Hypomethylated leptin receptor reduces cerebral ischaemia-reperfusion injury by activating the JAK2/STAT3 signalling pathway.

OBJECTIVE: To investigate the cerebroprotective effects of leptin in vitro and in vivo via the Janus kinase-2 (JAK2)/transcription factor signal transducer and activators of transcription-3 (STAT3) pathway and leptin receptors (LEPR). METHODS: The study used the cellular oxygen-glucose deprivation (OGD) model in PC12 cells and the middle cerebral artery occlusion (MCAO) rat model of cerebral ischaemia-reperfusion injury (CIRI) to assess changes in gene expression and protein levels following leptin pretreatment. The methylated DNA immunoprecipitation (MeDIP) assay measured DNA methylation levels. RESULTS: The optimal leptin concentration for exerting neuroprotective effects against ischaemia-reperfusion injury in PC12 cells was 200 ng/ml in vitro, but excessive leptin diminished this effect. Leptin pretreatment in the MCAO rat model demonstrated a similar effect to previously reported leptin administration post-CIRI. In addition to regulating the expression of inflammation-related cytokines, Western blot analysis showed that leptin pretreatment upregulated BCL-2 and downregulated caspase 3 levels. The MeDIP analysis demonstrated that DNA methylation regulated LEPR gene expression in the MCAO rat model when leptin pretreatment was used. CONCLUSION: Exogenous leptin might bind to extra-activated LEPR by reducing the methylation level of the LEPR gene promoter region, which leads to an increase in phosphorylated JAK2/STAT3 and apoptotic signalling pathways.

Atherosclerosis quantification and cardiovascular risk: the ISCHEMIA trial.

BACKGROUND AND AIMS: The aim of this study was to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA. METHODS: Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or myocardial infarction over a median follow-up of 3.3 (interquartile range 2.2-4.4) years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis. RESULTS: Analysable CCTA data were available from 3711 participants (mean age 64 years, 21% female, 79% multivessel coronary artery disease). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted hazard ratio 1.56, 95% confidence interval 1.25-1.97 per interquartile range increase [559 mm3]; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model's predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002). The findings were similar for the other reported outcomes. CONCLUSIONS: In ISCHEMIA, total plaque volume was associated with cardiovascular death or myocardial infarction. In this highly diseased, high-risk population, enhanced assessment of atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improved event prediction.

Ischaemic Colitis from an Unusual Cause: Oral Contraceptives.

Ischaemic colitis is responsible for more than half of the presentations of gastrointestinal ischaemia and develops due to an interruption of intestinal blood flow. Risk factors include increasing age and conditions associated with decreased perfusion. Infrequently, ischaemic colitis may develop in young females prescribed oral contraceptives. Here, we present a case of ischaemic colitis secondary to oral contraceptives that resolved with medication discontinuation. LEARNING POINTS: Ischaemic colitis is due to insufficiency of intestinal blood flow and is responsible for half of the cases of gastrointestinal ischaemia.Oral contraceptives have an increased odd of 1.05 predisposing development of ischaemic colitis.Symptoms typically resolve with removal of the oral contraceptive.

Major Adverse Limb Events in Patients Undergoing Revascularisation for Lower Limb Peripheral Arterial Disease: A Nationwide Observational Study☠.

