Pilot study of humanized glypican-3-targeted zirconium-89 immuno-positron emission tomography for hepatocellular carcinoma.

Purpose: Glypican-3 (GPC3)-targeted radioisotope immuno-positron emission tomography (immunoPET) may lead to earlier and more accurate diagnosis of hepatocellular carcinoma (HCC), thus facilitating curative treatment, decreasing early recurrence, and enhancing patient survival. We previously demonstrated reliable HCC detection using a zirconium-89-labeled murine anti-GPC3 antibody (89Zr-αGPC3M) for immunoPET. This study evaluated the efficacy of the humanized antibody successor (αGPC3H) to further clinical translation of a GPC3-based theranostic for HCC. Methods: In vitro αGPC3 binding to HepG2 cells was assessed by flow cytometry. In vivo 89Zr-αGPC3H and 89Zr-αGPC3M tumor uptake was evaluated by PET/CT and biodistribution studies in an orthotopic xenograft mouse model of HCC. Results: αGPC3H maintained binding to GPC3 in vitro and 89Zr-αGPC3H immunoPET identified liver tumors in vivo. PET/CT and biodistribution analyses demonstrated high 89Zr-αGPC3H tumor uptake and tumor-to-liver ratios, with no difference between groups. Conclusion: Humanized αGPC3 successfully targeted GPC3 in vitro and in vivo. 89Zr-αGPC3H immunoPET had comparable tumor detection to 89Zr-αGPC3M, with highly specific tumor uptake, making it a promising strategy to improve HCC detection.

Evaluating surgeon communication of pancreatic cancer prognosis using the VitalTalk ADAPT framework.

BACKGROUND AND OBJECTIVES: Few data exist to guide optimal communication practices for surgical oncologists. VitalTalk, an evidence-based communication skills training model for clinicians, offers the five-step ADAPT tool for discussing prognosis. This study aimed to characterize surgeon communication of pancreatic cancer prognosis using VitalTalk's ADAPT framework. METHODS: Contemporaneous audio recordings from 12 initial surgeon-patient encounters for borderline resectable pancreatic cancer were transcribed. Directed qualitative content analysis based on ADAPT (Ask, Discover, Anticipate, Provide, and Track) was used to deductively code transcripts. RESULTS: All encounters contained at least one ADAPT step while only one (8%) incorporated four or five steps. Surgeons provided prognostic information (Provide) in all but one encounter (92%); most was qualitative and clustered into themes: serious illness, surgical candidacy, prognostic ambiguity, and cancer recurrence. Surgeons elicited understanding (Ask), requested information preferences (Discover), anticipated ambivalence (Anticipate), and responded to emotion (Track) in a minority of encounters (25%-42%); of 15 patient emotional cues, six were not addressed by surgeons. CONCLUSIONS: During an initial encounter for pancreatic cancer, surgeons focus heavily on providing information but omit critical prognostic communication steps. Future studies are needed to investigate if surgeon training in palliative care-based communication is feasible and impacts patient-perceived quality of communication.

Novel metagenomics analysis of stony coral tissue loss disease.

Stony coral tissue loss disease (SCTLD) has devastated coral reefs off the coast of Florida and continues to spread throughout the Caribbean. Although a number of bacterial taxa have consistently been associated with SCTLD, no pathogen has been definitively implicated in the etiology of SCTLD. Previous studies have predominantly focused on the prokaryotic community through 16S rRNA sequencing of healthy and affected tissues. Here, we provide a different analytical approach by applying a bioinformatics pipeline to publicly available metagenomic sequencing samples of SCTLD lesions and healthy tissues from four stony coral species. To compensate for the lack of coral reference genomes, we used data from apparently healthy coral samples to approximate a host genome and healthy microbiome reference. These reads were then used as a reference to which we matched and removed reads from diseased lesion tissue samples, and the remaining reads associated only with disease lesions were taxonomically classified at the DNA and protein levels. For DNA classifications, we used a pathogen identification protocol originally designed to identify pathogens in human tissue samples, and for protein classifications, we used a fast protein sequence aligner. To assess the utility of our pipeline, a species-level analysis of a candidate genus, Vibrio, was used to demonstrate the pipeline's effectiveness. Our approach revealed both complementary and unique coral microbiome members compared to a prior metagenome analysis of the same dataset.

