Pulse Feature-Enhanced Classification of Microalgae and Cyanobacteria Using Polarized Light Scattering and Fluorescence Signals.

Harmful algal blooms (HABs) pose a global threat to the biodiversity and stability of local aquatic ecosystems. Rapid and accurate classification of microalgae and cyanobacteria in water is increasingly desired for monitoring complex water environments. In this paper, we propose a pulse feature-enhanced classification (PFEC) method as a potential solution. Equipped with a rapid measurement prototype that simultaneously detects polarized light scattering and fluorescence signals of individual particles, PFEC allows for the extraction of 38 pulse features to improve the classification accuracy of microalgae, cyanobacteria, and other suspended particulate matter (SPM) to 89.03%. Compared with microscopic observation, PFEC reveals three phyla proportions in aquaculture samples with an average error of less than 14%. In this paper, PFEC is found to be more accurate than the pulse-average classification method, which is interpreted as pulse features carrying more detailed information about particles. The high consistency of the dominant and common species between PFEC and microscopy in all field samples also demonstrates the flexibility and robustness of the former. Moreover, the high Pearson correlation coefficient accounting for 0.958 between the cyanobacterial proportion obtained by PFEC and the cyanobacterial density given by microscopy implies that PFEC serves as a promising early warning tool for cyanobacterial blooms. The results of this work suggest that PFEC holds great potential for the rapid and accurate classification of microalgae and cyanobacteria in aquatic environment monitoring.

Biofilm Microenvironment-Sensitive Piezoelectric Nanomotors for Enhanced Penetration and ROS/NO Synergistic Bacterial Elimination.

Sonodynamic therapy offers a highly accurate treatment for bacterial infections; however, its antibacterial efficacy is hindered by bacterial biofilms that limit the penetration of sonosensitizers. Herein, a nitric oxide (NO)-driven mushroom-like Janus nanomotor (BT@PDA-La) based on the unilateral coating of polydopamine (PDA) on piezoelectric tetragonal barium titanate (BT) and further modified with l-arginine (l-Arg) on the PDA side is fabricated. In the infected microenvironment with high levels of H2O2, NO is produced unilaterally from BT@PDA-La, thus leading to its self-propelled movement and facilitating its permeability in the biofilm. Under ultrasonic vibrations, the piezoelectric effect of BT@PDA-La is triggered by the exogenous mechanical wave, and toxic reactive oxygen species (ROS) are efficiently generated via an in situ catalytic reaction. The synergistic treatment with ROS/NO achieved the destruction of biofilms and embedded drug-resistant bacteria in vitro. Importantly, BT@PDA-La exhibits excellent biofilm penetration capacity, effectively eliminating biofilm infection while accelerating the healing of infected muscles by alleviating oxidative stress, regulating inflammatory factors, and accelerating angiogenesis. Collectively, this study provides a promising strategy for enhancing the penetration of pathological environment-driven nanomaterials through biofilms and advances the application of nanomotors for the therapy of bacterial infections in clinical medicine.

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. Design, Setting, and Participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. Main Outcomes and Measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. Results: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. Conclusions and Relevance: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. Trial Registration: ClinicalTrials.gov Identifier: NCT04660643.

Anticancer effect of hUC-MSC-derived exosome-mediated delivery of PMO-miR-146b-5p in colorectal cancer.

Antisense oligonucleotide (ASO) is a novel therapeutic platform for targeted cancer therapy. Previously, we have demonstrated that miR-146b-5p plays an important role in colorectal cancer progression. However, a safe and effective strategy for delivery of an ASO to its targeted RNA remains as a major hurdle in translational advances. Human umbilical cord mesenchymal cell (hUC-MSC)-derived exosomes were used as vehicles to deliver an anti-miR-146b-5p ASO (PMO-146b). PMO-146b was assembled onto the surface of exosomes (e) through covalent conjugation to an anchor peptide CP05 (P) that recognized an exosomal surface marker, CD63, forming a complex named ePPMO-146b. After ePPMO-146b treatment, cell proliferation, uptake ability, and migration assays were performed, and epithelial-mesenchymal transition progression was evaluated in vitro. A mouse xenograft model was used to determine the antitumor effect and distribution of ePPMO-146b in vivo. ePPMO-146b was taken up by SW620 cells and effectively inhibited cell proliferation and migration. The conjugate also exerted antitumor efficacy in a xenograft mouse model of colon cancer by systematic administration, where PPMO-146b was enriched in tumor tissue. Our study highlights the potential of hUC-MSC-derived exosomes anchored with PPMO-146b as a novel safe and effective approach for PMO backboned ASO delivery.

