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.

Artificial intelligence-assisted digital pathology for non-alcoholic steatohepatitis: current status and future directions.

The worldwide prevalence of non-alcoholic steatohepatitis (NASH) is increasing, causing a significant medical burden, but no approved therapeutics are currently available. NASH drug development requires histological analysis of liver biopsies by expert pathologists for trial enrolment and efficacy assessment, which can be hindered by multiple issues including sample heterogeneity, inter-reader and intra-reader variability, and ordinal scoring systems. Consequently, there is a high unmet need for accurate, reproducible, quantitative, and automated methods to assist pathologists with histological analysis to improve the precision around treatment and efficacy assessment. Digital pathology (DP) workflows in combination with artificial intelligence (AI) have been established in other areas of medicine and are being actively investigated in NASH to assist pathologists in the evaluation and scoring of NASH histology. DP/AI models can be used to automatically detect, localise, quantify, and score histological parameters and have the potential to reduce the impact of scoring variability in NASH clinical trials. This narrative review provides an overview of DP/AI tools in development for NASH, highlights key regulatory considerations, and discusses how these advances may impact the future of NASH clinical management and drug development. This should be a high priority in the NASH field, particularly to improve the development of safe and effective therapeutics.

Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation.

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.

NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models.

The 1.6 Mbp deletion on chromosome 3q29 is associated with a range of neurodevelopmental disorders, including schizophrenia, autism, microcephaly, and intellectual disability. Despite its importance towards neurodevelopment, the role of individual genes, genetic interactions, and disrupted biological mechanisms underlying the deletion have not been thoroughly characterized. Here, we used quantitative methods to assay Drosophila melanogaster and Xenopus laevis models with tissue-specific individual and pairwise knockdown of 14 homologs of genes within the 3q29 region. We identified developmental, cellular, and neuronal phenotypes for multiple homologs of 3q29 genes, potentially due to altered apoptosis and cell cycle mechanisms during development. Using the fly eye, we screened for 314 pairwise knockdowns of homologs of 3q29 genes and identified 44 interactions between pairs of homologs and 34 interactions with other neurodevelopmental genes. Interestingly, NCBP2 homologs in Drosophila (Cbp20) and X. laevis (ncbp2) enhanced the phenotypes of homologs of the other 3q29 genes, leading to significant increases in apoptosis that disrupted cellular organization and brain morphology. These cellular and neuronal defects were rescued with overexpression of the apoptosis inhibitors Diap1 and xiap in both models, suggesting that apoptosis is one of several potential biological mechanisms disrupted by the deletion. NCBP2 was also highly connected to other 3q29 genes in a human brain-specific interaction network, providing support for the relevance of our results towards the human deletion. Overall, our study suggests that NCBP2-mediated genetic interactions within the 3q29 region disrupt apoptosis and cell cycle mechanisms during development.

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development.

While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

Evaluation of implant stability and increase in bone height in indirect sinus lift done with the osseodensification and osteotome technique: A systematic review and meta-analysis.

