UNVEILING CANCER-RELATED METAPLASTIC CELLS IN BOTH HELICOBACTER PYLORI INFECTION AND AUTOIMMUNE GASTRITIS.

BACKGROUND AND AIMS: Gastric metaplasia may arise as a consequence of chronic inflammation and is associated with an increased risk of gastric cancer development. While Helicobacter pylori (Hp) infection and autoimmune gastritis (AIG) both induce gastric metaplasia, possible distinctions in resulting metaplastic cells and their respective cancer risks requires further investigation. METHODS: Employing both mouse models and human subjects, we scrutinized the metaplasia originating from Hp infection and AIG. Gastric pathology and metaplasia were examined through histopathologic assessment. Molecular features of metaplastic cells were defined using single-cell transcriptomics in murine models of Hp infection and AIG, as well as in human biopsies from patients with Hp infection and AIG. Expression of a newly defined cancer-related metaplastic biomarker was confirmed through immunofluorescence. RESULTS: Metaplasia in Hp infection and AIG displayed comparable histopathological and transcriptional features. Diverse metaplastic subtypes were identified across both disease settings, with subtle differences in the prevalence of certain subtypes between inflammatory contexts. Notably, Hp infection did not drive a unique metaplastic cell phenotype. One metaplastic subtype, which resembled incomplete intestinal metaplasia and shared transcriptional features with gastric cancer was identified in both diseases. This cancer-like metaplastic subtype was characterized by expression of the cancer-associated biomarker ANPEP/CD13. CONCLUSION: Both Hp infection and AIG trigger a diverse array of metaplastic cell types. Identification of a cancer-related metaplastic cell uniquely expressing ANPEP/CD13, present in both Hp- and AIG-induced gastritis, indicates the carcinogenic capacity of both diseases. This discovery can guide early detection and risk stratification for patients with chronic gastritis.

Bronchopulmonary Dysplasia with Pulmonary Hypertension Associates with Loss of Semaphorin Signaling and Functional Decrease in FOXF1 Expression.

Lung injury in preterm infants leads to structural and functional respiratory deficits, with a risk for bronchopulmonary dysplasia (BPD) that in its most severe form is accompanied by pulmonary hypertension (PH). To examine cellular and molecular dynamics driving evolving BPD in humans, we performed single-cell RNA sequencing of preterm infant lungs in early stages of BPD and BPD+PH compared to term infants. Analysis of the endothelium revealed a unique aberrant capillary cell-state primarily in BPD+PH marked by ANKRD1 expression. Predictive signaling analysis identified deficits in the semaphorin guidance-cue signaling pathway and decreased expression of pro-angiogenic transcription factor FOXF1 within the alveolar parenchyma in neonatal lung samples with BPD/BPD+PH. Loss of semaphorin signaling was replicated in a murine BPD model and in humans with alveolar capillary dysplasia (ACDMPV), suggesting a mechanistic link between the developmental programs underlying BPD and ACDMPV and a critical role for semaphorin signaling in normal lung development.

Unveiling fucoxanthin's fate: In vitro gastrointestinal digestion effects on bioaccessibility, antioxidant potential, colour changes, and metabolite profiles.

Limited knowledge of fucoxanthin's changes during digestion necessitates comprehensive investigation to ensure its efficacy as a functional ingredient. This study assessed the effects of digestion on fucoxanthin's bioaccessibility, antioxidant activity, colour changes, and metabolite formation through in vitro gastrointestinal digestion. Results indicated the highest bioaccessibility during gastric digestion (0.03 ± 0.00 mg/mL), followed by intestinal and mouth with 0.012 ± 0.00 and 0.011 ± 0.13 mg/mL, respectively. Antioxidant activity was the highest at the gastric stage, with significant activity persisting post-digestion (P < 0.05). Colour changes were significant, with total colour differences (∆E*) of 2.40, 2.86, and 2.76 at the mouth, gastric, and intestinal stages, respectively. LC-MS/MS-based metabolomics analysis revealed 15 key metabolites, with carboxylic acids as major metabolites during gastric and intestinal stages. Pearson correlation analysis demonstrated a significant correlation between identified metabolites with bioaccessibility, antioxidant activity, and colour changes, underscoring fucoxanthin's potential as a promising functional food ingredient.

