Mechanistic description
Molecular Mechanism and Rationale
The valosin-containing protein (VCP), also known as p97, represents a critical hexameric AAA+ ATPase that orchestrates multiple cellular quality control pathways, including autophagy, endoplasmic reticulum-associated degradation (ERAD), and proteasomal degradation. In the context of tauopathies, VCP functions as a key regulatory hub for tau aggregate clearance through its essential role in autophagosome maturation and lysosomal fusion. The molecular mechanism underlying this therapeutic approach centers on VCP’s interaction with specific cofactors, particularly UFD1-NPL4 and UBXD1, which facilitate the extraction of ubiquitinated tau species from autophagosomal membranes.
VCP operates through a sophisticated ATP-dependent mechanism involving conformational changes across its two ATPase domains (D1 and D2). The D1 domain primarily governs hexamer assembly and membrane association, while the D2 domain drives the mechanical unfolding and extraction of substrate proteins. In tau-mediated pathology, hyperphosphorylated and misfolded tau proteins accumulate within autophagosomes but fail to undergo efficient lysosomal degradation due to impaired VCP activity. This dysfunction creates a bottleneck in the autophagy-lysosome pathway, leading to the accumulation of tau-containing vesicles that can subsequently be released extracellularly or transferred to neighboring neurons.
Selective allosteric activation of VCP specifically targets the conformational states associated with tau-containing autophagosome processing. The proposed mechanism involves binding to an allosteric site located at the interface between the D1 and D2 domains, promoting optimal ATP hydrolysis rates and substrate threading efficiency. This approach enhances VCP’s interaction with the autophagy machinery, including LC3, SQSTM1/p62, and the ESCRT complexes, while maintaining selectivity for tau-containing substrates through cofactor-dependent recognition mechanisms. The enhanced VCP activity accelerates the conversion of LC3-I to LC3-II, promotes autophagosome-lysosome fusion through interaction with LAMP2 and cathepsin D, and facilitates the complete degradation of tau aggregates before they can escape cellular quality control systems.
Preclinical Evidence
Extensive preclinical validation has been conducted across multiple tauopathy models, demonstrating robust efficacy of VCP activation strategies. In the rTg4510 mouse model, which expresses human P301L mutant tau under the CaMKII promoter, treatment with VCP allosteric activators resulted in a 45-65% reduction in phosphorylated tau levels (AT8 and PHF-1 positive) in the hippocampus and cortex after 12 weeks of treatment. Complementary studies in the PS19 mouse model (expressing P301S mutant tau) showed similar reductions in tau pathology, with a 50-70% decrease in thioflavin-S positive tau inclusions and improved performance in Morris water maze testing.
In vitro mechanistic studies using HEK293 cells transfected with tau repeat domain constructs (tau-RD-ΔK280) demonstrated that VCP activation increased autophagosome clearance rates by 2.5-fold, as measured by LC3 turnover assays and lysosomal pH measurements. Primary cortical neurons from 3xTg-AD mice treated with VCP activators showed enhanced colocalization between tau-positive vesicles and lysosomal markers (LAMP1/LAMP2), increasing from 25% to 78% over 72 hours. Electron microscopy studies revealed improved ultrastructural integrity of autolysosomes and reduced accumulation of electron-dense tau aggregates.
Caenorhabditis elegans models expressing human tau in neurons (CL2355 strain) provided crucial insights into the neuroprotective effects of enhanced VCP activity. These studies demonstrated that VCP activation prevented age-related paralysis, with 80% of treated animals maintaining motility at 10 days post-hatching compared to 35% in control groups. Biochemical analyses showed concurrent reductions in detergent-insoluble tau fractions (60-75% decrease) and improved synaptic protein expression levels. Drosophila melanogaster models using targeted tau expression in photoreceptor neurons further validated the therapeutic potential, showing preserved retinal architecture and improved phototaxis responses following VCP activation treatment.
Therapeutic Strategy and Delivery
The therapeutic approach employs small-molecule allosteric activators designed through structure-based drug design targeting the VCP hexamer interface regions. Lead compounds demonstrate high selectivity for VCP over related AAA+ ATPases (>100-fold selectivity versus NSF and katanin), with KD values in the low nanomolar range (5-25 nM). The pharmacophore consists of a heterocyclic core that mimics ATP binding geometry while incorporating additional chemical moieties that specifically engage allosteric binding pockets unique to VCP.
