Resistant and uncontrolled hypertension remain major unmet needs, with aldosterone dysregulation or frank excess increasingly recognized as a central driver. To this end, aldosterone synthase inhibitors (ASIs) represent a novel therapeutic approach targeting CYP11B2, the key enzyme responsible for aldosterone biosynthesis. By reducing aldosterone production at its source, ASIs may overcome limitations associated with conventional renin-angiotensin-aldosterone system (RAAS) blockade and attenuate both genomic and non-genomic effects of aldosterone. Advances in drug development have led to second-generation ASIs, including baxdrostat, lorundrostat, dexfadrostat, and vicadrostat, characterized by high selectivity for CYP11B2 over CYP11B1, thereby preserving cortisol synthesis. Clinical trials across phases I-III demonstrate that second-generation ASIs, including baxdrostat, lorundrostat, dexfadrostat, and vicadrostat, effectively lower aldosterone levels and produce substantial blood pressure reductions, particularly in resistant or uncontrolled hypertension. ASIs are generally well tolerated. Hyperkalemia is the most common adverse event, particularly in patients with chronic kidney disease, but is typically manageable and appears less frequent than with mineralocorticoid receptor antagonists in comparable populations. No clinically significant suppression of the hypothalamic-pituitary-adrenal axis has been observed with second-generation compounds. These findings support ASIs as a promising addition to the therapeutic armamentarium for hypertension. The recent FDA approval of baxdrostat, the first second-generation ASI, represents an important milestone for this therapeutic class. However, further studies are required to establish long-term safety, optimal patient selection, and their role in combination therapies and cardiovascular risk reduction.

Aldosterone dysregulation is a key driver of difficult-to-control and resistant hypertension. Mineralocorticoid receptor antagonists (MRAs) target the aldosterone pathway but their use can be limited by side effects, particularly hyperkalemia and antiandrogenic hormonal effects. Selective aldosterone synthase inhibitors (ASIs) have shown clinically meaningful blood pressure reductions in patients with difficult-to-control and resistant hypertension in recent phase 2b and 3 trials. In this narrative review, we summarize pivotal evidence from phase 2b and phase 3 trials of the second-generation ASIs lorundrostat, baxdrostat, and dexfadrostat, reporting efficacy and core safety signals (hyperkalemia, hyponatremia, and an early functional reduction in estimated glomerular filtration rate (eGFR]). We further discuss the implications of these findings, economic and access considerations, remaining evidence gaps, future research directions, and potential practical treatment algorithms. ASIs offer clinically significant blood pressure lowering with moderate side effects when added on top of current therapies in short-term trials, though long-term outcome data are lacking. In May 2026, the US Food and Drug Administration (FDA) approved the first ASI, baxdrostat, for hypertension treatment in combination with other antihypertensive drugs in inadequately controlled adults. However, gaps remain, most notably the absence of comparative effectiveness trials versus MRAs, the standard fourth-line agent. ASIs target upstream aldosterone production and may offer a distinct, complementary role for patients with intolerance or contraindications for MRA or insufficient response. ASIs may be best reserved for the treatment of uncontrolled or resistant hypertension in combination with other antihypertensives and where MRAs are contraindicated, poorly tolerated, or insufficient.

Novel therapeutic agents are required to improve hypertension control globally, which remains one of the leading modifiable risk factors for premature cardiovascular mortality. Aldosterone synthase inhibitors (ASIs) are a novel class of agents that suppress aldosterone production and have demonstrated clinically meaningful blood pressure reductions in phase 2 and phase 3 trials in patients with uncontrolled and resistant hypertension. As these therapies approach clinical adoption, important questions remain regarding effects on cardiovascular and kidney outcomes, safety profile, and optimal positioning within existing treatment algorithms. This review synthesizes the current clinical evidence for ASIs, highlights key knowledge gaps, and examines practical considerations for their real-world implementation, including persistent pharmacodynamic effects after treatment withdrawal, short-term changes in glomerular filtration rate, the risk of hyperkalemia, and the potential role of multidisciplinary care models to support safe and effective adoption.

