Gait disturbances are common in older people and are associated with adverse consequences, e.g., falls and institutionalization. Enlarged perivascular spaces in the basal ganglia (BG-EPVS) are considered an magnetic resonance imaging (MRI) marker of cerebral small vessel diseases (CSVD). However, the consequences of BG-EPVS are largely unknown. Previous studies showed that other CSVD markers were related to gait disturbances. However, the relation between BG-EPVS and gait performance is unclear. Therefore, we aimed to explore the relation between BG-EPVS and gait performance in elderly individuals.n = 78), and the rest were classified into the control group (n = 164). Quantitative gait parameters and gait variability were provided by the Intelligent Device for Energy Expenditure and Activity  gait analysis system. Semiquantitative gait assessment was measured with the Tinetti test. Point-biserial correlation and multivariate linear regression analysis were performed to investigate the association between BG-EPVS and gait performance.We recruited older people with CSVD in the Neurology Department of our hospital from December 1, 2020 to October 31, 2021. Participants with BG-EPVS > 20 on the unilateral side of the basal ganglia slice containing the maximum number were classified into the BG-EPVS group (P < 0.05). There were no statistical differences in stride length variability and stride time variability between the two groups (P > 0.05). A correlation analysis showed that BG-EPVS were negatively related to gait speed, cadence, stride length, pre-swing angle, and footfall  and positively related to stance phase percentage . BG-EPVS was negatively related to the score of the Tinetti gait test  and the balance test . The multiple linear regression analysis indicated that BG-EPVS was an independent risk factor for gait disturbances and poor balance after adjusting for confounders, including other CSVD markers.The BG-EPVS group had a slower gait speed and cadence, shorter stride length, longer stance phase percentage, smaller pre-swing angle and footfall, and lower Tinetti gait test and balance test scores compared with those in the control group (Large numbers of BG-EPVS were independently related to gait disturbances in older people with CSVD. This finding provides information about the consequences of BG-EPVS and risk factors for gait disturbances. The exclusion criteria were the following: (1) dementia including Alzheimer’s disease, frontotemporal dementia, or dementia with Lewy bodies; (2) Parkinson’s diseases (PD) and Parkinson’s plus syndromes, including multiple system atrophy, cortical basal degeneration, and progressive supranuclear palsy; (3) history of severe stroke (the largest diameter of lesion size > 20 mm) that caused difficulties and inaccurate assessments of CSVD MRI markers or large-vessel cerebrovascular diseases defined as internal carotid, middle cerebral, or basilar intracranial artery stenosis > 50%; (4) lacunar syndrome within 6 months after the event to avoid acute effects on the outcomes, or the patients with stroke sequelae 6 months after cerebral infarction onset; (5) traumatic, toxic or infectious brain injury, brain tumor or brain metastases, or non-CSVD-rated white matter lesions, e.g., multiple sclerosis and irradiation induced gliosis; (6) inability to walk for 30 m unaided; (7) could not finish the tests because of prominent visual, hearing, or language impairments or psychiatric disease; (8) conditions not related to CSVD that affected gait ; (9) heart failure, myocardial infarction, or angina pectoris disorders during the previous 3 months or severe nephrosis or liver disease with a life expectancy of < 6 months; and (10) MRI contraindications, known claustrophobia, or the patient’s head moved during the MRI, resulting in poor imaging quality that affected the CSVD assessment.All enrolled patients were divided into two groups according to the number of BG-EPVS on axial T2-weighted images. Patients with BG-EPVS > 20 on the unilateral side of the basal ganglia slice containing the maximum number were classified into the BG-EPVS group ; otherwiThe study was approved by the Ethics Committee of Beijing Chaoyang Hospital Affiliated with Capital Medical University and was conducted in accordance with the Declaration of Helsinki. All participants provided informed written consent.The following data were collected: age, sex, body mass index (BMI), past medical history, including hypertension, diabetes mellitus, hyperlipidemia, and stroke, and smoking and alcohol consumption. All blood samples were collected in the morning after an overnight fast and sent to the clinical laboratory of our hospital for the measurement of serum indices, including total cholesterol (TC), triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), hemoglobin A1c (HbA1c), blood urea nitrogen (BUN), and creatinine.Using a 3 T MRI scanner , MRI was performed in the Radiology Department of our hospital. The standardized MRI sequences included T1-weighted, T2-weighted, diffusion-weighted imaging, fluid-attenuated inversion recovery, and susceptibility-weighted imaging.Imaging markers of CSVD, including BG-EPVS, WMH, CMB, and lacunes, were defined according to the Standards for Reporting Vascular Changes on Neuroimaging criteria described previously . The numAssessments of BG-EPVS, WMH, CMB, and lacunes were performed by two experienced neurologists blinded to the clinical data. Random scans of 50 individuals were independently examined by the two experienced neurologists blinded to the readings of the other. The intra-rater agreement for the ratings of BG-EPVS, WMH, CMB, and lacunes was assessed on a random sample of 50 individuals, with a 1-month interval between the first and second readings. The k statistics of the intra-rater and interrater agreements were 0.80 and 0.98, indicating good reliability. Disagreement was resolved by discussing it with the other co-authors.Quantitative gait analysis was performed with the Intelligent Device for Energy Expenditure and Activity , which had excellent test-retest reliability and validity . The IDESemiquantitative gait assessment was measured using the Tinetti test with 17 items: nine for balance (score 0–16) and eight for gait (score 0–12) with a maximum score of 28 . The TinSD or median (interquartile range) according to whether the data conformed to a normal distribution. Categorical variables were presented as absolute numbers and percentages. Continuous variables with both normal distributions and homogeneity of variance were compared using the Student’s t-test, whereas were compared using the Wilcoxon rank-sum test. Bonferroni correction was adopted to reset the p-value. The Chi-squared test was used for the comparison of categorical variables. Point-biserial correlation analysis was adopted to analyze the correlation between BG-EPVS (a binary variable) and gait parameters (continuous variables). The relationship between BG-EPVS and gait parameters was assessed with the point-biserial correlation coefficient. Partial correlation analysis and multivariate linear regression analysis were performed to analyze whether BG-EPVS was independently related to gait performance after adjusting for confounding factors. Analysis was performed with statistical product and service solutions 21.0 , and statistical significance was accepted at P < 0.05.Continuous variables were summarized as mean values ± A total of 354 elderly patients with CSVD and without acute cerebral infarction during the study period were identified. Among them, we excluded 43 patients who had a history of severe stroke and large-vessel diseases, 5 patients who had been diagnosed with PD, 36 patients who had severe arthritis, joint fusion, lumbar spondylopathy, or visual impairment that affected their walking, and 3 patients whose imaging quality was not high enough to assess markers of CSVD. The other 25 patients did not agree to participate in the study. Ultimately, 242 elderly patients were enrolled in the study and performed the tests, among which 78 patients were classified into the BG-EPVS group and 164 patients were classified into the control group according to the number of BG-EPVS.P < 0.001). The detailed statistical results are shown in The general clinical characteristics of all participants, the BG-EPVS group, and the control group are presented in Point-biserial correlation analysis showed that BG-EPVS were negatively related to gait speed, cadence, stride length, pre-swing angle, and foot control and positively related to stance phase percentage . BG-EPVSTo identify the effect of BG-EPVS on gait, we took the gait parameters and Tinetti test scores as dependent variables and conducted the multiple linear regression analysis. The results of the multiple linear regression analysis showed that BG-EPVS was an independent risk factor for gait disturbances and balance after adjusting for age, the proportion of male sex, hypertension, and stroke, level of blood creatinine, Fazekas score, the number of lacuna and CMB. The detailed analysis results are presented in P = 0.08] and stride time variability  between the BG-EPVS group and the control group. Point-biserial correlation analysis also showed that BG-EPVS was not related to gait variability (P > 0.05).There were no statistical differences in stride length variability [27.6 (13–30.4) vs. 24.3 (11.7–27.7), In the present study, we explored the association between BG-EPVS and gait performance in older individuals with CSVD after adjusting for WMH, CMB, and lacunes. We found that large numbers of BG-EPVS were independently related to gait disturbances, including lower gait speed, shorter stride length, longer stance phase, smaller pre-swing angle, and poorer foot control using a quantitative gait analysis system. In addition, we found that BG-EPVS was also independently related to poor body balance. However, BG-EPVS was not related to gait variability.The present clinical experience and previous studies indicated that, in subjects with CSVD, symptoms mainly arose in only moderate or severe cases . For exaPrevious studies investigated the relationship between gait performance and other CSVD MRI markers, such as WMH, lacunar infarction, and CMB . The RadGait velocity is determined by both the stride length and gait cadence. In the present study, the gait velocity, stride length, and gait cadence were reduced in patients with large numbers of BG-EPVS. However, large numbers of BG-EPVS were only significantly related to gait velocity and stride length and not related to gait cadence after adjusting for WMH, lacunes, and CMB. We propose that