Background and Aims: Primary aldosteronism (PA) is the most common cause of secondary hypertension, affecting 5-10% of individuals with hypertension and up to 30% of those with resistant hypertension. Despite its excess cardiovascular, renal, and metabolic risk beyond blood pressure-matched essential hypertension, PA remains markedly underdiagnosed. Rural, regional, and remote (RRR) communities experience a disproportionate cardiovascular disease burden, yet barriers to equitable PA care in these settings are poorly understood. We aimed to synthesise evidence on barriers and enablers to PA screening, diagnosis, and management in RRR populations using an implementation science framework, and to identify and classify implementation strategies used in reported interventions.

Methods: We searched PubMed, MEDLINE, Embase, CINAHL, CENTRAL, and Scopus (1 January 2000 - 31 March 2026). Reported barriers and enablers were coded to the five domains of the updated Consolidated Framework for Implementation Research (CFIR): Innovation, Outer Setting, Inner Setting, Individuals, and the Implementation Process domains. Strategies proposed to improve PA care were classified using the Expert Recommendations for Implementing Change (ERIC).

Results : Of 1,142 records, eight studies met inclusion criteria; none specifically targeted RRR populations. Barriers were concentrated in the Individuals (clinician knowledge and decision-making, patient complexity), Inner Setting (limited specialist and laboratory access, professional isolation), and Innovation (multi-step pathway, test interpretation, medication switching) domains. Proposed strategies aligned with six ERIC implementation clusters: stakeholder education, clinician support, contextual adaptation, infrastructure enhancement, stakeholder partnerships, and consumer engagement.

Conclusion: PA detection in RRR settings is under-researched with substantial health equity implications. Barriers reflect a complex, multilevel interplay across patient, clinician, and health-system domains, with Inner Setting constructs (such as resource availability, professional networks) carrying particular weight for RRR populations. Although the 2025 Endocrine Society guideline recommends broad PA screening, implementation in RRR settings will require context-specific strategies that strengthen workforce capability and improve diagnostic access to reduce inequities in PA detection and management.

Background: Delirium is common during sepsis, and many survivors develop persistent cognitive impairment. Cerebral hypoxia, ischemia and edema are implicated, but whether intracranial hypertension contributes to sepsis-associated neurological injury remains unclear.

Aim: To determine the effects of sepsis and intravenous megadose sodium ascorbate on plasma and cerebrospinal fluid (CSF) ascorbate concentrations, intracranial pressure (ICP), cerebral perfusion pressure (CPP), frontal cortical tissue oxidative stress (Malondialdehyde (MDA) and a plasma biomarker of neurodegeneration (neurofilament light (Nfl)) in an ovine model of Gram-negative sepsis.

Methods: Adult Merino female sheep were surgically instrumented with lateral cerebral ventricular, carotid arterial and jugular venous catheters. Conscious sheep received intravenous live Escherichia coli for 31 h. After 23 h of sepsis, animals were randomised to intravenous sodium ascorbate (3 g/kg; n=7), administered as a bolus followed by a 7-h infusion, or fluid-matched placebo (n=7). Plasma and CSF ascorbate, ICP, CPP, frontal cortical tissue MDA and plasma NfL were assessed at pre-morbid baseline, and at 23 h of sepsis and following treatment.

Results: At 23 h of untreated sepsis, plasma and CSF ascorbate concentrations were reduced from baseline (16±0.3 to 10±0.2 and 144±4 to 104±2 µmol/L, respectively; both P<0.05). Sepsis was associated with increased ICP and plasma NfL and reduced CPP. By 31 h, sodium ascorbate markedly increased plasma and CSF ascorbate concentrations compared with placebo (to 14,332±154 vs 11±0.1 and 4,918±165 vs 84±3 µmol/L, respectively; both P<0.001). Sodium ascorbate reduced ICP (17.0±3.4 to 9.3±1.9 vs 20.6±3.7 to 19.3±5.0 mmHg; P=0.024) and increased CPP (61±11 to 75±5 vs 48±16 to 49±12 mmHg; P=0.046) compared with placebo. Sodium ascorbate also reduced frontal cortical tissue MDA (12±1 to 7±3 nmol/mg; P=0.008) and reduced plasma NfL compared with placebo (165±24 to 125±19 vs 150±23 to 162±35 pg/ml; P=0.047).

Conclusion: Sepsis was associated with systemic and cerebral ascorbate depletion, intracranial hypertension, impaired cerebral perfusion and evidence of neuronal injury. Intravenous megadose sodium ascorbate restored circulating and CSF ascorbate concentrations, reduced ICP, improved CPP and reduced markers of brain oxidative and neuronal injury. These findings support further investigation of sodium ascorbate as a therapeutic strategy targeting cerebrovascular dysfunction in sepsis.

Background: High-dose intravenous ascorbic acid has raised safety concerns in critical illness, including a higher incidence of persistent organ dysfunction. In contrast, megadose sodium ascorbate reverses sepsis-associated cardiovascular and renal dysfunction in ovine sepsis and early phase clinical trials without overt toxicity. Whether these divergent effects reflect formulation-specific renal pharmacology remains unknown.

