AI-based automation of enrollment criteria and endpoint assessment in clinical trials in liver diseases.

Clinical trials in metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis) require histologic scoring for assessment of inclusion criteria and endpoints. However, variability in interpretation has impacted clinical trial outcomes. We developed an artificial intelligence-based measurement (AIM) tool for scoring MASH histology (AIM-MASH). AIM-MASH predictions for MASH Clinical Research Network necroinflammation grades and fibrosis stages were reproducible (κ = 1) and aligned with expert pathologist consensus scores (κ = 0.62-0.74). The AIM-MASH versus consensus agreements were comparable to average pathologists for MASH Clinical Research Network scores (82% versus 81%) and fibrosis (97% versus 96%). Continuous scores produced by AIM-MASH for key histological features of MASH correlated with mean pathologist scores and noninvasive biomarkers and strongly predicted progression-free survival in patients with stage 3 (P < 0.0001) and stage 4 (P = 0.03) fibrosis. In a retrospective analysis of the ATLAS trial (NCT03449446), responders receiving study treatment showed a greater continuous change in fibrosis compared with placebo (P = 0.02). Overall, these results suggest that AIM-MASH may assist pathologists in histologic review of MASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient responses.

Review article: New developments in biomarkers and clinical drug development in alpha-1 antitrypsin deficiency-related liver disease.

BACKGROUND: Alpha-1 antitrypsin liver disease (AATLD) occurs in a subset of patients with alpha-1 antitrypsin deficiency. Risk factors for disease progression and specific pathophysiologic features are not well known and validated non-invasive assessments for disease severity are lacking. Currently, there are no approved treatments for AATLD. AIMS: To outline existing understanding of AATLD and to identify knowledge gaps critical to improving clinical trial design and development of new treatments. METHODS: This report was developed following a multi-stakeholder forum organised by the Alpha-1 Antitrypsin Deficiency Related Liver Disease Expert Panel in which experts presented an overview of the available literature on this topic. RESULTS: AATLD results from a 'gain of toxic function' and primarily manifests in those with the homozygous Pi*ZZ genotype. Accumulation of misfolded 'Z' AAT protein in liver cells triggers intracellular hepatocyte injury which may ultimately lead to hepatic fibrosis. Male gender, age over 50 years, persistently elevated liver tests, concomitant hepatitis B or C virus infection, and metabolic syndrome, including obesity and type 2 diabetes mellitus, are known risk factors for adult AATLD. While the gold standard for assessing AATLD disease activity is liver histology, less invasive measures with low intra- and inter-observer variability are needed. Measurement of liver stiffness shows promise; validated thresholds for staging AATLD are in development. Such advances will help patients by enabling risk stratification and personalised surveillance, along with streamlining the development process for novel therapies. CONCLUSIONS: This inaugural forum generated a list of recommendations to address unmet needs in the field of AATLD.

Sexual dimorphism during integrative endocrine and immune responses to ionizing radiation in mice.

Exposure to cosmic ionizing radiation is an innate risk of the spaceflight environment that can cause DNA damage and altered cellular function. In astronauts, longitudinal monitoring of physiological systems and interactions between these systems are important to consider for mitigation strategies. In addition, assessments of sex-specific biological responses in the unique environment of spaceflight are vital to support future exploration missions that include both females and males. Here we assessed sex-specific, multi-system immune and endocrine responses to simulated cosmic radiation. For this, 24-week-old, male and female C57Bl/6J mice were exposed to simplified five-ion, space-relevant galactic cosmic ray (GCRsim) radiation at 15 and 50 cGy, to simulate predicted radiation exposures that would be experienced during lunar and Martian missions, respectively. Blood and adrenal tissues were collected at 3- and 14-days post-irradiation for analysis of immune and endocrine biosignatures and pathways. Sexually dimorphic adrenal gland weights and morphology, differential total RNA expression with corresponding gene ontology, and unique immune phenotypes were altered by GCRsim. In brief, this study offers new insights into sexually dimorphic immune and endocrine kinetics following simulated cosmic radiation exposure and highlights the necessity for personalized translational approaches for astronauts during exploration missions.