Clinical and Microbial Determinants of Upper Respiratory Colonization with Streptococcus pneumoniae and Native Microbiota in People with HIV-1 and Control Adults.

BACKGROUND: The substantial risk for respiratory and invasive infections with Streptococcus pneumoniae (Spn) among people with HIV-1 (PWH) begins with asymptomatic colonization. The frequency of Spn colonization among U.S. adults with and without HIV-1 infection is not well-characterized in the conjugate vaccine era. METHODS: We determined Spn colonization frequency by culture and specific lytA gene QPCR and microbiota profile by 16S rRNA gene sequencing in nasopharyngeal (NP) and oropharyngeal (OP) DNA from 138 PWH and 93 control adults and associated clinical characteristics. RESULTS: The frequencies of Spn colonization among PWH and controls did not differ (11.6% vs 8.6%, respectively; p=0.46) using combined results of culture and PCR, independent of vaccination or behavioral risks. PWH showed altered microbiota composition (i.e., beta-diversity. NP: p=0.0028, OP: p=0.0098), decreased alpha-diversity (NP: p=0.024, OP: p=0.0045), and differences in the relative abundance of multiple bacterial taxa. Spn colonization was associated with altered beta-diversity in the NP (p=0.011), but not OP (p=0.21). CONCLUSIONS: Despite widespread conjugate vaccine and antiretroviral use, frequencies of Spn colonization among PWH and controls are currently consistent with those reported in the pre-conjugate era. The persistently increased risk of pneumococcal disease despite ART may relate to behavioral and immunologic variables other than colonization.

Childcare disruptions and maternal health during the COVID-19 pandemic.

During the COVID-19 pandemic, nearly all US states enacted stay-at-home orders, upending usual childcare arrangements and providing a unique opportunity to study the association between childcare disruptions and maternal health. Using data from the 2021-2022 National Survey of Children's Health, we estimated the association between childcare disruptions due to the COVID-19 pandemic and self-reported mental and physical health among female parents of young children (ages 0-5 years). Further, we assessed racial, ethnic, and socioeconomic disparities in (1) the prevalence of childcare disruptions due to the COVID-19 pandemic and (2) the association between childcare disruptions and mental or physical health. Female parents who experienced childcare disruptions due to the COVID-19 pandemic were less likely to report excellent or very good mental (-7.4 percentage points) or physical (-2.5 percentage points) health. Further, childcare disruptions were more common among parents with greater socioeconomic privilege (ie, higher education, higher income), but may have been more detrimental to health among parents with less socioeconomic privilege (eg, lower education, lower income, and single parents). As state and federal policymakers take action to address the maternal health crisis in the United States, our findings suggest that measures to improve childcare stability may also promote maternal health and health equity.

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma.

Mutations in the microRNA processing genes DICER1 and DROSHA drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes. Pineal tumors driven by loss of Drosha or Dicer1 mimic tumors driven by Rb1 loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor Plagl2, which regulates expression of pro-growth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.

Pomegranate (Punica granatum L.) phytochemicals target the components of metabolic syndrome.