STATEMENT OF PROBLEM: Whether the use of osseodensification burs for indirect sinus lift improves primary implant stability and bone height as compared with the osteotome technique to overcome the challenges of the pneumatization of the maxillary sinus and vertical bone loss after extraction in the edentulous posterior maxilla is unclear. PURPOSE: The purpose of this systematic review and meta-analysis was to evaluate the difference in primary implant stability and increase in bone height in indirect sinus lift using osseodensification and the osteotome technique. MATERIAL AND METHODS: Two independent reviewers searched the MEDLINE/PubMed, EBSCO, and Cochrane Library databases and the Google Scholar Search engine for randomized clinical trials, nonrandomized clinical trials, and cross-sectional studies published from 2000 to 2022 to identify relevant studies evaluating the primary implant stability and increase in bone height in indirect sinus lift using osseodensification and the osteotome technique. A meta-analysis was performed to evaluate the cumulative data on primary implant stability and increase in bone height. RESULTS: A total of 8521 titles were obtained by electronic database search, of which 75 were duplicates. A total of 8446 abstracts were screened, and 8411 that were not relevant to the topic were excluded. Thirty-five articles were eligible for full-text assessment. After the screening of full-text articles as per the selection criteria, 26 studies were excluded. For qualitative synthesis, 9 studies were included. For quantitative synthesis, 5 studies were included. For an increase in bone height, no statistically significant difference was observed (I2 = 89%, P=.15, pooled mean difference=0.30 [-0.11, 0.70], CI=95%). For primary implant stability, the osseodensification group showed higher values than the osteotome group (I2 = 20%, P<.001, pooled mean difference=10.61 [7.14, 14.08], CI=95%). CONCLUSIONS: The evidence obtained from quantitative analysis of the studies determined that the osseodensification group showed higher primary implant stability than the osteotome group (P<.05). However, for mean increase in bone height, there was no statistically significant difference between the groups.

Diagnostic accuracy of ultrasonography compared with magnetic resonance imaging in diagnosing disc displacement of the temporomandibular joint: A systematic review and meta-analysis.

STATEMENT OF PROBLEM: Diagnosing temporomandibular disorders without an adjunctive chairside diagnostic tool has made the management of temporomandibular disorders challenging and subjective. The use of magnetic resonance imaging, considered the standard imaging modality, is hindered because of high cost, a long learning curve, availability, and a longer examination time. PURPOSE: The purpose of this systematic review and meta-analysis was to determine whether ultrasonography could be a chairside tool to help clinicians diagnose disc displacement in temporomandibular disorders. MATERIAL AND METHODS: An electronic search was conducted of the PubMed (including MEDLINE) and Cochrane Central database and the Google Scholar search engine for articles published from January 2000 to July 2020. Studies were chosen based on the inclusion criteria, which included the diagnostic technique's sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with respect to imaging the displacement of the articular disc. The quality assessment of diagnostic accuracy studies (QUADAS- 2) tool was applied to assess the risk of bias for the included studies. The Meta-Disc 1.4 and RevMan 5.3 software program were used to conduct the meta-analysis. RESULTS: Seventeen articles were included in this systematic review, and a meta-analysis of 14 articles was done after applying the inclusion and exclusion criteria. None of the included articles were considered to have applicability concerns; however, 2 articles had a high risk of bias. The sensitivities and specificities for the different selected studies vary substantially from 21% to 95% with a good pooled sensitivity estimate of 71% while the specificities varied from 15% to 96% with a good pooled specificity estimate of 76%. CONCLUSIONS: This systematic review and meta-analysis suggested that ultrasonography may have clinically acceptable diagnostic accuracy in diagnosing disc displacement of the temporomandibular joint, allowing the treatment of patients with temporomandibular disorders with greater assurance and success. Additional training in the operation and interpretation of ultrasonography is required to reduce the learning curve and make the use of ultrasonography relevant, straightforward, and routine in dentistry to supplement clinical examination and diagnosis in patients with suspected disc displacement of the temporomandibular joint. The evidence acquired needs to be standardized, and further research is required to provide stronger evidence.

Are we managing women with Recurrent Miscarriage appropriately? A snapshot survey of clinical practice within the United Kingdom.