Chronic kidney disease (CKD) is highly prevalent globally and affects approximately 1 in 10 adults, with a prevalence of 10% globally and ∼14.4% in North America. High blood pressure (BP) is one of the most common causes for the development of CKD. Conversely, hypertension occurs more frequently in patients with CKD and is found to be uncontrolled in 60%-80% of these patients. The rates of resistant hypertension are amongst the highest for any patient population, with estimates ranging between 40% and 50%. Deteriorating renal function is associated with increasing risk for co-morbid conditions including cardiac disease and stroke. Appropriate management of hypertension is important in patients with CKD but poses frequent challenges in clinical care with the need to balance the desired BP lowering and ideally reno-protective effects against increased risks for nephrotoxicity and medication side effects. Established therapeutic principles in the context of CKD include renin-angiotensin-aldosterone system (RAAS) blockade using either ACE inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose transport 2 (SGLT-2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (nsMRAs), and glucagon-like-peptide-1 (GLP-1) agonists. Aldosterone dysregulation is emerging as another key driver of persistently uncontrolled BP and deteriorating kidney function, not only through the associated sodium and fluid retention but also through BP-independent effects on endothelial function, inflammatory pathways, tissue fibrosis, and hypertrophic responses. The new drug class of aldosterone synthase inhibitors (ASIs), highly selective agents inhibiting CYP11B2 and thereby reducing circulating aldosterone levels, may offer a novel opportunity to effectively lower BP and reduce organ damage mediated by dysregulated aldosterone. Indeed, recently published data from phase 3 randomized controlled hypertension trials with various ASIs have demonstrated substantial office and ambulatory BP lowering efficacy with an acceptable safety profile. A reduction in albuminuria in early phase 2 trials in patients with hypertension and CKD may indicate reno-protective properties of ASIs. Dedicated outcome trials are ongoing to explore these prospects in detail.

Konjac glucomannan is a natural polysaccharide increasingly relevant as a matrix forming material for skin applied delivery systems. Its potential is linked to its glucose and mannose backbone, abundant hydroxyl groups, partial acetyl substitution, high molecular weight, and capacity for chain association. These features regulate hydration, swelling, rheology, viscoelasticity, film formation, gelation, and drug release. This narrative review examines konjac glucomannan from a structure based formulation perspective, covering physicochemical attributes, modification strategies, formulation platforms, release behavior, and evaluation requirements. Unlike previous reviews that broadly discuss polysaccharide based transdermal systems or glucomannan across pharmaceutical applications, this review focuses on the relationship between KGM structure, formulation design, and translational performance. Evidence shows its use in films, hydrogel reservoirs, injectable hydrogels, nanofibrous systems, carrier assisted systems, and multilayer matrices. In these platforms, konjac glucomannan functions as a hydration regulating matrix former, release modulator, and structural component. Blending, deacetylation, oxidation, crosslinking, freeze thaw treatment, electrospinning, and layered design can improve mechanical integrity, moisture control, and release performance. However, outcomes vary with molecular attributes, modification conditions, and evaluation methods. Most studies remain focused on material characterization and in vitro release, while durable skin adhesion, ex vivo permeation, skin deposition, long wear performance, and clinically meaningful transport are still insufficiently demonstrated. Further translation requires standardized molecular attributes, ex vivo and in vivo testing, scalable manufacturing, and regulatory evaluation.

Background: PADS combines two neural networks predicting ICU mortality and discharge within 48 h, placing critically ill patients into one of four clinically meaningful states. Developed on MIMIC-IV alone, it left open whether it generalizes to other ICUs, whether its models transfer across hospitals, and whether its predictions can be explained at the bedside. Methods: We evaluated PADS on four ICU databases from different hospitals and countries (MIMIC-IV, AmsterdamUMCdb, eICU-CRD, and HiRID), using the same routinely collected variables. Mortality is scored on the final 48-h window (terminal-window, not early-warning, discrimination). For each external database, we compared the MIMIC model used as-is, retrained from scratch, and retrained from the MIMIC weights, and added an explainability layer. Results: For mortality, reusing and retraining the MIMIC model gave the highest discrimination on every database (AUROC 0.955-0.986; terminal-window (near-outcome) discrimination) and stabilized training; used as-is, it ranged from chance (Amsterdam) to good (eICU, HiRID). For discharge, training fresh on local data matched or beat reusing MIMIC on every external database, consistent with discharge timing depending on local organization rather than physiology. The explainability layer produced clinically coherent, cross-checked explanations. Conclusions: Transportability was task-dependent: mortality transferred between hospitals, discharge did not. PADS demonstrated promising external transportability across heterogeneous ICU databases, particularly after local adaptation. Reusing and adapting the MIMIC-IV mortality model across hospitals improves accuracy. This approach also stabilizes training, providing a basis for potential federated deployment, whereas discharge is better trained locally. The mortality results reported here are terminal-window discrimination and do not support use of the framework as an early-warning model. A transparent explainability layer provides an interpretable representation of model predictions, addressing a key barrier to clinical adoption.