Pomegranate (Punica granatum L.) is a multipurpose dietary and medicinal plant known for its ability to promote various health benefits. Metabolic syndrome (MetS) is a complex metabolic disorder driving health and socioeconomic challenges worldwide. It may be characterized by insulin resistance, abdominal obesity, hypertension, and dyslipidemia. This study aims to conduct a review of pomegranate's effects on MetS parameters using a mechanistic approach relying on pre-clinical studies. The peel, juice, roots, bark, seeds, flowers, and leaves of the fruit present several bioactive compounds that are related mainly to anti-inflammatory and antioxidant activities as well as cardioprotective, antidiabetic, and antiobesity effects. The use of the juice extract can work as a potent inhibitor of angiotensin-converting enzyme activities, consequently regulating blood pressure. The major bioactive compounds found within the fruit are phenolic compounds (hydrolysable tannins and flavonoids) and fatty acids. Alkaloids, punicalagin, ellagitannins, ellagic acid, anthocyanins, tannins, flavonoids, luteolin, and punicic acid are also present. The antihyperglycemia, antihyperlipidemia, and weight loss promoting effects are likely related to the anti-inflammatory and antioxidant effects. When considering clinical application, pomegranate extracts are found to be frequently well-tolerated, further supporting its efficacy as a treatment modality. We suggest that pomegranate fruit, extract, or processed products can be used to counteract MetS-related risk factors. This review represents an important step towards exploring potential avenues for further research in this area.

Are minimally verbal autistic children's modality and form of communication associated with parent responsivity?

Prior work examined how minimally verbal (MV) children with autism used their gestural communication during social interactions. However, interactions are exchanges between social partners. Examining parent-child social interactions is critically important given the influence of parent responsivity on children's communicative development. Specifically, parent responses that are semantically contingent to the child's communication plays an important role in further shaping children's language learning. This study examines whether MV autistic children's (N = 47; 48-95 months; 10 females) modality and form of communication are associated with parent responsivity during an in-home parent-child interaction (PCI). The PCI was collected using natural language sampling methods and coded for child modality and form of communication and parent responses. Findings from Kruskal-Wallis H tests revealed that there was no significant difference in parent semantically contingent responses based on child communication modality (spoken language, gesture, gesture-speech combinations, and AAC) and form of communication (precise vs. imprecise). Findings highlight the importance of examining multiple modalities and forms of communication in MV children with autism to obtain a more comprehensive understanding of their communication abilities; and underscore the inclusion of interactionist models of communication to examine children's input on parent responses in further shaping language learning experiences.

Impact of COVID-19 on People Living With HIV: Data From Five Medical Monitoring Project Sites, 2020-2022.

BACKGROUND: The COVID-19 pandemic disrupted global economic and healthcare systems. People living with HIV (PLWH) represent a marginalized and stigmatized population who may have been particularly impacted. The purpose of this analysis was to describe the impact of the COVID-19 pandemic on PLWH in the United States. SETTING: United States. METHODS: We analyzed surveys of behavioral and clinical characteristics of PLWH residing in 5 states that participated in the Medical Monitoring Project between 2020 and 2022. We described the impact of COVID-19 illness, testing, and diagnoses; receipt of medical care; social service access; employment; and preventive measures by project site and demographic characteristics. RESULTS: Unweighted data from 1715 PLWH were analyzed. A high proportion of PLWH had medical care disrupted by the pandemic; 31% of PLWH missed medical appointments, 26% missed routine laboratory test results, and 7% missed antiretroviral therapy doses. In total, 30% of PLWH reported losing wages and 19% reported difficulty in accessing social services. Overall, 88% reported receiving at least 1 dose of COVID-19 vaccine, but vaccine uptake was low among younger, Black, and Hispanic or Latina/o/x PLWH. CONCLUSIONS: This descriptive analysis reinforces previous findings that show that COVID-19 negatively impacted PLWH and their ability to obtain medical care. Additional efforts will be critical to ameliorating the longer-term impacts of COVID-19 on the health of PLWH and supporting PLWH through future pandemics and healthcare system disruptions.

Antidepressant Prescriptions Increased For Privately Insured People With Perinatal Mood And Anxiety Disorder, 2008-20.

