Comparative efficacy of pharmacologic therapies for MASH in reducing liver fat content: Systematic review and network meta-analysis.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. Dynamic changes in MRI proton-density-fat fraction (PDFF) are associated with MASH resolution. We aimed to determine the relative efficacy of therapeutic agents for reducing hepatic fat, assessed by MRI-PDFF. APPROACH AND RESULTS: In this systematic review and network meta-analysis, we searched MEDLINE and Embase from inception until December 26, 2023, for published randomized controlled trials comparing pharmacological interventions in patients with MASH that assessed changes in MRI-PDFF. The primary outcome was the absolute change in MRI-PDFF. The secondary outcome was a ≥30% decline in MRI-PDFF. A surface under-the-curve cumulative ranking probabilities (SUCRA) analysis was performed. Of 1550 records, a total of 39 randomized controlled trials (3311 participants) met the inclusion criteria. For MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were ranked the most effective interventions. At 24 weeks, efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were ranked the most effective interventions for achieving a ≥30% decline in MRI-PDFF. CONCLUSIONS: This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat. These data may help inform the design and sample size calculation of future clinical trials and assist in the selection of combination therapy.

Chikungunya virus nonstructural protein 1 is a versatile RNA capping and decapping enzyme.

Chikungunya virus (CHIKV) nonstructural protein 1 (nsP1) contains both the N7-guanine methyltransferase and guanylyltransferase activities and catalyzes the 5' end cap formation of viral RNAs. To further understand its catalytic activity and role in virus-host interaction, we demonstrate that purified recombinant CHIKV nsP1 can reverse the guanylyl transfer reaction and remove the m7GMP from a variety of capped RNA substrates including host mRNAs. We then provide the structural basis of this function with a high-resolution cryo-EM structure of nsP1 in complex with the unconventional cap-1 substrate RNA m7GpppAmU. We show that the 5'ppRNA species generated by decapping can trigger retinoic acid-inducible gene I-mediated interferon response. We further demonstrate that the decapping activity is conserved among the alphaviral nsP1s. To our knowledge, this is a new mechanism through which alphaviruses activate the antiviral immune response. This decapping activity could promote cellular mRNA degradation and facilitate viral gene expression, which is functionally analogous to the cap-snatching mechanism by influenza virus.

Prevalence of Chronic liver disease in Cholangiocarcinoma: a Meta-Analysis.

INTRODUCTION: Chronic liver disease is a known risk factor for cholangiocarcinoma (CCA), but the proportion of people with CCA who have concurrent chronic liver disease is unclear. We aimed to evaluate the prevalence of chronic liver diseases in people with cholangiocarcinoma. METHODS: In this single-arm meta-analysis, we searched MEDLINE and EMBASE from inception to 10 August 2024 for articles in English containing data for cholangiocarcinoma with and without chronic liver diseases. Data were pooled to obtain the prevalence of different chronic liver diseases, with further stratification by geographical location and tumor location. RESULTS: In total, 118068 individuals diagnosed with cholangiocarcinoma were included, of whom 16771 had chronic liver diseases. A pooled analysis of 109 studies determined that the prevalence of chronic liver disease was 25.23% (95% CI: 20.82% - 30.23%; I2=99.0%), and 10.21% (7.75% - 13.35%; I2=98.6%) of CCA patients had cirrhosis. Chronic liver diseases were associated more with intrahepatic CCAs, compared to extrahepatic CCAs (RR: 2.46, CI: 2.37 - 2.55, p < 0.0001). This was observed across all etiologies of liver disease, except for primary sclerosing cholangitis which was associated with extrahepatic CCAs (RR: 0.49; CI: 0.43 - 0.57, p < 0.0001). CONCLUSION: Around one in four people with cholangiocarcinoma have chronic liver diseases, and one in ten have cirrhosis.

Diet-induced obesity does not exacerbate cachexia in male mice bearing Lewis-lung carcinoma tumors.