Baricitinib in juvenile idiopathic arthritis: an international, phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial.

BACKGROUND: Juvenile idiopathic arthritis can be refractory to some or all treatment regimens, therefore new medications are needed to treat this population. This trial assessed the efficacy and safety of baricitinib, an oral Janus kinase 1/2-selective inhibitor, versus placebo in patients with juvenile idiopathic arthritis. METHODS: This phase 3, randomised, double-blind, placebo-controlled, withdrawal, efficacy, and safety trial was conducted in 75 centres in 20 countries. We enrolled patients (aged 2 to <18 years) with polyarticular juvenile idiopathic arthritis (positive or negative for rheumatoid factor), extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or juvenile psoriatic arthritis, and an inadequate response (after ≥12 weeks of treatment) or intolerance to one or more conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). The trial consisted of a 2-week safety and pharmacokinetic period, a 12-week open-label lead-in period (10 weeks for the safety and pharmacokinetic subcohort), and an up to 32-week placebo-controlled double-blind withdrawal period. After age-based dosing was established in the safety and pharmacokinetic period, patients received a once-daily 4 mg adult-equivalent dose of baricitinib (tablets or suspension) in the open-label lead-in period. Patients meeting Juvenile Idiopathic Arthritis-American College of Rheumatology (JIA-ACR) 30 criteria (JIA-ACR30 responders) at the end of the open-label lead-in (week 12) were eligible for random assignment (1:1) to receive placebo or continue receiving baricitinib, and remained in the double-blind withdrawal period until disease flare or up to the end of the double-blind withdrawal period (week 44). Patients and any personnel interacting directly with patients or sites were masked to group assignment. The primary endpoint was time to disease flare during the double-blind withdrawal period and was assessed in the intention-to-treat population of all randomly assigned patients. Safety was assessed in all patients who received at least one dose of baricitinib throughout the three trial periods. For adverse events in the double-blind withdrawal period, exposure-adjusted incidence rates were calculated. The trial was registered on ClinicalTrials.gov, NCT03773978, and is completed. FINDINGS: Between Dec 17, 2018 and March 3, 2021, 220 patients were enrolled and received at least one dose of baricitinib (152 [69%] girls and 68 [31%] boys; median age 14·0 years [IQR 12·0-16·0]). 219 patients received baricitinib in the open-label lead-in period, of whom 163 (74%) had at least a JIA-ACR30 response at week 12 and were randomly assigned to placebo (n=81) or baricitinib (n=82) in the double-blind withdrawal period. Time to disease flare was significantly shorter with placebo versus baricitinib (hazard ratio 0·241 [95% CI 0·128-0·453], p<0·0001). Median time to flare was 27·14 weeks (95% CI 15·29-not estimable) in the placebo group, and not evaluable for patients in the baricitinib group (<50% had a flare event). Six (3%) of 220 patients had serious adverse events during the safety and pharmacokinetic period or open-label lead-in period. In the double-blind withdrawal period, serious adverse events were reported in four (5%) of 82 patients (incidence rate [IR] 9·7 [95% CI 2·7-24·9] per 100 patient-years at risk) in the baricitinib group and three (4%) of 81 (IR 10·2 [2·1-29·7]) in the placebo group. Treatment-emergent infections were reported during the safety and pharmacokinetic or open-label lead-in period in 55 (25%) of 220 patients, and during the double-blind withdrawal period in 31 (38%) of 82 (IR 102·1 [95% CI 69·3-144·9]) in the baricitinib group and 15 (19%) of 81 (IR 59·0 [33·0-97·3]) in the placebo group. Pulmonary embolism was reported as a serious adverse event in one patient (1%; IR 2·4 [95% CI 0·1-13·3]) in the baricitinib group in the double-blind withdrawal period, which was judged to be related to study treatment. INTERPRETATION: Baricitinib was efficacious with an acceptable safety profile in the treatment of polyarticular juvenile idiopathic arthritis, extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, and juvenile psoriatic arthritis, after inadequate response or intolerance to standard therapy. FUNDING: Eli Lilly and Company under licence from Incyte.