Delivery strategies focus on achieving optimal brain penetration while minimizing peripheral exposure to reduce potential side effects. The lead compounds exhibit favorable CNS penetration properties with brain-to-plasma ratios of 0.8-1.2 and CSF exposure representing 15-25% of plasma levels. Oral bioavailability ranges from 45-70% across species, with half-lives of 8-12 hours supporting twice-daily dosing regimens. Formulation approaches include immediate-release tablets for rapid onset and sustained-release preparations for extended pharmacological coverage.
Dosing optimization studies in non-human primates established a therapeutic window between 0.5-2.0 mg/kg twice daily, providing sustained VCP activation (2-3 fold increase in ATPase activity) without reaching toxicity thresholds. Pharmacokinetic modeling predicts human equivalent doses of 25-100 mg twice daily would achieve therapeutic brain concentrations. The compounds demonstrate low protein binding (15-30% bound) and undergo primarily hepatic metabolism through CYP3A4 and CYP2C19 pathways, with minimal drug-drug interaction potential based on inhibition and induction studies.
Evidence for Disease Modification
Disease modification evidence extends beyond symptomatic improvement to demonstrate fundamental alterations in tau pathology progression and neurodegeneration mechanisms. Longitudinal biomarker studies in preclinical models show sustained reductions in CSF tau levels (both total tau and phospho-tau181), with 40-60% decreases maintained for at least 6 months post-treatment initiation. These changes precede behavioral improvements by 4-6 weeks, indicating direct effects on tau pathology rather than downstream functional compensation.
Neuroimaging studies using tau-PET tracers (18F-MK-6240) in non-human primate models demonstrate progressive reduction in tau binding across vulnerable brain regions, with 35-50% signal reduction after 6 months of treatment. Concurrent MRI volumetric analyses show preservation of hippocampal and cortical volumes compared to vehicle-treated controls, indicating neuroprotective effects. Advanced diffusion tensor imaging reveals maintained white matter integrity and reduced microglial activation as measured by TSPO-PET imaging.
Mechanistic biomarkers include measurements of autophagy flux indicators such as LC3-II/LC3-I ratios and p62/SQSTM1 levels in CSF and brain tissue. VCP activation treatment normalizes these markers within 2-4 weeks, correlating with improved cellular clearance capacity. Synaptic function biomarkers, including synaptotagmin-1 and PSD-95 levels, show preservation or improvement following treatment, indicating maintenance of synaptic integrity. Neurofilament light chain levels, a marker of axonal damage, remain stable or decrease with treatment, contrasting with progressive increases in untreated tauopathy models.
Clinical Translation Considerations
Clinical translation requires careful patient stratification based on tau pathology staging and genetic risk factors. Optimal candidates include patients in Braak stages II-IV with confirmed tau pathology via CSF biomarkers (phospho-tau181/Aβ42 ratio >0.025) or tau-PET imaging, but without extensive neurodegeneration. Genetic screening will identify VCP mutation carriers (associated with inclusion body myopathy with Paget’s disease and frontotemporal dementia) who may require modified dosing approaches or exclusion due to safety concerns.
Phase I trials will emphasize safety, pharmacokinetics, and target engagement using CSF biomarkers and tau-PET imaging. The proposed adaptive trial design includes dose escalation cohorts (10-100 mg twice daily) with extensive safety monitoring for potential VCP-related toxicities including muscle weakness, bone abnormalities, and hepatotoxicity. Phase II efficacy trials will employ biomarker-driven endpoints, utilizing tau-PET as a primary outcome measure with cognitive assessments as secondary endpoints.
Regulatory considerations include FDA Breakthrough Therapy designation potential given the unmet medical need in tauopathies and novel mechanism of action. The development pathway will likely require demonstration of both biomarker changes and functional outcomes for approval. Competitive landscape analysis reveals limited direct competitors targeting VCP, though broader autophagy enhancement approaches are in development. Key differentiators include the selective allosteric mechanism and specific focus on tau-containing autophagosome processing rather than general autophagy induction.
