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Hemolysis is a recognized complication of mechanical circulatory support and may contribute to acute kidney injury in patients with cardiogenic shock. Early hemolysis during Impella support, particularly compared with intra-aortic balloon pump (IABP), remains incompletely characterized. We retrospectively analyzed a single-center registry of consecutive patients with cardiogenic shock treated with IABP or Impella between August 2022 and October 2024. Serum haptoglobin was measured at intensive care unit admission and every 12 hours during device support. Low haptoglobin was defined as <19 mg/dL. Among 91 patients (IABP, n=67; Impella CP, n=24), baseline haptoglobin levels were similar. Patients supported with Impella exhibited a significantly greater decline in haptoglobin beginning 12 hours after intensive care unit admission, particularly in the absence of concomitant venoarterial extracorporeal membrane oxygenation. Low haptoglobin occurred more frequently with Impella than with IABP (67% versus 31%, P=0.004), whereas the incidence of overt clinical hemolysis was low and comparable between devices. Impella use (odds ratio, 2.82 [95% CI, 1.45-5.95]; P=0.001), concomitant venoarterial extracorporeal membrane oxygenation support (odds ratio, 16.52 [95% CI, 4.65-174.56]; P<0.001), and lower mean arterial pressure at intensive care unit admission (OR, 0.95 [95% CI, 0.89-0.99]; P=0.006) were independently associated with low haptoglobin. In patients with cardiogenic shock, Impella CP support was associated with earlier and more frequent decline in serum haptoglobin compared with IABP, suggesting more frequent subclinical hemolysis. Although overt hemolysis was uncommon, early monitoring using serial serum haptoglobin measurements may help inform device management strategies.

Signal sequences (SS) target newly synthesized proteins to the endoplasmic reticulum and, eventually, the plasma membrane. Discoidin, CUB, and LCCL domain containing 2 (DCBLD2) is a transmembrane protein with an unusually long SS that interacts with vascular endothelial growth factor receptor (VEGFR)-2 and promotes VEGF-induced endothelial cell signaling, proliferation and migration, as well as angiogenesis. How DCBLD2 interacts with VEGFR-2 to modulate VEGF signaling remains unclear. We generated various constructs containing different combinations of DCBLD2 domains, including its SS, and conducted co-immunoprecipitation and signaling studies in HEK 293T and endothelial cells to identify the smallest DCBLD2 unit that interacts with VEGFR-2. Other proteins containing this unit were identified, and their interactions with VEGFR-2 were evaluated. The DCBLD2 SS interacted with VEGFR-2 and promoted VEGF signaling. The smallest unit in the DCBLD2 SS that interacted with VEGFR-2 was the L5VL5 sequence. Even after the central valine was removed, the L10 sequence mimicked the DCBLD2 SS effect on VEGF-signaling, while shorter or longer multi-leucine sequences were less effective. We identified several other human proteins containing such uncleaved multi-leucine SS, including CD45-associated protein (CD45-AP) and BRICHOS domain containing 5 (BRICD5). Both these proteins could interact with VEGFR-2, and CD45-AP could modulate VEGF signaling in endothelial cells. In conclusion, a multi-leucine motif in SS can directly engage in protein-protein interactions and modulate VEGF signaling. These findings refine the traditional view of SS as merely targeting elements, emphasizing their role in cellular signaling and opening new avenues for research and therapy.