Improving glioma drug delivery: A multifaceted approach for glioma drug development.

Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatments' gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment.

Syk inhibitors reduce tau protein phosphorylation and oligomerization.

Spleen tyrosine kinase (Syk), a non-receptor-type tyrosine kinase, has a wide range of physiological functions. A possible role of Syk in Alzheimer's disease (AD) has been proposed. We evaluated the localization of Syk in the brains of patients with AD and control participants. Human neuroblastoma M1C cells harboring wild-type tau (4R0N) were used with the tetracycline off (TetOff) induction system. In this model of neuronal tauopathy, the effects of the Syk inhibitors-BAY 61-3606 and R406-on tau phosphorylation and oligomerization were explored using several phosphorylated tau-specific antibodies and an oligomeric tau antibody, and the effects of these Syk inhibitors on autophagy were examined using western blot analyses. Moreover, the effects of the Syk inhibitor R406 were evaluated in vivo using wild-type mice. In AD brains, Syk and phosphorylated tau colocalized in the cytosol. In M1C cells, Syk protein (72 kDa) was detected using western blot analysis. Syk inhibitors decreased the expression levels of several tau phosphoepitopes including PHF-1, CP13, AT180, and AT270. Syk inhibitors also decreased the levels of caspase-cleaved tau (TauC3), a pathological tau form. Syk inhibitors increased inactivated glycogen synthase kinase 3ß expression and decreased active p38 mitogen-activated protein kinase expression and demethylated protein phosphatase 2 A levels, indicating that Syk inhibitors inactivate tau kinases and activate tau phosphatases. Syk inhibitors also activated autophagy, as indicated by increased LC3II and decreased p62 levels. In vivo, the Syk inhibitor R406 decreased phosphorylated tau levels in wild-type mice. These findings suggest that Syk inhibitors offer novel therapeutic strategies for tauopathies, including AD.

Centromedian thalamic deep brain stimulation for idiopathic generalized epilepsy: Connectivity and target optimization.

There are limited treatment options for individuals with drug-resistant idiopathic generalized epilepsy (IGE). Small, limited case series suggest that centromedian thalamus deep brain stimulation (CM-DBS) may be an effective treatment option. The optimal CM-DBS target for IGE is underexamined. Here, we present a retrospective analysis of CM-DBS targeting and efficacy for five patients with drug-resistant IGE. Volume of tissue activated (VTA) overlap with CM nucleus was performed using an open-source toolbox. Median follow-up time was 13 months. Median convulsive seizure frequency reduction was 66%. One patient had only absence seizures, with >99% reduction in absence seizure frequency. Four patients had electrode contacts positioned within the CM nucleus target, all of whom had >50% reduction in primary semiology seizure, with 85% median seizure reduction (p = .004, paired-sample t test). Volumetric "sweet-spot" mapping revealed that best outcomes were correlated with stimulation of the middle ventral CM nucleus. Connectivity strength between the sweet-spot region and central peri-Rolandic cortex was increased significantly relative to other cortical regions (p = 8.6 × 10-4, Mann-Whitney U test). Our findings indicate that CM-DBS can be an effective treatment for patients with IGE, highlight the importance of accurate targeting and targeting analysis, and within the context of prior work, suggest that ideal CM-DBS targets may be syndrome specific.

Maximally precise combinations to overcome metallo-ß-lactamase-producing Klebsiella pneumoniae.