The aim of this study was to evaluate clinicians' views of managing women with first-trimester Recurrent Miscarriage within the UK compared with RCOG guidance. An online survey of 150 Association of Early Pregnancy Units members was conducted using SurveyMonkey™. Analysis was limited to UK-based respondents (102). Of the three key investigations, 98% performed antiphospholipid antibodies (APA) screening, 93.1% performed karyotyping for subsequent miscarriages and 86.3% performed a pelvic ultrasound routinely. Other routine investigations included inherited thrombophilias (65.7%), thyroid function tests (51.9%), diabetes mellitus screening (35.3%), parental karyotyping (34.3%), androgen profile (25.5%), 3-D ultrasound (17.6%), hysteroscopy (12.7%), hysterosalpingogram (9.8%), Vitamin D (7.8%), peripheral natural killer cells (2.9%) and uterine natural killer cells (2.9%). APA-positive women were offered treatment by 97.1%; however, 23.5% routinely offered treatment for APA-negative women. Other treatments offered routinely included progesterone (27.5%) and metformin (1.9%). Most clinicians managed RM as recommended by RCOG, however we have highlighted considerable deviation from the RCOG guidelines.IMPACT STATEMENTWhat is already known on this subject? Recurrent miscarriage (RM) can cause significant distress to women and their partners prompting referrals for investigation and management of this condition. Although UK national clinical guidance exists published by RCOG, the adherence to the guidance in clinical practice is not known.What do the results of this study add? This study shows that most clinicians performed investigations recommended by RCOG when managing women with RM. However, we have highlighted considerable variation of practice; many additional investigations were routinely performed and a quarter of clinicians offered treatments outside the RCOG guidance.What are the implications of these findings for clinical practice and/or further research? This paper demonstrates considerable variation of practice across the UK. Clinical practice may continue to vary whilst there are separate guidelines available from different professional organisations worldwide. Collaboration to produce a general consensus could reduce the variation in the care that these women receive.

Molecular mechanisms of COMPLEXIN fusion clamp function in synaptic exocytosis revealed in a new Drosophila mutant.

The COMPLEXIN (CPX) proteins play a critical role in synaptic vesicle fusion and neurotransmitter release. Previous studies demonstrated that CPX functions in both activation of evoked neurotransmitter release and inhibition/clamping of spontaneous synaptic vesicle fusion. Here we report a new cpx mutant in Drosophila melanogaster, cpx(1257), revealing spatially defined and separable pools of CPX which make distinct contributions to the activation and clamping functions. In cpx(1257), lack of only the last C-terminal amino acid of CPX is predicted to disrupt prenylation and membrane targeting of CPX. Immunocytochemical analysis established localization of wild-type CPX to active zone (AZ) regions containing neurotransmitter release sites as well as broader presynaptic membrane compartments including synaptic vesicles. Parallel biochemical studies confirmed CPX membrane association and demonstrated robust binding interactions of CPX with all three SNAREs. This is in contrast to the cpx(1257) mutant, in which AZ localization of CPX persists but general membrane localization and, surprisingly, the bulk of CPX-SNARE protein interactions are abolished. Furthermore, electrophysiological analysis of neuromuscular synapses revealed interesting differences between cpx(1257) and a cpx null mutant. The cpx null exhibited a marked decrease in the EPSC amplitude, slowed EPSC rise and decay times and an increased mEPSC frequency with respect to wild-type. In contrast, cpx(1257) exhibited a wild-type EPSC with an increased mEPSC frequency and thus a selective failure to clamp spontaneous release. These results indicate that spatially distinct and separable interactions of CPX with presynaptic membranes and SNARE proteins mediate separable activation and clamping functions of CPX in neurotransmitter release.

The DISABLED protein functions in CLATHRIN-mediated synaptic vesicle endocytosis and exoendocytic coupling at the active zone.

Members of the DISABLED (DAB) family of proteins are known to play a conserved role in endocytic trafficking of cell surface receptors by functioning as monomeric CLATHRIN-associated sorting proteins that recruit cargo proteins into endocytic vesicles. Here, we report a Drosophila disabled mutant revealing a novel role for DAB proteins in chemical synaptic transmission. This mutant exhibits impaired synaptic function, including a rapid activity-dependent reduction in neurotransmitter release and disruption of synaptic vesicle endocytosis. In presynaptic boutons, Drosophila DAB and CLATHRIN were highly colocalized within two distinct classes of puncta, including relatively dim puncta that were located at active zones and may reflect endocytic mechanisms operating at neurotransmitter release sites. Finally, broader analysis of endocytic proteins, including DYNAMIN, supported a general role for CLATHRIN-mediated endocytic mechanisms in rapid clearance of neurotransmitter release sites for subsequent vesicle priming and refilling of the release-ready vesicle pool.