Cachexia is a muscle-wasting syndrome commonly observed in patients with cancer, which can significantly worsen clinical outcomes. Because of a global rise in obesity, the coexistence of cachexia in obese individuals poses unique challenges, with the impact of excessive adiposity on cachexia severity and underlying pathophysiology not well defined. Understanding the interplay between cachexia and obesity is crucial for improving diagnosis and treatment strategies for these patients; therefore, the present study examined differences in cachexia between lean and obese mice bearing Lewis lung carcinoma (LLC) tumors. Nine-week-old, male C57Bl6J mice were placed on either a chow or a high-fat diet (HFD) for 9 wk. After the diet intervention, mice were inoculated with LLC or vehicle. Markers of cachexia, such as body and muscle loss, were noted in both chow and HFD groups with tumors. Tumor weight of HFD animals was greater than that of chow. LLC tumors reduced gastrocnemius, plantaris, and soleus mass, regardless of diet. The tibialis anterior and plantaris mass and cross-sectional area of type IIb/x fibers in the gastrocnemius were not different between HFD-chow, HFD-tumor, and chow-tumor. Using RNA sequencing (RNA-seq) of the plantaris muscle from chow-tumor and HFD-tumor groups, we identified ∼400 differentially expressed genes. Bioinformatic analysis identified changes in lipid metabolism, mitochondria, bioenergetics, and proteasome degradation. Atrophy was not greater despite larger tumor burden in animals fed an HFD, and RNA-seq data suggests that partial protection is mediated through differences in mitochondrial function and protein degradation, which may serve as future mechanistic targets.NEW & NOTEWORTHY This study provides timely information on the interaction between obesity and cancer cachexia. Lean and obese animals show signs of cachexia with reduced body weight, adipose tissue, and gastrocnemius muscle mass. There was not significant wasting in the tibialis anterior, plantaris, or fast twitch fibers in the gastrocnemius muscle of obese animals with tumors. RNA-seq analysis reveals that obese tumor bearing animals had differential expression of mitochondria- and degradation-related genes, which may direct future studies in mechanistic research.

Transmission of Mycobacterium tuberculosis to Healthcare Personnel Resulting From Contaminated Bone Graft Material, United States, June 2021-August 2022.

A nationwide tuberculosis outbreak linked to a viable bone allograft product contaminated with Mycobacterium tuberculosis was identified in June 2021. Our subsequent investigation identified 73 healthcare personnel with new latent tuberculosis infection following exposure to the contaminated product, product recipients, surgical instruments, or medical waste.

Meta-analysis and systematic review: Prevalence, graft failure, mortality, and post-operative thrombosis in liver transplant recipients with pre-operative portal vein thrombosis.

AIMS: This study seeks to evaluate the association between pre-transplant portal vein thrombosis (PVT) and overall survival, graft failure, waitlist mortality, and post-operative PVT after liver transplantation. METHODS: A conventional pairwise meta-analysis between patients with and without pre-transplant PVT was conducted using hazard ratios or odds ratios where appropriate. RESULTS: Prevalence of preoperative PVT was 11.6% (CI 9.70-13.7%). Pre-operative PVT was associated with increased overall mortality (HR 1.45, 95% CI 1.27-1.65) and graft loss (HR 1.58, 95% CI 1.34-1.85). In particular, grade 3 (HR 1.59, 95% CI 1.00-2.51) and 4 (HR 2.24, 95% CI 1.45-3.45) PVT significantly increased mortality, but not grade 1 or 2 PVT. Patients with PVT receiving living donor (HR 1.54, 95% CI 1.24-1.91) and deceased donor (HR 1.52, 95% CI 1.21-1.92) liver transplantation had increased mortality, with no significant difference between transplant types (P = .13). Furthermore, pre-transplant PVT was associated with higher occurrence of post-transplant PVT (OR 5.06, 95% CI 3.89-6.57). Waitlist mortality was not significantly increased in patients with pre-transplant PVT. CONCLUSION: Graft failure, mortality, and post-operative PVT are more common in pre-transplant PVT patients, especially in grade 3 or 4 PVT. Prophylactic anticoagulation can be considered to reduce re-thrombosis and improve survival.

Effect of additional acupuncture to pelvic floor exercise on urinary incontinence: A randomized controlled trial.

