Bladder compliance dynamics of pelvic organ prolapse in women undergoing robotic-assisted sacrocolpopexy.

STUDY OBJECTIVE: Although mean/static compliance of bladder filling can be readily assayed via cystometry, a protocol measuring compliance dynamics at a specific stage of bladder filling has not been established in human patients. For patients with pelvic organ prolapse (POP), the objective benefits of robotic-assisted sacrocolpopexy (RSCP) surgical intervention for restoring bladder functions, primarily urine storage, have yet to be established. Also, bladder compliance is a viscoelastic parameter crucially defines the storage function. Therefore, we aimed to investigate the impact of RSCP on bladder compliance of POP patients using a pressure-volume analysis (PVA), which graphically illustrate bladder compliance. DESIGN: A retrospective pre- and post-operative study. SETTING: Multiple hospitals in Taiwan. PATIENTS: 27 female POP patients (stage ≥ II). INTERVENTION: RSCP for POP repair. MEASUREMENTS AND MAIN RESULTS: We retrospectively reviewed the pre- and post-operative PVAs for women with POP, who underwent RSCP. The mean compliance of the entire (Cm), the early half (C1/2), and the late half (C2/2) of bladder filling were analyzed as primary outcomes. Changes in intra-vesical volume (ΔVive) and detrusor pressure (ΔPdet) of bladder filling, ΔPdet in the early (ΔPdet1/2) and late (ΔPdet2/2) filling, and post-voiding residual volume (Vres) were analyzed as secondary outcomes. Compared with the pre-operative control, RSCP increased Cm (p=0.010, N=27) and C2/2 (p<0.001, N=27) but negligibly affected C1/2 (p=0.457, N=27). Mechanistically, RSCP decreased ΔPdet (p=0.001, N=27) without significantly affecting ΔVive (p=0.863, N=27). Furthermore, RSCP decreased the ΔPdet2/2 (p<0.001, N=27) but not ΔPdet1/2 (p=0.295, N=27). CONCLUSIONS: This is the first report of applying PVA in assaying dynamics of bladder compliance in patients with POP. Our results suggest that RSCP improved bladder storage in women with POP since it increased bladder compliance, particularly in the late filling possibly by restoring the anatomical location and geometric conformation for bladder expansion. CLINICAL TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (https://clinicaltrials.gov/study/NCT05682989); registration number: NCT05682989 submitted on 12/28, 2022.

Effect of intra-vaginal electric stimulation on bladder compliance in stress urinary incontinence patients: the involvement of autonomic tone.

Objective: In addition to the well-established advantage that strengthened pelvic musculature increases urethral resistance in stress urinary incontinence (SUI) patients, intra-vaginal electrical stimulation (iVES) has been shown in preclinical studies to improve bladder capacity via the pudendal-hypogastric mechanism. This study investigated whether iVES also benefits bladder storage in SUI patients by focusing on compliance, a viscoelastic parameter critically defining the bladder's storage function, in a clinical study. Moreover, the potential involvement of stimulation-induced neuromodulation in iVES-modified compliance was investigated by comparing the therapeutic outcomes of SUI patients treated with iVES to those who underwent a trans-obturator tape (TOT) implantation surgery, where a mid-urethral sling was implanted without electric stimulation. Patients and methods: Urodynamic and viscoelastic data were collected from 21 SUI patients treated with a regimen combining iVES and biofeedback-assisted pelvic floor muscle training (iVES-bPFMT; 20-min iVES and 20-min bPFMT sessions, twice per week, for 3 months). This regimen complied with ethical standards. Data from 21 SUI patients who received TOT implantation were retrospectively analyzed. Mean compliance (Cm), infused volume (Vinf), and threshold pressure (Pthr) from the pressure-flow/volume investigations were assessed. Results: Compared with the pretreatment control, iVES-bPFMT consistently and significantly increased Cm (18/21; 85%, p = 0.017, N = 21) and Vinf (16/21; 76%, p = 0.046; N = 21) but decreased Pthr (16/21; 76%, p = 0.026, N = 21). In contrast, TOT implantation did not result in consistent or significant changes in Cm, Vinf, or Pthr (p = 0.744, p = 0.295, p = 0.651, respectively; all N = 21). Conclusion: Our results provide viscoelastic and thermodynamic evidence supporting an additional benefit of iVES-bPFMT to bladder storage in SUI patients by modifying bladder compliance, possibly due to the potentiated hypogastric tone, which did not occur in TOT-treated SUI patients.Clinical trial registration: ClinicalTrials.gov, NCT02185235 and NCT05977231.