OBJECTIVE: Major adverse limb events (MALEs) are frequent in patients with lower extremity peripheral arterial disease (PAD). However, routine care MALE rate estimations after revascularisation are scarce. This study aimed to determine post-procedural MALE rates in revascularised patients with PAD and identify predictors for post-procedural MALEs. METHODS: This was a population based observational study on merged national registry data. Patients with PAD undergoing lower limb revascularisation between 2008 and 2016 were retrieved from the Swedish National Registry for Vascular Surgery. Information on comorbidities, medications, and post-procedural MALE endpoints were identified in national healthcare registries. Primary outcomes of interest were categorised as 2 - 4 point MALE composites that included limb amputation, acute lower limb ischaemia, progression to or relapse of chronic limb threatening ischaemia (CLTI), and ipsilateral re-interventions regardless of indication. Patients with intermittent claudication (IC) and CLTI were analysed separately using Kaplan-Meier estimates. Stepwise Cox proportional hazard models were used for predictor candidate analysis. RESULTS: Overall, 28 021 revascularised patients with PAD were analysed (IC, n = 10 506, 37.5%; CLTI, n = 17 515, 62.5%). During a mean follow up ± standard deviation of 3.2 ± 2.4 years, 5 226 (18.7%), 9 423 (33.6%), and 12 696 (45.3%) patients experienced a 2, 3, and 4 point MALE, respectively. The estimated one year 4 point MALE rates were 21.4% (95% confidence interval [CI] 20.6 - 22.2%) in IC and 46.9% (95% CI 46.1 - 47.7%) in CLTI. Adjusted predictors for experiencing a 4 point MALE in IC were chronic kidney disease (CKD) (hazard ratio [HR] 1.33, 95% CI 1.12 - 1.59) and previous lower limb revascularisation (HR 1.29, 95% CI 1.19 - 1.40). In CLTI, previous contralateral lower limb amputation (HR 1.60, 95% CI 1.47 - 1.73) and CKD (HR 1.25, 95% CI 1.17 - 1.34) were adjusted predictors. CONCLUSION: This study emphasises the very high MALE rates in revascularised patients with lower limb PAD, especially in CLTI. Prior lower limb revascularisation correlated with increased MALE rates in IC patients, while prior lower limb amputation was linked to subsequent MALEs in CLTI. In both IC and CLTI, CKD was associated with poorer outcomes, regardless of applied MALE definition.

Short and Mid Term Outcomes of Percutaneous Deep Venous Arterialisation for No-option Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-Analysis.

OBJECTIVE: Percutaneous deep venous arterialisation (pDVA) is a state of the art technique for treating patients with chronic limb threatening ischaemia (CLTI) with no conventional option for revascularisation. There are limited large scale data examining the clinical effectiveness of pDVA for patients with end stage CLTI. DATA SOURCES: MEDLINE, Embase, Google Scholar, and Cochrane databases. REVIEW METHODS: Four databases were searched from January 2018 to June 2024 to identify studies investigating the feasibility and clinical outcomes of pDVA for patients with CLTI with no conventional revascularisation options. Meta-analysis of time to event outcomes (mean ± standard deviation) was performed for amputation free survival as the primary outcome, and freedom from amputation and overall survival as secondary outcomes. Other secondary outcomes (mean and 95% confidence interval [CI]) were procedural success rate, patency, re-intervention, and complete wound healing. RESULTS: Ten non-randomised studies were included with 351 patients. Mean patient age was 70.3 years, and 67.6% were male. Most procedures utilised the posterior tibial artery. The aggregated rate of amputation free survival at six and 12 months (five studies, 260 patients) was 72.6 ± 2.8% and 66.0 ± 3.1%, respectively, while the overall survival at six and 12 months (five studies, 260 patients) was 85.0 ± 2.3% and 77.7 ± 2.9%, respectively. The procedural success rate (nine studies, 330 patients) was 95.5% (95% CI 92.4 - 98.7%). Primary and secondary patency at six months (four studies, 241 patients) was 23.4% (95% CI 13.6 - 33.2%) and 54.9% (95% CI 34.3 - 75.5%), respectively. The rates of re-intervention (four studies, 190 patients) and complete wound healing (seven studies, 266 patients) at six and 12 months were 15.5% (95% CI 1.4 - 29.6%) and 41.7% (95% CI 25.7 - 57.7%), respectively, for re-intervention, and 19.3% (95% CI 9.6 - 29.0%) and 46.0% (95% CI 31.7 - 60.3%) for wound healing. CONCLUSION: This meta-analysis demonstrated acceptable feasibility for no-option CLTI at highly specialised institutions for patients undergoing pDVA. Meta-analysis of time to event outcomes revealed that pDVA provides reasonable amputation free survival for up to 12 months, albeit with a overall low certainty of evidence. Wider adoption of pDVA may be considered in selective patients with CLTI, although its clinical impact and cost effectiveness require further evaluation.

Systematic Review of Outcome Reporting for Interventions to Treat Patients with Acute Lower Limb Ischaemia.

