Deep Sequencing and Phenotyping in an Australian Tuberous Sclerosis Complex "No Mutations Identified" Cohort.

Tuberous sclerosis complex (TSC) is a variable multisystem disorder. The "no mutations identified" (NMI) group are reportedly phenotypically milder than those with an identified molecular cause, and often have mosaic or intronic variants not detected by standard sequencing methods. METHODS: We describe the phenotypes in an Australian TSC NMI group (n = 18) and a molecular testing strategy implementable in a diagnostic laboratory. Massively parallel sequencing (MPS) of the whole genomic regions of TSC1 and TSC2 was performed using DNA extracted from multiple tissue samples per participant. RESULTS: Our study showed that the phenotype in TSC NMI individuals can be similar to those with heterozygous, particularly TSC1, variants. Although neurodevelopmental outcomes can be less severe, the number of organ systems involved was similar to the non-mosaic groups. A diagnostic yield of 72% (13/18) was achieved, with the majority (10/13) being mosaic variants and the remainder heterozygous variants missed on previous testing. CONCLUSION: Testing DNA from multiple tissue samples allowed for validation of otherwise discarded low-level mosaic variants and detection of mosaic variants by MPS without excessive cost or the need for specialised techniques. Implementing this approach in a diagnostic setting is viable and allows optimal clinical care of patients with NMI TSC.

Glaucoma Rehabilitation using ElectricAI Transcranial Stimulation (GREAT)-study protocol for randomized controlled trial using combined perceptual learning and transcranial electrical stimulation for vision enhancement.

BACKGROUND: Glaucoma patients with irreversible visual field loss often experience decreased quality of life, impaired mobility, and mental health challenges. Perceptual learning (PL) and transcranial electrical stimulation (tES) have emerged as promising interventions for vision rehabilitation, showing potential in restoring residual visual functions. The Glaucoma Rehabilitation using ElectricAI Transcranial stimulation (GREAT) project aims to investigate whether combining PL and tES is more effective than using either method alone in maximizing the visual function of glaucoma patients. Additionally, the study will assess the impact of these interventions on brain neural activity, blood biomarkers, mobility, mental health, quality of life, and fear of falling. METHODS: The study employs a three-arm, double-blind, randomized, superiority-controlled design. Participants are randomly allocated in a 1:1:1 ratio to one of three groups receiving: (1) real PL and real tES, (2) real PL and sham tES, and (3) placebo PL and sham tES. Each participant undergoes 10 sessions per block (~ 1 h each), with a total of three blocks. Assessments are conducted at six time points: baseline, interim 1, interim 2, post-intervention, 1-month post-intervention, and 2-month post-intervention. The primary outcome is the mean deviation of the 24-2 visual field measured by the Humphrey visual field analyzer. Secondary outcomes include detection rate in the suprathreshold visual field, balance and gait functions, and electrophysiological and biological responses. This study also investigates changes in neurotransmitter metabolism, biomarkers, self-perceived quality of life, and psychological status before and after the intervention. DISCUSSION: The GREAT project is the first study to assess the effectiveness of PL and tES in the rehabilitation of glaucoma. Our findings will offer comprehensive assessments of the impact of these treatments on a wide range of brain and vision-related metrics including visual field, neural activity, biomarkers, mobility, mental health, fear of falling, and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05874258 . Registered on May 15, 2023.

Subchondral bone expansion in advanced knee osteoarthritis: Relation with radiographic severity and role in surgical decision-making.

Background: Joint space width (JSW) is a traditional imaging marker for knee osteoarthritis (OA) severity, but it lacks sensitivity in advanced cases. We propose tibial subchondral bone area (TSBA), a new CT imaging marker to explore its relationship with OA radiographic severity, and to test its performance for classifying surgical decisions between unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA) compared to JSW. Methods: We collected clinical, radiograph, and CT data from 182 patients who underwent primary knee arthroplasty (73 UKA, 109 TKA). The radiographic severity was scored using Kellgren-Lawrence (KL) grading system. TSBA and JSW were extracted from 3D CT-reconstruction model. We used independent t-test to investigate the relationship between TSBA and KL grade, and binary logistic regression to identify factors associated with TKA risk. The accuracy of TSBA, JSW and established classification model in differentiating between UKA and TKA was assessed using AUC. Results: All parameters exhibited inter- and intra-class coefficients greater than 0.966. Patients with KL grade 4 had significantly larger TSBA than those with KL grade 3. TSBA (0.708 of AUC) was superior to minimal/average JSW (0.547/0.554 of AUC) associated with the risk of receiving TKA. Medial TSBA, together with gender and Knee Society Knee Score, emerged as independent classification factors in multivariate analysis. The overall AUC of composite model for surgical decision-making was 0.822. Conclusion: Tibial subchondral bone area is an independent imaging marker for radiographic severity, and is superior to JSW for surgical decision-making between UKA and TKA in advanced OA patients.