Gram-negatives harboring metallo-ß-lactamases (MBLs) and extended-spectrum ß-lactamases (ESBLs) pose a substantial risk to the public health landscape. In ongoing efforts to combat these "superbugs," we explored the clinical combination of aztreonam and ceftazidime/avibactam together with varying dosages of polymyxin B and imipenem against Klebsiella pneumoniae (Kp CDC Nevada) in a 9-day hollow fiber infection model (HFIM). As previously reported by our group, although the base of aztreonam and ceftazidime/avibactam alone leads to 3.34 log10 fold reductions within 72 hours, addition of polymyxin B or imipenem to the base regimen caused maximal killing of 7.55 log10 and 7.4 log10 fold reduction, respectively, by the 72-hour time point. Although low-dose polymyxin B and imipenem enhanced the bactericidal activity as an adjuvant to aztreonam +ceftazidime/avibactam, regrowth to ~9 log10CFU/mL by 216 hours rendered these combinations ineffective. When aztreonam +ceftazidime/avibactam was supplemented with high-dose polymyxin B and or low-dose polymyxin B + imipenem, it resulted in effective long-term clearance of the bacterial population. Time lapse microscopy profiled the emergence of long filamentous cells in response to PBP3 binding due to aztreonam and ceftazidime. The emergence of spheroplasts via imipenem and damage to the outer membrane via polymyxin B was visualized as a mechanism of persister killing. Despite intrinsic mgrB and blaNDM-1 resistance, polymyxin B and ß-lactam combinations represent a promising strategy. Future studies using an integrated molecularly precise pharmacodynamic approach are warranted to unravel the mechanistic details to propose optimal antibiotic combinations to combat untreatable, pan-drug-resistant Gram-negatives.

Demographic and clinical characteristics of individuals with psychosis symptoms who died by suicide: Findings of a psychological autopsy study.

Suicide is a critical public health concern among individuals with schizophrenia spectrum disorders (SSDs). Still, significant gaps remain in understanding relationships between suicide outcomes and both demographic and clinical characteristics. Data were examined from 57 adults of a psychological autopsy study who had psychosis symptoms and died between 1989 and 2017 in the Midwestern United States. This study compared demographic and clinical characteristics of those who died by suicide (n = 26) to those who died by natural (n = 26) or accidental (n = 5) causes. Those who died by suicide were more often younger, white/Caucasian, more educated, and more often employed than those who died by natural or accidental causes (p < .05). Furthermore, symptoms of depression, recurrent suicidal ideation, history of suicide attempt, and being in a first episode of psychosis were experienced significantly more by those who died by suicide in comparison to natural or accidental causes (p < .05). Findings highlight the need to consider depression in suicide risk for psychosis populations, intervene in early stages of psychosis illness, and implement suicide prevention strategies tailored to individuals with psychosis and SSDs. Implications point towards the need for tailored interventions to mitigate risk for suicide death in this vulnerable population.

Quantification of persulfidation on specific proteins: are we nearly there yet?

Hydrogen sulfide (H2S) played a pivotal role in the early evolution of life on Earth before the predominance of atmospheric oxygen. The legacy of a persistent role for H2S in life's processes recently emerged through its discovery in modern biochemistry as an endogenous cellular signalling modulator involved in numerous biological processes. One major mechanism through which H2S signals is protein cysteine persulfidation, an oxidative post-translational modification. In recent years, chemoproteomic technologies have been developed to allow the global scanning of protein persulfidation targets in mammalian cells and tissues, providing a powerful tool to elucidate the broader impact of altered H2S in organismal physiological health and human disease states. While hundreds of proteins were confirmed to be persulfidated by global persulfidome methodologies, the targeting of specific proteins of interest and the investigation of further mechanistic studies are still underdeveloped due to a lack of stringent specificity of the methods and the inherent instability of persulfides. This review provides an overview of the processes of endogenous H2S production, oxidation, and signalling and highlights the application and limitations of current persulfidation labelling approaches for investigation of this important evolutionarily conserved biological switch for protein function.

White matter hyperintensity on MRI and plasma Aß42/40 ratio additively increase the risk of cognitive impairment in hypertensive adults.