stride length may be a more sensitive indicator than gait cadence. Aside from the lower velocity, we found that gait in subjects with severe BG-EPVS was characterized by an increased stance phase percentage, smaller pre-swing angle, reduced footfall, and lower Tinetti balance score, which indicated that severe BG-EPVS is related to poor balance.via the perivascular spaces, where it combines with interstitial fluid prior to exiting the brain. This perivascular drainage system also allows for the clearance of toxic metabolites within the parenchyma and possibly plays a role in the brain’s immunological response  for the publication of any potentially identifiable images or data included in this article.WH and SY conceived and designed the study. XL and SY participated in the screening participants and data collection. WQ and LY assessed the imagings. SY participated in the data analysis and drafted the manuscript. WH revised the manuscript. All authors read and approved the final manuscript to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Ophthalmology is a field of medicine that has grown rapidly during the last few decades. Several new and promising treatments have become available for eye conditions, including age-related macular degeneration, glaucoma, retinal vein occlusions, diabetic macular oedema, genetic disorders, uveitis, and inflammations. On the other hand, recent technological developments and advanced surgical techniques have drastically changed the daily practice of eye surgeons, with new surgical options resulting in safer, faster, and more precise surgery.This Research Topic summarized modern therapeutic and surgical approaches to ocular diseases, adding a valuable contribution to our existing knowledge, describing the current state-of-the-art, and providing directions for future research.Sun et al. demonstrated that in patients who have already undergone corneal refractive surgery, presbyopia-correcting intraocular lenses (IOLs) deliver satisfactory outcomes in terms of efficacy, safety, and predictability, but have a higher risk of photopic side effects such halos and glare. Wy et al. compared the clinical outcomes of maximum tolerated medical therapy in patients with penetrating keratoplasty with those of Ahmed glaucoma valve implantation and found no significant differences in the visual acuity, corneal thickness and in survival time. Zhang et al. compared visual outcomes and corneal optical quality after small incision lenticule extraction (SMILE), wavefront-optimized (WFO) FS-LASIK, and topography-guided customized ablation treatment (TCAT) FS-LASIK for myopia and found that all techniques provided similar visual results with the TCAT FS-LASIK to be superior in terms of corneal optical quality. The Management of Vernal Keratoconjunctivitis in Asia (MOVIA) Expert Working Group completed a consensus program to evaluate, review, and develop best-practice recommendations for the assessment, diagnosis, and management of Vernal Keratoconjunctivitis in Asia which was published in this Research Topic .A systematic review and meta-analysis conducted by Chen X. et al. showed that XEN gel stent was effective and safe for primary and secondary open angle glaucoma with an overall complete success rate varying between 21.0 and 70.8% after 2 years and an incidence of sight-threatening complications below 1%. In a prospective case series, Chen M. et al. assessed the safety and efficiency of carbon dioxide (CO2) laser-assisted sclerectomy surgery (CLASS) in Chinese patients with primary open-angle glaucoma and found that CLASS was a safe and effective approach, while Xiang et al. demonstrated that that pars plana Ahmed valve implantation can be safely performed for managing vitrectomised eyes with refractory glaucoma.A meta-analysis conducted by Irawati et al., the modified tarsoraphy technique was found to be more efficient than the gold weight implant as a surgical treatment for paralytic lagophthalmos in patients with leprosy. Chi and Lai compared the endoscopic dacryocystorhinostomy with short-term, pushed-type bicanalicular intubation vs. the pulled-type monocanalicular intubation in patients with primary acquired nasolacrimal duct obstruction and found both techniques comparable in terms of surgical outcomes. Supramaximal horizontal rectus recession–resection surgery was found to be an effective treatment method for complete abduction deficiency in a retrospective study by Wang et al., while Lee et al. proposed a new simple marking system for accurate intraoperative monitoring and adjustment of cyclotorsion strabismus surgery.In a prospective randomized control trial by Zhou et al. found that age, disease duration, baseline central macular thickness and visual acuity are predictive factors for the visual outcomes at 6-month of anti-VEGF treatment for macular oedema secondary to retinal vein occlusion and that a further metric that can be used to forecast improved long-term outcomes is the “2-week CMT decrease rate >37%” after the initial injection. Anti-VEGF agents as the primary treatment provide potential advantages over laser therapy for eyes with zone I type 1 ROP and A-ROP, according to a large retrospective study from China by Linghu et al.. Laser photocoagulation and anti-VEGF agent therapy were equally effective for treating eyes with zone II type 1 ROP, but the rate of reactivation with laser therapy was much lower than that with anti-VEGF agents. Finally, Lumi et al. described a new technique for macular pucker peeling without forceps by using a 25-gauge vitrectomy probe.Ye et al. described a modified technique for the scleral fixation of a secondary foldable three-piece intraocular lens, and reported successful outcomes in 10 eyes. The long-term endothelial cell count was better in low-energy femtosecond laser-assisted cataract surgery (FLACS) while the rest of the intraoperative and post-operative outcomes were comparable between these two procedures, according to Liu et al. randomized clinical trial. In a retrospective comparative study, Chen Z.-X. et al. demonstrated that supra-capsular and scleral-fixated intraocular lens (IOL) implantation was comparable to modified capsular tension ring and in-the-bag intraocular lens implantation in patients with microspherophakia. Finally, in an experimental study, Xie et al. identified primary calcification and vacuaoles as the main causes of US-860 UV and L-312 IOL opacification, respectively.We hope that you will enjoy this Research Topic as much as we enjoyed editing it.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


At a median follow-up of 17 months (IQR 10–24), 94.5% of patients reported to be continent. Conclusions: In experienced hands, most patients fully recover urinary continence after RALP at mid-term follow-up. On the contrary, the proportion of patients who reported early incontinence in our series was modest but not negligible. The implementation of surgical techniques advocating anterior and/or posterior fascial reconstruction might improve the early continence rate in candidates for RALP. Background: The aim of our study is to evaluate the prevalence and predictive factors of short- (30 d) and mid-term continence in a contemporary cohort of patients treated with robotic-assisted laparoscopic prostatectomy (RALP) without any posterior or anterior reconstruction at our referral academic center. Methods: Data from patients undergoing RALP between January 2017 and March 2021 were prospectively collected. RALP was performed by three highly experienced surgeons following the principles of the Montsouris technique, with a bladder-neck-sparing intent and maximal preservation of the membranous urethra  without any anterior/posterior reconstruction. (Self-assessed urinary incontinence (UI) was defined as the need of one or more pads per die . Results: A total of 925 patients were included; of these, 353 underwent RALP (38.2%) without nerve-sparing intent. The median patient age and BMI were 68 years (IQR 63–72) and 26 (IQR 24.0–28.0), respectively. Overall, 159 patients (17.2%) reported early (30 d) incontinence. In multivariable analysis adjusting for patient- and tumor-related features, a non-nerve-sparing procedure (OR: 1.57 [95% CI: 1.03–2.59],  Robotic-assisted laparoscopic prostatectomy (RALP) has been shown to achieve excellent oncological outcomes with a low rate of complications in patients with prostate cancer ,2,3,4. DHowever, several factors have been related to the risk of post-surgery urinary incontinence, including both patient characteristics  and provider-related factors  ,13.From a pure surgical perspective, several techniques have been recently described in order to achieve early recovery of urinary continence after RALP; among these, the most relevant include bladder neck preservation ,15, recoAlthough many of these reconstructive techniques aim at restoring the normal anatomical and functional relationships of the pelvic floor, there is no consensus on which reconstruction might be related the most to early continence recovery .Given the absence of absolute recommendations on whether or not to perform these reconstructive procedures, which are time-consuming and might require additional training and experience, in this study we aimed to evaluate the pattern of urinary continence recovery after RALP with no anterior/posterior reconstruction at a referral academic center.After Institutional Ethical Committee approval, data from consecutive patients undergoing RALP between January 2017 and March 2021 were prospectively collected in our institutional web-based database. Patients were considered eligible for RALP if they had a non-metastatic disease, histologically confirmed prostate cancer, and a life expectancy of more than 10 years. Patients reporting clinically significant urinary incontinence before RALP were excluded from the study.Diagnosis of prostate cancer was performed with transrectal or transperineal US-guided biopsy, with or without multiparametric magnetic resonance imaging (mpMRI) guidance. All mpMRIs were evaluated by dedicated uroradiologists.The decision to perform RALP was based on shared decision-making with patients after proper counseling on all potential alternatives . No patient underwent preoperative androgen deprivation therapy. All procedures were performed by three high-volume surgeons (>100 RALP at the beginning of the study period and >40 RALP/year) at our referral institution.After the induction of anesthesia, the patients were placed in a modified lithotomy position and a four-arm approach with six trocars was used . The porRALP was performed following the principles of