Adaptive Fusion of Deep Learning With Statistical Anatomical Knowledge for Robust Patella Segmentation From CT Images.

Kneeosteoarthritis (KOA), as a leading joint disease, can be decided by examining the shapes of patella to spot potential abnormal variations. To assist doctors in the diagnosis of KOA, a robust automatic patella segmentation method is highly demanded in clinical practice. Deep learning methods, especially convolutional neural networks (CNNs) have been widely applied to medical image segmentation in recent years. Nevertheless, poor image quality and limited data still impose challenges to segmentation via CNNs. On the other hand, statistical shape models (SSMs) can generate shape priors which give anatomically reliable segmentation to varying instances. Thus, in this work, we propose an adaptive fusion framework, explicitly combining deep neural networks and anatomical knowledge from SSM for robust patella segmentation. Our adaptive fusion framework will accordingly adjust the weight of segmentation candidates in fusion based on their segmentation performance. We also propose a voxel-wise refinement strategy to make the segmentation of CNNs more anatomically correct. Extensive experiments and thorough assessment have been conducted on various mainstream CNN backbones for patella segmentation in low-data regimes, which demonstrate that our framework can be flexibly attached to a CNN model, significantly improving its performance when labeled training data are limited and input image data are of poor quality.

Radiomics analysis of patellofemoral joint improves knee replacement risk prediction: Data from the Multicenter Osteoarthritis Study (MOST).

Objective: Knee replacement (KR) is the last-resort treatment for knee osteoarthritis. Although radiographic evidence of tibiofemoral joint has been widely adopted for prognostication, patellofemoral joint has gained little attention and may hold additional value for further improvements. We aimed to quantitatively analyse patellofemoral joint through radiomics analysis of lateral view radiographs for improved KR risk prediction. Design: From the Multicenter Osteoarthritis Study dataset, we retrospectively retrieved the initial-visit lateral left knee radiographs of 2943 patients aged 50 to 79. They were split into training and test cohorts at a 2:1 ratio. A comprehensive set of radiomic features were extracted within the best-performing subregion of patellofemoral joint and combined into a radiomics score (RadScore). A KR risk score, derived from Kellgren-Lawrence grade (KLG) of tibiofemoral joint and RadScore of patellofemoral joint, was developed by multivariate Cox regression and assessed using time-dependent area under receiver operating characteristic curve (AUC). Results: While patellofemoral osteoarthritis (PFOA) was insignificant during multivariate analysis, RadScore was identified as an independent risk factor (multivariate Cox p-value < 0.001) for KR. The subgroup analysis revealed that RadScore was particularly effective in predicting rapid progressor (KR occurrence before 30 months) among early- (KLG < 2) and mid-stage (KLG â€‹= â€‹2) patients. Combining two joints radiographic information, the AUC reached 0.89/0.87 for predicting 60-month KR occurrence. Conclusions: The RadScore of the patellofemoral joint on lateral radiographs emerges as an independent prognostic factor for improving KR prognosis prediction. The KR risk score could be instrumental in managing progressive knee osteoarthritis interventions.

Radiomics signature of osteoarthritis: Current status and perspective.

Osteoarthritis (OA) is one of the fast-growing disability-related diseases worldwide, which has significantly affected the quality of patients' lives and brings about substantial socioeconomic burdens in medical expenditure. There is currently no cure for OA once the bone damage is established. Unfortunately, the existing radiological examination is limited to grading the disease's severity and is insufficient to precisely diagnose OA, detect early OA or predict OA progression. Therefore, there is a pressing need to develop novel approaches in medical image analysis to detect subtle changes for identifying early OA development and rapid progressors. Recently, radiomics has emerged as a unique approach to extracting high-dimensional imaging features that quantitatively characterise visible or hidden information from routine medical images. Radiomics data mining via machine learning has empowered precise diagnoses and prognoses of disease, mainly in oncology. Mounting evidence has shown its great potential in aiding the diagnosis and contributing to the study of musculoskeletal diseases. This paper will summarise the current development of radiomics at the crossroads between engineering and medicine and discuss the application and perspectives of radiomics analysis for OA diagnosis and prognosis. The translational potential of this article: Radiomics is a novel approach used in oncology, and it may also play an essential role in the diagnosis and prognosis of OA. By transforming medical images from qualitative interpretation to quantitative data, radiomics could be the solution for precise early OA detection, progression tracking, and treatment efficacy prediction. Since the application of radiomics in OA is still in the early stages and primarily focuses on fundamental studies, this review may inspire more explorations and bring more promising diagnoses, prognoses, and management results of OA.

ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.

The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors. SIGNIFICANCE: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188.

Cross-Cultural Adaptation and Psychometric Properties of the Chinese Version of the Knee Osteoarthritis Fears and Beliefs Questionnaire.

This study aimed to adapt and validate the Knee Osteoarthritis Fears and Beliefs Questionnaire (KOFBeQ) for Chinese patients, thereby advancing the understanding of fear-avoidance behaviors. Adopting a cross-sectional design, data were collected for 241 subjects (78.8% women; mean age 68.0 ± 7.8 years) across various healthcare settings in Hong Kong. Exploratory factor analysis resulted in an 11-item questionnaire with three distinct subscales, covering fears and beliefs related to physicians and disease (six items), daily living activities (three items), and sports and leisure activities (two items). The overall Cronbach's α coefficient was 0.86, indicating strong internal consistency. The questionnaire exhibited favorable convergent validity. Confirmatory factor analyses confirmed a good model fit. Test-retest reliability analysis indicated a high intraclass correlation coefficient of 0.93 (95% confidence interval: 0.88, 0.96), and a Bland-Altman plot revealed a slight bias in two measurements (0.97 [0.19]) without a systematic trend. The adapted Chinese version of the KOFBeQ demonstrated robust psychometric properties in terms of validity and reliability, providing an effective tool for surveying Chinese patients with knee osteoarthritis. These findings offer valuable insights for clinicians and patients, aiding in informed decision-making and improved rehabilitation strategies.

PRMT5 and CDK4/6 inhibition result in distinctive patterns of alternative splicing in melanoma.

Drugs targeting cyclin-dependent kinases 4 and 6 (CDK4/6) are promising new treatments for melanoma and other solid malignancies. In studies on CDK4/6 inhibitor resistance, protein arginine methyltransferase 5 (PRMT5) regulation of alternative splicing was shown to be an important downstream component of the CDK4/6 pathway. However, the full effects of inhibition of CDK4/6 on splicing events in melanoma and the extent to which they are dependent on PRMT5 has not been established. We performed full-length mRNA sequencing on CHL1 and A375 melanoma cell lines treated with the CDK4/6 inhibitor palbociclib and the PRMT5 inhibitor GSK3326595 and analysed data for differential gene expression and differential pre-mRNA splicing induced by these agents. Changes in gene expression and RNA splicing were more extensive under PRMT5 inhibition than under CDK4/6 inhibition. Although PRMT5 inhibition and CDK4/6 inhibition induced common RNA splicing events and gene expression profiles, the majority of events induced by CDK4/6 inhibition were distinct. Our findings indicate CDK4/6 has the ability to regulate alternative splicing in a manner that is distinct from PRMT5 inhibition, resulting in divergent changes in gene expression under each therapy.

Selenite as a dual apoptotic and ferroptotic agent synergizes with EGFR and KRAS inhibitors with epigenetic interference.

BACKGROUND: Selenium, an essential trace element, has previously been investigated as a pro-apoptotic and DNA demethylation agent. It sensitizes the response to chemotherapy in patients who were refractory to cytotoxic agents. Meanwhile, ferroptosis is a novel approach to cancer treatment by triggering cell death and reversing drug resistance. The role of selenium in treating cancer cells harboring druggable oncogenic alterations and its underlying mechanism are largely unknown. RESULTS: We treated lung adenocarcinoma cell lines-EGFR-mutant H1975 (H1975 EGFR p.L858R and p.T790M) and KRAS-mutant H358 (H358 KRAS p.G12C), with sodium selenite to examine its effect on cell apoptosis, ferroptosis, and DNA methylation, as well as its interaction with existing targeted therapy, osimertinib, and adagrasib. We observed selenite to be a dual apoptotic and ferroptotic agent on lung cancer cells, associated with the activation of p38-ATF4-DDIT3 axis in the unfolded protein response. Ferroptosis induction was more remarkable in H1975 than H358. Selenite also altered cellular DNA methylation machinery through downregulating DNMT1 and upregulating TET1, though not as a major mechanism of its activity. Low-dose selenite synergized with osimertinib in EGFR-mutant H1975, and with adagrasib in KRAS-mutant H358, with stronger synergism observed in H1975. CONCLUSION: These results suggest that selenite is a potential apoptotic and ferroptotic drug candidate for the treatment of especially EGFR- and potentially KRAS-mutant lung cancer.