6'-Sialyllactose Enhances Exercise Performance via Increased Muscle Mass and Strength.

Sialyllactose (SL) is a functional human milk oligosaccharide essential for immune support, brain development, intestinal maturation, and antiviral defense. However, despite its established health benefits, the effect of SL on exercise performance and muscle mass in mice remains unknown. Here, we aimed to investigate, for the first time, the effects of 6'-SL on muscle functions. Seven-week-old male C57BL/6J mice were administered 100 mg/kg 6'-SL for 12 weeks, after which exhaustive treadmill performance was conducted. Moreover, muscle strength was examined by grip strength, and muscle phenotype characteristics such as muscle mass, muscle fiber size, and muscle protein expression were also examined. The administration of 6'-SL significantly improved exhaustive treadmill performance metrics, including distance and exhaustion time. Grip strength was also increased by 6'-SL administration. Additionally, 6'-SL increased muscle mass in both the gastrocnemius (GAS) and soleus. 6'-SL administration led to an increase in the minimum Feret's diameter and the protein expression of total myosin heavy chain in the GAS muscle. In conclusion, 6'-SL administration in vivo led to increased running distance and time by increasing muscle mass and strength. These findings collectively indicate that 6'-SL is a potential agent for improving muscle health and exercise performance.

Feasibility, safety and outcomes of conduction system pacing for bradycardia amongst the very elderly.

The impact of age (≥ 85 vs < 85 years) on clinical outcomes and pacemaker performance of conduction system pacing (CSP) compared to right ventricular pacing (RVP) were examined. Consecutive patients from a prospective, observational, multicenter study with pacemakers implanted for bradycardia were studied. The primary endpoint was a composite of heart failure (HF)-hospitalizations, pacing-induced cardiomyopathy requiring cardiac resynchronization therapy or all-cause mortality. Secondary endpoints were acutely successful CSP, absence of pacing-complications, optimal pacemaker performance defined as pacing thresholds < 2.5 V, R-wave amplitude ≥ 5 V and absence of complications, threshold stability (no increases of > 1 V) and persistence of His-Purkinje capture on follow-up. Among 984 patients (age 74.1 ± 11.2 years, 41% CSP, 16% ≥ 85 years), CSP was independently associated with reduced hazard of the primary endpoint compared to RVP, regardless of age-group (< 85 years: adjusted hazard ratio [AHR] 0.63, 95% confidence interval [CI] 0.40-0.98; ≥ 85 years: AHR 0.40, 95% CI 0.17-0.94). Among patients with CSP, age did not significantly impact the secondary endpoints of acute CSP success (86% vs 88%), pacing complications (19% vs 11%), optimal pacemaker performance (64% vs 69%), threshold stability (96% vs 96%) and persistent His-Purkinje capture (86% vs 91%) on follow-up (all p > 0.05). CSP improves clinical outcomes in all age-groups, without compromising procedural safety or pacemaker performance in the very elderly.

Interpretable machine learning model based on clinical factors for predicting muscle radiodensity loss after treatment in ovarian cancer.