INTRODUCTION: Dementia often involves comorbid Alzheimer's and vascular pathology, but their combined impact warrants additional study. METHODS: We analyzed the Systolic Blood Pressure Intervention Trial and categorized white matter hyperintensity (WMH) volume into highest versus lowest/mid tertile and the amyloid beta (Aß)42/40 ratio into lowest versus mid/highest ratio tertile. Using these binary variables, we created four exposure categories: (1) combined low risk, (2) Aß risk, (3) WMH risk, and (4) combined high risk. RESULTS: In the cohort of 467 participants (mean age 69.7 ± 7.1, 41.8% female, 31.9% nonwhite or Hispanic) during 4.8 years of follow-up and across the four exposure categories the rates of cognitive impairment were 5.3%, 7.8%, 11.8%, and 22.6%. Compared to the combined low-risk category, the adjusted hazard ratio for cognitive impairment was 4.12 (95% confidence interval, 1.71 to 9.94) in the combined high-risk category. DISCUSSION: This study emphasizes the potential impact of therapeutic approaches to dementia prevention that target both vascular and amyloid pathology. HIGHLIGHTS: White matter hyperintensity (WMH) and plasma amyloid (Aß42/40) are additive risk factors for the development of cognitive impairment in the SPRINT MIND trial. Individuals in the high-risk categories of both WMH and Aß42/40 had a near fivefold increase in risk of cognitive impairment during 4.8 years of follow-up on average. These findings suggest that treatment strategies targeting both vascular health and amyloid burden warrant further research.

Moving beyond the mean: an analysis of faecal corticosterone metabolites shows substantial variability both within and across white-tailed deer populations.

Glucocorticoid (GC) levels have significant impacts on the health and behaviour of wildlife populations and are involved in many essential body functions including circadian rhythm, stress physiology and metabolism. However, studies of GCs in wildlife often focus on estimating mean hormone levels in populations, or a subset of a population, rather than on assessing the entire distribution of hormone levels within populations. Additionally, explorations of population GC data are limited due to the tradeoff between the number of individuals included in studies and the amount of data per individual that can be collected. In this study, we explore patterns of GC level distributions in three white-tailed deer (Odocoileus virginianus) populations using a non-invasive, opportunistic sampling approach. GC levels were assessed by measuring faecal corticosterone metabolite levels ('fCMs') from deer faecal samples throughout the year. We found both population and seasonal differences in fCMs but observed similarly shaped fCM distributions in all populations. Specifically, all population fCM cumulative distributions were found to be very heavy-tailed. We developed two toy models of acute corticosterone elevation in an effort to recreate the observed heavy-tailed distributions. We found that, in all three populations, cumulative fCM distributions were better described by an assumption of large, periodic spikes in corticosterone levels every few days, as opposed to an assumption of random spikes in corticosterone levels. The analyses presented in this study demonstrate the potential for exploring population-level patterns of GC levels from random, opportunistically sampled data. When taken together with individual-focused studies of GC levels, such analyses can improve our understanding of how individual hormone production scales up to population-level patterns.

Genomic Data Characterize Reproductive Ecology Patterns in Michigan Invasive Red Swamp Crayfish (Procambarus clarkii).

The establishment and spread of invasive species are directly related to intersexual interactions as dispersal and reproductive success are related to distribution, effective population size, and population growth. Accordingly, populations established by r-selected species are particularly difficult to suppress or eradicate. One such species, the red swamp crayfish (Procambarus clarkii) is established globally at considerable ecological and financial costs to natural and human communities. Here, we develop a single nucleotide polymorphism (SNP) loci panel for P. clarkii using restriction-associated DNA-sequencing data. We use the SNP panel to successfully genotype 1800 individuals at 930 SNPs in southeastern Michigan, USA. Genotypic data were used to reconstruct pedigrees, which enabled the characterization of P. clarkii's mating system and statistical tests for associations among environmental, demographic, and phenotypic predictors and adult reproductive success estimates. We identified juvenile cohorts using genotype-based pedigrees, body size, and sampling timing, which elucidated the breeding phenology of multiple introduced populations. We report a high prevalence of multiple paternity in each surveyed waterbody, indicating polyandry in this species. We highlight the use of newly developed rapid genomic assessment tools for monitoring population reproductive responses, effective population sizes, and dispersal during ongoing control efforts.

Assessment of transcriptional markers for the differentiation of Mycobacterium mungi infection status in free-ranging banded mongoose (Mungos mungo).