We aimed to determine whether antidepressant prescriptions for perinatal mood and anxiety disorder (PMAD) increased after several professional organizations issued clinical recommendations in 2015 and 2016. This serial, cross-sectional, logistic regression analysis evaluated changes in antenatal and postpartum antidepressant prescriptions among commercially insured people who had a live-birth delivery as well as a PMAD diagnosis during the period 2008-20. For people with antenatal PMAD, the odds of an antenatal antidepressant prescription decreased 3 percent annually from 2008 to 2016 and increased by 32 percent in 2017, and the annual rate of change increased 5 percent for 2017-20 compared with 2008-16. For people with postpartum PMAD, the odds of a postpartum antidepressant prescription decreased 2 percent annually from 2008 to 2016 and experienced no significant change in 2017, but the annual rate of change increased 3 percent for 2017-20 compared with 2008-16. The clinical recommendations issued in 2015 and 2016 were associated with increased antidepressant prescriptions for PMAD, particularly for antenatal PMAD. These findings indicate that clinical recommendations represent an effective tool for changing prescribing patterns.

Perinatal Posttraumatic Stress Disorder Diagnoses Among Commercially Insured People Increased, 2008-20.

Posttraumatic stress disorder (PTSD) is a burdensome disorder, affecting 3-4 percent of delivering people in the US, with higher rates seen among Black and Hispanic people. The extent of clinical diagnosis remains unknown. We describe the temporal and racial and ethnic trends in perinatal PTSD diagnoses among commercially insured people with live-birth deliveries during the period 2008-20, using administrative claims from Optum's Clinformatics Data Mart Database. Predicted probabilities from our logistic regression analysis showed a 394 percent increase in perinatal PTSD diagnoses, from 37.7 per 10,000 deliveries in 2008 to 186.3 per 10,000 deliveries in 2020. White people had the highest diagnosis rate at all time points (208.0 per 10,000 deliveries in 2020), followed by Black people, people with unknown race, Hispanic people, and Asian people (188.7, 171.9, 146.9, and 79.8 per 10,000 deliveries in 2020, respectively). The significant growth in perinatal PTSD diagnosis rates may reflect increased awareness, diagnosis, or prevalence of the disorder. However, these rates fall well below the estimated prevalence of PTSD in the perinatal population.

Kaposi sarcoma herpesvirus viral load in bronchoalveolar lavage as a diagnostic marker for pulmonary Kaposi sarcoma.

OBJECTIVE: Kaposi sarcoma is a vascular tumor that affects the pulmonary system. However, the diagnosis of airway lesions suggestive of pulmonary Kaposi sarcoma (pKS) is reliant on bronchoscopic visualization. We evaluated the role of Kaposi sarcoma herpesvirus (KSHV) viral load in bronchoalveolar lavage (BAL) as a diagnostic biomarker in patients with bronchoscopic evidence of pKS and evaluated inflammatory cytokine profiles in BAL and blood samples. DESIGN: In this retrospective study, we evaluated KSHV viral load and cytokine profiles within BAL and blood samples in patients who underwent bronchoscopy for suspected pKS between 2016 and 2021. METHODS: KSHV viral load and cytokine profiles were obtained from both the circulation and BAL samples collected at the time of bronchoscopy to evaluate compartment-specific characteristics. BAL was centrifuged and stored as cell pellets and KSHV viral load was measured using primers for the KSHV K6 gene regions. RESULTS: We evaluated 38 BAL samples from 32 patients (30 with HIV co-infection) of whom 23 had pKS. In patients with airway lesions suggestive of pKS, there was higher KSHV viral load (median 3188 vs. 0 copies/10 6 cell equivalent; P  = 0.0047). A BAL KSHV viral load cutoff of 526 copies/10 6 cells had a sensitivity of 72% and specificity of 89% in determining lesions consistent with pKS. Those with pKS also had higher IL-1ß and IL-8 levels in BAL. The 3-year survival rate for pKS patients was 55%. CONCLUSION: KSHV viral load in BAL shows potential for aiding in pKS diagnosis. Patients with pKS also have evidence of cytokine dysregulation in BAL.

Virtual Care: Perspectives From Family Physicians.

