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Label-free evaluation of mouse embryo quality using time-lapse bright field and optical coherence microscopy
Full text linkThe selection of high-quality embryos is essential to enhance the implantation rate for in vitro fertilization (IVF). Optical coherence microscopy (OCM) can noninvasively provide three-dimensional (3D) high-resolution imaging of developing embryos. The revealed microstructures can be used for accurate embryo evaluation. Here, we acquire time-lapse 3D OCM images with co-registered bright-field imaging on mouse embryo development from the one-cell stage to the fully hatched blastocyst inside an incubator. Our results demonstrate the capability of OCM to detect structural features of the developing embryos. The second and third embryonic cell cycles are indicated to be associated with blastocyst formation and the hatching capability. OCM-based time-lapse technology holds the potential to enrich early embryo development insights and streamline embryo selection within IVF clinics
Functional screening identifies kinesin spindle protein inhibitor filanesib as a potential treatment option for hepatoblastoma
Full text linkHepatoblastoma is a rare pediatric liver malignancy usually treated with surgery and chemotherapy. To explore new treatment options for hepatoblastoma, drug screening was performed using six cell models established from aggressive hepatoblastoma tumors and healthy pediatric primary hepatocytes. Of the 527 screened compounds, 98 demonstrated cancer-selective activity in at least one hepatoblastoma model. The kinesin spindle protein (KSP) inhibitor filanesib was effective in all models and was further evaluated. Filanesib induced G2/M arrest and apoptosis in hepatoblastoma cells at concentrations tolerable to primary hepatocytes. Prominent nuclear fragmentation was observed in filanesib-treated hepatoblastoma cells. Genes participating in cell cycle regulation were noted to be differentially expressed after filanesib treatment. Filanesib reduced the rate of tumor growth in 4/5 hepatoblastoma mice models. One of these models showed complete growth arrest. Our results suggest that filanesib is a potential candidate for hepatoblastoma treatment and should be investigated in future clinical trials
Effect of midwife-led pelvic floor muscle training on prolapse symptoms and quality of life in women with pelvic organ prolapse in Ethiopia: A cluster-randomized controlled trial
Full text linkBACKGROUND: Pelvic organ prolapse (POP) is a common condition that can significantly impact a woman\u27s quality of life. Pelvic floor muscle training (PFMT) is recommended as a first-line conservative treatment for prolapse, but evidence on its effectiveness from low-resource settings is limited. This study aimed to assess the effect of midwife-led PFMT on prolapse symptoms and health-related quality of life (HRQoL) among women with mild-to-moderate POP in Ethiopia.
METHODS AND FINDINGS: A community-based, parallel-groups, two-arm cluster-randomized controlled trial was conducted in Dale and Wonsho districts of Sidama Region, Ethiopia. Women with symptomatic POP stages I-III were randomized by cluster to receive either midwife-led PFMT plus lifestyle counseling (intervention group) or lifestyle counseling alone (control group). The participants and counselors knew what the women were receiving, but they were not aware of the other group. The outcome assessors, who collected data at the end of intervention, were blinded to the participants\u27 treatment allocation. The primary outcomes were changes in prolapse symptom score (POP-SS) and prolapse quality of life (P-QoL). Mixed-effects generalized linear model was used to determine the effect of PFMT on prolapse symptoms and P-QoL at 99% confidence level. Adjusted β coefficients were used as effect measures. The level of significance was adjusted for multiple comparisons. A total of 187 women were randomized to intervention (n = 86) from four clusters and control (n = 101) arms from another four clusters. At sixth months, the intervention group showed significantly greater improvements both in prolapse symptoms and P-QoL. The mean change difference in POP-SS was -4.11 (99% CI [-5.38, -2.83]; p \u3c 0.001). Similarly, the mean change difference was: -8.86 (99% CI [-13.84, -3.89]; p \u3c 0.001) in physical domain of P-QoL; -11.18 (99% CI [-15.03, -7.32]; p \u3c 0.001) in psychological domain of P-QoL, and -9.01 (99% CI [-10.49, -5.54]; p \u3c 0.001) in personal relationship domain of P-QoL. A significantly higher proportion (83.72%) of women in the intervention group perceived their condition as better after the intervention as compared to 41.58% in the control group. Women with earlier stages of prolapse (stages I and II) experienced higher benefits compared to those in stage III.
CONCLUSIONS: A midwife-led PFMT combined with lifestyle counseling significantly improves prolapse symptoms and quality of life in mild-to-moderate POP. This strategy can be integrated into the existing maternal and reproductive health programs to address POP in low-income settings where access to trained specialist is limited.