PURPOSE: Muscle radiodensity loss after surgery and adjuvant chemotherapy is associated with poor outcomes in ovarian cancer. Assessing muscle radiodensity is a real-world clinical challenge owing to the requirement for computed tomography (CT) with consistent protocols and labor-intensive processes. This study aimed to use interpretable machine learning (ML) to predict muscle radiodensity loss. METHODS: This study included 723 patients with ovarian cancer who underwent primary debulking surgery and platinum-based chemotherapy between 2010 and 2019 at two tertiary centers (579 in cohort 1 and 144 in cohort 2). Muscle radiodensity was assessed from pre- and post-treatment CT acquired with consistent protocols, and a decrease in radiodensity ≥ 5% was defined as loss. Six ML models were trained, and their performances were evaluated using the area under the curve (AUC) and F1-score. The SHapley Additive exPlanations (SHAP) method was applied to interpret the ML models. RESULTS: The CatBoost model achieved the highest AUC of 0.871 (95% confidence interval, 0.870-0.874) and F1-score of 0.688 (95% confidence interval, 0.685-0.691) among the models in the training set and outperformed in the external validation set, with an AUC of 0.839 and F1-score of 0.673. Albumin change, ascites, and residual disease were the most important features associated with a higher likelihood of muscle radiodensity loss. The SHAP force plot provided an individualized interpretation of model predictions. CONCLUSION: An interpretable ML model can assist clinicians in identifying ovarian cancer patients at risk of muscle radiodensity loss after treatment and understanding the contributors of muscle radiodensity loss.

Hernandonine-mediated autophagic cell death in hepatocellular carcinoma: Interplay of p53 and YAP signaling pathways.

Hepatocellular carcinoma (HCC), the primary form of liver cancer, is the third leading cause of cancer-related death globally. Hernandonine is a natural alkaloid derived from Hernandia nymphaeifolia that has been shown to exert various biological functions. In a previous study, hernandonine was shown to suppress the proliferation of several solid tumor cell lines without affecting normal human cell lines. However, little is known about the effect of hernandonine on HCC. Therefore, this study aimed to investigate the effect and mechanism of hernandonine on HCC in relation to autophagy. We found that hernandonine inhibited HCC cell growth in vitro and in vivo. In addition, hernandonine elicited autophagic cell death and DNA damage in HCC cells. RNA-seq analysis revealed that hernandonine upregulated p53 and Hippo signaling pathway-related genes in HCC cells. Small RNA interference of p53 resulted in hernandonine-induced autophagic cell death attenuation. However, inhibition of YAP sensitized HCC cells to hernandonine by increasing the autophagy induction. This is the first study to illustrate the complex involvement of p53 and YAP in the hernandonine-induced autophagic cell death in human HCC cells. Our findings provide novel evidence for the potential of hernandonine as a therapeutic agent for HCC treatment.

A PRMT5-ZNF326 axis mediates innate immune activation upon replication stress.

DNA replication stress (RS) is a widespread phenomenon in carcinogenesis, causing genomic instability and extensive chromatin alterations. DNA damage leads to activation of innate immune signaling, but little is known about transcriptional regulators mediating such signaling upon RS. Using a chemical screen, we identified protein arginine methyltransferase 5 (PRMT5) as a key mediator of RS-dependent induction of interferon-stimulated genes (ISGs). This response is also associated with reactivation of endogenous retroviruses (ERVs). Using quantitative mass spectrometry, we identify proteins with PRMT5-dependent symmetric dimethylarginine (SDMA) modification induced upon RS. Among these, we show that PRMT5 targets and modulates the activity of ZNF326, a zinc finger protein essential for ISG response. Our data demonstrate a role for PRMT5-mediated SDMA in the context of RS-induced transcriptional induction, affecting physiological homeostasis and cancer therapy.

Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

BACKGRUOUND: It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. METHODS: This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. RESULTS: After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. CONCLUSION: The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Checklist of land snail species of Gua Rumbang, Sarawak, Malaysian Borneo (Mollusca, Gastropoda), with a description of a new species, Diplommatinarumbangensis sp. nov.