Creep Monitoring of Submersible Observation Windows Using Mueller Matrix Imaging.

Safety of the observation window is one of the core concerns for manned submersibles. When subjected to underwater static pressure, extrusion and creep deformation always occur in the observation window, which can pose a threat to both safety and optical performance. To assess the deformation, real-time and non-contact monitoring methods are necessary. In this study, a conceptual setup based on the waveplate rotation and dual-DoFP (division of focal-plane polarimeter) polarization camera is built for the observation window's creep monitoring by measuring the Mueller matrix images of the samples under different pressures and durations. Then, a series of characteristic parameters, such as t1, R, r, R', are extracted from the Muller matrix images by Mueller matrix transformation (MMT), Mueller matrix polar decomposition (MMPD), correlation analysis and phase unwrapping method. The results demonstrate that these parameters can effectively describe the observation window's creep at different pressure levels which are simulated by finite element analysis. Additionally, more characterization parameters, such as ψ, A and D, are given from the Mueller matrix images and discussed to illustrate the method's potential for further applications and investigations. Ultimately, future devices based on this method could serve as a valuable tool for real-time and non-contact creep monitoring of the submersible observation windows.

Platform trials to evaluate the benefit-risk of COVID-19 therapeutics: Successes, learnings, and recommendations for future pandemics.

BACKGROUND: In response to the COVID-19 global pandemic, multiple platform trials were initiated to accelerate evidence generation of potential therapeutic interventions. Given a rapidly evolving and dynamic pandemic, platform trials have a key advantage over traditional randomized trials: multiple interventions can be investigated under a master protocol sharing a common infrastructure. METHODS: This paper focuses on nine platform trials that were instrumental in advancing care in COVID-19 in the hospital and community setting. A semi-structured qualitative interview was conducted with the principal investigators and lead statisticians of these trials. Information from the interviews and public sources were tabulated and summarized across trials, and recommendations for best practice for the next health crisis are provided. RESULTS: Based on the information gathered takeaways were identified as 1) the existence of some aspect of trial design or conduct (e.g., existing network of investigators or colleagues, infrastructure for data capture and relevant statistical expertise) was a key success factor; 2) the choice of treatments (e.g., repurposed drugs) had major impact on the trials as did the choice of primary endpoint; and 3) the lack of coordination across trials was flagged as an area for improvement. CONCLUSION: These trials deployed during the COVID-19 pandemic demonstrate how to achieve both speed and quality of evidence generation regarding clinical benefit (or not) of existing therapies to treat new pathogens in a pandemic setting. As a group, these trials identified treatments that worked, and many that did not, in a matter of months.

Recognition of microplastics suspended in seawater via refractive index by Mueller matrix polarimetry.

Microplastics have become the marine pollution posing a human health risk, but they are difficult to be detected and recognized for different materials, irregular shapes, and broad size distributions. Microplastics' refractive index (RI) is related to the materials and can be characterized by the Mueller matrix. In this work, the particles are suspended in water and their Mueller matrices are measured by a particulate Mueller matrix polarimetry setup. Four kinds of spherical particles including microplastics are effectively classified by their Mueller matrices. Moreover, two kinds of common microplastics with broad size distributions, irregular shapes, and random orientations are also well recognized by the Mueller matrix. These results imply that RI plays a vital role in the recognition of microplastics suspended in water. By using the Mie theory and discrete dipole approximation simulation, the discussions explain in physics origin how RI affects Mueller matrix coupling with size and structure, and give some decoupling methods. Results in this work help advance future tools to in situ recognize the microplastics in seawater.

Atmospheric microplastics at a southern China metropolis: Occurrence, deposition flux, exposure risk and washout effect of rainfall.