OBJECTIVE: Inconsistencies in outcome data of therapeutic strategies for acute lower limb ischaemia (ALI) have hindered the synthesis of findings. A core outcome set (COS) may offer a solution to this problem by defining a minimum set of outcomes that are considered essential to all stakeholders involved. The first step in developing a COS is to review the previously reported outcomes on various treatment strategies for ALI. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases were searched from inception to August 2023. REVIEW METHODS: This systematic review was conducted in accordance with the Core Outcome Measures in Effectiveness Trials (COMET) initiative framework, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and was pre-registered with PROSPERO (CRD42022320073). Abstracts were independently screened by two authors for full text review. All outcomes and their definitions were extracted from selected papers. Outcomes with different terminologies were then categorised into an "agreed outcome term". The list of agreed outcomes was given a standardised outcome domain and core area using a 38 item standardised taxonomy. RESULTS: Of 6 184 articles identified, 176 relevant studies were included, yielding 1 325 verbatim outcomes. After deduplication, 72 unique verbatim outcomes were categorised into five broad outcome domains. Outcomes considered key to the evaluation of treatment of ALI were further categorised as delivery of care (19.4%), vascular outcomes (13.8%), and adverse events (12.5%). The three most frequently reported agreed outcomes were amputation (14.1%), mortality (12.3%), and general bleeding (11.6%). CONCLUSION: This systematic review provides an overview of currently reported outcomes in the literature of interventions for ALI. After categorisation into agreed outcome terms, 72 outcomes were identified that can be used in the development of a COS.

Plasma exchange and intravenous immunoglobulin for the peri-operative management of type 2 heparin-induced thrombocytopaenia in a patient requiring urgent surgery for critical limb ischaemia.

We report the case of a 61-year-old female who developed heparin-induced thrombocytopaenia following treatment of a submassive pulmonary embolism, and who then required an above knee amputation for critical limb ischaemia. Heparin-induced thrombocytopaenia is a rare, immune-mediated complication associated with an in-hospital mortality rate of 10%. It is more common in surgical patients, with patients undergoing orthopaedic surgery more likely to develop it than patients undergoing cardiac surgery, but heparin-dependent immunoglobulin G antibodies are more likely to be formed in the latter. Peri-operative management remains a challenge. Ideally, it is preferable to wait for the platelet count to improve; but in certain cases, surgery cannot be delayed. Heparin-induced thrombocytopaenia is usually managed with direct thrombin inhibitors, such as argatroban and bivalirudin. Newer therapeutic modalities, such as plasmapheresis and intravenous immunoglobulin, as used in this case, can rapidly remove antibodies, but the certainty of evidence is low. Our case adds to the literature regarding the use of these modalities and highlights the multidisciplinary team approach required to manage such complex cases.

Assessment of the Ischaemic Effects of Myocardial Bridge by Echocardiographic Exercise Stress Test.

Background: Detection of myocardial bridge (MB) at angiography suggests it has a role in ischaemic-related symptoms in patients with angina without obstructive coronary artery disease. However, evidence that MB may cause myocardial ischaemia is limited. Methods: We studied 41 patients with MB of the left anterior descending coronary artery and otherwise normal coronary arteries. Fourteen patients with normal coronary arteries and without MB served as controls. All subjects underwent a maximal treadmill exercise stress test (EST) under ECG monitoring. Standard and speckle-tracking echocardiography were performed at baseline and immediately after peak EST. Results: EST duration and peak heart rate and systolic pressure were similar in the two groups. A positive EST (ST-segment depression .1 mm) was found in 18 patients in the MB group (43.9%) and none in the control group (p=0.001). No abnormalities in both left ventricle systolic and diastolic function were found between the two groups in the standard echocardiographic evaluation. Global and segmental (anterior, inferior) longitudinal strain (LS) did not differ at baseline between the groups. There was a small increase in global LS during EST in MB patients but not in the control group (p=0.01). Similar trends were found for regional LSs, with differences being significant for the medium (p=0.028) and apical (p=0.032) anterior segments. No differences in echocardiographic parameters and both global and segmental LSs were observed between MB patients with ischaemic ECG changes during EST versus those without. Conclusion: Our findings do not support the notion that MB results in significant degrees of myocardial ischaemia during maximal myocardial work.

Examining Psychological Factors in Peripheral Artery Disease: Affective Temperament, Anxiety, and Depression in Patients Undergoing Revascularization Procedures.