AIMS: To investigate the additional benefit of acupuncture to pelvic floor exercise (PFE) on the improvement of urinary incontinence (UI) and quality of life (QoL) in women. METHODS: This was a single-blinded randomized controlled trial in a tertiary university hospital. Women with UI in various severity and types were randomized to receive either a weekly course of acupuncture with PFE or PFE alone for 6 weeks and then followed up for 24 weeks in every 6 weeks. Investigators were blinded to group allocation in pre- and postintervention assessments. Primary outcome was subjective changes of UI symptoms at 24 weeks. Secondary outcomes were episodes and severity of UI from bladder diary, severity by Visual Analogue Scale, and QoL scores by validated Chinese short-form of Urogenital Distress Inventory (UDI-6) and Incontinence Impact Questionnaire (IIQ-7). RESULTS: One hundred seventy-nine women were screened while 137 were randomized. Significant subjective improvement in UI symptoms was demonstrated at all follow-up, latest at 24 weeks (odds ratio [OR]: 2.29, 95% confidence Interval [CI]: 1.02-5.12, respectively), with reduced episodes and severity of UI after (p < 0.05), and a trend of improvement in IIQ-7 score (p = 0.05). No major adverse events occurred. History of 2 years or longer duration of UI symptoms was associated with lower effectiveness of acupuncture (OR: 0.08, 95% CI: 0.01-0.68).

All-Cause Failure Rates Increase With Time Following Meniscal Repair Despite Favorable Outcomes: A Systematic Review and Meta-analysis.

PURPOSE: The purpose of this review is to perform a meta-analysis of studies reporting meniscus repair outcomes. Pooled analyses of such studies will provide an accurate estimate of the outcomes that can be expected following meniscal repair at various postoperative time points. METHODS: A meta-analysis of meniscal repair failure (defined as persistent symptoms, lack of healing on magnetic resonance imaging or revision surgery) and other clinical outcomes was performed following meniscal repair. Patients included had traumatic, nondegenerative meniscal tears, were skeletally mature, and had specific time-points after surgery. Repairs included were performed either in isolation, or with concomitant ACL reconstruction. Because of the inherent heterogeneity of single-arm meta-analyses, pooled analyses were performed using a random-effects model. RESULTS: Rates of all-cause meniscal repair failure was pooled to be 12% at 0-1 years (95% CI: .09-.16), 15% at 2-3 years (95% CI: .11-.20), and 19% at 4-6 years (95% CI: .13-.24). Sensitivity analysis for studies performing meniscal repair entirely on patients with concomitant ACL reconstruction (ACLR) showed comparable rates of failure at similar time intervals. Development of osteoarthritis, in patients with knees previously free from articular pathologies, was 4% at 2-3 years (95% CI: .02-.07), and 10% at 4-6 years (95% CI: .03-.25). CONCLUSION: Meniscus repair for traumatic injuries have an all-cause failure rate that increases from 12% to 19% through a time period ranging from 1-6 years following surgery. The failure rates were comparable for patients with meniscal repairs performed with concomitant ACLRs. LEVEL OF EVIDENCE: IV; Systematic Review of Level II-IV Studies.

Exacerbation of dystrophic cardiomyopathy by phospholamban deficiency mediated chronically increased cardiac Ca2+ cycling in vivo.