Lignin depolymerization by white-rot fungi generates diverse aromatic compounds derived from hydroxyphenyl (H), guaiacyl (G), and syringyl (S) units. Although the metabolic pathways for G- and H-unit-derived aromatics have been studied, the enzymatic step responsible for the oxidative decarboxylation of the S-unit intermediate syringic acid (SA) has remained unknown. Here, we identify PcMNX1, a group A flavoprotein monooxygenase (FPMO) from the white-rot fungus Phanerochaete chrysosporium, as the enzyme catalyzing this missing step. Recombinant PcMNX1 catalyzed the NAD(P)H-dependent oxidative decarboxylation of SA to dimethoxyhydroquinone (DMHQ) and also converted other lignin-derived aromatics, including vanillic acid and 4-hydroxybenzoic acid, with markedly higher catalytic efficiency than the closely related enzyme GsMNX1 from Gelatoporia (Ceriporiopsis) subvermispora. The crystal structure of PcMNX1 was determined at 2.00 &#xc5; resolution, revealing a typical group A FPMO fold with FAD bound in the "out" conformation. Structure-guided mutagenesis demonstrated that His247 functions as the catalytic base required for decarboxylative hydroxylation. Comparative structural analysis with bacterial 3-hydroxybenzoate 6-hydroxylase (3HB6H) indicated that subtle substitutions in active-site residues alter substrate positioning and reaction outcomes. Consistent with this hypothesis, introduction of PcMNX1-type residues into 3HB6H conferred decarboxylation activity toward lignin-derived aromatics. Furthermore, enlargement of the PcMNX1 active-site cavity through the L264A substitution markedly enhanced SA conversion. Together, these findings demonstrate that PcMNX1 catalyzes the oxidative decarboxylation of SA and reveal how subtle active-site remodeling diversifies the catalytic repertoire of closely related group A FPMOs involved in lignin-derived aromatic metabolism.

Nonalcoholic fatty liver disease (NAFLD), prevalent in bariatric surgery patients, is a leading indication for liver transplantation. However, class III obesity is a relative contraindication for transplantation. To evaluate the safety of bariatric surgery in patients with mild to moderate liver disease of any cause. 2023 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database. Patients who underwent sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) were included. We performed a 1:1 propensity score matching analysis with 27 preoperative characteristics. We compared 30-day postoperative outcomes for patients with body mass index (BMI) < 40 with versus without liver disease after SG (Analysis 1) or RYGB (Analysis 2) and for patients with BMI &#x2265; 40 with versus without liver disease after SG (Analysis 3) or RYGB (Analysis 4). From 182,673 patients (71% SG; 29% RYGB), outcomes in analysis 1 showed that patients with liver disease are associated with higher rates of surgical site infection (SSI), and blood transfusions (P < .05). Analysis 2 showed that patients with liver disease are associated with higher rates of emergency visits, readmissions, reoperations, and SSI (P < .05). In analysis 3, patients with liver disease had higher rates of unplanned intensive care unit admission, emergency visits, SSI, blood transfusions, and readmissions (P < .05). In analysis 4, patients with liver disease had higher rates of emergency visits and SSI (P < .05). However, there were no differences across the four analyses in mortality and cardiopulmonary complications. Bariatric surgery in patients with liver disease is safe and feasible with similar mortality and cardiopulmonary complications compared to patients without liver disease. However, patients with liver disease have a higher rate of complications, including emergency visits, SSI, readmissions, and blood transfusions after bariatric surgery. Furthermore, patients with liver disease and BMI &#x2265;40 have higher rates of unplanned intensive care unit admission, emergency visits, readmissions, and reoperations.