Purpose: This study aimed to assess the prevalence of depressive and anxiety symptoms in peripheral artery disease (PAD) patients, correlating these symptoms with clinical parameters and examining affective temperaments within the study group. Material and Methods: A total of 159 PAD patients, predominantly male, admitted for vascular surgery due to lower limb atherosclerosis, participated in this cross-sectional study. Various assessments were conducted, including the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A) for affective temperaments, the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression symptoms, and the Numerical Rating Scale (NRS) for pain intensity. Additionally, the Ankle-Brachial Index (ABI) was measured to assess circulation in the legs. Results: The findings revealed a higher prevalence of depressive and anxiety symptoms in the PAD patient group compared to the control group. Notably, depressive and anxiety symptoms correlated with the severity of PAD, as indicated by lower ABI values in the operated leg. Patients undergoing surgical revascularizations exhibited higher depressive symptoms than those undergoing endovascular procedures. Furthermore, correlations were observed between depressive symptoms and the number of previous vascular procedures and amputations, alongside increased pain levels at admission. Clinical factors such as diabetes, hypertension, heart failure, ischemic heart disease, previous revascularization procedures, amputations, and the intensity of affective temperaments did not correlate with HADS scores. Discussion: The study highlighted the intricate relationship between mood disorders and PAD severity, emphasizing the potential prognostic implications of untreated depression and anxiety in PAD patients. These findings suggest the importance of closely monitoring and addressing psychological well-being in PAD management. However, the study encountered limitations such as varying assessment timing and sample size discrepancies among comorbidities, impacting the observation of associations between mood disorders and certain conditions. Conclusion: In conclusion, depressive and anxiety symptoms are often in PAD. Further research is needed to explore therapeutic interventions targeting mental health and pain management to improve the course and outcomes of PAD.

Heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation.

AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies. METHODS: Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography. RESULTS: Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl3. Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion. CONCLUSIONS/INTERPRETATION: These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR.

Metastatic testicular seminoma presenting as acute lower limb ischaemia.

We describe a unique presentation of acute lower limb ischaemia due to metastatic seminoma in a middle-aged man with a large retroperitoneal mass. The patient underwent vascular bypass surgery of the right lower limb, completed chemotherapy, and had a right scrotal orchiectomy. The patient had pre-existing vascular risk factors including peripheral vascular disease and smoking. To our knowledge this is the first published case in the literature that has described a large retroperitoneal seminoma compressing the abdominal aorta resulting in acute lower limb ischaemia.

Cardiovascular diseases as risk factors of post-COVID syndrome: a systematic review.

BACKGROUND: A growing proportion of people experience incomplete recovery months after contracting coronavirus disease 2019 (COVID-19). These COVID-19 survivors develop a condition known as post-COVID syndrome (PCS), where COVID-19 symptoms persist for > 12 weeks after acute infection. Limited studies have investigated PCS risk factors that notably include pre-existing cardiovascular diseases (CVD), which should be examined considering the most recent PCS data. This review aims to identify CVD as a risk factor for PCS development in COVID-19 survivors. METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) checklist, systematic literature searches were performed in the PubMed, Scopus, and Web of Science databases from the earliest date available to June 2023. Data from observational studies in English that described the association between CVD and PCS in adults (≥ 18 years old) were included. A minimum of two authors independently performed the screening, study selection, data extraction, data synthesis, and quality assessment (Newcastle-Ottawa Scale). The protocol of this review was registered under PROSPERO (ID: CRD42023440834). RESULTS: In total, 594 studies were screened after duplicates and non-original articles had been removed. Of the 11 included studies, CVD including hypertension (six studies), heart failure (three studies), and others (two studies) were significantly associated with PCS development with different factors considered. The included studies were of moderate to high methodological quality. CONCLUSION: Our review highlighted that COVID-19 survivors with pre-existing CVD have a significantly greater risk of developing PCS symptomology than survivors without pre-existing CVD. As heart failure, hypertension and other CVD are associated with a higher risk of developing PCS, comprehensive screening and thorough examinations are essential to minimise the impact of PCS and improve patients' disease progression.

Effectiveness of a Glyceryl Trinitrate (GTN) Patch in Preventing Amputation, Improving Pain Control and Reducing the Size of Tissue Loss for a Patient With Critical Limb-Threatening Ischaemia (CLTI).