the Montsouris technique, with a bladder-neck-sparing intent and maximal preservation of the membranous urethra  without any anterior/posterior reconstruction. In particular, at the beginning of the procedure, the reflection of the peritoneum in the recto-vesicle pouch (pouch of Douglas) is identified. After identification and dissection of both vas deferens and seminal vesicles, the posterior plane between the prostate and the Denonvillier’s fascia is developed until the prostatic apex. Then, if a neurovascular bundle preservation is planned, an intra- or inter-fascial dissection plane is identified and carefully developed monolaterally or bilaterally B. In casThen, the plane between the bladder neck and the prostate is carefully developed, ideally with a bladder-neck-sparing intent if oncologically safe C. Upon rBilateral extended pelvic lymph node dissection is performed in patients for whom the probability of lymph node metastases exceeded the threshold defined by the Briganti nomogram .The following data were collected in our prospective database: patient age, body mass index (BMI), diabetes, Charlson comorbidity index (CCI), anticoagulant/antiplatelet medication, cardiovascular disease , previous abdominal or pelvic surgery, preoperative PSA, clinical stage according to the digital rectal examination (DRE), prostate volume measurement and imaging data. The presence of neurovascular bundle thickening, bulge, loss of capsule integrity, capsular enhancement or measurable extracapsular disease detected at high-volume T2-weighted images in the radiological report was used to define extracapsular extension (ECE) at mpMRI. For grading, ISUP categories, grade group, and the modified Gleason scoring system according to the International Society of Urological Pathology 2005 and 2014 consensus conferences were adopted. Preoperative exams, imaging, and follow-up after surgery were performed following the EAU Guidelines recommendations. Patients were stratified according to either the D’Amico risk groups  or the EAll patients, during the urethral catheter removal, received detailed information and booklets about pelvic floor muscle training to improve continence recovery after RALP.Urinary incontinence (UI) was recorded according to the Expanded Prostate Cancer Composite (EPIC) Score (EPIC) criteria , based oOncological outcomes, as well as intraoperative, early (30 d) and late (>30 d) post-operative complications (prospectively according to the modified Clavien–Dindo system ) were coDescriptive statistics were obtained reporting median and interquartile ranges (IQR) for continuous variables, while numbers and proportions for categorical variables, as appropriate.The statistical analysis plan for this study included two steps: first, we obtained the baseline clinical characteristics of patients, focusing on the proportion of those reporting urinary continence recovery. Then, a sub-analysis was performed in patients who underwent preoperative mpMRI. Lastly, we explored the independent predictors of early postoperative incontinence using multivariable logistic regression analysis.We could not evaluate the predictors of mid-term urinary incontinence due to the small number of events.p < 0.05.Statistical analyses were performed using SPSS v. 26 . All tests were two-sided with a significance set at 2, and 1, respectively. Median PSA value at diagnosis was 6.8 ng/mL  were 68 years, 26 kg/m.8 ng/mL . In our .8 ng/mL . No majoRegarding UI recovery, 82.8 % of patients in our cohort reported to be continent at 1 month after surgery. An improvement in continence recovery was evident during the follow-up, with 94.5% of patients reporting to be fully continent at the last follow-up .In the multivariate analysis, the only independent predictors for early (30 d) continence were the presence of baseline cardiovascular disease and a non-nerve-sparing surgical intent during RALP. None of the other patient- or tumor-related factors, including the EAU risk category, was associated with the risk of UI at a short-term follow-up .Results did not change in the sub-analysis including patients who underwent preoperative mpMRI .Urinary incontinence after radical prostatectomy may significantly impact patient wellbeing and quality of life . RoboticFor this reason, the surgeon should always pursue surgical strategies that aim at preserving the anatomical structures involved in the continence mechanism .In the last few years, different strategies that led to an overall improvement of postoperative functional outcomes have been identified: bladder-neck preservation, reconstruction of puboprostatic ligaments, creation of posterior urethral support, and variation of suspension structures ,50,51,52In this scenario, whether specific reconstruction techniques should be routinely employed by surgeons to improve continence recovery after RALP is controversial.Our study provides several insights for surgeons to contextualize the current debate over the merits and limitations of different reconstruction techniques. First, our findings should be interpreted in light of the specific surgical technique performed by surgeons involved in our series. From a purely technical standpoint, the two main surgical strategies that are always performed are the anatomical dissection of the bladder neck coupled with maximal urethral length preservation. In addition, pubo-prostaic ligaments are routinely spared (even in non-nerve-sparing procedures), while the endopelvic fascia and the pubo-prostatic “Afrodite” veil is entirely spared only in intrafascial nerve-sparing RALPs. Lastly, nerve-sparing procedures are often carried out in a “clipless” fashion to minimize the potential detrimental impact of energy on neurovascular bundles.Overall, following the principles of the Montsouris technique, our strategy involves careful, anatomical bladder-neck preservation  and aims to maximize the length of the membranous urethra during the dissection of the prostatic apex. Yet, it did not involve any specific anterior or posterior reconstruction before/after the urethra-vesical anastomosis, providing an opportunity to analyze the functional outcomes achieved by RALP without reconstructive phases.The temporal pattern of urinary continence recovery after RALP reported in our study confirms the safety of our technique for RALP  from a function viewpoint. In particular, the occurrence of postoperative UI at a mid-term follow-up (median follow-up of 17 months) was a rare event (<5%). On the contrary, we noted a non-negligible proportion of patients (self)-reporting UI at a short-term follow-up (30d), suggesting that the very immediate postoperative period offers further chances of improvement. In the multivariable analysis adjusting for several patient-, tumor- and surgery-related features, only the baseline presence of cardiovascular diseases and the performance of RALP with a radical (non-nerve-sparing) intent were associated with a higher risk of experiencing short-term UI. Taken together, our data suggest that patient-related characteristics , rather than specific technical nuances, might decrease the chance of full continence recovery after RALP in our cohort. Yet, in our analysis we could not analyze the differential impact of specific steps of the procedure, such as bladder-neck preservation, nerve-sparing technique, etc., on the risk of early UI, mainly due to lack of granular data on these technical details for all patients.Importantly, our sub-analysis including only patients who underwent a mpMRI-guided diagnostic pathway for prostate cancer diagnosis (namely preoperative mpMRI followed by mpMRI-guided fusion biopsy) confirmed the findings reported for the overall cohort, suggesting that the information gained by surgeons from mpMRI (which might have guided the performance of a nerve-sparing procedure and other strategic steps of RALP) did not significantly impact on the risk of UI at both a short- and mid-term follow-up. Lastly, mirroring the results in the overall cohort, in a multivariable model including only patients who underwent preoperative mpMRI, neither established tumor-related features nor the four novel categories predicting the risk of early biochemical recurrence proposed by Mazzone et al.  based onOur findings, which come from a tertiary referral academic center and which are grounded on an established surgical technique employed by high-volume surgeons, provide a robust foundation for implementing preoperative patient counseling regarding the expected functional outcomes of RALP in daily clinical practice. In particular, while patients who are candidates for RALP should be reassured that, in experienced hands, postoperative UI is a rare “adverse event” in the mid-term follow-up, at the same time they should be properly informed regarding the risk of transient stress UI in the short-term period, occurring in almost one out of five patients in our series. In this regard, the implementation of specific anterior/posterior reconstructive techniques, as proposed by several authors , might iOur study is not devoid of limitations. First, despite prospective data collection in the pre- and perioperative period, the assessment of UI during the follow-up is prone to attrition bias and detection bias. Second, the evaluation of UI after RALP was based on patients’ self-assessments rather than objective metrics, which could have influenced our results. Third, we could not evaluate the proportion of patients experiencing UI at longer follow-up periods, limiting the generalizability of our findings. Third, our cohort included patients who underwent RALP by highly experienced surgeons; as such, our UI rates could not be directly interpreted in our clinical scenarios. Lastly, we could not evaluate the differential impact of specific technical steps of RALP on the risk of UI. We also have missing data about which were the specific modalities and pelvic floor muscle training that allowed 95% of the patients to achieve complete urinary continence at their last follow-up.In experienced hands, most patients fully recover urinary continence after RALP performed without specific anterior or posterior reconstruction techniques at a mid-term follow-up. On the contrary, a non-negligible proportion of patients reported stress urinary incontinence 1 month after surgery, suggesting that the implementation of surgical reconstructive techniques might still improve continence recovery in the early postoperative period. Prospective multicenter studies are needed to confirm the need of and to select the best candidates for anterior and/or posterior reconstructive techniques after RALP.