Aim: To compare the renal effects of equimolar megadose sodium ascorbate and ascorbic acid in established Gram-negative sepsis, with particular focus on renal oxygenation, structural injury and oxalate crystallisation.

Methods: Thirteen adult Merino female sheep received live Escherichia coli for 31 h to establish sepsis. Following fluid resuscitation, noradrenaline was titrated to maintain mean arterial pressure at ~70 mmHg. Animals were randomised to equimolar intravenous sodium ascorbate (3.0 g/kg; n=6) or ascorbic acid (2.67 g/kg; n=7), administered as a loading dose followed by a 7-h infusion. Renal medullary oxygenation and perfusion were continuously monitored, with serial blood and urine sampling. Renal cortical and medullary injury and oxalate deposition were assessed histologically. In vitro calcium oxalate crystallisation was compared between formulations.

Results: Ascorbic acid worsened renal medullary hypoxia, whereas sodium ascorbate restored medullary oxygenation; renal medullary pO₂ at 31 h was 20.9 ± 5.6 versus 44.6 ± 6.0 mmHg, respectively (P=0.02). Creatinine clearance was markedly lower with ascorbic acid compared to sodium ascorbate (0.37 ± 0.08 versus 41.6 ± 16.9 mL/kg/min; P=0.03). Ascorbic acid was associated with more frequent acute tubular necrosis (71.4% versus 16.7%; P=0.02), with trends toward greater incidence of polymorphonuclear infiltration and tubular casts (both P=0.07). Oxalate crystals were detected exclusively following ascorbic acid treatment. In vitro, ascorbic acid promoted greater calcium oxalate monohydrate maturation relative to sodium ascorbate.
Conclusion. Equimolar megadose sodium ascorbate, unlike ascorbic acid, improved renal oxygenation and restored kidney function in established sepsis, with less structural injury and no detectable oxalate deposition. These findings identify formulation-dependent renal pharmacology and suggest that sodium ascorbate and ascorbic acid are not therapeutically interchangeable at pharmacological doses.

Background: Metabolic associated fatty liver disease (MAFLD) is associated with increased risk for cardiovascular (CV) and cardiometabolic disease. The exact mechanisms that link MAFLD to CV risk remain obscure. We hypothesized that activation of the sympathetic nervous system (SNS) and its downstream consequences such as systemic-inflammation, nocturnal hypertension, arterial stiffness may be key pathophysiological mechanisms of MAFLD.

Methods: We performed a pilot cross-sectional analysis of patients with MAFLD stratified by MRI proton density fat fraction (PDFF): Mild/Normal (<11%, n=7), Moderate (11–17%, n=6), Severe (>17%, n=13). Measurements included direct muscle sympathetic nerve activity (MSNA) via microneurography, hepatic steatosis severity quantification (MRI-PDFF), hemodynamic assessments (24-hour ambulatory blood pressure monitoring [ABPM], pulse wave analysis and velocity [PWA/PWV], metabolic markers (fasting glucose, fasting insulin [HOMA-IR], HbA1C) and relevant serum biomarkers [hsCRP, ALT, triglycerides, HLD, LDL]. Age-adjusted linear regression and Pearson coefficient analyzed associations across variables were performed.

Results: A total of 26 MAFLD patients (15 male,11 female; mean age 55.9±12.3 years; BMI 34.6±5.5 kg/m²) were analyzed. MSNA was elevated across the entire MAFLD cohort (25.8±10.2 bursts/min) independent of steatosis severity (p>0.70) yet significantly correlated with HbA1C 6.3±1.0% (r=0.581, p<0.05),whilst MRI-PDFF did not (r=−0.088, p =ns). Severe hepatic steatosis when compared to mild/normal group was associated with significant elevation in nocturnal DBP (71.7± 10.5 vs 65.4±9.8 mmHg, p=0.009), arterial stiffness (PWV: 8.72±1.32 vs 7.61±1.03 m/s, p=0.015), central DBP (85.9±16.0 vs76.6 ± 5.7mmHg, p=0.045) and heart rate (71.7±10.5 vs 64.1±9.6bpm, p=0.009). Abnormal dipping prevalence pattern trended higher across severity categories (28.6% to 58.8%). Serum biomarkers were elevated in the severe compared to mild/normal groups: ALT;37.0vs74.1U/L, p=0.024; hsCRP:1.53 vs 6.42mg/L, p=0.052; and TG:2.69±2.58 vs1.28±0.89 mmol/L, p=0.255; TG/HDL p=0.200 respectively.

Conclusion: The results suggest elevated SNS was evident across MAFLD cohort, independent of hepatic steatosis severity. Prognostic markers of CV disease (i.e. arterial stiffness, nocturnal hypertension, abnormal blood pressure dipping, and progressive heart rate elevation) increased across MAFD severity. Our findings indicate that metabolic disturbances may be the driver and underlie observed hemodynamic dysfunction in the MAFLD cohort. A large-scale prospective study is warranted to establish correlation between hepatic steatosis severity and SNS activation in patients with MALFD.