Background  Foot ulcer is a common complication of poorly controlled diabetes and peripheral vascular disease (PVD). The current standard of treatment for diabetic foot ulcers includes the management of underlying risk factors, wound debridement, use of antibiotics for infection, off-loading with cast, and revascularisation surgery. The glyceryl trinitrate (GTN) patch is currently off-licence in treating PVD or diabetic foot ulcers. This study aims to evaluate the effectiveness of the GTN patch in preventing amputation, improving pain control, and reducing the size of tissue loss (ulcer/gangrene) or localised ischaemic area. Method This is a pilot study of 30 patients who were started on the GTN patch from February 2020 to October 2021. Inclusion criteria were patients who have critical limb-threatening ischaemia (CLTI) and with no viable options or are at high risk for revascularisation, both endovascular and open surgery. Patients who were on a GTN patch for less than six weeks at the time of data collection or had unclear outcomes were excluded. The outcomes were retrospectively collected on prevention of amputation, improvement in pain control, and reduction in tissue loss (the size of ulcer/gangrene) or localised ischaemic area with the use of a GTN patch. The binomial test was used to compare the observed outcome of the GTN patch and the expected outcome, which was assumed to be 50% in this study. Results  Ninety-three per cent (93%) of the patients who had GTN patches successfully avoided amputation (p<0.0001). Eighty-four per cent (84%) of patients reported better pain control (p=0.0022) and improvement in the size of ulcer/gangrene/localised ischaemic areas (p=0.0005). Conclusion The GTN patch is effective in preventing amputation, improving pain control, and reducing the size of ulcer/gangrene/localised ischaemic areas in patients who have end-stage CLTI and no viable options or who are at high risk for revascularisation surgery.

Reversal of cerebral ischaemia and hypoxia and of sickness behaviour by megadose sodium ascorbate in ovine Gram-negative sepsis.

BACKGROUND: The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis. METHODS: Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg-1 over 30 min+0.5 g kg-1 h-1 for 6.5 h) or vehicle (n=6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70-80 mm Hg. RESULTS: At 23 h of sepsis, MAP (mean [sem]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] µM) decreased (both P<0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P<0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all PTreatment<0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both PGroupxTime<0.01), and increased plasma ascorbate (20 000 [300] µM; PGroup<0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate. CONCLUSIONS: Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load.

Hydrogen alleviates hypoxic-ischaemic brain damage in neonatal rats by inhibiting injury of brain pericytes.

Hypoxia-ischaemia (HI) can induce the death of cerebrovascular constituent cells through oxidative stress. Hydrogen is a powerful antioxidant which can activate the antioxidant system. A hypoxia-ischaemia brain damage (HIBD) model was established in 7-day-old SD rats. Rats were treated with different doses of hydrogen-rich water (HRW), and brain pericyte oxidative stress damage, cerebrovascular function and brain tissue damage were assessed. Meanwhile, in vitro-cultured pericytes were subjected to oxygen-glucose deprivation and treated with different concentrations of HRW. Oxidative injury was measured and the molecular mechanism of how HRW alleviated oxidative injury of pericytes was also examined. The results showed that HRW significantly attenuated HI-induced oxidative stress in the brain pericytes of neonatal rats, partly through the Nrf2-HO-1 pathway, further improving cerebrovascular function and reducing brain injury and dysfunction. Furthermore, HRW is superior to a single-cell death inhibitor for apoptosis, ferroptosis, parthanatos, necroptosis and autophagy and can better inhibit HI-induced pericyte death. The liver and kidney functions of rats were not affected by present used HRW dose. This study elucidates the role and mechanism of hydrogen in treating HIBD from the perspective of pericytes, providing new theoretical evidence and mechanistic references for the clinical application of hydrogen in neonatal HIE.

Implementation of an optimised tele-medicine platform for stroke in South Australia improves patient care.