Super-resolution microscopy has become increasingly robust and performant over the last decade. Here, we report a server infrastructure that combines robust community-tested open-source processing algorithms with a workflow management system and database to enable production-grade processing of high-content super-resolution data. Picasso-server combines community-tested algorithms of Picasso, a workflow management system, and database in a server interface for high-throughput super-resolution studies. Recently, SMLM applications have been demonstrated with unprecedented throughput, resolution, and increased multiplexing capabilities7.Single-molecule localization microscopy (SMLM), such as PALMDespite these advancements, the application in routine and high-content super-resolution studies of several hundred to thousand samples is still limited. Performant and robust SMLM is technically demanding and requires optimally maintained instruments and excellently prepared samples, making routine measurements challenging.Another technology, mass spectrometry-based proteomics, that is similarly technically demanding, already allows the routine measurement of large-scale studies and can serve as a proxy on what is needed for SMLM to achieve a similar throughput. Here, instrument and reagent performance can be continually assessed. This is achieved by tracking technical instrument parameters and testing the complete pipeline, e.g., via frequently measuring standardized quality control samples and reporting the measured proteome depth.While similar analysis can be performed in SMLM, this is often not done automatically, and existing software packages typically are not tailored for large-scale analysis.8. Picasso is a popular open-source collection of tools and algorithms for analyzing SMLM data , and kinetics. While these properties are often manually calculated and inspected when examining a reconstructed image, Picasso-server chains them to the localization part in the pipeline  become readily visible, facilitating the technical assessment and effectively scheduling maintenance cycles, identifying optimal imaging conditions or localization settings. (Fig. Second, Picasso-server provides a web interface to interact with the local database Fig. . Here, wgs. Fig. . In an aThird, Picasso-server incorporates a file watcher that can automatically detect new files and process them with preselected settings. This includes functionality to call other Picasso functions or completely custom commands like Notifications to build tailored automation pipelines. The intended use case of the watcher relates to a lab environment with multiple instruments that continuously produce data and a central processing computer to which files are transferred Fig. . Users cPicasso-server extends the community-tested algorithms of Picasso and makes them accessible from a server interface. By connecting summary statistics and additionally quality metrics as part of a default analysis workflow, users can effectively conduct and monitor large-scale experiments. Ultimately, we hope that Picasso-server enables the next generation of high-throughput super-resolution studies. Further extensions to Picasso-server could include notification systems, automated performance warnings, or tailored recommendations on how to improve imaging quality. Like Picasso, Picasso-server is readily available as open-source with a one-click installer and a permissive MIT license.Further information on research design is available in the Peer Review FileSupplementary InformationReporting Summary


Bile acid (BA) plays a crucial role in various neurodegenerative diseases, including Parkinson's disease (PD). However, no clinical evidence supports BA's potential role in patients with PD with mild cognitive impairment (PD-MCI).This study aimed at investigating the differential BA profile between patients with PD-MCI and those with normal cognitive function (PD-NC).Ultra-high performance liquid chromatography-MS/MS was applied for BA quantitation. After between-group differences of the BA profile were addressed, orthogonal projections to latent structures—discriminant analysis (OPLS-DA) and the area under the receiver-operating-characteristic curve (AUC-ROC) were implemented for further verification.p < 0.01 for both; VIP ≈ 2.67, 1.66, and 1.26, respectively). AUC-ROC were 78.1, 74.2, and 74.5% for CDCA, CA, and UDCA, respectively.Lower levels of chenodeoxycholic acid (CDCA), cholic acid (CA), and ursodeoxycholic acid (UDCA) were significantly associated with PD-MCI (CA, CDCA, and UDCA might be distinct BA signatures for patients with PD-MCI. Cognitive impairment is considered one of the common non-motor symptoms (NMS) of Parkinson's disease (PD). There has been increasing awareness of the high incidence and damaging effects of cognitive impairment in PD in recent years. At the time when a PD diagnosis is established, almost all patients with PD suffer from some level of cognitive impairment . HoweverMild cognitive impairment in PD (PD-MCI) is defined as an intermediate cognitive stage between PD with normal cognition (PD-NC) and PDD. Compared with patients with PD-NC, patients with PD-MCI have a higher risk of developing into PDD . LongituThe Movement Disorder Society (MDS) Task Force on MCI in PD has established an operative definition of PD-MCI to homogenize clinical practice and research . AccordiBile acids (BA) are amphoteric molecules that mainly act as a solvent for dietary lipids and fat-soluble vitamins. The liver synthesizes primary bile acids, including cholic acid (CA), chenodeoxycholic acid (CDCA), and their conjugated form with glycine or taurine . Under tPlasma is an ideal sample for biomarker discovery and clinical diagnosis because it is simple to collect, relatively noninvasive, and easy to analyze. To test our hypothesis that the patients with PD-MCI showed changes in the bile acid profile, we performed a metabonomics analysis of plasma bile acids in the patients with PD-MCI and the patients with PD-NC.This study was conducted in the Department of Neurology, Guangdong Provincial People's Hospital, Guangzhou, People's Republic of China. A diagnosis of idiopathic PD was assigned according to the MDS-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)  by 2 neuDemographic information was collected from each subject, including sex, gender, age, education level, age of the onset, duration, medications, smoking, and drinking history. A detailed medical history and physical examination were collected from all the participants. Unified Parkinson's Disease Rating Scale Part III (UPDRS III) and Hoehn-Yahr Scale (H-Y) were used to assess motor function. Mental status was assessed by Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD).Our neuropsychological protocol included Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to assess general cognitive functioning, memory impairment, and executive dysfunction. The attention/working memory domain was tested by Symbol Digit Modalities Test (SDMT) and Digit Span Test (DST). Executive functions were evaluated by the Verbal Fluency Test (VFT) and Clock Drawing Test. Memory was assessed by visual reproduction (VR) and logical memory. Language function was tested by the Similarities Test and Category Fluency Task. Visuo-spatial and visuo-perceptive functions were assessed by the Block design Test. The patients were diagnosed with PD-MCI based on Movement Disorders Society Task Force Level II 20 using a cut-off of 1.5 standard deviations below standard scores in one or more cognitive domains in neuropsychological tests as previously described .A fasting venous blood sample was collected with a lithium heparin tube from all the subjects in the morning. The serum was separated and stored in the refrigerator at −80°C until experimental analysis. Thirty BA metabolites in serum were detected by ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS). After quality-control checks, the data set included 19 BAs  for a total of 67 subjects.t-tests or Mann–Whitney U-test for continuous variables and χ2 for categorical variables. False discovery rate (FDR)-based multiple comparison adjustment with the Benjamini-Hochberg procedure was used for BAs comparison to increase the significance of the findings.Statistical analyses were performed using SPSS25 software. Between-group (PD-MCI vs. PD-NC) differences in terms of demographics, clinical data, and BA characteristics were addressed by independent-sample p-values < 0.05. Then, according to the HMDB database, these differentially expressed metabolites were chemically classified. The area under the receiver-operating-characteristic curve (AUC-ROC) was also calculated.To simplify the complexity of the high-dimensional metabolome data, orthogonal projections to latent structures—discriminant analysis (OPLS-DA) was implemented to identify the differential expression of patients with BAs in PD with or without cognitive impairment. Two iterations of the permutation test verified the model. Through OPLS-DA, a variable importance in projection (VIP) value could be obtained for each metabolite. The larger the VIP is, the more significant the contribution of the metabolite to distinguish the two groups. Differential metabolites were defined as VIP >1.0 and FDR-corrected This study was performed following the principles