Atmospheric microplastics (AMPs) have raised much concern for public health due to their potential for exposure. In this study, temporal distribution, characteristics and exposure risk of AMPs were studied in the urban area of Guangzhou, a metropolis in Southern China, and the washout effect of rainfall on AMPs was investigated. It was found that AMP abundances in Guangzhou were in a range of 0.01-0.44 items/m3, with higher abundance in the wet season (0.19 ± 0.01 items/m3) than in the dry season (0.15 ± 0.02 items/m3). The distribution of AMPs did not correspond to that of common air pollutants (e.g., PM2.5 and PM10), implying that their pollution sources might be distinct. In Guangzhou, a total of 1.26 × 1011 items AMPs are in the air every year, and annual inhalation exposure of adults was estimated to be in the range of 79.65-3.50 × 103 items. The annual deposition flux of AMPs is 65.94 ± 7.53 items/m2/d, and the deposition flux in the wet season (84.00 ± 6.95 items/m2/d) was much greater than that in the dry season (47.88 ± 8.35 items/m2/d). Furthermore, rainfall has an effective mechanism for removing AMPs from the atmosphere, with an average washout ratio of (19.39 ± 6.48) × 104 for rainfall washing AMPs out. Compared to moderate rain (2.5-10 mm/h) and heavy rain (10-50 mm/h), light rain (rainfall intensity <2.5 mm/h) had a better washout effect. This study contributes to the evaluation of AMP exposure risk and understanding of AMP environmental behavior and fate by providing long-term monitoring data on AMPs and quantifying the washout effect of rainfall on AMPs for the first time.

Estimands, Handling of Missing Data and Impact on Assumed Effect Size and Power in Pivotal COVID-19 Treatment Trials.

Estimands play an important role for aligning study objectives, study design and analyses through a precise definition of the quantity of interest. For COVID-19 studies, apart from intercurrent events, high volume of missing data has been observed. We explore their impact on several estimands through a synthetic COVID-19 data generated from a discrete-time multi-state model. We compare estimators of these estimands based on their ability to closely match the true response rates and retain assumed power. The final choice of the estimand then needs to be aligned with clinically meaningful quantities of interest to patients, clinicians, regulators and payers.

Uncovering the disposable face masks as vectors of metal ions (Pb(â ¡), Cd(â ¡), Sr(â ¡)) during the COVID-19 pandemic.

The demand for disposable face masks (DFMs) increased sharply in response to the COVID-19 pandemic. However, information regarding the underlying roles of the largely discarded DFMs in the environment is extremely lacking. This study focused on the pristine and UV-aged DFMs as vectors of metal ions (Pb(Ⅱ), Cd(Ⅱ), and Sr(Ⅱ)). Further, the aging mechanism of DFMs with UV radiation as well as the interaction mechanisms between DFMs and metal ions were investigated. Results revealed that the aging process would help to promote more metal ions adsorbed onto DFMs, which was mainly attributed to the presence of oxygen-containing groups on the aged DFMs. The adsorption affinity of pristine and aged DFMs for the metal ions followed Pb(Ⅱ) > Cd(Ⅱ) > Sr(Ⅱ), which was positively corrected with the electronegativity of the metals. Interestingly, we found that even if DFMs were not disrupted, DFMs had similar or even higher adsorption affinity for metals compared with other existing microplastics. Besides, regarding environmental factors, including salinity and solution pH played a crucial role in the adsorption processes, with greater adsorption capacities for pristine and aged DFMs at higher pH values and low salinity. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and density functional theory further confirmed that the pristine DFMs interacted with the metals mainly through electrostatic interaction, while electrostatic interaction and surface complexation jointly regulated the adsorption of the metals onto aged DFMs. Overall, these findings would help to evaluate environmental behaviors and risks of DFMs associated with metals.

Biomimetic photosensitizer nanocrystals trigger enhanced ferroptosis for improving cancer treatment.