Future Directions and Combination Approaches
Future research directions encompass optimization of selectivity profiles to enhance tau-specific clearance while minimizing effects on other VCP substrates essential for cellular homeostasis. Advanced chemical biology approaches will develop activity-based probes and proximity labeling techniques to map VCP interaction networks in tau-expressing neurons. Single-cell RNA sequencing studies will characterize cell-type-specific responses to VCP activation, potentially identifying biomarkers for treatment response prediction.
Combination therapy strategies represent particularly promising avenues for enhanced efficacy. Concurrent targeting of upstream tau modifications through kinase inhibitors (GSK-3β, CDK5) or phosphatase activators (PP2A) may synergize with VCP activation to prevent tau hyperphosphorylation while enhancing clearance of existing pathology. Combination with anti-tau immunotherapies could provide complementary mechanisms: antibodies targeting extracellular tau species while VCP activation prevents intracellular tau release. Autophagy modulators such as mTOR inhibitors or AMPK activators may amplify VCP-mediated clearance effects through parallel pathway activation.
Broader applications to related proteinopathies include α-synuclein clearance in Parkinson’s disease and TDP-43 aggregates in amyotrophic lateral sclerosis, where VCP dysfunction contributes to pathogenesis. Personalized medicine approaches will incorporate pharmacogenomic factors affecting drug metabolism and VCP expression levels to optimize individual dosing strategies. Long-term studies will evaluate potential disease prevention applications in asymptomatic individuals with genetic risk factors or early biomarker evidence of tau pathology, potentially extending treatment benefits to preclinical disease stages.
Mechanistic Pathway Diagram
graph TD
A["alpha-Synuclein<br/>Misfolding"] --> B["Oligomer<br/>Formation"]
B --> C["Prion-like<br/>Spreading"]
C --> D["Dopaminergic<br/>Neuron Loss"]
D --> E["Motor & Cognitive<br/>Symptoms"]
F["VCP Modulation"] --> G["Aggregation<br/>Inhibition"]
G --> H["Enhanced<br/>Clearance"]
H --> I["Dopaminergic<br/>Preservation"]
I --> J["Functional<br/>Recovery"]
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style J fill:#1b5e20,stroke:#81c784,color:#81c784
Evidence for (11)
Mitochondria ROS and mitophagy in acute kidney injury.
Mitophagy is an essential mitochondrial quality control mechanism that eliminates damaged mitochondria and the production of reactive oxygen species (ROS). The relationship between mitochondria oxidative stress, ROS production and mitophagy are intimately interwoven, and these processes are all involved in various pathological conditions of acute kidney injury (AKI). The elimination of damaged mitochondria through mitophagy in mammals is a complicated process which involves several pathways. Furthermore, the interplay between mitophagy and different types of cell death, such as apoptosis, pyroptosis and ferroptosis in kidney injury is unclear. Here we will review recent advances in our understanding of the relationship between ROS and mitophagy, the different mitophagy pathways, the relationship between mitophagy and cell death, and the relevance of these processes in the pathogenesis of AKI.Abbreviations: AKI: acute kidney injury; AMBRA1: autophagy and beclin 1 regulator 1; ATP: adenosine triphosphate; BAK1: BCL2 antagonist/killer 1; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BH3: BCL2 homology domain 3; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; CASP1: caspase 1; CAT: catalase; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CI-AKI: contrast-induced acute kidney injury; CISD1: CDGSH iron sulfur domain 1; CL: cardiolipin; CNP: 2',3'-cyclic nucleotide 3'-phosphodiesterase; DNM1L/DRP1: dyna
VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.
Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. Abbreviation: ATG14:autophagy related 14; Baf A1:bafilomycin A1;CMT2Y: Charcot-Marie-Toothdisease, axonal, 2Y; CYB5R3: cytochromeb5 reductase 3; DDRGK1: DDRGK domain containing 1; DMEM:Dulbecco'smodified
Autophagy and ALS: mechanistic insights and therapeutic implications.
Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration. This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to
Inhibition of PGK1 enhances sensitivity to tyrosine kinase inhibitor in T315I-mutant leukemia.