Impact of immediate interim restoration on peri-implant tissues around immediately placed single dental implants in the esthetic region: A systematic review and meta-analysis.

STATEMENT OF PROBLEM: Immediate implant placement with an immediate interim restoration is a well-established protocol. Nevertheless, a consensus regarding the impact of immediate interim restoration on peri-implant tissues around single dental implants is lacking. PURPOSE: The purpose of this systematic review and meta-analysis was to address the research question: "Does the placement of an immediate interim restoration influence the mid-facial mucosal (MFM) marginal and interdental papilla (IDP) levels around single dental implants placed in the anterior esthetic region by using an immediate implant placement protocol?" MATERIAL AND METHODS: A comprehensive literature search was made in the Medline/PubMed, Scopus, Cochrane, and Science Direct electronic databases for articles published in English evaluating the impact of immediate interim restoration on peri-implant tissues around single dental implants in the anterior esthetic region. The primary outcomes assessed were changes in the MFM marginal and IDP levels. Additional outcomes were marginal bone (MB) loss, esthetic outcomes involving the pink and white esthetic scores (PES and WES), implant survival rates, and patient reported outcome measures (PROMs). The risk of bias assessment was performed by using the RoB 2 tool for randomized trials and the Newcastle-Ottawa scale for nonrandomized studies. Meta-analysis was performed by using random and fixed effects model (α=.05) in the RevMan software program. RESULTS: Sixteen studies were included that analyzed 836 single dental implants involving 823 patients. The meta-analysis showed no significant differences in implants with and without interim restoration in terms of MFM marginal level (MD=0.01; 95% CI=-1.23 to 1.25; P=.98), mesial IDP level (MD=0.12; 95% CI=-0.23 to 0.47; P=.50), distal IDP level (MD=0.20; 95% CI=-0.40 to 0.79; P=.52), and MB loss (MD=0.01; 95% CI=-0.42 to 0.43; P=.97). The systematic analysis for survival rates determined no notable difference in implants with or without an interim restoration. However, the esthetic outcomes and PROMs substantially improved with immediate interim restorations. The RoB 2 tool showed a moderate to low risk of bias, and the Newcastle-Ottawa scale indicated high-quality studies. CONCLUSIONS: After a 12-month follow-up, immediate interim restoration had no significant impact on peri-implant soft (MFM marginal and IDP levels) and hard tissues (MB loss) around immediately placed single dental implants. Nevertheless, additional well-designed and well-implemented clinical trials with long-term follow-up periods are needed to provide more precise evidence-based recommendations.

Evaluation of marginal bone level, technical and biological complications between screw-retained and cement-retained all-ceramic implant-supported crowns on zirconia abutment: A systematic review and meta-analysis.

PURPOSE: The purpose of this study was to evaluate the difference in marginal bone level, technical and biological complications between screw-retained and cemented all-ceramic implant-supported crowns fabricated on zirconia abutment at different follow-up periods. MATERIALS AND METHODS: Independent search was conducted in Cochrane Library, EBSCO, and PubMed/PubMed Central/MEDLINE databases and the Google Scholar search engine for prospective studies and randomized controlled trials published between January 2014 and June 2023 evaluating the marginal bone level, technical and biological complications between screw-retained and cemented all-ceramic implant-supported crowns fabricated on zirconia abutment. Meta-analysis was conducted to assess the quantitative data on the marginal bone level and biological complications. RESULTS: A total of eight studies were included for qualitative synthesis and six studies for quantitative synthesis. For marginal bone level, no statistically significant difference was observed (P = 0.83 and P = 0.69, respectively) during the follow-up period of 3 years and 5 years. For probing depth, the cemented group showed more amount of probing depth than the screw-retained group at a follow-up period of 3 years (P < 0.05) whereas no statistically significant difference was observed at a follow-up period of 5 years (P = 0.73). For bleeding on probing, the cemented group showed more probing depth than the screw-retained group at a follow-up period of 5 years (P = 0.10). CONCLUSION: The evidence suggests that the screw-retained group showed no statistically significant difference in marginal bone level, comparatively fewer biological complications, and relatively higher technical complications than the cemented group at different follow-up periods.

A systematic review and meta-analysis of accuracy between protrusive interocclusal record and horizontal condylar guidance angle recording methods in dentulous patients.

