeatedly lifted by 100–300 km on timescales of about an hour resulting in enhanced plasma densities. This intensified and lifted plasma is then drawn into the polar cap inducing variations in GNSS amplitude and phase. As the storm evolves, heating drives mixing of the thermosphere and causes an extreme depletion in ionospheric plasma. After 24 hr, despite severe geomagnetic conditions persisting, the depleted plasma environment results in only relatively weak plasma transport into the polar cap and significantly reduced impacts on GNSS. Key Points Plasma lifting during the storm caused midlatitude displacements of ionospheric peak height by as much as 300 km over the course of 1 hour Sporadic‐E is observed at the sub‐auroral convective boundary edge of the storm‐enhanced density with strong plasma drift shears present Severe depletion of electron density at mid and high latitudes significantly reduced the impact of subsequent geomagnetic activity on GNSS
Journal Article
Seroprevalence of SARS-CoV-2 antibodies in children: a prospective multicentre cohort study
BackgroundStudies based on molecular testing of oral/nasal swabs underestimate SARS-CoV-2 infection due to issues with test sensitivity, test timing and selection bias. The objective of this study was to report the presence of SARS-CoV-2 antibodies, consistent with previous infection.DesignThis multicentre observational cohort study, conducted between 16 April to 3 July 2020 at 5 UK sites, recruited children of healthcare workers, aged 2–15 years. Participants provided blood samples for SARS-CoV-2 antibody testing and data were gathered regarding unwell contacts and symptoms.Results1007 participants were enrolled, and 992 were included in the final analysis. The median age of participants was 10·1 years. There were 68 (6.9%) participants with positive SARS-CoV-2 antibody tests indicative of previous SARS-CoV-2 infection. Of these, 34/68 (50%) reported no symptoms prior to testing. The presence of antibodies and the mean antibody titre was not influenced by age. Following multivariable analysis four independent variables were identified as significantly associated with SARS-CoV-2 seropositivity: known infected household contact OR=10.9 (95% CI 6.1 to 19.6); fatigue OR=16.8 (95% CI 5.5 to 51.9); gastrointestinal symptoms OR=6.6 (95% CI 3.0 to 13.8); and changes in sense of smell or taste OR=10.0 (95% CI 2.4 to 11.4).DiscussionChildren demonstrated similar antibody titres in response to SARS-CoV-2 irrespective of age. Fatigue, gastrointestinal symptoms and changes in sense of smell or taste were the symptoms most strongly associated with SARS-CoV-2 antibody positivity.Trial registration number NCT0434740.
Journal Article
Proteomic-based biomarker discovery reveals panels of diagnostic biomarkers for early identification of heart failure subtypes
Background
Limited access to echocardiography can delay the diagnosis of suspected heart failure (HF), which in turn postpones the initiation of optimal guideline-directed medical therapy. Although natriuretic peptides like B-type natriuretic peptide (BNP) are valuable biomarkers for diagnosing and managing HF, the utility of combining BNP with other blood-based biomarkers to predict subtypes of new-onset HF remains underexplored.
Objectives
This study sought to investigate and evaluate the diagnostic significance of adding blood-based biomarkers to BNP for identifying heart failure with preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF), with the goal of enhancing diagnostic assays beyond BNP measurements.
Methods
We identified candidate blood protein biomarkers using untargeted proteomics workflows from a cohort of individuals recruited to the STOP-HF trial who were at risk of HF and subsequently developed either HFpEF or HFrEF over time (“HF progressors”; n = 40). Candidate biomarkers were verified in an independent cohort (n = 52) from a community-based rapid access HF diagnostic clinic. The biological processes associated with these proteins were assessed, and the diagnostic values of biomarker panels were evaluated using a machine learning approach.
Results
Within HF progressors, we identified 3 proteins associated with HFpEF development: vascular cell adhesion protein 1 (VCAM1), insulin-like growth factor 2 (IGF2), and inter-alpha-trypsin inhibitor heavy chain 3 (ITIH3). Additionally, 4 proteins were linked to HFrEF development: C-reactive protein (CRP), interleukin-6 receptor subunit beta (IL6RB), phosphatidylinositol-glycan-specific phospholipase D (PHLD), and noelin (NOE1). These findings were verified in an independent cohort to distinguish HF subtypes from controls. Moreover, a random forest algorithm demonstrated that combining these candidate biomarkers with BNP measurement significantly improved the prediction of HF subtypes.
Conclusions
We identified candidate proteins linked to HFpEF and HFrEF in a longitudinal HF progressor cohort and validated them in a community-based cohort. Adding these proteins to BNP led to a significant improvement in HF subtype prediction. Study results have clinical implications for blood-based screening of HF subtypes using panels of biomarkers, particularly in resource-limited settings.
Journal Article
Sacubitril/Valsartan attenuates progression of diabetic cardiomyopathy through immunomodulation properties: an opportunity to prevent progressive disease
Background and aims
Diabetic cardiomyopathy (DbCM) is recognised as a key mediator and determinant of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Improved understanding of mechanisms underlying transition from early-stage DbCM to HFpEF will inform innovative evidence-based treatment approaches, which are urgently required to alleviate increasing disease burden. This study aimed to determine whether inhibition of neprilysin activity by Sacubitril/Valsartan in both experimental and clinical DbCM attenuates adverse remodelling through promotion of cardioprotective signalling.
Methods and results
Sacubitril/Valsartan effectively reduced plasma neprilysin activity in both diabetic patients with pre-clinical HFpEF from the PARABLE trial (baseline (Val n = 25; Sac/Val n = 35) and 3 months after treatment (Val n = 21/25; Sac/Val n = 33/35)) and DbCM (high-fat diet and streptozotocin) mice. Plasma neprilysin activity at baseline was correlated with worsening cardiac performance at 18 months indicated by left atrial stiffness index in patients (n = 44/60), whilst diastolic dysfunction and pathological remodelling in DbCM mice were improved by Sacubitril/Valsartan, but not Valsartan. snRNA-sequencing showed that progressive experimental DbCM is characterised by chronic low-grade inflammation, reflected by increased infiltration of pro-inflammatory monocytes (Ccr2
+
Ly6c
hi
) and reduction in MHC-II macrophages, which was prevented by Sacubitril/Valsartan. Informatics analysis implicated
IRF7
as a central mediator of Sacubitril/Valsartan-induced immunomodulation in DbCM, whilst treatment of M2-like pro-repair macrophages with the neprilysin inhibitor, LBQ657 and Valsartan suppressed glucose-induced
IRF7
expression and paracrine activation of cardiac fibroblast differentiation in vitro.
Conclusion
Immune cells are significantly involved in DbCM progression, impacting myocardial homeostasis and HF progression. Neprilysin inhibition by Sacubitril/Valsartan improved adverse cardiac remodelling in experimental DbCM through direct regulation of inflammation, highlighting immunomodulation as a novel mechanism underlying established its cardioprotective actions.
Graphical abstract
Journal Article