TRIAL REGISTRATION: The trial was registered at the Pan African Clinical Trial Registry (https://pactr.samrc.ac.za) database, with the registration number PACTR202302505126575 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=24311)
Subgroup evaluation to understand performance gaps in deep learning-based classification of regions of interest on mammography
Full text linkThis study evaluates a deep learning model for classifying normal versus potentially abnormal regions of interest (ROIs) on mammography, aiming to identify imaging, pathologic, and demographic characteristics that may induce suboptimal model performance in certain patient subgroups. We utilized the EMory BrEast imaging Dataset (EMBED), containing 3.4 million mammographic images from 115,931 patients. Full-field digital mammograms from women aged 18 years or older were used to create positive and negative patches with the patches matched based on size, location, patient demographics, and imaging features. Several convolutional neural network (CNN) architectures were tested, with ResNet152V2 demonstrating the best performance. The dataset was split into training (29,144 patches), validation (9,910 patches), and testing (13,390 patches) sets. Performance metrics included accuracy, AUC, recall, precision, F1 score, false negative rate, and false positive rate. Subgroup analysis was conducted using univariate and multivariate regression models to control for confounding effects. The classification model achieved an AUC of 0.975 and a recall of 0.927. False negative predictions were significantly associated with White patients (RR = 1.208; p = 0.050), those never biopsied (RR = 1.079; p = 0.011), and cases with architectural distortion (RR = 1.037; p \u3c 0.001). Higher breast density significantly increased the risk of false positives, with BI-RADS density C (RR = 1.891; p \u3c 0.001) and D (RR = 2.486; p \u3c 0.001). Race and age were not significant predictors for false positives in multivariate analysis. These findings suggest that deep learning models for mammography may underperform in specific subgroups. The study underscores the need for more precise patient subgroup analysis and emphasizes the importance of considering confounding factors in deep learning model evaluations. These insights can help develop fair and interpretable decision-making models in mammography, ultimately enhancing the performance and equity of CADe and CADx applications
LRRC8 channel complexes counterbalance KATP channels to mediate swell-secretion coupling in mouse pancreatic β cells
Full text linkInsulin secretion from pancreatic β cells is initiated by membrane potential depolarization, followed by activation of voltage-gated Ca2+ channels to trigger Ca2+-mediated insulin vesicle fusion with the β cell plasma membrane. Here, we show that β cell swelling associated with glucose metabolism was sensed by LRRC8 channel complexes and contributed to insulin secretion. Hypertonic perfusate (360-380 mOsm) dose dependently impaired glucose-stimulated insulin secretion by counteracting β cell swelling. Hypotonic perfusate alone, independent of glucose stimulation or KATP channel closure, was sufficient to increase β cell intracellular Ca2+ and trigger insulin secretion. Inhibition of sodium-potassium-chloride cotransporter-1 with bumetanide, which diminished the intracellular Cl- concentration in β cells and consequently reduced Cl- efflux via LRRC8 channel complexes, also significantly reduced hypotonic-stimulated insulin secretion. Finally, stimulation of insulin secretion by the glucokinase activator GKA50, which is known to induce β cell swelling, was entirely suppressed in β cell-targeted Lrrc8a KO islets. These data support a model wherein the LRRC8 channel complex senses β cell swelling triggered by glucose metabolism and regulates β cell insulin secretion through activation of LRRC8-mediated Cl- efflux
Altered joint forces found in symptomatic dysplastic hips in women during sport-specific activities
Full text linkBACKGROUND: Many patients with developmental dysplasia of the hip (DDH) are young and highly active but often become limited by activity-induced pain. Characterizing how the abnormal bony geometry of DDH affects hip joint loading and multiplanar kinematics during sport-specific motions relevant to active patients may provide insight into injury mechanisms and inform optimal treatment options.
PURPOSE/HYPOTHESIS: The purpose of this study was to determine how hip joint loading and kinematics are altered in DDH during 2 common sport activities: running and multidirectional hop-cutting. It was hypothesized that superior and medial joint-reaction forces (JRFs) would be elevated during running and that medial JRFs would be elevated during hop-cutting when compared with controls.
STUDY DESIGN: Controlled laboratory study.
METHODS: Using patient-specific musculoskeletal modeling, both running and hop-cutting motions were analyzed for female patients with symptomatic DDH (DDH group) and female controls without hip disorders who were enrolled from October 2017 to August 2022. Hip joint angles, JRFs, and muscle forces were compared between the groups using 1-dimensional statistical parametric mapping.
RESULTS: Overall, 19 women in the DDH group and 19 female controls were included in the running analysis, and 13 women in the DDH group and 10 female controls were included in the hop-cutting analysis. During the running motion, medial hip JRFs and gluteal muscle forces were significantly elevated in the DDH group, while rectus femoris muscle forces were reduced. During the hop-cutting motion, medial hip JRFs, gluteus minimus, and gluteus medius muscle forces were elevated, while gluteus maximus forces were reduced in the DDH group. There were no significant group differences in hip joint angles for either activity.
CONCLUSION: The lack of kinematic differences between women with symptomatic DDH and controls suggests that the JRF differences between groups stemmed from the abnormal joint geometry in the DDH group. These activities may have greater damaging potential than previously studied lower impact activities such as walking.