AIM: This systematic review and meta-analysis aimed to evaluate the accuracy of different methods used for measuring horizontal condylar guidance (HCG) angle in comparison with protrusive interocclusal record (IOR) for dentulous patients. SETTINGS AND DESIGN: The design involves systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. MATERIALS AND METHODS: An electronic search was carried out by two reviewers in the Google Scholar search engine and the EBSCO host, Cochrane Library, and PubMed/MEDLINE databases for quasi-experimental studies, in vivo studies, and cross-sectional studies published from January 2005 to February 2023 determining the HCG angle in dentulous patients. STATISTICAL ANALYSIS USED: Meta-analysis was performed to evaluate the quantitative data. RESULTS: A total of 577 articles were identified, 29 analytical cross-sectional studies that fulfilled the eligibility criteria were included for qualitative synthesis and 26 studies were included for meta-analysis. A statistically significant difference was observed for the right and left HCG angles obtained by the panoramic radiograph method and cone-beam computed tomography (CBCT) method and for the right side HCG angle obtained by cephalogram method showing higher values than the protrusive IOR method. No statistically significant difference was observed for the left side HCG angle obtained by the cephalogram method and both the right and left side HCG angles obtained by the intraoral tracer method. CONCLUSIONS: The panoramic radiograph, cephalogram, and CBCT obtained higher HCG angles in dentulous patients than the protrusive IOR method.

Drosophila parasitoids go to space: Unexpected effects of spaceflight on hosts and their parasitoids.

While fruit flies (Drosophila melanogaster) and humans exhibit immune system dysfunction in space, studies examining their immune systems' interactions with natural parasites in space are lacking. Drosophila parasitoid wasps modify blood cell function to suppress host immunity. In this study, naive and parasitized ground and space flies from a tumor-free control and a blood tumor-bearing mutant strain were examined. Inflammation-related genes were activated in space in both fly strains. Whereas control flies did not develop tumors, tumor burden increased in the space-returned tumor-bearing mutants. Surprisingly, control flies were more sensitive to spaceflight than mutant flies; many of their essential genes were downregulated. Parasitoids appeared more resilient than fly hosts, and spaceflight did not significantly impact wasp survival or the expression of their virulence genes. Previously undocumented mutant wasps with novel wing color and wing shape were isolated post-flight and will be invaluable for host-parasite studies on Earth.

Artificial intelligence scoring of liver biopsies in a phase II trial of semaglutide in nonalcoholic steatohepatitis.

BACKGROUND AND AIMS: Artificial intelligence-powered digital pathology offers the potential to quantify histological findings in a reproducible way. This analysis compares the evaluation of histological features of NASH between pathologists and a machine-learning (ML) pathology model. APPROACH AND RESULTS: This post hoc analysis included data from a subset of patients (n=251) with biopsy-confirmed NASH and fibrosis stage F1-F3 from a 72-week randomized placebo-controlled trial of once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4 mg (NCT02970942). Biopsies at baseline and week 72 were read by 2 pathologists. Digitized biopsy slides were evaluated by PathAI's NASH ML models to quantify changes in fibrosis, steatosis, inflammation, and hepatocyte ballooning using categorical assessments and continuous scores. Pathologist and ML-derived categorical assessments detected a significantly greater percentage of patients achieving the primary endpoint of NASH resolution without worsening of fibrosis with semaglutide 0.4 mg versus placebo (pathologist 58.5% vs. 22.0%, p < 0.0001; ML 36.9% vs. 11.9%; p =0.0015). Both methods detected a higher but nonsignificant percentage of patients on semaglutide 0.4 mg versus placebo achieving the secondary endpoint of liver fibrosis improvement without NASH worsening. ML continuous scores detected significant treatment-induced responses in histological features, including a quantitative reduction in fibrosis with semaglutide 0.4 mg versus placebo ( p =0.0099) that could not be detected using pathologist or ML categorical assessment. CONCLUSIONS: ML categorical assessments reproduced pathologists' results of histological improvement with semaglutide for steatosis and disease activity. ML-based continuous scores demonstrated an antifibrotic effect not measured by conventional histopathology.