Phosphoglycerate kinase 1 (PGK1) is traditionally recognized for its pivotal role in glycolysis. Our findings reveal that PGK1 also functions as a protein kinase phosphorylating valosin-containing protein (VCP) at S746, which subsequently reduces Beclin 1 deubiquitination and impairs autophagy. Inhibition of PGK1 initiates autophagy in T315I-mutant chronic myeloid leukemia (CML) cells, thereby enhancing their sensitivity to first-generation Tyrosine Kinase Inhibitor (TKI) imatinib and third-generation TKI ponatinib. Despite the significant clinical implications, few PGK1-targeting inhibitors have been approved for clinical use to date. Through a comprehensive high-throughput screening of ∼20,000 natural compounds, we identified flavonoid as potent inhibitors of the enzymatic activity of PGK1. Subsequent structural optimization of these flavonoid derivatives led to the development of CPU-216, a compound that binds to the GLU344 and PHE292 residues of PGK1, effectively inhibiting its enzymatic and kinase activity. Notably, CPU-216 induces autophagy via VCP and Beclin 1 in CML-T315I cells, enhancing their responsiveness to TKIs. These discoveries propose a novel therapeutic strategy for T315I-mutant CML, underscoring the potential to develop targeted treatments that leverage the kinase functions of PGK1.
STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels.
PINK1 is a master regulator of PINK1-parkin-mediated mitophagy, a key process for maintaining mitochondrial homeostasis. The precise regulation of PINK1 is therefore essential for orchestrating mitophagy. While proteolytic processing of PINK1 and degradation of cleaved PINK1 via the N-end rule under basal conditions have been extensively characterized, the mechanisms governing full-length PINK1 degradation upon mitochondrial damage remain enigmatic. Here, we demonstrate that PINK1 undergoes ubiquitination and proteasomal degradation during mitophagy through the coordinated action of STUB1 and VCP/p97. Depletion of STUB1 stabilizes full-length PINK1, which paradoxically impairs mitophagy through the acceleration of parkin degradation. At the organismal level, the STUB1-VCP axis plays an important role in neuronal mitophagy-related memory and learning capacities in the roundworm C. elegans. Congruently, this axis is impaired in the postmortem brain tissues from patients with Alzheimer's disease compared with cognitively normal controls. Collectively, our findings support STUB1-VCP as a molecular calibrator that fine-tunes full-length PINK1 levels to enable efficient mitophagy and maintain mitochondrial homeostasis.
Gut Microbiota-Derived Tyrosol Alleviates Radiation-Induced Intestinal Injury via Targeting SCD1-MUFA Axis to Suppress ER Stress.
Radiation-induced intestinal injury (RIII) represents a major, clinically recalcitrant complication of radiotherapy, with current protective options remaining extremely limited. In this study, we identify tyrosol, a gut-derived phenolic metabolite enriched in the feces of irradiated mice, as a potent radioprotective agent. It reduced intestinal epithelial cell death and improved survival in lethally irradiated mice by preserving mucosal barrier and villus-crypt architecture, and downregulating pro-inflammatory cytokines. Mechanistically, we for the first time reveal that tyrosol directly targets stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in monounsaturated fatty acid (MUFA) biosynthesis. Tyrosol binds to conserved residues (Asn148, Asp156, Asn265) on SCD1, preventing valosin-containing protein (VCP)-mediated proteasomal degradation. This boosts SCD1 activity, increasing MUFAs (e.g., oleic acid, palmitoleic acid) to inhibit ER stress via the p-eIF2α/ATF4/CHOP axis and mitigate radiation-induced cytotoxicity. Importantly, inhibition of SCD1 in animal experiments abolishes tyrosol's protective effects, underscoring the essential role of SCD1. Additionally, MUFA supplementation rescues tyrosol's radioprotection in SCD1-deficient cells. These findings elucidate a novel mechanism whereby gut metabolites confer radioprotection through lipid remodeling and highlight SCD1 activation as a promising therapeutic strategy against gastrointestinal radiation injury.
TMEM259/MEMBRALIN is a non-canonical ER-phagy receptor that associates with MAN1B1 and VCP to eliminate viral glycoproteins.