The current study presents an annotated checklist of the land snail species in the vicinity of the limestone hill of Gua (= cave) Rumbang, an outcrop located at the district of Padawan, Sarawak, Malaysian Borneo. The sampling was conducted at the surrounding areas and near the cave's entrance. A total of 62 species, involving 19 families and 38 genera, were recorded. Comparison with previous surveys made in the Bau limestone hills revealed similarities with respect to the species-rich families Diplommatinidae and Cyclophoridae, and the genera Kaliella and Diplommatina, highlighting the regional consistency of the land snail diversity of the Bau-Padawan-Serian cluster. Possibly because of its smaller size, Gua Rumbang is home to two endemic species, while there are eight endemic species in the Bau limestone karsts. This suggests a potential for a significant species diversity within the areas of the limestone ranges that remain to be explored. Nonetheless, the occurrence of endemic species in Gua Rumbang highlights the need to conserve certain areas within the Padawan limestone range since hitherto no protected areas have been proposed in this region. In this checklist, a new species for science is also described, namely, Diplommatinarumbangensissp. nov.

Abnormalities of serum magnesium levels in dialysis patients undergoing parathyroidectomy.

In primary hyperparathyroidism, postoperative hypocalcemia can be exacerbated by magnesium deficiency. However, the significance of magnesium homeostasis in surgery for secondary hyperparathyroidism is unknown. In this study, 268 consecutive adult patients on renal replacement therapy who underwent parathyroidectomy for secondary hyperparathyroidism were included for analysis. We found that about one fifth presented with hypomagnesemia (5.6%) or hypermagnesemia (14.6%). Hypomagnesemia was associated with lower calcium levels and longer postoperative hospital stays. Hypermagnesemia was associated with higher calcium-phosphorus products and lower parathyroid hormone levels. In multivariate analysis, patient age, alkaline phosphatase, and osteocalcin were independent predictors of prolonged stay after parathyroidectomy. There was a positive correlation between serum magnesium levels and severity of itching in these patients. Calcium-phosphorus products and serum magnesium levels were independently associated with pruritus. In conclusion, magnesium abnormalities play a minor role in hungry bone syndrome after parathyroidectomy for secondary hyperparathyroidism. Patients with higher serum magnesium levels had greater severity of pruritus.

Automatic Wake and Deep-Sleep Stage Classification Based on Wigner-Ville Distribution Using a Single Electroencephalogram Signal.

This research paper outlines a method for automatically classifying wakefulness and deep sleep stage (N3) based on the American Academy of Sleep Medicine (AASM) standards. The study employed a single-channel EEG signal, leveraging the Wigner-Ville Distribution (WVD) for time-frequency analysis to determine EEG energy per second in specific frequency bands (δ, θ, α, and entire band). Particle Swarm Optimization (PSO) was used to optimize thresholds for distinguishing between wakefulness and stage N3. This process aims to mimic a sleep technician's visual scoring but in an automated fashion, with features and thresholds extracted to classify epochs into correct sleep stages. The study's methodology was validated using overnight PSG recordings from 20 subjects, which were evaluated by a technician. The PSG setup followed the 10-20 standard system with varying sampling rates from different hospitals. Two baselines, T1 for the wake stage and T2 for the N3 stage, were calculated using PSO to ascertain the best thresholds, which were then used to classify EEG epochs. The results showed high sensitivity, accuracy, and kappa coefficient, indicating the effectiveness of the classification algorithm. They suggest that the proposed method can reliably determine sleep stages, being aligned closely with the AASM standards and offering an intuitive approach. The paper highlights the strengths of the proposed method over traditional classifiers and expresses the intentions to extend the algorithm to classify all sleep stages in the future.

Prognostic benefits of His-Purkinje capture in physiological pacemakers for bradycardia.