In Japan, helicopter emergency medical service (HEMS) requests may be initiated either before emergency medical services personnel make patient contact (pre-contact request) or after on-scene assessment (post-contact request). Pre-contact requests may facilitate earlier HEMS activation but may also increase overtriage because dispatch decisions are based on limited pre-arrival information. Trauma-specific nationwide evidence comparing these 2 request patterns remains limited. We therefore compared pre-contact and post-contact HEMS requests among trauma patients in the Japanese Society for Aeromedical Services Registry to examine differences in severity, urgency, transport patterns, and outcomes, to inform dispatch policy and physician-staffed HEMS utilization. Data from the Japanese Society for Aeromedical Services Registry cases between January 1, 2020, and December 31, 2022 were retrospectively analyzed, focusing on 24,195 patients with trauma. Patients with trauma/external-cause cases were included, whereas internal medical cases, cases with missing trauma/external-cause classification, and cases with missing or unclassifiable request-timing data were excluded. Severity was assessed using the National Advisory Committee for Aeronautics score, and urgency was evaluated using the Japan Triage and Acuity Scale. Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables using Pearson's Chi-squared test. Of the 24,195 patients with trauma, there were 7321 in the pre-contact request group and 16,874 in the post-contact request group. Patients in the pre-contact request group were younger (p = 0.008), and the percentage of males was higher (p < 0.001). The median National Advisory Committee for Aeronautics scores were similar between groups (p = 0.873), whereas the Japan Triage and Acuity Scale differed statistically between groups (p = 0.010). Transportation by helicopter and intensive care unit/high care unit-level disposition were more frequent in the post-contact group (p < 0.001). Although some time intervals were shorter in the pre-contact group, the absolute differences were small. No clinically meaningful differences were observed in hospital length of stay or survival-related outcomes. In this retrospective nationwide trauma registry analysis, pre-contact requests did not demonstrate a clinically meaningful advantage in major outcomes compared with post-contact requests. Although some process intervals were shorter in the pre-contact group, the absolute differences were small. Because several outcome-related variables had substantial missingness, these comparisons should be interpreted cautiously. Refinement of dispatch criteria may help optimize physician-staffed HEMS utilization.

BackgroundInterventions aimed at providing oral motor stimulation improve the preparedness for oral feeding and support the earlier attainment of full oral feeding in preterm infants. However, utilizing the Premature Infant Oral Motor Intervention (PIOMI) as a structured method may prolong the time needed to reach complete oral feeding and enhance feeding efficiency regarding weight gain and exclusive breastfeeding, compared to an unstructured approach.ObjectiveThe current study aimed to evaluate the impact of PIOMI on the progression of oral feeding and weight gain in premature infants.MethodsThis study represents a randomized controlled trial that took place in a neonatal intensive care unit in 2024. The intervention group received PIOMI, and the control group did not receive the intervention. The participants of the two groups were compared based on weight gain, mean height, head circumference, and length of hospitalization.ResultsThe findings of this study showed that the mean of studied parameters, such as weight, height, and head circumference of the infants in the intervention group, was higher than that of the control group, and this difference was statistically significant (p < 0.05). Moreover, the mean number of uninterrupted sucking of infants in the intervention group was higher, and it was statistically significant (p < 0.001).DiscussionThe PIOMI intervention enhances the sucking strength and consequently boosts the growth metrics of premature infants.ConclusionIt was concluded that the PIOMI intervention increases the sucking power and, as a result, improves the growth indicators of premature neonates, such as weight, height, and head circumference, which is clinically important. Additionally, it reduces the mean hospitalization time.

A meaningful quality strategy is essential for a pharmaceutical or device company to achieve its strategic objectives. As companies evolve and move through the product development lifecycle, an early understanding of quality risks and gaps is essential to ensure success with regulatory approval, partner due-diligence, and agency audits. Using a unique approach which combines the concepts of Quality Risk Management (QRM) and Quality Management Maturity (QMM) with the FDA Six-Systems model, a strategic quality plan can be developed which identifies and prioritizes the improvement efforts needed to ensure a compliant and efficient approach to quality. This model can be applied to the US, EU and global expectations for compliance at every stage of the product lifecycle.This approach is unique in that it considers the organizational and strategic context of the quality unit when identifying risks and necessary mitigation actions. The result is a holistic action plan aligned with the company's strategic goals which addresses structural and behavioral deficiencies in addition to the technical compliance gaps normally identified during a typical gap assessment process.

Hematopoietic stem and progenitor cells (HSPCs) are characterized by the ability to proliferate, differentiate into multiple lineages, self-renew and repopulate the hematopoietic system. Development of functional assays enabling qualitative and quantitative measurements of these different features are cornerstones of the field. In this review, we summarize key approaches, from early transplantation and spleen colony-forming unit assays to in vitro clonogenic systems, long-term culture assays, xenotransplantation models, and single-cell platforms with historical perspectives and evaluation of their utilities as well as limitations. We emphasize the principles of functional definition of stem and progenitor cells and the discoveries of clonal origin and functional heterogeneity within phenotypically defined HSPC populations.