There is an increasingly urgent need to improve our ability to accurately forecast and control zoonotic diseases in wildlife reservoirs. We are confronted, however, with the continued challenge of accurately determining host infection status across space and time. This dilemma is epitomized with the Mycobacterium tuberculosis Complex (MTBC) pathogens and particularly in free-ranging wildlife, a critical global challenge for both human and animal health. In humans, transcriptional markers have been increasingly identified as a robust tool for diagnosing Mycobacterium tuberculosis (MTB) infection status but have rarely been utilized for diagnosing TB in free-ranging wildlife populations. Here, we report the first use of transcriptional markers to evaluate TB infection status in a free-ranging wildlife species, banded mongoose (Mungos mungo), infected with the MTBC pathogen, Mycobacterium mungi. In this study, we found that GBP5 and DUSP3 were significantly upregulated in free-ranging banded mongoose infected with M. mungi. These results provide the first step in developing an antemortem diagnostic tool for use in free-ranging wildlife species. Our results highlight the potential of transcriptional marker-based assays to advance our ability to detect and manage TB in free-ranging wildlife, especially in field studies and other scenarios when conventional diagnostics are not feasible.

Impact of Extended Prophylactic Antibiotics on Risk of Prosthetic Joint Infection in Primary Total Hip Arthroplasty: A Matched Cohort Analysis.

BACKGROUND: Extended oral prophylactic antibiotics have been increasingly used in arthroplasty with the goal of reducing the risk of prosthetic joint infection (PJI). While a reduction in the rate of PJI has been noted with extended oral antibiotic regimens in high-risk patients, no large database study has assessed infection risk after primary total hip arthroplasty among well-balanced cohorts receiving and not receiving postoperative extended oral antibiotics. METHODS: A retrospective cohort study was conducted using a national database, TriNetX, to identify patients who underwent primary total hip arthroplasty. This cohort was stratified by oral antibiotic prescription within one day of procedure. A one-to-one propensity score matching based on age, sex, class of obesity, and medical comorbidities was conducted. Outcomes explored in this study were 90-day risk of PJI, superficial skin infection, deep skin infection, and all-cause revision. RESULTS: 90-day postoperative infection complications of PJI were higher in the group receiving antibiotics (hazard ratio: 1.83, P -value = 0.012). Other complications such as superficial skin infection, deep skin infection, and all-cause revision showed no statistically significant differences. CONCLUSION: This database analysis of 5,476 patients demonstrated no decrease in complications of PJI, superficial or deep skin infection, or revision at 90 days. Future randomized controlled trials are needed to evaluate the efficacy of extended oral antibiotics. LEVEL OF EVIDENCE: III.

The landscape of drug sensitivity and resistance in sarcoma.

Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information.

Vestibular schwannoma-related increased labyrinthine post-gadolinium 3D-FLAIR signal intensity and association with hearing impairment.

BACKGROUND AND PURPOSE: Vestibular schwannomas (VSs) are benign neurogenic tumors commonly associated with progressive unilateral hearing loss, tinnitus, and vestibular symptoms. Growing evidence links signal changes in the VS-adjacent labyrinth with sensorineural hearing loss. This study seeks to quantify the association of labyrinthine signal on post-gadolinium 3D-FLAIR imaging correlates with hearing loss and to evaluate potential longitudinal changes over time. MATERIALS AND METHODS: Selected patients were identified from a prospectively maintained VS registry. Mean signal intensity ratios of the bilateral labyrinth and pons were measured on 3D-FLAIR post-gadolinium MRI. Correlations with paired audiometric data including pure tone average (PTA), word recognition score (WRS), and AAO-HNS hearing class within one year were evaluated. RESULTS: 125 studies obtained from 2015 to 2022 among 66 patients undergoing observational management for sporadic VS were analyzed. Increased signal intensity was noted of the VS-affected labyrinth/contralateral labyrinth (mean ratio 1.56, SD 0.58). Increased signal intensity was associated with increased PTA on both labyrinthine (correlation coefficient [CC] 0.20, p=0.03) and pontine comparisons (CC 0.24, p=0.006), and with decreased WRS on pontine comparisons (CC -0.18, p=0.04). Increased signal intensity was significantly associated with non-serviceable AAO-HNS C/D hearing when intensities were compared to the pons (p=0.01) but not the contralateral labyrinth (p=0.1). Among 44 patients with available follow-up, no statistically significant associations were identified between audiometric data and signal changes over the same interval. CONCLUSIONS: Increased 3D-FLAIR post-gadolinium labyrinthine signal is associated with sensorineural hearing loss; however, its relationship with hearing trajectory remains unclear. Overall findings suggest that while post-gadolinium 3D-FLAIR techniques are sensitive to inner ear involvement associated with VS, the driving mechanism and their temporal relationships with labyrinthine signal intensity and hearing impairment remain unknown. ABBREVIATIONS: AAO-HNS =American Academy of Otolaryngology -Head and Neck Surgery. BLB =blood-labyrinth barrier. CPA = cerebellopontine angle. IAC = internal auditory canal. PTA = pure tone average; SIR = signal intensity ratio. VS = vestibular schwannoma. WRS = word recognition score.