INTRODUCTION: Clinical outcomes of long-term ventricular septal pacing (VSP) without His-Purkinje capture remain unknown. This study evaluated the differences in clinical outcomes between conduction system pacing (CSP), VSP, and right ventricular pacing (RVP). METHODS: Consecutive patients with bradycardia indicated for pacing from 2016 to 2022 were prospectively followed for the clinical endpoints of heart failure (HF)-hospitalizations and all-cause mortality at 2 years. VSP was defined as septal pacing due to unsuccessful CSP implant or successful CSP followed by loss of His-Purkinje capture within 90 days. RESULTS: Among 1016 patients (age 73.9 ± 11.2 years, 47% female, 48% atrioventricular block), 612 received RVP, 335 received CSP and 69 received VSP. Paced QRS duration was similar between VSP and RVP, but both significantly longer than CSP (p < .05). HF-hospitalizations occurred in 130 (13%) patients (CSP 7% vs. RVP 16% vs. VSP 13%, p = .001), and all-cause mortality in 143 (14%) patients (CSP 7% vs. RVP 19% vs. VSP 9%, p < .001). The association of pacing modality with clinical events was limited to those with ventricular pacing (Vp) > 20% (pinteraction < .05). Adjusting for clinical risk factors among patients with Vp > 20%, VSP (adjusted hazard ratio [AHR]: 4.74, 95% confidence interval [CI]: 1.57-14.36) and RVP (AHR: 3.08, 95% CI: 1.44-6.60) were associated with increased hazard of HF-hospitalizations, and RVP (2.52, 95% CI: 1.19-5.35) with increased mortality, compared to CSP. Clinical endpoints did not differ between VSP and RVP with Vp > 20%, or amongst groups with Vp < 20%. CONCLUSION: Conduction system capture is associated with improved clinical outcomes. CSP should be preferred over VSP or RVP during pacing for bradycardia.

The land snail fauna of Batu Kudik, isolated limestone outcrop near Simunjan, Sarawak, Malaysian Borneo (Mollusca, Gastropoda).

Background: The present study provides a checklist of land snails collected from Batu Kudik, a small and isolated limestone outcrop in Simunjan, Sarawak. A total of 24 species of land snails, representing 18 genera and 14 families were recorded, including one newly-described subspecies. The most species-rich of the families in Batu Kudik are Diplommatinidae (17%) and Chronidae (17%) with four recorded species from each of the families. Based on our analysis, Plectostomawallaceikudikense subsp. nov., Opisthostomajavanica and Georissapyrrhoderma were identified as the most abundant land snails at this isolated outcrop, whereas Diplommatinaonyx and Everettiaminuta were recorded as the least abundant. All of the land snails at Batu Kudik were exclusively found sheltered between limestone boulders, underscoring the critical role of this outcrop as their refuge for survival. Consequently, conserving this biodiversity-rich limestone area becomes paramount to prevent the local extinction of these land snail species and possibly other organisms that depend on the unique attributes of the limestone for their survival. We also provide detailed descriptions of Plectostomawallaceikudikense, a new subspecies of the genus Plectostoma which is endemic to Batu Kudik. New information: A description of a new subspecies Plectostomawallaceikudikense subsp. nov.

Chiral anomaly and Weyl orbit in three-dimensional Dirac semimetal Cd3As2grown on Si.

Preparing Cd3As2, which is a three-dimensional (3D) Dirac semimetal in certain crystal orientation, on Si is highly desirable as such a sample may well be fully compatible with existing Si CMOS technology. However, there is a dearth of such a study regarding Cd3As2films grown on Si showing the chiral anomaly. Here,for the first time, we report the novel preparation and fabrication technique of a Cd3As2(112) film on a Si (111) substrate with a ZnTe (111) buffer layer which explicitly shows the chiral anomaly with a nontrivial Berry's phase ofπ. Despite the Hall carrier density (n3D≈9.42×1017cm-3) of our Cd3As2film, which is almost beyond the limit for the portents of a 3D Dirac semimetal to emerge, we observe large linear magnetoresistance in a perpendicular magnetic field and negative magnetoresistance in a parallel magnetic field. These results clearly demonstrate the chiral magnetic effect and 3D Dirac semimetallic behavior in our silicon-based Cd3As2film. Our tailoring growth of Cd3As2on a conventional substrate such as Si keeps the sample quality, while also achieving a low carrier concentration.