Cu2+ and H2S participate in vital physiological activities, especially mitochondrial function. Endogenous H2S has served as a critical biomarker of liver injury. Accordingly, detecting Cu2+ and H2S in mitochondria, as well as monitoring H2S fluctuations in living cells and intact organisms (especially in the liver), is of great significance for elucidating their mitochondrial physiological roles and evaluating the progression of liver-related disorders. Herein, two mitochondria-targeted phosphorescent probes (Ir and its Cu2+ complex Ir-Cu) were rationally designed for mitochondrial and in vivo sensing of Cu2+ and H2S via a metal displacement strategy. Each probe integrates a lipophilic cationic cyclometalated Ir(III) luminophore with mitochondrial targeting capability and a cyclen unit for specific Cu2+ recognition. The system undergoes distinct "on-off" and "off-on" phosphorescence switching at 580&#x202f;nm and 630&#x202f;nm upon sequential addition of Cu2+ and H2S. The as-prepared probes possess superior properties including an ultra-large Stokes shift (>200&#x202f;nm), long lifetime (800 ns), rapid response (Cu2+: 5&#x202f;min; H2S: 10&#x202f;s) and high selectivity. They were successfully utilized for imaging Cu2+ and H2S in mitochondria and model organisms such as zebrafish, mice and Arabidopsis thaliana. In particular, Ir-Cu achieved visualization of H2S fluctuations in LPS-induced cells, liver tissues of hepatic inflammatory mice, and serum from normal and diseased mice. The developed mitochondria-targeted phosphorescent probes achieve in vitro and in vivo imaging of Cu2+ and H2S. Distinct from conventional organic fluorophores, these Ir(III) complexes (Ir and Ir-Cu) can effectively eliminate false-positive signals and enhance spatial resolution, exhibiting great promise for studying biological processes and mitochondria-related liver injury.

Culture-based monitoring of bacterial load is slow and susceptible to missing data, contributing to the length and cost of TB clinical trials. Non-culture-based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB-MBLA), could represent a solution. Our objectives were to evaluate TB-MBLA as a biomarker in early bactericidal activity (EBA) studies and explore whether combining biomarkers with joint modeling could provide insight into underlying biological processes. We generated TB-MBLA (LifeArc) data from sputum samples from all 78 patients from the PanACEA BTZ-043 Phase Ib/IIa trial and derived a summary measure of the joint distribution of the three TB-MBLA, colony forming units (CFU), and time-to-positivity (TTP) biomarkers as the first principal component derived from a probabilistic principal component analysis (pPCA). With TB-MBLA marker and the principal component 1 (PC1) values, we reevaluated the original stage IIa dose-response and stages Ib/IIa pharmacokinetics-pharmacodynamics (PK-PD) exposure-response analyses, applying linear and non-linear mixed models, respectively. For TB-MBLA, we could not detect an exposure-response effect in the PK-PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced Emax exposure-response between days 0-3 compared with CFU and TTP alone. We also successfully applied pPCA as a modeling framework and show evidence that combining CFU and TTP in a joint latent component can improve detection of treatment effects compared with either biomarker alone. In this study, we present novel EBA data for the first-in-class antimycobacterial compound BTZ-043 and contextualize the value of emerging bacteriological markers within the EBA trial framework. Trial Registration: ClinicalTrials.gov identifier: NCT04044001.