Background: Patients with a large vessel occlusion require a transfer from a primary stroke centre to access thrombectomy, often over significant distances in regional areas. We sought to optimise stroke care access in the regional South Australian Tele-Strokeservice (SATS) to improve patient access to thrombectomy. Methods: We undertook a 24-month interventional historically controlled cohort study comparing acute stroke care metrics in the SATS. This consisted of a 12-month control period and a 12-month intervention monitoring period. The study intervention considered of an education package provided to the regional hospitals, a stroke neurologist roster to receive consultations and the intervention of a centralised tele-stroke system to provide treatment advice and organise patient transfers where needed. The SATS services 61 rural hospitals in South Australia, and Alice Springs in the Northern Territory. Suspected acute stroke patients presenting to the participating regional hospitals in SATS network where a telehealth consultation took place. Results: Over the study period, there were 919 patient referrals, with 449 consultations in the pre-intervention phase and 470 in the post-intervention phase. Demographic features in both epochs were similar. The post-intervention phase was associated with shorter door-to-scan time (35 min, IQR: 18,70; vs. 49 min, IQR:25,102, p < 0.0001), faster door-to-thrombolysis time (58 min, IQR: 39,91, vs.83 min, IQR: 55,100, p = 0.0324) and a higher portion of patients treated with thrombectomy (54, 11.5% vs. 26, 5.8%, p = 0.002). Conclusion: An optimised implementation of a streamlined telehealth platform with ongoing education and feedback to referring sites was associated with improved stroke workflow metrics and higher thrombectomy rates.

Antimicrobial resistance is not increasing in subsequent cases of ischaemic foot infections, a single-centre cohort from 2012 to 2021.

Patients with chronic limb-threatening ischaemia (CLTI) are at risk of foot infections, which is associated with an increase in amputation rates. The use of antibiotics may lead to a higher incidence of antimicrobial resistance (AMR) in subsequent episodes of ischaemic foot infections (IFI). This retrospective single-centre cohort study included 130 patients with IFI undergoing endovascular revascularisation. Staphylococcus aureus and Pseudomonas aeruginosa were the two most common pathogens, accounting for 20.5% and 10.8% of cases, respectively. The prevalence of antimicrobial resistance (AMR) and multi-drug resistance did not significantly increase between episodes (10.2% vs. 13.4%, p = 0.42). In 59% of subsequent episodes, the identified pathogens were unrelated to the previous episode. However, the partial concordance of identified pathogens significantly increased to 66.7% when S. aureus was identified (p = 0.027). Subsequent episodes of IFI in the same patient are likely to differ in causative pathogens. However, in the case of S. aureus, the risk of reinfection, particularly with S. aureus, is increased. Multi-drug resistance does not appear to change between IFI episodes. Therefore, recommendations for empirical antimicrobial therapy should be based on local pathogen and resistance statistics without the need to broaden the spectrum of antibiotics in subsequent episodes.

Achieving trifecta outcomes in robotic-assisted partial nephrectomy within a fellowship training centre.

To assess the robotic-assisted partial nephrectomy (RAPN) trifecta rate within a fellowship program. Patients undergoing RAPN 01/01/2010-01/07/2023 were enrolled from a prospectively maintained database. All cases were performed jointly with surgical fellows, except when privately insured. Patients were excluded if they were converted to open or radical nephrectomy. The primary outcome was achieving the 'trifecta' of negative surgical margins, no complications < 30 days post-operatively and warm ischaemia time (WIT) < 25 min. The secondary outcomes were factors associated with trifecta success. Ethics approval was obtained. In the enrolment period, 355 patients underwent intended RAPN, of whom seven were excluded due to conversion to conversion to radical nephrectomy (6 patients) or conversion to open (one). Amongst the 348 eligible patients, median age was 60 years, 115 (33%) were female and 19 were private patients. WIT was < 25 min for 324/337 patients (96%), surgical margins were negative in 325 (93%), 294 (84%) were complication-free at 30 days and 301/320 (94%) had a < 30% decline in estimated glomerular filtration rate at 3-6 months postoperatively. Subsequently, trifecta outcomes were achieved in 253/337 (75%) patients. Comparing with patients without those with trifecta success were similar in all thirteen measured patients and tumour factors. In a teaching hospital, with a fellowship training programme, trifecta outcome is achievable for most RAPN patients, and at a rate comparable to international standards. Fellowship centres should monitor their outcomes to ensure high patient outcomes are maintained alongside training requirements.

Biomarkers In Prediction of Acute Mesenteric Ischaemia: a prospective multicentre study (BIPAMI study): a study protocol.