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.

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.

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.

Evaluation of accuracy between extraoral Gothic arch tracing and various other methods assessing horizontal condylar guidance angle in completely edentulous patients: A systematic review and meta-analysis.

Aim: The aim of this systematic review and meta-analysis was to determine the accuracy of different methods of measuring horizontal condylar guidance (HCG) angle in comparison with extraoral Gothic arch tracing for completely edentulous patients. Settings and Design: This was a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Materials and Methods: Two reviewers searched the EBSCOhost, Cochrane Library, and PubMed/MEDLINE databases and the Google Scholar search engine for in vivo studies, randomized controlled trials, cross-sectional studies, and quasi-experimental studies published from January 2005 to December 2022 on various other methods of determining HCG angle in completely edentulous patients compared with extraoral Gothic arch tracing method. Statistical Analysis Used: Meta-analysis was conducted from the reported quantitative data. Results: A total of 513 articles were obtained from different electronic databases, of which 22 studies were included for qualitative synthesis and 20 studies were included for meta-analysis. For the right side, a statistically significant difference was observed for panoramic radiograph (P < 0.05, pooled mean difference = 5.08 [2.17, 7]) and cephalogram (P < 0.05, pooled mean difference = 10.65 [8.81, 12.49]), whereas no statistically significant difference was observed for cone-beam computed tomography (CBCT) (P = 0.41, pooled mean difference = 4.39 [-6.10, 14.87]) and protrusive interocclusal wax record (P = 0.92, pooled mean difference = -0.45 [-9.62, 8.72]) as compared with extraoral Gothic arch tracing method. For the left side, a statistically significant difference was observed for panoramic radiograph (P < 0.05, pooled mean difference = 5.07 [1.95, 8.18]) and cephalogram (P < 0.05, pooled mean difference = 10.24 [8.65, 11.83]), whereas no statistically significant difference was observed for CBCT (P = 0.31, pooled mean difference = 4.05 [-3.74, 11.84]) and protrusive interocclusal wax record (P = 0.72, pooled mean difference = -1.21 [-7.86, 5.43]) as compared with extraoral Gothic arch tracing method. Conclusion: The cephalogram and panoramic radiograph obtained higher HCG angles in completely edentulous patients than extraoral Gothic arch tracing.

Galactic Cosmic Irradiation Alters Acute and Delayed Species-Typical Behavior in Male and Female Mice.

Exposure to space galactic cosmic radiation is a principal consideration for deep space missions. While the effects of space irradiation on the nervous system are not fully known, studies in animal models have shown that exposure to ionizing radiation can cause neuronal damage and lead to downstream cognitive and behavioral deficits. Cognitive health implications put humans and missions at risk, and with the upcoming Artemis missions in which female crew will play a major role, advance critical analysis of the neurological and performance responses of male and female rodents to space radiation is vital. Here, we tested the hypothesis that simulated Galactic Cosmic Radiation (GCRSim) exposure disrupts species-typical behavior in mice, including burrowing, rearing, grooming, and nest-building that depend upon hippocampal and medial prefrontal cortex circuitry. Behavior comprises a remarkably well-integrated representation of the biology of the whole animal that informs overall neural and physiological status, revealing functional impairment. We conducted a systematic dose-response analysis of mature (6-month-old) male and female mice exposed to either 5, 15, or 50 cGy 5-ion GCRSim (H, Si, He, O, Fe) at the NASA Space Radiation Laboratory (NSRL). Behavioral performance was evaluated at 72 h (acute) and 91-days (delayed) postradiation exposure. Specifically, species-typical behavior patterns comprising burrowing, rearing, and grooming as well as nest building were analyzed. A Neuroscore test battery (spontaneous activity, proprioception, vibrissae touch, limb symmetry, lateral turning, forelimb outstretching, and climbing) was performed at the acute timepoint to investigate early sensorimotor deficits postirradiation exposure. Nest construction, a measure of neurological and organizational function in rodents, was evaluated using a five-stage Likert scale 'Deacon' score that ranged from 1 (a low score where the Nestlet is untouched) to 5 (a high score where the Nestlet is completely shredded and shaped into a nest). Differential acute responses were observed in females relative to males with respect to species-typical behavior following 15 cGy exposure while delayed responses were observed in female grooming following 50 cGy exposure. Significant sex differences were observed at both timepoints in nest building. No deficits in sensorimotor behavior were observed via the Neuroscore. This study revealed subtle, sexually dimorphic GCRSim exposure effects on mouse behavior. Our analysis provides a clearer understanding of GCR dose effects on species typical, sensorimotor and organizational behaviors at acute and delayed timeframes postirradiation, thereby setting the stage for the identification of underlying cellular and molecular events.