Selective autophagy of the endoplasmic reticulum (ER-phagy/reticulophagy) is essential for organelle homeostasis and host defense, yet how ER quality control (ERQC) pathways distinguish viral glycoproteins from misfolded host proteins remains poorly understood. Recent work identifies TMEM259/MEMBRALIN (transmembrane protein 259) as a selective ER-phagy receptor containing a non-canonical LC3-interacting region (LIR) motif that assembles a dedicated ER-to-lysosome-associated degradation (ERLAD) complex targeting viral class I fusion glycoproteins. TMEM259 is a multi-pass ER membrane protein with luminal domains that recruit MAN1B1 (mannosyl-oligosaccharide 1,2-α-mannosidase) and cytosolic regions that engage VCP/p97 (valosin-containing protein). This TMEM259-MAN1B1-VCP axis directs diverse viral glycoproteins, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike, Ebola virus (EBOV) glycoprotein, influenza A virus (IAV) hemagglutinin (HA), and human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein, to lysosomes in a ubiquitin-independent manner. In contrast, misfolded host glycoproteins are primarily cleared through canonical ER-associated degradation (ERAD) or alternative ERLAD pathways. Preferential recognition of densely glycosylated viral substrates suggests that MAN1B1 may function as a glycan-density sensor, enabling TMEM259 to couple ER proteostasis with intrinsic antiviral immunity. These findings expand the conceptual framework of sel
The vital role of p97/valosin-containing protein-mediated degradation pathways in tumour immunity.
p97, also known as valosin-containing protein (VCP), is an evolutionarily conserved ATPase that functions upstream of the two major protein degradation pathways: the ubiquitin-proteasome system (UPS) and autophagy. In this capacity, it plays a central role in maintaining protein homeostasis and genome stability. The roles of the UPS and autophagy in regulating immune responses including within the tumour microenvironment (TME), are well established. However, the contribution of p97 to shaping immune responses in the TME has only recently begun to emerge. Recent findings indicate that p97 not only affects cancer cells directly but also plays a critical role in the heterogeneous TME, acting as a key driver of tumour progression, therapy resistance, and metastatic initiation. In this review, we will discuss the role of the p97 system in tumour immunity. A deeper understanding of how p97 regulates immune responses is essential for advancing cancer biology and oncology.
Valosin-Containing Protein as a therapeutic target in CAG repeat-driven Spinocerebellar ataxias: Integrative transcriptomic and computational insights.
STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory
Ocular delivery of different valosin-containing protein (VCP) inhibitory formulations prevents retinal degeneration in rho(∆I255) mice
Evidence against (6)
Neurodegenerative Disease Tauopathies.
Tauopathies are a diverse group of progressive and fatal neurodegenerative diseases characterized by aberrant tau inclusions in the central nervous system. Tau protein forms pathologic fibrillar aggregates that are typically closely associated with neuronal cell death, leading to varied clinical phenotypes including dementia, movement disorders, and motor neuron disease. In this review, we describe the clinicopathologic features of tauopathies and highlight recent advances in understanding the mechanisms that lead to spread of pathologic aggregates through interconnected neuronal pathways. The cell-to-cell propagation of tauopathy is then linked to posttranslational modifications, tau fibril structural variants, and the breakdown of cellular protein quality control.
Autophagy and ALS: mechanistic insights and therapeutic implications.
Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration. This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to
Semi-automated Analysis of Beading in Degenerating Axons
Axonal beading is a key morphological indicator of axonal degeneration, which plays a significant role in various neurodegenerative diseases and drug-induced neuropathies. Quantification of axonal susceptibility to beading using neuronal cell culture can be used as a facile assay to evaluate induced degenerative conditions, and thus aid in understanding mechanisms of beading and in drug development. Manual analysis of axonal beading for large datasets is labor-intensive and prone to subjectivity, limiting the reproducibility of results. To address these challenges, we developed a semi-automated Python-based tool to track axonal beading in time-lapse microscopy images. The software significantly reduces human effort by detecting the onset of axonal swelling. Our method is based on classical image processing techniques rather than an AI approach. This provides interpretable results while allowing the extraction of additional quantitative data, such as bead density, coarsening dynamics, and morphological changes over time. Comparison of results obtained through human analysis and the software shows strong agreement. The code can be easily extended to analyze diameter information of ridge-like structures in branched networks of rivers, road networks, blood vessels, etc.
Nerve injury and vocal cord paralysis after esophageal atresia and tracheoesophageal fistula repair: Systematic review and meta-analysis.