BACKGROUND: Acute mesenteric ischaemia (AMI) is a life-threatening disease where early diagnosis is critical to avoid morbidity and mortality from extensive irreversible bowel necrosis. Appropriate prediction of presence of bowel necrosis is currently not available but would help to choose the optimal method of treatment. The study aims to identify combinations of biomarkers that can reliably identify AMI and distinguish between potentially reversible and irreversible bowel ischaemia. METHODS: This is a prospective multicentre study. Adult patients with clinical suspicion of AMI (n = 250) will be included. Blood will be sampled on admission, at and after interventions, or during the first 48 h of suspicion of AMI if no intervention undertaken. Samples will be collected and the following serum or plasma biomarkers measured at Tartu University Hospital laboratory: intestinal fatty acid-binding protein (I-FABP), alpha-glutathione S-transferase (Alpha- GST), interleukin 6 (IL-6), procalcitonin (PCT), ischaemia-modified albumin (IMA), D-lactate, D-dimer, signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1) and lipopolysaccharide-binding protein (LBP). Additionally, more common laboratory markers will be measured in routine clinical practice at study sites. Diagnosis of AMI will be confirmed by computed tomography angiography, surgery, endoscopy or autopsy. Student's t or Wilcoxon rank tests will be used for comparisons between transmural vs. suspected (but not confirmed) AMI (comparison A), confirmed AMI of any stage vs suspected AMI (comparison B) and non-transmural AMI vs transmural AMI (comparison C). Optimal cut-off values for each comparison will be identified based on the AUROC analysis and likelihood ratios calculated. Positive likelihood ratio > 10 (> 5) and negative likelihood ratio < 0.1 (< 0.2) indicate high (moderate) diagnostic accuracy, respectively. All biomarkers with at least moderate accuracy will be entered as binary covariates (using the best cutoffs) into the multivariable stepwise regression analysis to identify the best combination of biomarkers for all comparisons separately. The best models for each comparison will be used to construct a practical score to distinguish between no AMI, non-transmural AMI and transmural AMI. DISCUSSION: As a result of this study, we aim to propose a score including set of biomarkers that can be used for diagnosis and decision-making in patients with suspected AMI. TRIAL REGISTRATION: NCT06212921 (Registration Date 19-01-2024).

Recombinant Human Hepatocyte Growth Factor Plasmids for Treating Patients with Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-analysis.

OBJECTIVE: Recombinant human hepatocyte growth factor (HGF) plasmids are novel alternatives to salvage limbs in patients with chronic limb threatening ischaemia (CLTI). A systematic review and meta-analysis of data were conducted to assess the therapeutic efficacy of HGF plasmids in patients with CLTI. DATA SOURCES: Randomised controlled studies evaluating HGF plasmid efficacy in patients with CLTI were identified using Medline, Embase, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov databases. REVIEW METHODS: Meta-analyses of the reported relative risks (RR) or mean differences (MD) were conducted. Subgroup analyses determined the efficacy of HGF plasmids in cohorts excluding Buerger's disease. Certainty of evidence for each outcome was assessed. RESULTS: Seven studies (n = 655) were included. Based on low certainty evidence, patients treated with HGF had a significantly higher complete ulcer healing rate (RR 1.99, 95% CI 1.30 - 3.04; p = .015) than patients treated with placebo. The HGF treatment was associated with reduced visual analogue scale (VAS) scores of pain severity (MD -1.56, 95% CI -2.12 - -1.00; p < .001) vs. placebo in patients with CLTI assessed at the 3 month follow up (low certainty evidence); no significant differences were observed in major amputation (RR 0.91, 95% CI 0.48 - 1.73; p = .77) (low certainty evidence), or all-cause mortality (RR 0.93, 95% CI 0.38 - 2.27; p = .87) (low certainty evidence) between patients treated with HGF and placebo. Low certainty evidence suggested no significant differences in change in ankle-brachial index at 6 months (MD 0.00, 95% CI -0.09 - 0.09; p = 1.0) between patients treated with HGF and placebo. The complete ulcer healing rate and improved 3 month VAS scores of pain severity benefits persisted in subgroup analyses (low certainty evidence). CONCLUSION: Hepatocyte growth factor treatment is associated with an increased complete ulcer healing rate and reduced ischaemic pain in patients with CLTI.