BACKGROUND: During the COVID-19 pandemic, virtual care expanded rapidly at Michigan Medicine and other health systems. From family physicians' perspectives, this shift to virtual care has the potential to affect workflow, job satisfaction, and patient communication. As clinics reopened and care delivery models shifted to a combination of in-person and virtual care, the need to understand physician experiences with virtual care arose in order to improve both patient and provider experiences. This study investigated Michigan Medicine family medicine physicians' perceptions of virtual care through qualitative interviews to better understand how to improve the quality and effectiveness of virtual care for both patients and physicians. METHODS: We employed a qualitative descriptive design to examine physician perspectives through semistructured interviews. We coded and analyzed transcripts using thematic analysis, facilitated by MAXQDA (VERBI) software. RESULTS: The results of the analysis identified four major themes: (a) chief concerns that are appropriate for virtual evaluation, (b) physician perceptions of patient benefits, (c) focused but contextually enriched patient-physician communication, and (d) structural support needed for high-quality virtual care. CONCLUSIONS: These findings can help further direct the discussion of how to make use of resources to improve the quality and effectiveness of virtual care.

Diabetic Osteomyelitis: Oral versus Intravenous Antibiotics at a Single Level 1 Academic Medical Trauma Center.

Residual osteomyelitis is a frequent problem following surgical intervention for diabetic foot infection. The Infectious Disease Society of America guidelines recommend a prolonged course of antibiotics for treatment of residual osteomyelitis. Recent literature suggests oral antibiotic therapy is not inferior to IV therapy. The primary aim of this study was to evaluate treatment success in 128 patients receiving oral versus IV antibiotics for residual osteomyelitis in the diabetic foot after amputation at a Level 1 academic medical trauma center. Treatment success was defined as completion of at least 4 weeks of antibiotic therapy, complete surgical wound healing, and no residual infection requiring further debridement or amputation within 1 year of the initial surgery. Patients with peripheral arterial disease were excluded. A retrospective chart review was performed, and we found no statistically significant difference in treatment success between these two groups (p = .2766). The median time to healing for oral antibiotic treatment was 3.17 months compared to 4.06 months for IV treatment (p = .1045). Furthermore, there was no significant difference in group demographics or comorbidities, aside from more patients in the IV group having coronary artery disease (p = .0416). The type of closure and whether the infection was single or polymicrobial were also not associated with a difference in outcomes between the two treatment arms. The results of the present study suggest oral antibiotics for treatment of residual osteomyelitis are not inferior to IV therapy and may be more efficacious for certain patients regarding cost and ease of administration.

Walking as a method for epistemic justice in sustainability.

We argue that walking as a method provides an integrative approach to advance epistemic justice in sustainability research. The theory and practice of walking as a method has grown quickly within the social sciences and arts but remains underrepresented in sustainability research, where walking is typically an object of study (e.g., urban walkability). We argue that walking should be valued as an important mode of knowledge production that simultaneously widens sustainability knowledge, integrates diverse knowledge systems, and supports transdisciplinary sustainability solutions. In this perspective article, we consider the following questions: (1) Why is walking important to sustainability knowledge? (2) How can walk-based methods advance epistemic justice in sustainability knowledge? (3) What outcomes might we expect from cultivating walking as a method for sustainability knowledge? We reflect on how walking as a method centers equity and the contributions of walk-based sustainability knowledge for research and policy.

Climate change disrupts the seasonal coupling of plant and soil microbial nutrient cycling in an alpine ecosystem.

The seasonal coupling of plant and soil microbial nutrient demands is crucial for efficient ecosystem nutrient cycling and plant production, especially in strongly seasonal alpine ecosystems. Yet, how these seasonal nutrient cycling processes are modified by climate change and what the consequences are for nutrient loss and retention in alpine ecosystems remain unclear. Here, we explored how two pervasive climate change factors, reduced snow cover and shrub expansion, interactively modify the seasonal coupling of plant and soil microbial nitrogen (N) cycling in alpine grasslands, which are warming at double the rate of the global average. We found that the combination of reduced snow cover and shrub expansion disrupted the seasonal coupling of plant and soil N-cycling, with pronounced effects in spring (shortly after snow melt) and autumn (at the onset of plant senescence). In combination, both climate change factors decreased plant organic N-uptake by 70% and 82%, soil microbial biomass N by 19% and 38% and increased soil denitrifier abundances by 253% and 136% in spring and autumn, respectively. Shrub expansion also individually modified the seasonality of soil microbial community composition and stoichiometry towards more N-limited conditions and slower nutrient cycling in spring and autumn. In winter, snow removal markedly reduced the fungal:bacterial biomass ratio, soil N pools and shifted bacterial community composition. Taken together, our findings suggest that interactions between climate change factors can disrupt the temporal coupling of plant and soil microbial N-cycling processes in alpine grasslands. This could diminish the capacity of these globally widespread alpine ecosystems to retain N and support plant productivity under future climate change.