Current risk stratification after radical prostatectomy (RP) relies on Grade Group (GG) and genomics, which may not fully capture metastatic potential. Unfavorable histology (UH), defined by adverse architectural patterns such as large cribriform carcinoma and intraductal carcinoma, has emerged as a strong predictor. We evaluated whether integrating genomic and other clinicopathologic variables improves prediction beyond quantitative UH burden. We analyzed 418 men from an event-enriched RP cohort (1987-2004) with centralized pathology review, Genomic Prostate Score (GPS), and long-term follow-up. We recorded the percentage of tumor with UH (UH%), cribriform size, GG, stage, margin status, prostate-specific antigen, and GPS. Multivariable Cox models and a sequential modeling framework evaluated independent associations and incremental predictive performance for metastasis at 15 years. During median 15.5-year follow-up, 102 men (24%) developed metastases, all within UH-positive tumors. UH &#x2265;10% was strongly associated with metastasis (hazard ratios [HR] 50.95, 95% confidence intervals [CI] 10.4-249). GPS (HR 1.03 per unit, 95% CI 1.01-1.05) and cribriform size (HR 1.0007 per &#x3bc;m, 95% CI 1.0003-1.0010) were independently associated but added only modest discrimination. UH% alone achieved high 15-year discrimination (c-index &#x223c;0.85); inclusion of GPS and cribriform size increased this to 0.901. Limitations include retrospective design and single-institution pathology review. UH% is the dominant determinant of metastatic risk after RP, offering greater prognostic discrimination than GG, stage, and other clinicopathologic variables. Genomic classifiers and cribriform size provide secondary refinement but do not materially alter risk once UH burden is established. These findings support pathology-anchored risk models.

Selecting an optimal C-arm working view is critical in endovascular coiling of intracranial aneurysms, influencing procedural safety and efficiency. Current practice relies on operator experience and manual angulation adjustments, leading to inter-operator variability and increased radiation exposure. In this preliminary feasibility study, we investigate whether a generative adversarial framework can learn to predict clinically meaningful C-arm viewing directions from 3D rotational angiography (3DRA) data. We developed a generator-discriminator framework in which the generator predicts a 3D unit view vector from segmented vascular and aneurysm volumes, and the discriminator evaluates differentiable 2D projections along the predicted view. Three projection strategies (soft first-hit ray casting, digitally reconstructed radiographs (DRR), and label-aware maximum-intensity projections with soft label encoding (MIP-OR)) were tested with two generator architectures (CNN and U-Net). Performance was assessed on a held-out test set using absolute dot product (ADP) error between predicted and expert-annotated views, complemented by qualitative assessment from two experienced interventional neuroradiologists. Experiments on a preliminary cohort of 18 patients demonstrate that the CNN generator combined with MIP-OR projections achieves the lowest mean ADP error and high expert scores, demonstrating improved alignment with clinically acceptable working views. Training analysis indicated that low ADP values alone do not guarantee clinical usability, highlighting the need for combined geometric and expert-based evaluation. Adversarial learning with anatomically informed projections is a promising approach for automated C-arm view prediction. Future work will integrate procedural ground-truth views, larger datasets, and additional endovascular procedures to evaluate reliability and generalizability.

This study estimates the cost of managing infertility, including intrauterine insemination (IUI) from health system perspective in India. This was a retrospective cross-sectional microcosting study using mixed approach. Unit costs were estimated at the cost-centre level based on average resource utilisation and aggregated by facility type and cause of infertility. The cost data was collected for the year 2022-2023&#x2009;and adjusted for inflation in 2025. The study was conducted at five healthcare facilities providing infertility services, of which three were public and two were private hospitals situated in different parts of country. The cost data was collected from different departments of hospitals. To determine the service utilisation, 100 infertility patients were enrolled at each hospital. Patients undergoing infertility treatment (including IUI) for five selected causes of infertility and willing to participate in the study were included. The cost of providing infertility treatment for 1 year was the primary outcome measure. The share of different cost-components in the total cost was the secondary outcome measure. The one-year health system cost of infertility management ranged from INR 5515 (USD 63) to INR 15 139 (USD 173). Median costs were generally higher in public hospitals compared to private hospitals. Outpatient consultations contributed about two-thirds of total costs. The mean cost of one IUI cycle ranged from INR 8272 (USD 94) to INR 8887 (USD 101). This first-of-its-kind study provides robust evidence on the health system cost of infertility management in India. The findings highlight significant cost variations by infertility cause and facility type, underscoring the need for inclusion of infertility services, particularly IUI, within public health financing packages. These results offer a foundation for future cost-effectiveness analyses and policy decisions related to infertility treatment in India.