Cardiomyopathy is a significant contributor to morbidity and mortality in Duchenne muscular dystrophy (DMD). Membrane instability, leading to intracellular Ca2+ mishandling and overload, causes myocyte death and subsequent fibrosis in DMD cardiomyopathy. On a cellular level, cardiac myocytes from mdx mice have dysregulated Ca2+ handling, including increased resting Ca2+ and slow Ca2+ decay, especially evident under stress conditions. Sarco(endo)plasmic reticulum Ca2+ ATPase and its regulatory protein phospholamban (PLN) are potential therapeutic targets for DMD cardiomyopathy owing to their key role in regulating intracellular Ca2+ cycling. We tested the hypothesis that enhanced cardiac Ca2+ cycling would remediate cardiomyopathy caused by dystrophin deficiency. We used a genetic complementation model approach by crossing dystrophin-deficient mdx mice with PLN knockout (PLNKO) mice [termed double-knockout (DKO) mice]. As expected, adult cardiac myocytes isolated from DKO mice exhibited increased contractility and faster relaxation associated with increased Ca2+ transient peak height and faster Ca2+ decay rate compared with control mice. However, compared with wild-type, mdx, and PLNKO mice, DKO mice unexpectedly had reduced in vivo systolic and diastolic function as measured by echocardiography. Furthermore, Evans blue dye uptake was increased in DKO hearts compared with control, mdx, and PLNKO hearts, demonstrating increased membrane damage, which subsequently led to increased fibrosis in the DKO myocardium in vivo. In conclusion, despite enhanced intracellular Ca2+ handling at the myocyte level, DMD cardiomyopathy was exacerbated owing to unregulated chronic increases in Ca2+ cycling in DKO mice in vivo. These findings have potentially important implications for ongoing therapeutic strategies for the dystrophic heart. NEW & NOTEWORTHY This study examined the effects of phospholamban ablation on the pathophysiology of cardiomyopathy in dystrophin-deficient mice. In this setting, contractility and Ca2+ cycling were enhanced in isolated myocytes; however, in vivo heart function was diminished. Additionally, sarcolemmal integrity was compromised and fibrosis was increased. This is the first study, to our knowledge, examining unregulated Ca2+ cycling in the dystrophin-deficient heart. Results from this study have implications for potential therapies targeting Ca2+ handling in dystrophic cardiomyopathy. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/unregulated-ca2-cycling-exacerbates-dmd-cardiomyopathy/ .

Systematic contact investigation: An essential infection prevention skill to prevent tuberculosis transmission in healthcare settings.

A systematic approach to contact investigations has long been a cornerstone of interrupting the transmission of tuberculosis in community settings. This paper describes the implementation of a systematic 10-step contact investigation within an acute care setting during a multistate outbreak of healthcare-associated tuberculosis. A systematic approach to contact investigations might have applicability to the prevention of other communicable infections within healthcare settings.

Inflammatory risk contributes to post-COVID endothelial dysfunction through anti-ACKR1 autoantibody.

Subclinical vascular impairment can be exacerbated in individuals who experience sustained inflammation after COVID-19 infection. Our study explores the prevalence and impact of autoantibodies on vascular dysfunction in healthy COVID-19 survivors, an area that remains inadequately investigated. Focusing on autoantibodies against the atypical chemokine receptor 1 (ACKR1), COVID-19 survivors demonstrated significantly elevated anti-ACKR1 autoantibodies, correlating with systemic cytokines, circulating damaged endothelial cells, and endothelial dysfunction. An independent cohort linked these autoantibodies to increased vascular disease outcomes during a median 6.7-yr follow-up. We analyzed a single-cell transcriptome atlas of endothelial cells from diverse mouse tissues, identifying enriched Ackr1 expressions in venous regions of the brain and soleus muscle vasculatures, which holds intriguing implications for tissue-specific venous thromboembolism manifestations reported in COVID-19. Functionally, purified immunoglobulin G (IgG) extracted from patient plasma did not trigger cell apoptosis or increase barrier permeability in human vein endothelial cells. Instead, plasma IgG enhanced antibody-dependent cellular cytotoxicity mediated by patient PBMCs, a phenomenon alleviated by blocking peptide or liposome ACKR1 recombinant protein. The blocking peptide uncovered that purified IgG from COVID-19 survivors possessed potential epitopes in the N-terminal extracellular domain of ACKR1, which effectively averted antibody-dependent cellular cytotoxicity. Our findings offer insights into therapeutic development to mitigate autoantibody reactivity in blood vessels in chronic inflammation.

Variable body and tissue weight reporting in preclinical cachexia literature may alter study outcomes and interpretation.