outlined in the Declaration of Helsinki. Informed consent was obtained from all the individual participants included in the study.p > 0.05), indicating comparability . The OPLS-DA model was also constructed to show statistical differences in CDCA (VIP ≈ 2.67), Glycochenodeoxycholic acid , CA (VIP ≈ 1.658), glycoursodeoxycholic acid , and UDCA (VIP ≈ 1.26) levels between the PD-MCI and PD-NC groups. We identified CA, CDCA, and UDCA with VIP > 1 and corrected p-value < 0.05 as the differential BA metabolites in patients with PD-MCI , a membrane receptor that alleviates neuroinflammation and inhibits cell apoptosis , 32. BesAt a macro-level, abnormalities in BA metabolism may affect disease progression by altering structural networks in specific brain regions. Researchers have found that changes in BA of AD and patients with MCI were associated with changes in particular areas in brain imaging , which mBidirectional biochemical communication between the brain and the gut is associated with various neurodegenerative diseases, including Parkinson's disease. α-synuclein, a pathological marker of PD, was found to accumulate in the gastrointestinal tract of patients with early PD . After iIntestinal flora is an integral part of bile acid metabolism. In rats with PD symptoms that overexpress α- synuclein, intestinal microbial diversity was changed, and the levels of related primary bile acids were significantly increased and thus affecting motor symptoms . AnotherBecause the inclusion criteria were relatively strict, the total number of samples included was relatively small, which might decrease statistical power and cause some false-negative results. In addition, only the patients with PD-MCI and the patients with PD-NC were included in this study to explore the bile acid metabolites in PD cognitive impairment preliminarily. We will recruit more patients with PD with cognitive impairment in future studies, including those with dementia.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Research Ethics Committee, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences. The patients/participants provided their written informed consent to participate in this study.KN, YL, and JZ contributed to conception and design of the study. KN and JZ organized the database. JZ performed the statistical analysis. YL wrote the first draft of the manuscript. KN, JZ, YQ, RG, and YG wrote sections of the manuscript. All the authors contributed to manuscript revision and read and approved the submitted version.This work was supported by Science and Technology Planning Project of Guangzhou (202102080054); Guangdong Medical Research Foundation (A2021308); Science and Technology Planning Project of Guangdong Province (2020A0505140006).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The study aimed to critically review and synthesize the best available evidence about the effectiveness of therapist-guided internet-delivered cognitive behavioral therapy (iCBT) in terms of reducing sickness absence (SA).We searched Medline (PubMed), Embase, PsycInfo, CINAHL, and Cochrane Central (up to November 2020) for English language peer-reviewed papers that described randomized controlled trials of therapist-guided iCBT compared with usual treatment for SA in adults with common mental disorders. Eligible studies were assessed with the Cochrane Risk of Bias 1 tool, meta-analysis was conducted using a random-effects model, and standardized mean differences (SMD) with 95% confidence intervals (CI) were reported. A subgroup analysis investigated potential moderating variables .We identified 2788 references, of which 68 remained after the completion of the systematic screening process. A hand search of reference lists yielded no additional studies. The full texts of these 68 studies were appraised critically, and 11 were deemed to be suitable for a meta-analysis. SA was similar for iCBT and usual treatment groups , and remained similar even after the removal of two studies in which the recall time was over 3 months . Similar SA levels in intervention and control groups at 6-month and 12-month follow-up were observed in studies of participants with depression symptoms.iCBT did not appear to be effective in terms of reducing (largely self-assessed) SA in adults with common mental disorders. There is a need to improve the method and consistency of assessing SA. Common mental disorders (CMDs) are significant contributors increasingly to the global burden of disease . ConditiFurthermore, SA has direct negative economic consequences for workers with mental ill-health, employers, and society at large , and indThe search for readily available and cost-efficient treatment approaches to the treatment of common mental disorders led to the development of Internet-delivered therapies, especially Internet-delivered cognitive behavioral therapy (iCBT). Several systematic reviews point to a body of evidence indicating the effectiveness of iCBT at least in terms of symptom relief –15. GuidThis study aimed to critically review and synthesize the best available evidence about the effectiveness of therapist-guided iCBT in terms of reducing SA. This is the first systematic review and meta-analysis of studies of iCBT interventions that focused on common mental disorders, reported SA, and examined whether iCBT offered any advantages or disadvantages in terms of lost workdays.The PRISMA  standards were followed throughout the process  and the study protocol was registered with PROSPERO (CRD42020151604) before proceeding with the systematic searches.Trials were eligible for inclusion in the review if they included an adult (18–64 years old) sample with clinically determined common mental health conditions or sleep disorders, particularly insomnia . These codes cover phobic anxiety disorders, other anxiety disorders, obsessive-compulsive disorder, depressive episode, recurrent depressive disorder, persistent mood disorders, other mood disorders, and unspecified mood disorders. In addition, we included studies of adults with self-reported mental illness if they met the definition of a “case” as defined according to an empirically verified cut-off point on a validated scale. Trials were excluded if patients had psychiatric disorders outside this pre-defined group of diagnoses, for example, personality disorder, substance abuse, severe post-traumatic stress disorder, psychotic disorders, learning disability, attention deficit, or other neurodevelopmental/neuropsychiatric disorders. Also, studies that focused solely on seniors, children, or adolescents were excluded.We excluded patients with bipolar and axis I disorders, post-traumatic stress disorder, neuropsychiatric disorders, and neurologic comorbidities disorders and substance abuse due to general differences in treatment and prognosis. Furthermore, there is some evidence to suggest that guided internet-based interventions may be superior to unguided interventions , thus wehttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=151604) a range of comparators  and face-to-face CBT as well as intervention evaluations with various degrees of control in their study designs. The volume of studies was much larger than expected and the protocol was revised (purely for review project management reasons) to cover only randomized controlled trials (RCTs) of iCBT versus treatment as usual/waitlist/information control or placebo.Outcome was SA for any cause, as mental illnesses such as depression and anxiety increase the risk of all types of health-related absence ,3. UncerAn RCT was eligible if the intervention consisted of therapist guided, internet-delivered  therapy, in an outpatient, primary care, or similar, setting, in which patients were exposed to the same intervention components that comprise conventional CBT, but the material, instructions and assistance were provided through an Internet-based treatment platform. Assistance by telephone did not lead to the exclusion of a study, and studies with or without combined [selective serotonin reuptake inhibitors/serotonin and norepinephrine reuptake inhibitors (SSRI/SNRI)] medication and a variable number of sessions were eligible. The comparator was a wait-list or care-as-usual control group or a face-to-face CBT intervention group of working age adults.In addition, studies were required to report data on post-intervention self-reported and/or confirmed SA  to be eligible for inclusion in the review. We included studies that measured other outcomes such as work ability, work satisfaction, work functioning, and unemployment as long as they measured SA outcome. Only English language papers in the specified databases were included in the review.Medline through PubMed (1966–present), Embase (1966–present), PsycINFO (1967–present), CINAHL (1937–present), and Cochrane Central Register of Controlled Trials (1992–present), were searched in November 2020. Please see online supplemental material (PRISMA checklist) for a full description of the search terms and strategies that were applied to the databases.Results of the database searches were imported into the Covidence bibliographic format . Two autsupplemental files). Two members of this review team reviewed the full texts independently against the inclusion and exclusion criteria, and disagreements were resolved by a third author. Papers based on the same trial were