Impact of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcome in gynecological cancer.

Purpose: To investigate the effect of reduced margin pelvic radiotherapy on gastrointestinal toxicity and outcomes in gynecological cancer. Materials and methods: This retrospective study analyzed data of 590 patients who underwent hysterectomy and adjuvant pelvic radiotherapy between 2010 and 2020 at two tertiary centers. The pelvic nodal region was delineated based on a reduced margin definition or the Radiation Therapy Oncology Group (RTOG) guidelines. All patients were treated with intensity-modulated radiotherapy with imaging guidance. Gastrointestinal toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) and the Patient-Reported Outcome version (PRO-CTCAE). Results: Overall, 352 (59.7%) and 238 (40.3%) patients underwent RTOG and reduced margin pelvic radiotherapy, respectively. Median follow-up was 6.4 years (IQR: 3.7-9.6). Reduced margin pelvic radiotherapy significantly lowered the radiation dose to the small bowel. For CTCAE grade ≥ 2 or 3, acute gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (16.4% vs. 33.5%, p < 0.001; 2.9% vs. 8.5%, p < 0.001). The reduced margin group reported less severe acute gastrointestinal toxicity (PRO-CTCAE score ≥ 3) than the RTOG group (12.5% vs. 28.7%, p < 0.001). Late grade 3 gastrointestinal toxicity was lower in the reduced margin group than in the RTOG group (0.8% vs. 4.8%, p = 0.006). The 5-year pelvic recurrence-free survival and disease-free survival in the RTOG and reduced margin pelvic radiotherapy groups were 97.4% and 97.9% (p = 0.55) and 80.7% and 83.5% (p = 0.18), respectively. Conclusion: Reduced margin pelvic radiotherapy decreased acute and late gastrointestinal toxicity and achieved favorable outcomes.

Comparison of Pacing Performance and Clinical Outcomes Between Left Bundle Branch and His Bundle Pacing.

BACKGROUND: Left bundle branch (LBBP) and His-bundle pacing (HBP) provide physiological ventricular activation. OBJECTIVES: This study investigated differences in feasibility, device performance, and clinical outcomes between LBBP and HBP. METHODS: Consecutive patients with LBBP and HBP from 2018 to 2021 in 2 centers were prospectively studied. The primary endpoint was optimal device performance during follow-up, defined as the presence of pacing thresholds <2.5 V, R-wave amplitude ≥5 V, and absence of conduction system pacing (CSP)-related complications. The secondary endpoint was the composite of heart failure hospitalizations or all-cause mortality. RESULTS: Among 338 patients, 282 underwent successful CSP (119 HBP, 163 LBBP). Success rates, CSP-related complications, and need for reoperations did not differ between LBBP and HBP (P > 0.05). Pacing thresholds were lower, whereas R-wave amplitudes and lead impedance were higher in LBBP (P < 0.05). The primary endpoint was more frequent in LBBP than HBP (79% vs 34%; P < 0.001), with LBBP independently associated with 9-fold increased odds of optimal device performance (adjusted OR: 9.31; 95% CI: 5.14-16.86). LBBP was less likely to have increased pacing thresholds by >1 V (1% vs 19% HBP, P < 0.001). The secondary outcome was less frequent in LBBP than HBP (9% vs 24%, P = 0.001), with LBBP trending towards higher event-free survival (HR: 0.62; 95% CI: 0.31-1.23). The secondary outcome was independent of pacing burden or pacing indication. CONCLUSIONS: Despite similar feasibility and safety profiles, LBBP confers additional benefits in pacing performance and reliability, shows trends towards improved survival compared to HBP, and should be the preferred first-line CSP modality of choice.