Cancer cachexia is a multifactorial syndrome of body weight loss, muscle wasting and progressive functional decline, affecting many advanced cancer patients and leading to worsened clinical outcomes. Despite inherent limitations of many preclinical cachexia models, including large tumor burden, rapid tumor growth and young age of animals, these animal models are widely used and imperative for the study of cachexia mechanisms and experimental therapeutics. However, there are currently no guidelines for the reporting and representation of data in preclinical cachexia literature. We examined the current state of data reporting in publications using the colon-26 adenocarcinoma (C26) model of cachexia and compared statistical differences in reporting mechanisms using animals from our laboratory. We show that data reporting and representation in C26 preclinical cachexia literature are diverse, making comparison of study outcomes difficult. Further, different expression of body and tissue weights in our animals led to differential statistical significance, which could significantly alter data interpretation. This study highlights a need for consistent data reporting in preclinical cancer cachexia literature to effectively compare outcomes between studies and increase translatability to the human condition.

Targeting the alphavirus virus replication process for antiviral development.

Many alphaviruses, including chikungunya virus (CHIKV) are known human pathogens that lack specific and effective antivirals or vaccines available. The upstream portion of the positive-sense single-stranded RNA genome of alphaviruses encodes four nonstructural proteins: nsP1 to nsP4. They are expressed and autoprocessed to nonstructural proteins which assemble into a replication complex (RC) playing multiple essential roles on viral RNA replication and communication with the host components. The assembly of alphavirus RC and its RNA genome initiates the membrane-derived ultrastructure known as spherule which facilitates viral RNA synthesis protected from host immune responses. Recent advances in the molecular understanding of the high-resolution CHIKV RC heteromeric ultrastructure have provided new insights into the viral replication process. Hence, alphavirus RC presents as an ideal multi-enzyme target for the development of structure-based antiviral drugs. Moreover, the alphavirus RC has therapeutic potential in the form of self-amplifying RNA technology against both infectious and non-infectious diseases.

Cancer cachexia: Pathophysiology and association with cancer-related pain.

Cachexia is a syndrome of unintentional body weight loss and muscle wasting occurring in 30% of all cancer patients. Patients with cancers most commonly leading to brain metastases have a risk for cachexia development between 20 and 80%. Cachexia causes severe weakness and fatigue and negatively impacts quality and length of life. The negative energy balance in cachectic patients is most often caused by a combination of increased energy expenditure and decreased energy intake. Basal metabolic rate may be elevated due to tumor secreted factors and a systemic inflammatory response leading to inefficiency in energy production pathways and increased energy demand by the tumor and host tissues. A growing body of research explores physiological and molecular mechanisms of metabolic dysregulation in cachexia. However, decreased energy intake and physical functioning also remain important contributors to cachexia pathogenesis. Pain associated with metastatic malignancy is significantly associated with inflammation, thus making inflammation a common link between cancer pain and cachexia. Pain may also influence appetite and food intake and exacerbate fatigue and functional decline, potentially contributing to cachexia severity. Cancer pain and cachexia often occur simultaneously; however, causal relationships remain to be established. Appropriate assessment and treatment of pain in advanced cancer patients may positively impact nutrition status and physical functioning, slowing the progression of cachexia and improving quality and length of life for patients.

Cardiac Remodeling in Cancer-Induced Cachexia: Functional, Structural, and Metabolic Contributors.

Cancer cachexia is a syndrome of progressive weight loss and muscle wasting occurring in many advanced cancer patients. Cachexia significantly impairs quality of life and increases mortality. Cardiac atrophy and dysfunction have been observed in patients with cachexia, which may contribute to cachexia pathophysiology. However, relative to skeletal muscle, little research has been carried out to understand the mechanisms of cardiomyopathy in cachexia. Here, we review what is known clinically about the cardiac changes occurring in cachexia, followed by further discussion of underlying physiological and molecular mechanisms contributing to cachexia-induced cardiomyopathy. Impaired cardiac contractility and relaxation may be explained by a complex interplay of significant heart muscle atrophy and metabolic remodeling, including mitochondrial dysfunction. Because cardiac muscle has fundamental differences compared to skeletal muscle, understanding cardiac-specific effects of cachexia may bring light to unique therapeutic targets and ultimately improve clinical management for patients with cancer cachexia.

Leucine Supplementation in Cancer Cachexia: Mechanisms and a Review of the Pre-Clinical Literature.