Continuous Medicaid Eligibility During the COVID-19 Pandemic and Postpartum Coverage, Health Care, and Outcomes.

Importance: Pursuant to the Families First Coronavirus Response Act (FFCRA), continuous Medicaid eligibility during the COVID-19 public health emergency (PHE) created a de facto national extension of pregnancy Medicaid eligibility beyond 60 days postpartum. Objective: To evaluate the association of continuous Medicaid eligibility with postpartum health insurance, health care use, breastfeeding, and depressive symptoms. Design, Setting, and Participants: This cohort study using a generalized difference-in-differences design included 21 states with continuous prepolicy (2017-2019) and postpolicy (2020-2021) participation in the Pregnancy Risk Assessment Monitoring System (PRAMS). Exposures: State-level change in Medicaid income eligibility after 60 days postpartum associated with the FFCRA measured as a percent of the federal poverty level (FPL; ie, the difference in 2020 income eligibility thresholds for pregnant people and low-income adults/parents). Main Outcomes and Measures: Health insurance, postpartum visit attendance, contraceptive use (any effective method; long-acting reversible contraceptives), any breastfeeding and depressive symptoms at the time of the PRAMS survey (mean [SD], 4 [1.3] months postpartum). Results: The sample included 47 716 PRAMS respondents (64.4% aged <30 years; 18.9% Hispanic, 26.2% non-Hispanic Black, 36.3% non-Hispanic White, and 18.6% other race or ethnicity) with a Medicaid-paid birth. Based on adjusted estimates, a 100% FPL increase in postpartum Medicaid eligibility was associated with a 5.1 percentage point (pp) increase in reported postpartum Medicaid enrollment, no change in commercial coverage, and a 6.6 pp decline in uninsurance. This represents a 40% reduction in postpartum uninsurance after a Medicaid-paid birth compared with the prepolicy baseline of 16.7%. In subgroup analyses by race and ethnicity, uninsurance reductions were observed only among White and Black non-Hispanic individuals; Hispanic individuals had no change. No policy-associated changes were observed in other outcomes. Conclusions and Relevance: In this cohort study, continuous Medicaid eligibility during the COVID-19 PHE was associated with significantly reduced postpartum uninsurance for people with Medicaid-paid births, but was not associated with postpartum visit attendance, contraception use, breastfeeding, or depressive symptoms at approximately 4 months postpartum. These findings, though limited to the context of the COVID-19 PHE, may offer preliminary insight regarding the potential impact of post-pandemic postpartum Medicaid eligibility extensions. Collection of longer-term and more comprehensive follow-up data on postpartum health care and health will be critical to evaluating the effect of ongoing postpartum policy interventions.

Targeting Peroxisome Proliferator-Activated Receptor-ß/δ, Reactive Oxygen Species and Redox Signaling with Phytocompounds for Cancer Therapy.

Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-ß/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-ß/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-ß/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-ß/δ.

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk. The MASLD proteome was encoded by genes that demonstrated transcriptional enrichment in liver, with spatial transcriptional activity in areas of steatosis in human liver biopsy and dynamicity for select targets in human liver across stages of steatosis. We replicated several top relations from proteomics and spatial tissue transcriptomics in a humanized "liver-on-a-chip" model of MASLD, highlighting the power of a full translational approach to discovery in MASLD. Collectively, these results underscore utility of blood-based proteomics as a dynamic "liquid biopsy" of human liver relevant to clinical biomarker and mechanistic applications.