Association of malignant ascites with systemic inflammation and muscle loss after treatment in advanced-stage ovarian cancer.

BACKGROUND: Malignant ascites is prevalent in advanced-stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the association of ascites with changes in systemic inflammation and muscle after treatment of advanced-stage ovarian cancer. METHODS: We evaluated 307 patients with advanced-stage (III/IVA) ovarian cancer who underwent primary debulking surgery and adjuvant platinum-based chemotherapy between 2010 and 2019. The changes in skeletal muscle index (SMI) and radiodensity (SMD) were measured using pre-surgery and post-chemotherapy portal-venous phase contrast-enhanced computed tomography scans at L3. Systemic inflammation was measured using albumin levels, prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR). Primary endpoint was the changes in SMI and SMD after treatment. Linear regression analysis was used to test associations between muscle change and other covariates. Mediation analysis was used to determine the mediator. RESULTS: The median (range) age was 53 (23-83) years. The median duration (range) of follow-up was 5.2 (1.1-11.3) years. Overall, 187 (60.9%) patients had ascites. The changes in muscle and systemic inflammatory markers after treatment were significantly different between patients with and without ascites (SMI: -3.9% vs. 2.2%, P < 0.001; SMD: -4.0% vs. -0.4%, P < 0.001; albumin: -4.4% vs. 2.1%, P < 0.001; PNI: -8.4% vs. -0.1%, P < 0.001; NLR: 20.6% vs. -29.4%, P < 0.001; and PLR: 1.7% vs. -19.4%, P < 0.001). The changes in SMI and SMD were correlated with the changes in albumin, PNI, NLR, and PLR (all P < 0.001). In multiple linear regression, ascites and NLR changes were negatively while albumin change was positively correlated with SMI change (ascites: ß = -3.19, P < 0.001; NLR change: ß = -0.02, P = 0.003; albumin change: ß = 0.37, P < 0.001). Ascites and NLR changes were negatively while PNI change was positively correlated with SMD change (ascites: ß = -1.28, P = 0.02; NLR change: ß = -0.02, P < 0.001; PNI change: ß = 0.11, P = 0.04). In mediation analysis, ascites had a direct effect on SMI change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.61, 95% confidence interval [CI]: -2.22 to -1.08) and albumin change (indirect effects = -2.92, 95% CI: -4.01 to -1.94). Ascites had a direct effect on SMD change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = -1.76, 95% CI: -2.34 to -1.22) and PNI change (indirect effects = -2.00, 95% CI: -2.79 to -1.36). CONCLUSIONS: Malignant ascites was associated with enhanced systemic inflammation and muscle loss after primary debulking surgery and adjuvant chemotherapy in advanced-stage ovarian cancer. The association between ascites and muscle loss may be mediated by systemic inflammation.

Explainable machine learning model for predicting skeletal muscle loss during surgery and adjuvant chemotherapy in ovarian cancer.

BACKGROUND: Skeletal muscle loss during treatment is associated with poor survival outcomes in patients with ovarian cancer. Although changes in muscle mass can be assessed on computed tomography (CT) scans, this labour-intensive process can impair its utility in clinical practice. This study aimed to develop a machine learning (ML) model to predict muscle loss based on clinical data and to interpret the ML model by applying SHapley Additive exPlanations (SHAP) method. METHODS: This study included the data of 617 patients with ovarian cancer who underwent primary debulking surgery and platinum-based chemotherapy at a tertiary centre between 2010 and 2019. The cohort data were split into training and test sets based on the treatment time. External validation was performed using 140 patients from a different tertiary centre. The skeletal muscle index (SMI) was measured from pre- and post-treatment CT scans, and a decrease in SMI ≥ 5% was defined as muscle loss. We evaluated five ML models to predict muscle loss, and their performance was determined using the area under the receiver operating characteristic curve (AUC) and F1 score. The features for analysis included demographic and disease-specific characteristics and relative changes in body mass index (BMI), albumin, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The SHAP method was applied to determine the importance of the features and interpret the ML models. RESULTS: The median (inter-quartile range) age of the cohort was 52 (46-59) years. After treatment, 204 patients (33.1%) experienced muscle loss in the training and test datasets, while 44 (31.4%) patients experienced muscle loss in the external validation dataset. Among the five evaluated ML models, the random forest model achieved the highest AUC (0.856, 95% confidence interval: 0.854-0.859) and F1 score (0.726, 95% confidence interval: 0.722-0.730). In the external validation, the random forest model outperformed all ML models with an AUC of 0.874 and an F1 score of 0.741. The results of the SHAP method showed that the albumin change, BMI change, malignant ascites, NLR change, and PLR change were the most important factors in muscle loss. At the patient level, SHAP force plots demonstrated insightful interpretation of our random forest model to predict muscle loss. CONCLUSIONS: Explainable ML model was developed using clinical data to identify patients experiencing muscle loss after treatment and provide information of feature contribution. Using the SHAP method, clinicians may better understand the contributors to muscle loss and target interventions to counteract muscle loss.