High-flow oxygen therapy (HFOT) is increasingly used for respiratory support in preterm newborns (PTNBs). However, there is still limited evidence regarding the impact of its early and prolonged use in this population, as well as its association with clinical outcomes such as bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). The aim of our study was to describe our experience with the use of HFOT in PTNBs and to analyze its association with the prevalence of BDP and ROP. Retrospective descriptive study conducted in a cohort of PTNBs born between May 2019 and May 2024 with gestational age &#x2264; 32 weeks who received HFOT during their stay in the neonatal intensive care unit of a tertiary care hospital. We analyzed data on variables related to HFOT exposure (duration, maximum flow, and FiO2) and the presence of BPD and ROP. In the analyzed cohort, we found a potential association between HFOT exposure parameters (days of use, maximum flow, and FiO2) and the presence of BPD. Likewise, we found evidence of a potential negative impact, as the duration of HFOT and the FiO2 were associated with the presence of ROP. The frequency of both complications increased with lower gestational age and lower birth weight. In this cohort, we observed a possible negative impact of the use of HFNC on the development of BPD and ROP, which was more evident in infants with lower gestational ages and birth weights. These findings should be interpreted with caution due to the descriptive design of the study and the lack of a comparison group, and analytical studies with appropriate control groups are required to further investigate these associations.

There is limited real-world evidence on the diagnosis, treatment, and outcomes of refractory status epilepticus (RSE) in Latin America. This study describes the clinical characteristics, management, and outcomes of RSE in a tertiary neurological intensive care unit (NICU) in Mexico. We conducted a retrospective cohort study of adults (&#x2265;&#x2009;18&#xa0;years) with RSE admitted from 2010 to 2022. All patients were initially analyzed as a single cohort; a prespecified secondary analysis stratified patients by preexisting epilepsy and identified those with new-onset RSE (NORSE). Patients were identified via electronic medical records and met the International League Against Epilepsy (ILAE) definition. Clinical, imaging, laboratory, and EEG data were collected. Outcomes included seizure cessation, functional status at NICU discharge (mRS), and prognostic scores (STESS and END-IT). Statistical analysis involved descriptive measures, chi-square/Fisher's exact tests, t-test or Mann-Whitney U test, and multinomial logistic regression. Significance was set at p&#x2009;<&#x2009;0.05. We analyzed 102 patients with RSE; 52.9% were women, median age 34 (26-44) years. Preexisting epilepsy was present in 70.6%, and 29.4% had NORSE. Most common etiologies were infections (23.5%), structural/vascular (22.5%), and treatment-related (16.7%). EEG most commonly showed slowing; interictal epileptiform discharges appeared in 27.7%. Treatment was heterogeneous; 82.4% required third-line therapy. Median hospitalization was 21.5&#xa0;days, with mechanical ventilation averaging 8&#xa0;days. Resolution occurred in 87.3%. One patient underwent surgery, without complications. Preexisting epilepsy was significantly associated with prior SE (p&#x2009;=&#x2009;0.011), resolution (p&#x2009;=&#x2009;0.001), unfavorable mRS (p&#x2009;=&#x2009;0.046), and higher STESS (p&#x2009;=&#x2009;0.001) and END-IT (p&#x2009;=&#x2009;0.021) scores. END-IT also correlated with third-line treatment (p&#x2009;<&#x2009;0.001). This study offers real-world insights into RSE in a resource-limited setting, highlighting preventable causes, management complexity, and high care demands. Despite limitations, favorable outcomes are often achievable.