merged. The review team’s psychiatrist studied the reported descriptions of interventions and excluded two studies because it was unclear whether or not they were CBT-based [Ten full texts were obtained through direct contact with the authors .Data was extracted according to the Cochrane handbook for systematic reviews of interventions , by dividing the baseline mean number of SA days with the recall time for collecting the outcome and then, in turn, dividing this result with the respective national average of SA days published by the Organization for Economic Co-operation and Development (OECD) . In thisSupplemental Table S1, characteristics of studies), and 10 out of 11 were secondary analyses of trials that were designed to address intervention effectiveness. Only Beiwinkel et al. [3537All 11 included studies were conducted in Europe within the last decade  was skewed by one study and suggested that there may be some publication bias towards favoring publication of reduced SA in the intervention group or condition . Egger’s t-test also indicated possible publication bias and no evidence of small study effects (P = 0.60). An indicative meta-analysis of SA data from all time points in every study showed a statistically non-significant SMD of 0.0 (95% CI –0.1 to 0.1)  and an analysis of the longest follow-up time point in each study (I2 of 26%) resulted in a non-significant SMD of 0.02 (95% CI –0.08 to 0.11). iCBT did not appear to have a positive or negative effect on SA compared with treatment as usual for people with the common mental disorders represented in the studies. A similar statistically non-significant total SMD of 0.00 (–0.11 to 0.12) was found when standardized mean SAs of study arms were compared , and revealed a total SMD of 0.03 (95% CI –0.06 to 0.12), see SA outcome data from follow-up time points, that is, SA after the intervention program had been completed, were available for 10 out of 11 studies . The longest follow up time points of each study were comparable with a low heterogeneity, , and technically heterogeneous, as the study in which the result favored the control group differed from the other studies in terms of offering an “attention control” condition that comprised intense follow-up and online peer-group activities had a total SMD for the control group that was still close to zero .Analysis of the post-intervention time points 2–3 months from baseline . The total SMD was statistically non-significant . Similar results were observed when these data were analyzed according to the 6-month follow-up time point  was added to the analysis.A meta-analysis of the six studies that comprised participants with depression had low heterogeneity , I2 = 35% .Control of the baseline SA indicators did not affect SA scores after receipt of an iCBT intervention. The studies with baseline SA above the national average had a total SMD of –0.02 (95% CI –0.15 to 0.12), IThe main finding of this study is that SA among patients with common mental disorders, mainly depression, does not appear to be reduced significantly by iCBT. This is the first systematic review to address SA as a key outcome of interest in the evaluation of iCBT for people with common mental disorders. There is a need for RCTs that are designed and powered to test the effectiveness of iCBT  in terms of SA as a primary endpoint or outcome.A previous review investigated the effectiveness of psychological treatments and return-to-work interventions for common mental disorders , includiThe outcome of this review should be interpreted mindful of several limitations. SA is not a primary endpoint or a commonly assessed outcome in clinical trials of iCBT judging from the relatively small number of studies that were included in this review compared with other systematic reviews of studies about the effectiveness of iCBT ,15. NoneSecondly, it is reasonable to argue that, in the current context, a register-based SA outcome may be regarded as a gold standard. Registry data, however, may be unavailable for ethical or practical reasons, and only absences above or below certain day limits may be recognized. This review found that most studies (10 out of11) used self-reports to determine SA. Self-reporting of SA may be subject to bias and under-reporting, and accuracy tends to decrease as recall duration time increases . AggregaThirdly, the Trimbos/iMTA questionnaire for costs associated with psychiatric illness, “Treatment Inventory of Costs in Patients with psychiatric disorders” (TiC-P), which was used in 8 out of 11 studies as the method of self-reporting SA, has been validated for a recall period of 2 weeks . The shoA further limitation of the review is the possibility of missing relevant studies published in languages other than English. Only one abstract in this review was excluded from full text screening due to the article being published in another language. Therefore, it is reasonable to assume that this limitation is minor considering that one or more databases tend to post study abstract translations in English.In conclusion, based on the studies reviewed here, it seems unlikely that the provision and delivery of an iCBT intervention as defined in this review will be a sufficient measure to reduce SA among people with CMDs. Mhealth, e-health, telehealth and other remote modes of patient treatment have gained increased significance in the context of the coronavirus disease 2019 (COVID-19) pandemic and there is a pressing need to investigate and test ways of combining technology such as the internet with treatments such as CBT. Rigorous studies (and subsequently reviews of studies) of the impact of iCBT on employment status and on absence from school or education are needed. Also, we need to improve our understanding about how iCBT impacts on the functioning of an individual in their various social, family, and community contexts. It is important to be mindful that our study exclusion criteria meant that the review did not include substance abuse studies comorbid with common mental disorders. We recognize the importance of this omission and that further research is required into SA in the relation to substance abuse and its set of interrelated social, behavioral, economic, and occupational factors. Further research is needed, too, to clarify the mechanisms of action in occupational mental health interventions  in order to design effective, tailored programs that include iCBT as an individual or integrated mode of addressing SA specifically. There remains a need for trials of iCBT  in order to address the paucity of rigorous studies that address this outcome of SA. Improving the reliability and validity of the assessment of SA data would inform discussion beyond days of SA and decisions about the efficient distribution of resources in occupational health care between rehabilitation of employees with common mental disorders already on long-term sick-leave , and preClick here for additional data file.Supplemental material, sj-docx-1-sjp-10.1177_14034948221075016 for Internet-delivered cognitive behavioral therapy (iCBT) for common mental disorders and subsequent sickness absence: a systematic review and meta-analysis by Lina Udd-granat, Jouni Lahti, Michael Donnelly, Charlene Treanor, Sami P. Pirkola, Tea Lallukka and Anne Kouvonen in Scandinavian Journal of Public HealthClick here for additional data file.Supplemental material, sj-docx-2-sjp-10.1177_14034948221075016 for Internet-delivered cognitive behavioral therapy (iCBT) for common mental disorders and subsequent sickness absence: a systematic review and meta-analysis by Lina Udd-granat, Jouni Lahti, Michael Donnelly, Charlene Treanor, Sami P. Pirkola, Tea Lallukka and Anne Kouvonen in Scandinavian Journal of Public HealthClick here for additional data file.Supplemental material, sj-docx-3-sjp-10.1177_14034948221075016 for Internet-delivered cognitive behavioral therapy (iCBT) for common mental disorders and subsequent sickness absence: a systematic review and meta-analysis by Lina Udd-granat, Jouni Lahti, Michael Donnelly, Charlene Treanor, Sami P. Pirkola, Tea Lallukka and Anne Kouvonen in Scandinavian Journal of Public HealthClick here for additional data file.Supplemental material, sj-docx-4-sjp-10.1177_14034948221075016 for Internet-delivered cognitive behavioral therapy (iCBT) for common mental disorders and subsequent sickness absence: a systematic review and meta-analysis by Lina Udd-granat, Jouni Lahti, Michael Donnelly, Charlene Treanor, Sami P. Pirkola, Tea Lallukka and Anne Kouvonen in Scandinavian Journal of Public Health