Captopril Alleviates Chondrocyte Senescence in DOCA-Salt Hypertensive Rats Associated with Gut Microbiome Alteration.

Gut microbiota is the key controller of healthy aging. Hypertension and osteoarthritis (OA) are two frequently co-existing age-related pathologies in older adults. Both are associated with gut microbiota dysbiosis. Hereby, we explore gut microbiome alteration in the Deoxycorticosterone acetate (DOCA)-induced hypertensive rat model. Captopril, an anti-hypertensive medicine, was chosen to attenuate joint damage. Knee joints were harvested for radiological and histological examination; meanwhile, fecal samples were collected for 16S rRNA and shotgun sequencing. The 16S rRNA data was annotated using Qiime 2 v2019.10, while metagenomic data was functionally profiled with HUMAnN 2.0 database. Differential abundance analyses were adopted to identify the significant bacterial genera and pathways from the gut microbiota. DOCA-induced hypertension induced p16INK4a+ senescent cells (SnCs) accumulation not only in the aorta and kidney (p < 0.05) but also knee joint, which contributed to articular cartilage degradation and subchondral bone disturbance. Captopril removed the p16INK4a + SnCs from different organs, partially lowered blood pressure, and mitigated cartilage damage. Meanwhile, these alterations were found to associate with the reduction of Escherichia-Shigella levels in the gut microbiome. As such, gut microbiota dysbiosis might emerge as a metabolic link in chondrocyte senescence induced by DOCA-triggered hypertension. The underlying molecular mechanism warrants further investigation.

Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation.

Metastatic breast cancer remains a major cause of cancer-related deaths in women, and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, a combination of WDR5 targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.

Which features of patients are morally relevant in ventilator triage? A survey of the UK public.

BACKGROUND: In the early stages of the COVID-19 pandemic, many health systems, including those in the UK, developed triage guidelines to manage severe shortages of ventilators. At present, there is an insufficient understanding of how the public views these guidelines, and little evidence on which features of a patient the public believe should and should not be considered in ventilator triage. METHODS: Two surveys were conducted with representative UK samples. In the first survey, 525 participants were asked in an open-ended format to provide features they thought should and should not be considered in allocating ventilators for COVID-19 patients when not enough ventilators are available. In the second survey, 505 participants were presented with 30 features identified from the first study, and were asked if these features should count in favour of a patient with the feature getting a ventilator, count against the patient, or neither. Statistical tests were conducted to determine if a feature was generally considered by participants as morally relevant and whether its mean was non-neutral. RESULTS: In Survey 1, the features of a patient most frequently cited as being morally relevant to determining who would receive access to ventilators were age, general health, prospect of recovery, having dependents, and the severity of COVID symptoms. The features most frequently cited as being morally irrelevant to determining who would receive access to ventilators are race, gender, economic status, religion, social status, age, sexual orientation, and career. In Survey 2, the top three features that participants thought should count in favour of receiving a ventilator were pregnancy, having a chance of dying soon, and having waited for a long time. The top three features that participants thought should count against a patient receiving a ventilator were having committed violent crimes in the past, having unnecessarily engaged in activities with a high risk of COVID-19 infection, and a low chance of survival. CONCLUSIONS: The public generally agreed with existing UK guidelines that allocate ventilators according to medical benefits and that aim to avoid discrimination based on demographic features such as race and gender. However, many participants expressed potentially non-utilitarian concerns, such as inclining to deprioritise ventilator allocation to those who had a criminal history or who contracted the virus by needlessly engaging in high-risk activities.

A web-based personalized decision support tool for patients diagnosed with ductal carcinoma in situ: development, content evaluation, and usability testing.

PURPOSE: Patients diagnosed with ductal carcinoma in situ (DCIS) face trade-offs when deciding among different treatments, including surgery, radiation, and endocrine therapy. A less chosen option is active monitoring. While evidence from clinical trials is not yet available, observational studies show comparable results for active monitoring and immediate treatment on cancer outcomes in select subgroups of patients. We developed and tested a web-based decision support tool (DST) to help patients explore current knowledge about DCIS and make an informed choice. METHODS: The DST, an interactive web application, was informed by literature reviews and formative work with patients, breast surgeons, and health communication experts. We conducted iterative interviews to evaluate the DST content among women with and without a history of breast cancer, as well as breast cancer experts. For usability testing, we conducted an online survey among women with and without a history of breast cancer. RESULTS: For content evaluation, 5 women with and 10 women without a history of DCIS were interviewed. The sample included 11 White and 4 non-White women, with a mean age of 64 years. The expert sample consisted of 5 attendings and a physician assistant. The feedback was used to add, clarify, or reorganize information in the DST. For usability testing, 22 participants with a mean age of 61 years were recruited including 15 White and 7 Black women and 6 women with a history of DCIS. The mean usability score was 3.7 out of 5. Most participants (86%) found that the DST provided unbiased information about treatments. To improve usability, we reduced the per-page content and added navigation cues. CONCLUSION: Content and usability evaluation showed that the DST helps patients explore trade-offs of active monitoring and immediate treatment. By adopting a personalized approach, the tool will enable informed decisions aligned with patients' values and expectations.

CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression.

Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as TNC, MMP2, and VEGFA, and cytokine genes CSF1 and CXCL1, which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB-mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.

Elective Laparoscopic Cholecystectomy as an Entrustable Professional Activity (EPA) for General Surgical Trainees in Australia.

INTRODUCTION: To evaluate the operation time and surgical outcomes of elective laparoscopic cholecystectomy performed by surgical trainees at different levels of training at Eastern health and hence, to establish the efficacy and safety of elective laparoscopic cholecystectomy as an Entrustable Professional Activity for surgical trainees in general surgery. OBJECTIVE: Elective laparoscopic cholecystectomies performed at our institution between January 2018 and January 2019 were included. Analyses were divided among three groups - consultants (C), fellows (F) and registrars (R). Standard technique with critical view of safety was used. RESULTS: A total of 592 patients was included, with a mean age of 54 ± 63 years old. The average operation time was 84 ± 51 minutes. Surgical education and training (SET) 2 trainees took significantly longer when compared to their SET3 and above counterparts as a primary operator (SET2: 131 ± 32 min, Reference; SET3: 78 ± 21 min, p = 0.003; SET4: 80 ± 33 min, p = 0.004; SET5: 77 ± 28 min, p = 0.003; F: 93 ± 77 min, p = 0.036; C: 85 ± 59 min; p = 0.007). Consultant primary operators took an average of 15 minutes longer to complete the operation when assisted by a SET trainee compared to the non-SET registrars (p = 0.03). The overall complication rate was 3.2% and was not significantly different among all three groups (p = 0.17). No death was recorded during the study period. The readmission and return to theatre rates were 7.8% and 0.8% respectively and were not significantly different among the groups (p-values = 0.61 and 0.69). All conversion to open were performed by the consultant primary operator. CONCLUSIONS: Elective laparoscopic cholecystectomy can be safely performed by surgical trainees at all SET levels when under appropriate supervision, although junior surgical trainees that is SET 2 took longer to complete the procedure. This operation seems to have a steep, but relatively short, learning curve and it may be broken down into various components. These components, with the addition of time, may be suitable as an Entrustable Professional Activity tool for assessing the competency of early SET trainees.

Efficacy and Safety of Intravascular Lithotripsy in Lower Extremity Peripheral Artery Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Intravascular lithotripsy (IVL) is a novel technique for plaque modification during endovascular revascularisation for peripheral artery disease (PAD) with severe calcification. The aim of this paper was to perform a systematic review and meta-analysis of contemporary data to elucidate the efficacy and safety of IVL in lower extremity PAD. DATA SOURCES: A systematic literature search with pre-defined search terms was performed using PubMed, Web of Sciences, OvidSP, and EMBASE. REVIEW METHODS: A meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Patient characteristics, lesion calcification, pre-IVL and post-IVL diameter stenosis, complications, and stent rates were evaluated. RESULTS: Nine studies were included, encompassing a total of 681 patients (769 lesions) with IVL performed for PAD, of which 75.53% (95% confidence interval [CI] 66.08% - 83.03%) of the lesions were reported to have severe calcification. Comparison between pre-IVL and post-IVL diameter stenosis demonstrated a diameter stenosis reduction of 59.3% (95% CI 53.30% - 65.31%). Vascular complications were rare, with flow limiting or type D/E/F dissection occurring in only 1.25% (95% CI 0.60% - 2.61%) of cases. The overall pooled event rate for stent placement was 15.89% (95% CI 5.22% - 39.34%). CONCLUSION: This meta-analysis supports IVL as an effective and safe approach for calcified plaque modification in lower extremity PAD, achieving a diameter stenosis reduction of 59.3% (95% CI 53.30% - 65.31%) with minimal vascular complications. Routine use of this device is not recommended; further high quality evidence is required to elucidate the efficacy of IVL with respect to different clinical characteristics such as lesion location and length, and in comparison with other treatment modalities such as atherectomy.