Clinical trial: Effects of pegozafermin on the liver and on metabolic comorbidities in subjects with biopsy-confirmed nonalcoholic steatohepatitis.

BACKGROUND: An approved therapy for nonalcoholic steatohepatitis (NASH) and fibrosis remains a major unmet medical need. AIM: To investigate the histological and metabolic benefits of pegozafermin, a glycoPEGylated FGF21 analogue, in subjects with biopsy-confirmed NASH. METHODS: This proof-of-concept, open-label, single-cohort study, part 2 of a phase 1b/2a clinical trial, was conducted at 16 centres in the United States. Adults (age 21-75 years) with NASH (stage 2 or 3 fibrosis, NAS≥4) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) ≥8% received subcutaneous pegozafermin 27 mg once weekly for 20 weeks. Primary outcomes were improvements in liver histology, and safety and tolerability. RESULTS: Of 20 enrolled subjects, 19 completed the study. Twelve subjects (63%) met the primary endpoint of ≥2-point improvement in NAFLD activity score with ≥1-point improvement in ballooning or lobular inflammation and no worsening of fibrosis. Improvement of fibrosis without worsening of NASH was observed in 26% of subjects, and NASH resolution without worsening of fibrosis in 32%. Least-squares mean relative change from baseline in MRI-PDFF was -64.7% (95% CI: -71.7, -57.7; p < 0.0001). Significant improvements from baseline were also seen in serum aminotransferases, noninvasive fibrosis tests, serum lipids, glycaemic control and body weight. Adverse events (AEs) were reported in 18 subjects (90%). The most frequently reported AEs were mild/moderate nausea and diarrhoea. There were no serious AEs, discontinuations due to AEs, or deaths. CONCLUSIONS: Pegozafermin treatment for 20 weeks had beneficial effects on hepatic and metabolic parameters and was well tolerated in subjects with NASH. CLINICALTRIALS: gov: NCT04048135.

Circuits and Biomarkers of the Central Nervous System Relating to Astronaut Performance: Summary Report for a NASA-Sponsored Technical Interchange Meeting.

Biomarkers, ranging from molecules to behavior, can be used to identify thresholds beyond which performance of mission tasks may be compromised and could potentially trigger the activation of countermeasures. Identification of homologous brain regions and/or neural circuits related to operational performance may allow for translational studies between species. Three discussion groups were directed to use operationally relevant performance tasks as a driver when identifying biomarkers and brain regions or circuits for selected constructs. Here we summarize small-group discussions in tables of circuits and biomarkers categorized by (a) sensorimotor, (b) behavioral medicine and (c) integrated approaches (e.g., physiological responses). In total, hundreds of biomarkers have been identified and are summarized herein by the respective group leads. We hope the meeting proceedings become a rich resource for NASA's Human Research Program (HRP) and the community of researchers.