Minimal residual disease (MRD) is considered the strongest relevant predictor of prognosis and an effective decision-making factor during the treatment of hematological malignancies. Remarkable breakthroughs brought about by new strategies, such as epigenetic therapy and chimeric antigen receptor-T (CAR-T) therapy, have led to considerably deeper responses in patients than ever, which presents difficulties with the widely applied gold-standard techniques of MRD monitoring. Urgent demands for novel approaches that are ultrasensitive and provide sufficient information have put a spotlight on high-throughput technologies. Recently, advances in methodology, represented by next-generation sequencing (NGS)-based clonality assays, have proven robust and suggestive in numerous high-quality studies and have been recommended by some international expert groups as disease-monitoring modalities. This review demonstrates the applicability of NGS-based clonality assessment for MRD monitoring of B-cell malignancies by summarizing the oncogenesis of neoplasms and the corresponding status of immunoglobulin (IG) rearrangements. Furthermore, we focused on the performance of NGS-based assays compared with conventional approaches and the interpretation of results, revealing directions for improvement and prospects in clinical practice.The online version contains supplementary material available at 10.1186/s40164-022-00300-2. The adv [–4 [–6 . Anotherormation , 19.Compared with other MRD monitoring methods, the NGS-based IG clonality approach possesses substantial potential for a wide range of applications due to the distinct features of the technique, such as the comprehensiveness of the information gained, the ability to recognize clonal evolution, and the ability to standardize the workflow –23. FurtDuring the process of maturation, the immunoglobulin genes in normal B cells undergo a process referred to as V(D)J recombination to produce a unique receptor  for combination with its specific antigen J gene segments. The 123–129 VH gene segments, of which 38–46 segments are functional and 36 are considered pseudogenes, can be approximately grouped into 7 families (VH1–VH7) . The posDuring adaptive immune responses, B cells react to antigenic stimulation and rapidly proliferate, forming clones with the same V(D)J pattern and possible intraclonal diversity at the nucleotide level attributed to SHM. Similarly, after malignant transformation at a certain time point during B cell differentiation triggered by either activation of oncogenes or inactivation of tumor suppressor genes, B-lineage cancer cells carrying the same complete V(D)J or incomplete DJ rearrangement unlimitedly multiply with possible subclone characteristics caused by ongoing SHM or ongoing V(D)J recombination, respectively –42. GiveThe deletion–recombination reactions of V(D)J rearrangement, SHM, and CSR require a double-strand break (DSB) at a specific locus, introducing potential aberrant translocation events that can serve as distinguishing signs in fluorescence in situ hybridization or IG-based clonality assessment –46. CharALL is considered to originate from pre-B cells, which are aberrantly blocked at the transition to immature B cells. This mechanism explains the unmutated or low-mutated status due to lack of SHM, the high frequency of unproductive IGH rearrangements due to continuously active recombinase enzyme, and the initiation of IGK/IGL rearrangements that go against allelic exclusion rules due to improper in-frame selection , 47, 59.CCND1/IGH), leading to the overexpression of CCND1 protein [CCND2 or CCND3 translocation with IGK or IGL [The origins of conventional MCL (cMCL) cells and nonnodal MCL (nnMCL) cells are believed to be naïve mature B cells and memory-like B cells, respectively , 55. The protein , 62, whiK or IGL . AberranK or IGL . SimilarK or IGL . SeveralK or IGL , 54, 55.Opinions on the origin of CLL cells are widely divided due to the existence of unmutated (U-CLL) and mutated (M-CLL) subtypes, classified by the level of SHM with a cutoff value of 2% , 49. CurDLBCL, not otherwise specified , is classified into two distinct groups, the germinal center B-cell-like (GCB) subtype and non-GCB subtype, characterized by different cells-of-origin (COO) and responses to chemotherapies or targeted therapies . Both suFL cells originate from GC B cells, marked by t  (IGH/BCL2), resulting in the overexpression of BCL2 . RecentlCompared with other B-lineage lymphomas, MM possesses more stable properties at the molecular level due to its origin from plasma cells, which have completed the GC reaction and consequently exhibit more mature features. CDR3 regions of either heavy chain or light chain in MM cells are highly mutated without intraclonal variation, while most MM secretes class-switched Igs, indicating the initiation of pathogenesis at the relatively late phase of the GC reaction , 81, 82.Because almost all B-lineage malignancies have distinct and stable V(D)J recombination patterns, the BIOMED-2 protocol was first designed by a European BIOMED-2 collaborative study as a PCR-based technology for routine clonality diagnostics . This clConsidering the abundance of information produced by the NGS IG method, it is plausible and practical to apply this strategy for clonality assessment in diagnosis at baseline and MRD monitoring follow-up assessments.The variance of clinical remission (CR) among different regimens and diseases has revealed the limitation of the current definition by clinical manifestation and imaging tests, raising a claim for a more stringent version. MRD is generally acknowledged as one of the most powerful approaches for the prediction of relapse and prognosis. MRD-positive patients have far less favorable event-free survival outcomes than MRD-negative patients , 88–91. 5 nucleated cells [–6 is used [However, MRD monitoring is not widely available in lymphoma care despite the benefits shown in therapeutic outcomes and scientific research. Several obstacles have impeded the improvement of MRD and the ability to obtain feedback from real experiences, including the lack of incorporation of MRD monitoring in prospective trials involving novel treatment, the relatively high cost of high-throughput sequencing per sample, the long delays between technical evolution and the ultimate outcome , the labor and special care required in the trial and the complex statistics required for analysis . Furthered cells , 22. How is used , 93, 94.–5. The functionality of MRD monitoring based on this assay can be influenced by several technical limitations of sampling and sequencing, including the amount of input DNA, the cellularity of a BM sample, and possible significant overestimation of residual tumor cells due to the calculations  [The complete process of IG-based diagnosis and MRD monitoring by NGS in lymphoma is shown in Fig. g reads) .Fig. 3StThe strategy designed to amplify specific regions in the IGH/IGK gene is based on a set of consensus primers targeted at the conserved FR region Fig. A. For IGFor some cases, the IGHV mutational status plays an important role in prognosis prediction, such as in CLL. The matched bioinformatics software Lymphotrack IGH FR1 Assay Master Mixes can be used to meet the needs for evaluating the SHM rate of the IGHV region. The IGHV mutational status will be determined based on the percent of mismatch between the clonal amplicons and the corresponding germline reference genes, the prediction of in-frame or out-of-frame translation, the possibility of a premature codon introduced by the mutation, and the percentage of VH gene coverage in the region targeted. SHM, in turn, may hamper the identification of clonal immunoglobulin rearrangements due to the possible prevention of primer annealing during multiplex PCR. Nonetheless, to identify distinct IGHV genes in the IGHV subgroup, commercial kit software will require a match using the IgBLAST or IMGT database and list the candidate IGHV genes in order of identity. The best match is preferentially chosen for subsequent analyses. The result will be considered dubious and excluded when a stop codon or frameshift mutation is produced. Although the bias resulting from SHM is hard to avoid, the comparison step ensures the validity of the interpretation as much as possible.The information presented in the analysis report is as follows: (1) a summary of a sorted list of unique sequences, including the best-matched V–J family recombination event, length of the read, the actual and cumulative rate of the unique read in total reads, coverage of the identified V-gene by the unique read, the mutation rate to partial V gene and the prediction of in-frame mutation and stop codon; (2) graphs of V–J usage/sequence frequency and (3) a FASTA file of the unique sequences sorted by count.The advantages and drawbacks of the methods for clonality assessment are presented in Table The gold standard for clonality assessment is the BIOMED-2 multiplex PCR-based protocol for IG/TCR targets, but it is not suitable for MRD monitoring . The wor–4 ~ 10–5. In this approach, IG regions are targeted and amplified by consensus primers and then sequenced to design more precise, patient-specific primers and probes [ASO-RQ-PCR can be applied for diagnosis and MRD monitoring of lymphoma with a sensitivity of 10d probes . ASO-RQ-Compared with the BIOMED-2 protocol and ASO-RQ-PCR method, the IG-based NGS approach performed better on many levels, such as higher sensitivity, the ability to obtain more information about the IG repertoire, and the ability to track clonal evolution; additionally, the workflow is well-standardized  assay, can also be applied for MRD monitoring. ddPCR was proven to be an efficient method for MRD monitoring in malignancies with distinct translocation/fusion transcripts/recurrently mutated gene markers, such as BCL/IGH rearrangements in FL , BCR-ABL precise , 112. Ba precise . The hig precise , 114. Ho precise . High mu precise . AdditioThe comparison of FC-based, NGS-based, and PCR-based approaches is shown in Table Statistics from clinical trials in which treatment decisions were