CLINICAL RELEVANCE: Better understanding of how loading varies from activity to activity can help patients with DDH, and clinicians understand the mechanistic causes of DDH-related hip pain and damage and plan appropriate intervention strategies
Comparing Analgesic Regimen Effectiveness and Safety after Surgery (CARES): Protocol for a pragmatic, international multicentre randomised trial
Full text linkINTRODUCTION: Acute pain is commonly experienced by millions of patients who undergo outpatient surgical procedures. Moreover, an increasing number of procedures are performed on an outpatient basis, requiring greater postoperative planning to ensure effective pain management. Analgesic approaches commonly involve prescription opioids and non-steroidal anti-inflammatory drugs (NSAIDs), but an optimal regimen that balances pain and adverse effects has not been identified. In addition, critical gaps in evidence exist regarding how opioids and NSAIDs compare as analgesic regimens after surgery.
METHODS AND ANALYSIS: The Comparing Analgesic Regimen Effectiveness and Safety after Surgery (CARES) trial is a pragmatic, international, multicentre randomised trial that enrols adults undergoing three elective surgical procedures (laparoscopic cholecystectomy, breast lumpectomy, hernia repair). Participants are randomised to receive discharge analgesic prescriptions that consist of either NSAIDs or low-dose opioids (ie, 10 pills of oxycodone 5 mg or equivalent), with both groups prescribed acetaminophen around-the-clock. The primary effectiveness outcome is patient-reported worst daily pain intensity over the first 7 days after surgery. The primary safety outcome is the occurrence of opioid and/or NSAID side effects over the first 7 days after surgery. Secondary outcomes are assessed by patient report and medical record review at 1 week, 1 month, 3 months and 6 months after surgery and include sleep disturbance, patient perception of improvement/change after treatment, pain interference, anxiety, depression, health-related quality of life, clinically important adverse events, substance use, opioid misuse, chronic pain, healthcare utilisation related to pain and quality of recovery.
ETHICS AND DISSEMINATION: Investigational review boards at the University of Michigan and other sites have approved the CARES trial. The first patient enrolled in CARES in February 2023, with recruitment anticipated through 2026. Dissemination builds on the input of patient partners and other members of an engaged Stakeholder Advisory Board, with activities spanning co-production of summaries to share results with study participants, publications in biomedical journals and lay press, presentations to scientific and community organisations, and other multimedia communication materials.
TRIAL REGISTRATION NUMBER: NCT05722002
Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure
Full text linkThe prevailing view of fibulin-4 deficient mice is that the cardiac phenotype is the result of aortic and/or valvular disease. In the present study, we have tested whether the cardiac phenotype is, at least in part, the consequence of primary cardiac effects of fibulin-4. We have found fibulin-4 expression to be activated throughout the myocardium in wildtype (fibulin-
The promise and peril of comparing fluorescence lifetime in biology revealed by simulations
Full text linkSignaling dynamics are crucial in biological systems, and biosensor-based real-time imaging has revolutionized their analysis. Fluorescence lifetime imaging microscopy (FLIM) excels over the widely used fluorescence intensity imaging by allowing the measurement of absolute signal levels independent of sensor concentration. This capability enables the comparison of signaling dynamics across different animals, body regions, and timeframes. However, FLIM\u27s advantage can be compromised by factors like autofluorescence in biological experiments. To address this, we introduce FLiSimBA, a flexible computational framework for realisti
Wb5, a novel biomarker for monitoring efficacy and success of mass drug administration programs for Wuchereria bancrofti elimination
Full text linkThe success of mass drug administration at reducing the prevalence of lymphatic filariasis in endemic areas has led to an increased need for highly sensitive and specific diagnostic assays. To be useful in post-elimination surveillance in areas with low to zero prevalence, high test performance characteristics are required to enable the early detection of infection recrudescence. As current testing suffers from either sensitivity or specificity levels that fail to meet adopted target product profiles, additional targets that could be used as confirmatory tests or in multiplexed assays could overcome these issues. To this end, bioinformatic analyses coupled with stage-specific expression data for W. bancrofti (Wb) and/or B. malayi (Bm) resulted in the identification of 12 targets that were: 1) present in Wb and/or Bm; 2) had very little to no homology with proteins from other filariae; and 3) were enriched in the microfilarial or L3 stages. Screening of these 12 antigens by a Luciferase Immunoprecipitation System assay for IgG with serum from Wb-infected and uninfected individuals identified a single antigen, termed Wb5, that was specific for Wb infections only. Recombinant Wb5 proteins were generated in multiple expression systems for use in a variety of IgG4-based immunoassays. To assess if Wb5 could provide additional sensitivity to assays using IgG4 antibodies to Wb123, head-to-head comparisons were performed using serum from 466 samples (231 Wb-infected, 235 controls). Using IgG4-based immunoassays at 100% specificity against uninfected controls and other helminth species (O. volvulus, L. loa, S. stercoralis, M. perstans), Wb5 and Wb123 had individual sensitivities of 53.7% and 75.3%, respectively, while a combination resulted in 81.0% sensitivity. Moreover, kinetic studies of patients that were treated and followed up longitudinally suggest that Wb5 titers may decline more sharply than those of Wb123, thus paving the way for Wb5 as a complementary tool to Wb123