Pressure-Volume Loop Analysis of Voiding Workload: An Application in Trans-Vaginal Mesh-Repaired Pelvic Organ Prolapse Patients.

Although trans-vaginal mesh (TVM) offers a successful anatomical reconstruction and can subjectively relieve symptoms/signs in pelvic organ prolapse (POP) patients, its objective benefits to the voiding function of the bladder have not been well established. In this study, we investigated the therapeutic advantage of TVM on bladder function by focusing on the thermodynamic workload of voiding. The histories of 31 POP patients who underwent TVM repair were retrospectively reviewed. Cystometry and pressure volume analysis (PVA) of the patients performed before and after the operation were analyzed. TVM postoperatively decreased the mean voiding resistance (mRv, p < 0.05, N = 31), reduced the mean and peak voiding pressure (mPv, p < 0.05 and pPv, p < 0.01, both N = 31), and elevated the mean flow rate (mFv, p < 0.05, N = 31) of voiding. While displaying an insignificant effect on the voided volume (Vv, p < 0.05, N = 31), TVM significantly shortened the voiding time (Tv, p < 0.05, N = 31). TVM postoperatively decreased the loop-enclosed area (Apv, p < 0.05, N = 31) in the PVA, indicating that TVM lessened the workload of voiding. Moreover, in 21 patients who displayed postvoiding urine retention before the operation, TVM decreased the residual volume (Vr, p < 0.01, N = 21). Collectively, our results reveal that TVM postoperatively lessened the workload of bladder voiding by diminishing voiding resistance, which reduced the pressure gradient required for driving urine flow.

Structure-Guided Development of Bivalent Aptamers Blocking SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused devastation to human society through its high virulence, infectivity, and genomic mutations, which reduced the efficacy of vaccines. Here, we report the development of aptamers that effectively interfere with SARS-CoV-2 infection by targeting its spike protein, which plays a pivotal role in host cell entry of the virus through interaction with the viral receptor angiotensin-converting enzyme 2 (ACE2). To develop highly effective aptamers and to understand their mechanism in inhibiting viral infection, we determined the three-dimensional (3D) structures of aptamer/receptor-binding domain (RBD) complexes using cryogenic electron microscopy (cryo-EM). Moreover, we developed bivalent aptamers targeting two distinct regions of the RBD in the spike protein that directly interact with ACE2. One aptamer interferes with the binding of ACE2 by blocking the ACE2-binding site in RBD, and the other aptamer allosterically inhibits ACE2 by binding to a distinct face of RBD. Using the 3D structures of aptamer-RBD complexes, we minimized and optimized these aptamers. By combining the optimized aptamers, we developed a bivalent aptamer that showed a stronger inhibitory effect on virus infection than the component aptamers. This study confirms that the structure-based aptamer-design approach has a high potential in developing antiviral drugs against SARS-CoV-2 and other viruses.