Resistant hypertension (RH) is a high-risk phenotype associated with increased cardiovascular and renal morbidity despite multidrug therapy. Dysregulation of the renin-angiotensin-aldosterone system (RAAS), particularly excess aldosterone activity, plays a central role in the pathophysiology of RH. Although conventional RAAS-targeted therapies including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists improve outcomes, their effectiveness is limited by aldosterone breakthrough, persistent non-genomic aldosterone effects, hyperkalaemia, and off-target adverse effects. Aldosterone synthase inhibitors (ASIs) have emerged as a novel therapeutic strategy targeting CYP11B2, the terminal enzyme responsible for aldosterone biosynthesis. This review summarises the physiological basis of aldosterone synthesis, the pathological consequences of aldosterone excess, and the pharmacological evolution of ASIs. Early-generation agents were limited by inadequate selectivity between CYP11B2 and the closely related CYP11B1 enzyme, resulting in cortisol suppression and deoxycorticosterone accumulation. Advances in structural biology and medicinal chemistry enabled the development of second-generation ASIs with markedly improved selectivity and preserved cortisol biosynthesis. Recent clinical trials of baxdrostat, lorundrostat, vicadrostat, and dexfadrostat have demonstrated clinically meaningful reductions in blood pressure and albuminuria with acceptable safety profiles. Based on the positive trial data, baxdrostat has become the first in class ASI to be approved by regulatory authorities for management of uncontrolled hypertension.

Gastrointestinal endoscopes require high-level disinfection (HLD) between uses, yet their complex internal architecture poses significant challenges for effective reprocessing. Conventional monitoring tools, particularly ATP bioluminescence, have limited sensitivity to detect residual pro-inflammatory molecules that may persist after reprocessing. This study evaluated a peripheral blood mononuclear cell (PBMC)-based inflammatory stimulation assay alongside ATP bioluminescence to assess endoscope reprocessing efficacy. Twenty-seven gastrointestinal endoscopes were reprocessed under three protocols: Standard HLD, HLD without brushing, and HLD without bedside flushing. Water samples were collected after bedside flushing, after manual cleaning, and after automated endoscope reprocessor (AER) processing. ATP levels declined substantially across all reprocessing stages but showed no statistically significant inter-group differences, reflecting the limited discriminatory capacity of bioluminescence in this setting. In contrast, IL-1β mRNA expression in PBMC cultures stimulated with endoscope water samples revealed persistent pro-inflammatory responses in endoscopes reprocessed without brushing or bedside flushing. After manual cleaning, IL-1β expression returned to baseline in Standard HLD, while remaining significantly elevated in both modified protocols. Residual pro-inflammatory response was still detectable after AER completion in these groups, with a 1.3-1.6-fold induction above sterile water control levels (q = 0.0106 and q = 0.0125, respectively), whereas Standard HLD endoscopes showed no significant difference from controls. These preliminary findings suggest that the PBMC-based assay may offer greater sensitivity than ATP bioluminescence for detecting residual pro-inflammatory responses associated with reprocessing critical step omissions. This pilot study supports the potential of PBMC-based assays as an audit tool in endoscope reprocessing, pending validation in large-scale multicentre studies.

Mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), and epithelial sodium channel (ENaC) blockade target different levels of the aldosterone-related sodium-retention pathway in resistant hypertension (RH), but the comparative efficacy of individual agents remains uncertain. We conducted a focused drug-level network meta-analysis of randomized controlled trials (RCTs) comparing pathway-directed therapies in adults with RH. PubMed, Scopus, Embase, Cochrane CENTRAL, Cochrane Reviews, and ClinicalTrials.gov were searched from inception to July 20, 2026. The primary outcome was change in office systolic blood pressure (BP). Secondary outcomes included office diastolic BP and 24-hour ambulatory systolic and diastolic BP. Ten RCTs including 2865 participants were analyzed. In the primary drug-level analysis, amiloride, spironolactone, baxdrostat, eplerenone, and lorundrostat significantly reduced office systolic BP compared with placebo, with mean differences (MDs) of -14.08, -10.78, -9.09, -8.14, and -6.80 mmHg, respectively. Osilodrostat showed a statistically uncertain effect, with an MD of -2.61 mmHg. At the class level, both MRAs and ASIs showed clinically meaningful reductions in office systolic BP. Secondary outcomes were generally consistent with the primary analysis, although fewer trials contributed to these networks. Sensitivity analyses did not materially change the primary findings. These results support the aldosterone-related sodium-retention pathway as an important therapeutic target in RH. MRAs remain the established reference add-on therapy, whereas newer ASIs and amiloride may represent pathway-based alternatives for selected patients. Trial Registration: INPLASY202670099.