Cancer cachexia (CC) is a complex syndrome of bodily wasting and progressive functional decline. Unlike starvation, cachexia cannot be reversed by increased energy intake alone. Nonetheless, targeted nutritional support is a necessary component in multimodal syndrome management. Due to the highly catabolic nature of cancer cachexia, amino acid supplementation has been proposed. Interestingly, leucine has been found to increase protein synthesis and decrease protein degradation via mTORC1 pathway activation. Multiple pre-clinical studies have explored the impact of leucine supplementation in cachectic tumor-bearing hosts. Here, we provide an overview of leucine's proposed modes of action to preserve lean mass in cachexia and review the current pre-clinical literature related to leucine supplementation during CC. Current research indicates that a leucine-rich diet may attenuate CC symptomology; however, these works are difficult to compare due to methodological differences. There is need for further pre-clinical work exploring leucine's potential ability to modulate protein turnover and immune response during CC, as well as the impact of additive leucine on tumor growth.

Molecular architecture of the Chikungunya virus replication complex.

To better understand how positive-strand (+) RNA viruses assemble membrane-associated replication complexes (RCs) to synthesize, process, and transport viral RNA in virus-infected cells, we determined both the high-resolution structure of the core RNA replicase of chikungunya virus and the native RC architecture in its cellular context at subnanometer resolution, using in vitro reconstitution and in situ electron cryotomography, respectively. Within the core RNA replicase, the viral polymerase nsP4, which is in complex with nsP2 helicase-protease, sits in the central pore of the membrane-anchored nsP1 RNA-capping ring. The addition of a large cytoplasmic ring next to the C terminus of nsP1 forms the holo-RNA-RC as observed at the neck of spherules formed in virus-infected cells. These results represent a major conceptual advance in elucidating the molecular mechanisms of RNA virus replication and the principles underlying the molecular architecture of RCs, likely to be shared with many pathogenic (+) RNA viruses.

Molecular basis of specific viral RNA recognition and 5'-end capping by the Chikungunya virus nsP1.

Many viruses encode RNA-modifying enzymes to edit the 5' end of viral RNA to mimic the cellular mRNA for effective protein translation, genome replication, and evasion of the host defense mechanisms. Alphavirus nsP1 synthesizes the 5' end Cap-0 structure of viral RNAs. However, the molecular basis of the capping process remains unclear. We determine high-resolution cryoelectron microscopy (cryo-EM) structures of Chikungunya virus nsP1 in complex with m7GTP/SAH, covalently attached m7GMP, and Cap-0 viral RNA. These structures reveal details of viral-RNA-capping reactions and uncover a sequence-specific virus RNA-recognition pattern that, in turn, regulates viral-RNA-capping efficiency to ensure optimal genome replication and subgenomic RNA transcription. This sequence-specific enzyme-RNA pairing is conserved across all alphaviruses.

Revealing the millipede and other soil-macrofaunal biodiversity in Hong Kong using a citizen science approach.

Background: Soil biodiversity plays important roles in nutrient recycling in both the environment and agriculture. However, they are generally understudied worldwide. To reveal the diversity of soil macrofauna in Hong Kong, here we initiated a citizen science project involving university, non-governmental organisations and secondary school students and teachers. It is envisioned that the citizen science approach used in this study could be used as a demonstration to future biodiversity sampling and monitoring studies. New information: Throughout a year of monitoring and species sampling across different localities in Hong Kong, 150 soil macrofaunal morphospecies were collected. Eighty five of them were further identified by morphology and DNA barcoding was assigned to each identified morphospecies, yielding a total of 646 DNA barcodes, with new millipede sequences deposited to the GenBank. The soil macrofauna morphospecies in Hong Kong found in this study are mainly dominated by millipedes (23 out of 150) and oligochaetes (15 out of 150). Amongst the twenty three identified millipedes, two polyxenid millipedes, Monographisqueenslandica Huynh & Veenstra, 2013 and Alloproctoidesremyi Marquet and Condé, 1950 are first recorded in Hong Kong. Information has been curated on an online platform and database (http://biodiversity.sls.cuhk.edu.hk/millipedes). A postcard summarising the findings of millipedes in Hong Kong has also been made as a souvenir and distributed to citizen participants. The identified macrofauna morphospecies and their 646 DNA barcodes in this study established a solid foundation for further research in soil biodiversity.