Despite widespread statin use, atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality worldwide. Monoclonal antibodies targeting circulating proprotein convertase subtilisin-kexin type 9 (PCSK9) substantially reduce low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular events. However, the requirement for self-administration every 2-4 weeks may limit adherence to treatment. Inclisiran, a first-in-class small interfering ribonucleic acid (siRNA) therapy targeting hepatic PCSK9 production, has several potential advantages over the anti-PCSK9 monoclonal antibodies, principally longer duration of action. To date, however, the efficacy and safety of inclisiran have not been proven in a cardiovascular outcomes trial. The ORION-4 study is the first large-scale clinical outcomes trial of an siRNA therapy, aiming to assess the efficacy and safety of inclisiran among participants with pre-existing atherosclerotic cardiovascular disease. The primary assessment is an intention-to-treat comparison of the effect of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran), given by subcutaneous injection at randomization, at approximately 3 months and then approximately every 6 months thereafter, on major adverse cardiovascular events (MACE), defined as the composite of coronary death, myocardial infarction, fatal or non-fatal ischaemic stroke, or urgent coronary revascularization. Participants will be followed until the median time since randomization is at least 5 years and at least 1700 participants have a recorded adjudicated MACE. With a planned sample size of &#x223c;15,000 participants, ORION-4 was designed to have >99% power to detect a relative reduction in the primary outcome of about one quarter, while also providing an opportunity to assess efficacy in different subgroups as well as on secondary outcomes of interest. Between 2019 and 2023 a total of 16,124 participants were randomized in the UK and the US. The mean (SD) age was 70 (8.1) years and 30% were female. At baseline, 78% had a history of coronary heart disease, 22% of ischaemic stroke, 15% of revascularization for peripheral arterial disease, and 23% had diabetes mellitus. 85% were on statin therapy (53% high intensity statin, 29% moderate and 3% low intensity statins). Overall, baseline mean (SD) LDL-C was 96 (32) mg/dL, and was similar among participants on high- and moderate/low-intensity statin regimens (87 (27) mg/dL and 93 (26) mg/dL respectively), with higher levels in those receiving no statin therapy (133 (33) mg/dL). Follow-up will complete during 2026 and results will be available in early 2027. Inclisiran potentially offers a scalable lipid-lowering treatment, either alone or in combination with other agents. ORION-4 will evaluate the clinical efficacy of inclisiran, and provide a robust assessment of the safety of prolonged use of an siRNA therapeutic.

Malaria blood-stage parasites digest ~80% of host cell hemoglobin within a degradative vacuole, releasing heme that is detoxified by sequestration into hemozoin crystals. Although essential for survival and a validated drug target, the mechanisms of heme biomineralization remain unclear. Here, we study the parasite's Heme Detoxification Protein (HDP), previously proposed to mediate hemozoin formation, using genetic, microscopic, bioenergetic, and proteomic approaches. Endogenous tagging reveals that HDP localizes to the mitochondrion, not the digestive vacuole. HDP inactivation has no effect on heme biomineralization, but causes mitochondrial depolarization, proguanil hypersensitivity, and developmental arrest, which is rescued by bypassing respiratory-chain-dependent pyrimidine biosynthesis. HDP knockout abolishes mitochondrial electron flow due to loss of complexes III and IV, consistent with impaired mitochondrial protein synthesis. Integration of structural modelling with quantitative proteomics places HDP within the mitoribosomal large subunit. Here, we show that HDP is essential for mitochondrial function and does not contribute to hemozoin formation.

The industrial translation of liposome production processes remains challenging, particularly in achieving scalability while maintaining critical quality attributes and formulation stability. In this study, a supercritical CO2-based PGSS process was successfully transferred from the laboratory to the pilot scale (50 to 500&#xa0;mL reactor). Using a Quality by Design approach and a design of experiments on a simplified soy phosphatidylcholine formulation, we identified optimal production process parameters. These parameters were then validated and transferred to other drug-encapsulating liposome formulations, demonstrating process robustness. Under these conditions, liposomes measuring less than 200&#xa0;nm and polydispersity indices close to 0.30 were reproducibly obtained at pilot scale. The process was successfully applied to drug-loaded formulations, achieving high encapsulation efficiencies while maintaining suitable physicochemical properties. Cryo-TEM confirmed the formation of consistent vesicular structures. Importantly, lipid chemical stability was preserved, with minimal hydrolysis and no significant increase in oxidation, even for unsaturated lipids. Overall, this study demonstrates the robustness, scalability, and relevance of the PGSS process as a solvent-free, single-step technology for liposome production.