Lipid oxidation is a key determinant of nutritional quality, palatability, and shelf life in extruded dog foods. This study evaluated how lipid source, kibble matrix, and antioxidant inclusion influence oxidation and shelf life of coated extruded dog kibble. Two kibble matrices (grain-inclusive and grain-free) were formulated to meet adult maintenance recommendations and externally coated at 10% (as-is) with 1 of 10 lipid sources [algae, fish, flax, camelina, canola, sunflower, coconut, black soldier fly larvae oil, chicken fat, duck fat] or left uncoated (control). Each coated treatment was produced with or without a natural antioxidant blend (tocopherols + rosemary extract; 200 ppm), then stored under ambient (22°C, 50% RH; 15 mo) and accelerated conditions (37°C, 40% RH; 3 mo). Oxidation was assessed via peroxide value (PV), hexanal, 2,4-decadienal, and tocopherols, and time to failure was defined as PV ≥ 5 mEq/kg or (hexanal + 2,4-decadienal) ≥ 25 ppm. Proximate, mineral, and fatty acid profiles were assessed during ambient storage. Under ambient storage, PV and aldehydes increased with time (P < 0.05), and oil source influenced oxidation markers and fatty acid losses (P ≤ 0.01). Oils rich in polyunsaturated fatty acids (PUFA; algae, flax, and camelina) had greater oxidation, more rapid tocopherol depletion, and shorter time to failure than more saturated lipid sources (coconut and poultry fats). Baseline double bond index (DBI) predicted oxidative failure (P < 0.0001). Mean eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations across treatments decreased by 98.7% and 77.9%, respectively, from 0 to 15 mo. Grain-inclusive kibble was associated with greater aldehyde accumulation (P < 0.05), greater antioxidant depletion (P < 0.0001), and shorter time to failure than grain-free kibble (P = 0.001). Antioxidant inclusion increased baseline tocopherol concentrations but did not consistently affect PV or secondary aldehyde concentrations or extend time to failure across oil types at the inclusion level used (P > 0.10). In this article, lipid source was the dominant determinant of oxidative stability, with baseline DBI supporting degree of fatty acid unsaturation as an important contributor, alongside meaningful contributions from the kibble matrix. Effective preservation of long-chain n-3 PUFA requires formulation-specific stabilization strategies, beyond a uniform antioxidant solution, or alternative delivery approaches.

Silvopastoral systems and other tree-based land uses are increasingly promoted for soil conservation and climate-change mitigation in tropical livestock landscapes. However, their relationships with soil organic carbon (SOC), litter decomposition, and soil macrofauna remain poorly characterized in Amazonian production systems. In this single-farm case study, we assessed SOC distribution and stocks, soil bulk density (ρb), early litter decomposition, and soil macrofaunal communities across five contrasting land-use sites in the Colombian Amazonian foothills. The silvopastoral site had been established 18 months before sampling, allowing characterization of its early-stage soil conditions. Depth-stratified sampling showed pronounced SOC enrichment in the 0-10 cm layer at the silvopastoral site, which also had lower overall ρb than open pasture (1.29 vs. 1.48 g cm-3). However, SOC stocks from the independently sampled 0-30 cm profile were comparable between these sites. Cumulative litter mass loss increased during the 60-day evaluation and varied among forage species and sites, whereas C and N concentrations and C:N showed no statistically supported temporal changes. Macrofaunal organization varied among sites and soil depths; the silvopastoral site had the highest observed Shannon diversity in the 0-10 cm layer (H' = 1.14), although no site consistently showed the greatest diversity and evenness across all depths. Overall, the silvopastoral site combined favorable surface soil attributes with comparatively high upper-layer macrofaunal diversity. Given the cross-sectional design and single-site representation of each land use, these findings constitute a baseline characterization of site-specific conditions rather than evidence of changes attributable to silvopastoral establishment.