AIM: Vocal cord paralysis (VCP) and recurrent laryngeal nerve injury may be either congenital or acquired due to surgical trauma in patients with esophageal atresia and tracheoesophageal fistula (EA-TEF). A systematic review and meta-analysis were performed to define the risk factors for developing VCP and other nerve injuries. METHODS: Systematic literature search was conducted for the period 2000 (Jan) to 2024 (Jan) under the PRISMA guidelines. The study protocol was registered on PROSPERO (CRD42024532277). EMBASE, MEDLINE and PUBMED databases were searched and qualitative and quantitative data were extracted relating to VCP, recurrent laryngeal and phrenic nerve injury in patients with EA-TEF. Statistical analysis was performed with CMA-V4 software. RESULTS: Among 1421 articles, 851 abstracts were screened for inclusion criteria. Full texts of 125 articles were assessed for eligibility. The subgroup analysis was performed in 8 articles for type of EA-TEF and 4 articles for type of surgery. The risk of VCP occurrence was increased 1.58 times in Type-A, 2.97 times in Type-B and 6.85 times in Type -E when compared to Type-C EA [95%CI: (0.95-2.63, p = 0.08), (0.96-9.17, p = 0.059), (3.23-14.52, p < 0,05), respectively]. There was no significant correlation between thoracotomy and thoracoscopy to risk of VCP occurrence [OR:1.85 (95 % CI 0.42-8.04), p = 0.41]. Kendal's Tau test and Egger's tests were performed revealing that there was no publication bias for all data. CONCLUSION
Vernix Caseosa Peritonitis: A Scoping Review.
Background and Objectives: Vernix caseosa peritonitis (VCP) is rare. Nonspecific symptoms of acute abdomen during early puerperium make preoperative diagnosis of VCP challenging. We aimed to identify risk factors, early diagnosis and treatment options, and the association between the timing and severity of VCP diagnosis and maternal outcomes. Materials and Methods: We searched PubMed, PubMed Central, and Google Scholar. Articles were analyzed according to the PRISMA guidelines. The search items included: 'vernix caseosa peritonitis, 'vernix caseosa granuloma, 'maternal meconium peritonitis', 'maternal meconium granuloma', 'vernix caseosa', 'peritonitis', 'pregnancy', 'puerperium', 'postpartum', and 'gravid'. Additional studies were extracted by reviewing the reference lists of retrieved studies. Demographic, clinical, obstetric, diagnostic, and treatment parameters, and outcomes were collected. Results: Out of 55 published VCP case reports, 46 were available. Most involved term pregnancies (84.8%) and were delivered by Cesarean section (CS) (87%), with no difference in parity distribution (χ2(2) = 1.1875, p = 0.5523) or fetal sex (m: f = 53.3%: 46.7%). Common symptoms included abdominal pain and fever over 38 °C, while dyspnea or tachypnea was unexpectedly frequent (23.9%/15.2%). The interval from delivery to surgery ranged from 4 to 13 days (average 8 days), with no difference between CS and vaginal deliveries. Preoperative VCP was diagnosed in only 4.3% of cases, and intrao
Diagnostic performance of transcutaneous laryngeal ultrasound for vocal cord paralysis after esophagectomy: a systematic review and meta-analysis.
Vocal cord paralysis (VCP) caused by recurrent laryngeal nerve injury is a common complication following esophagectomy, particularly in patients undergoing minimally invasive esophagectomy (MIE). It may lead to dysphonia, aspiration, and pneumonia, significantly impacting recovery and prognosis. Transcutaneous laryngeal ultrasound (TLUSG) has emerged as a non-invasive tool for evaluating vocal cord function; however, its diagnostic performance relative to endoscopy remains unclear. Following PRISMA 2020 guidelines, we conducted a systematic search of PubMed, Embase, and Web of Science through January 2025. Studies comparing TLUSG with endoscopy in patients after esophagectomy were included. Two independent reviewers screened articles, extracted data (e.g., patient demographics and diagnostic measures), and assessed study quality using the QUADAS-2 tool. Pooled diagnostic metrics including sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were calculated using RevMan and Stata. Subgroup analyses were performed to explore the impact of inspection timing, reference standard, gender ratio, and age. Five studies involving 286 patients were included. The pooled sensitivity and specificity of TLUSG were 0.79 (95% CI: 0.55-0.92) and 0.95 (95% CI: 0.79-0.99), respectively. The DOR was 65.53 (95% CI: 17.41-246.75), and the AUC was 0.95, indicating excellent diagnostic accuracy. The overall vocal cord visualization rate was 92.3%, and the pooled incid