Mitigating Misinformation Toolkit: Online Simulation and Standardized Patient Cases for Interprofessional Students to Address Vaccine Hesitancy and Misinformation.

Introduction: Medical misinformation, which contributes to vaccine hesitancy, poses challenges to health professionals. Health professions students, while capable of addressing and advocating for vaccination, may lack the confidence to engage with vaccine-hesitant individuals influenced by medical misinformation. Methods: An interprofessional in-person simulation activity (90 minutes) using standardized patients was developed and instituted for students in medicine, nursing, pharmacy, and public health programs. Student volunteers were recruited from classes approximately halfway through their respective degree programs (i.e., second or third year of a 4-year program). Online simulation was used as a method to prepare for in-person simulation. Impact on students was assessed primarily through a postprogram student self-assessment. Results: A total of 220 students participated in the program; 206 (94%) had paired data available to analyze. Following program participation, self-assessed abilities increased from pre to post, from 2.8 out of 5 (good) to 3.9 out of 5 (very good; p < .001). Ninety-eight percent of students felt that their ability to address medical misinformation was somewhat/much better after the activity, compared to before, and that their ability to address vaccine hesitancy was somewhat/much better. The overall program was rated highly, with mean scores for each program evaluation item >4 out of 5 (very good). Discussion: An interprofessional cohort of students demonstrated improvement in self-assessed skills to participate in a conversation with an individual with hesitancy to receive vaccines and/or beliefs informed by misinformation. Students felt that this program was relevant and important to their professional development.

Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic.

Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based systems, imdusiran possessed pan-genotypic nanomolar potency and retained activity against HBV target site polymorphisms. Imdusiran was active against nucleos(t)ide analogue- and capsid assembly modulator-resistant HBV isolates, and combination with standard-of-care agents was additive. In an HBV adeno-associated virus mouse model, HBsAg was reduced up to 3.7 log10 after a single imdusiran dose, with sustained suppression for 10 weeks. Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure.

Recommendations for clinical trial design in acute kidney injury from the 31st acute disease quality initiative consensus conference. A consensus statement.

PURPOSE: Novel interventions for the prevention or treatment of acute kidney injury (AKI) are currently lacking. To facilitate the evaluation and adoption of new treatments, the use of the most appropriate design and endpoints for clinical trials in AKI is critical and yet there is little consensus regarding these issues. We aimed to develop recommendations on endpoints and trial design for studies of AKI prevention and treatment interventions based on existing data and expert consensus. METHODS: At the 31st Acute Disease Quality Initiative (ADQI) meeting, international experts in critical care, nephrology, involving adults and pediatrics, biostatistics and people with lived experience (PWLE) were assembled. We focused on four main areas: (1) patient enrichment strategies, (2) prevention and attenuation studies, (3) treatment studies, and (4) innovative trial designs of studies other than traditional (parallel arm or cluster) randomized controlled trials. Using a modified Delphi process, recommendations and consensus statements were developed based on existing data, with > 90% agreement among panel members required for final adoption. RESULTS: The panel developed 12 consensus statements for clinical trial endpoints, application of enrichment strategies where appropriate, and inclusion of PWLE to inform trial designs. Innovative trial designs were also considered. CONCLUSION: The current lack of specific therapy for prevention or treatment of AKI demands refinement of future clinical trial design. Here we report the consensus findings of the 31st ADQI group meeting which has attempted to address these issues including the use of predictive and prognostic enrichment strategies to enable appropriate patient selection.