made based on MRD are scarce due to the obstacles to practically applying MRD monitoring. However, several studies have focused on the functionality of the NGS-based MRD method by comparing it with other gold-standard approaches in registered clinical trials evaluating different B-lineage malignancies Table . In summ–6, which is usually unavailable from patients who have experienced intensive treatment elsewhere and is also time-and labor-consuming. Although it is difficult to find and achieve the right balance of economic benefits and optimal results, the combination of higher sensitivity for detection and risk stratification based on the number of residual tumor cells can be an inspiration to develop next-generation techniques for MRD monitoring. The second question is associated with the sample types. Diagnosis and MRD monitoring are generally performed by analyzing the infiltration of tumor cells in the BM. It should be noted that BM aspiration and biopsy are invasive procedures with potential risks, limiting the ability of doctors to take repeated samples.MRD monitoring has already become a relatively mature and widely acceptable technology despite insufficient reliability when independently guiding treatment-associated decisions. However, the answers to several questions remain obscure or controversial. The first is the significance of sensitivity in real-world utilization. Theoretically, the deeper the detection is, the more accurate the results will be, which was emphasized in some articles that demonstrated a higher relapse rate of NGS or NGF MRD-positive patients compared with those assessed with other techniques with lower sensitivity , 125. HoCompared with those for examining BM aspirations, tests for peripheral blood are more convenient and accessible. Recently, liquid biopsy technology has emerged to capture information about SHM, V(D)J rearrangements, amplification and gene copy variations. By using circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), or other cell-free nucleic acids , liquid biopsy can be conducted in a noninvasive manner . The resThis review provides a comprehensive evaluation of IG NGS-based MRD monitoring, including the necessity of MRD monitoring, the scope of application of the IG NGS method, the superiority of the IG NGS method for diagnosing and tracking MRD, the existing limitations, future trends, and potential development directions. With the continuing increasing sensitivity and affordability of HTS technology, the routine use of IG NGS-based MRD monitoring in clinical practice is expected within the near future, with robust performance and reasonable per-sample cost.Additional file1: Fig. S1 Schematic representation of Ig heavy and light chain rearrangements in normal B cells. (A) Complete VH-D-JH recombination in the IGH locus (14q32). (B) The classical Vκ-Jκ recombination in the IGK locus (2p11) (up), the inversion Vκ(D)-Jκ rearrangement (middle), and Kde-mediated deletions by RSS-intron or Cκ (below). V, variable. D, diversity. J, joining. C, constant.


A portion of gastric cancer patients with negative lymph node metastasis at an early stage eventually die from tumor recurrence or advanced metastasis. Occult lymph node metastasis /computed tomography (CT) is used to assess lymph node metastasis in gastric cancer due to its advantages in anatomical and functional imaging and non-invasive nature. Among the major metabolic parameters of PET, the maximum standardized uptake value (SUVmax) is commonly used for examining lymph node status. However, SUVmax is susceptible to interference by a variety of factors. In recent years, the exploration of new PET metabolic parameters, new PET imaging agents and radiomics, has become an active research topic. This paper aims to explore the feasibility and predict the effectiveness of using PET/CT to detect OLNM. The current landscape and future trends of primary metabolic parameters and new imaging agents of PET are reviewed. For gastric cancer patients, the possibility to detect OLNM non-invasively will help guide surgeons to choose the appropriate lymph node dissection area, thereby reducing unnecessary dissections and providing more reasonable, personalized and comprehensive treatments. Gastric cancer is one of the most common diseases, ranking fifth in incidence and third in mortality worldwide in 2020. Specifically, it accounted for approximately 769,000 deaths, with at least 1 in 13 due to stomach cancer ,5. Howev18F-FDG PET/CT  FLT (3′-deoxy-3′-fluorothymidine) is a stable PET tracer.  1 (TK1) . 18FLT ireatment . Because-FDG-PET . Staniuk-FDG-PET  evaluatec cancer . Hermannc cancer  concludec cancer . However18F-FDG is a common diagnostic modality in current clinical practice, in some patients with mucinous adenocarcinoma and indolent cell carcinoma, 18F-FDG PET/CT gives negative results due to the high mucus component and low tumor cell density [18F-FDG is used. Although some studies have demonstrated the superiority of new imaging agents to 18F-FDG, these can only be considered potential modalities due to the limited coverage and smaller sample size compared with 18F-FDG studies. A modality with high accuracy still needs to be explored.Although  density . TherefoThe field of medical image analysis has been growing rapidly in recent decades. Innovations in medical imaging technology are driving the field towards quantitative imaging and facilitating the development of automated and reproducible analysis methods. Radiomics is a novel field in medical imaging , and perIn our study, we found that PET/CT is of substantial value for the diagnosis of OLNM. SUVmax is the most commonly used semi-quantitative parameter in clinical practice, but it reflects the metabolic activity of tumor cell components instead of the whole tumor and is susceptible to image resolution issues and noise. Therefore, other parameters reflecting tumor load and metabolic activity from the whole tumor lesion, such as MTV and TLG, are being evaluated. TLG and MTV can be factored in as complementary parameters to determine the presence of metastasis. The current development of new tumor tracers has helped to improve the detection rate of OLNM by PET/CT. Novel technologies ,123 inclWith the development of new technologies to be used in combination with PET, the accuracy of OLNM detection is subject to great improvements. For example, multi-helical CT (MDCT) has the advantages of high resolution and easy operation, and advanced techniques such as multi-planar reconstruction or three-dimensional imaging are capable of detecting almost all positive lymph nodes . The comAs a large amount of data is required to build mathematical models for artificial intelligence analyses, the establishment of a multicentre database is important for disease prediction. It has been suggested that these machine learning models can be used to predict gastric cancer lymph node metastasis and benefit its staging and treatment. For example, faster region-based convolutional neural networks (FR-CNN) can contribute to reconstructing the distribution of lymph nodes in the body from multiple angles and provide an improved detection rate. The identification accuracy of FR-CNN for lymph node metastasis is 95.4%, which indicates its significant potential value in the diagnosis and treatment of gastric cancer . Convolu18F-FDG is still a common clinical parameter for the diagnosis of lymph nodes and distant metastases, and, as mentioned before, 18F-FDG remains extremely challenging for the detection of OLNM in gastric cancer. Data from studies with larger sample sizes are lacking to support the value of PET/CT in predicting OLNM in patients with gastric cancer. A large number of studies, such as those demonstrating the utility of various metabolic parameters in assessing patient response to treatment and prognostic evaluation, are needed to further investigate and confirm this. Although new imaging agents have shown some advantages, prospective studies are lacking. Additionally, although the noninvasive, quantified, and visualized features extracted by radiomics can reflect tumor heterogeneity, the extraction of 18F-FDG PET/CT histological features is still strongly influenced by image acquisition and reconstruction parameters. Overall, various technical difficulties are yet to be overcome.This article is subject to certain limitations. First, this is a retrospective review and 18F-FDG PET/CT is important and remains the most popular parameter for this purpose. Meanwhile, new imaging agents for PET are being developed with the aim of complementing the limitation of PET in that it only characterizes OLNM in terms of glucose metabolism, and novel technologies such as radiomics in synergy with artificial intelligence are advancing to provide more accurate and effective predictive tools.The latest trends in improving occult lymph node metastasis through non-invasive methods are reviewed. Currently, PET/CT still has many limitations for the detection of lymph node metastasis in gastric cancer. SUVmax of Conceptualization, J.W. and C.W.; methodology, C.W.; writing—original draft preparation, D.M.; data curation, D.M. and Y.Z.; writing—review and editing, X.S., Y.Z. and C.W.; project administration, J.W; funding acquisition, J.W. and C.W. All authors have read and agreed to the published version of the manuscript.