As a novel non-apoptotic cell death pathway, ferroptosis can effectively enhance the antitumor effects of photodynamic therapy (PDT) by disrupting intracellular redox homeostasis. However, the reported nanocomposites that combined the PDT and ferroptosis are cumbersome to prepare, and the unfavorable tumor microenvironment also severely interferes with their tumor suppressive effects. To address this inherent barrier, this study attempted to explore photosensitizers that could activate ferroptosis pathway and found that the photosensitizer aloe-emodin (AE) could induce cellular ferroptosis based on its specific inhibiting activity to Glutathione S-transferase P1(GSTP1), a key protein for ferroptosis. Herein, we prepared AE@RBC/Fe nanocrystals (NCs) with synergistic PDT and ferroptosis therapeutic effects by one-step emulsification to obtain AE NCs cores and further modification of red blood cells (RBC) membranes and ferritin. Benefiting from the involvement of ferritin, the prepared AE@RBC/Fe NCs provide not only sufficient oxygen for oxygen-dependent PDT, but also Fe3+ for iron-dependent ferroptosis in tumor cells. Furthermore, the biomimetic surface functionalization facilitated the prolonged circulation and cancer targeting of AE@RBC/Fe NCs in vivo. The in vitro and in vivo results demonstrate that AE@RBC/Fe NCs exhibit significantly enhanced therapeutic effects for the combined two antitumor mechanisms and provide a promising prospect for achieving PDT/ferroptosis synergistic therapy.

Mueller matrix imaging with a spatially modulated polarization light source.

In this paper, we present a Mueller matrix imaging system consisting of a spatially modulated polarization light source (SMPL) and a dual division-of-focal-plane (DoFP) polarimeters as the PSA and 2D detector. The system does not contain moving parts such as a rotating stage, which leads to more robust and reliable operations for applications in hostile settings. By taking Muller matrix images at variable distances between the SMPL and the target, we examine in details errors due to different spatial distributions in angle and intensity of different polarized lights. A calibration method is proposed to reduce such errors introduced by SMPL. The performances of the new imaging technique and the calibration method are tested in Mueller matrix imaging of different samples.

Serum exosomal and serum glypican-1 are associated with early recurrence of pancreatic ductal adenocarcinoma.

Background: The diagnostic performance and prognostic value of serum exosomal glypican 1 (GPC-1) in pancreatic ductal adenocarcinoma (PDAC) remain controversial. In this study, we detected serum exosomal GPC-1 using enzyme-linked immunosorbent assay (ELISA) and determined whether it serves as a predictor of diagnosis and recurrence for early-stage PDAC. Methods: Serum samples were obtained from patients with 50 PDAC, 6 benign pancreatic tumor (BPT), or 9 chronic pancreatitis (CP) and 50 healthy controls (HCs). Serum exosomes were isolated using an exosome isolation kit. Exosomal and serum GPC-1 levels were measured using ELISA. The freeze-thaw process was carried out to analyze the stability of GPC-1. Receiver operating characteristic (ROC) analysis was employed to assess the diagnostic value of GPC-1. Kaplan-Meier and multivariate Cox analyses were used to evaluate the prognostic value of GPC-1. Results: The average concentrations of serum exosomal and serum GPC-1 were 1.5 and 0.8 ng/ml, respectively. GPC-1 expression levels were stable under repeated freezing and thawing (d1-5 freeze-thaw cycles vs. d0 P > 0.05). Serum exosomal and serum GPC-1 were significantly elevated in patients with PDAC compared with HCs (P < 0.0001) but were slightly higher compared with that in patients with CP and BPT (P > 0.05). The expression levels of exosomal and serum GPC-1 were elevated 5 days after surgery in patients with PDAC, CP, and BPT (P < 0.05). Patients with high levels of exosomal and serum GPC-1 had a shorter relapse-free survival (RFS) (P = 0.006, and P = 0.010). Multivariate analyses showed that serum exosomal and serum GPC-1 were independent prognostic indicators for early RFS (P = 0.008, and P = 0.041). Conclusion: ELISA is an effective and sensitive method to detect exosomal and serum GPC-1. The detection of GPC-1 was stable under repeated freezing and thawing cycles and could distinguish early-stage PDAC from HCs but not CP and BPT. Exosomal and serum GPC-1 may be good independent predictors of early recurrence in early-stage PDAC.

MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis.

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels.

Dual division of focal plane polarimeters-based collinear reflection Mueller matrix fast imaging microscope.

SIGNIFICANCE: Reflection Mueller matrix imaging is suitable for characterizing the microstructure of bulk specimens and probing dynamic processes in living animals, there are always demands for speed and accuracy for such applications to avoid possible artifacts and reveal a sample's intrinsic properties. AIM: To demonstrate a design of collinear reflection Mueller matrix fast imaging microscope based on dual division of focal plane (DoFP) polarimeters (DoFPs-CRMMM) which has high measurement speed and accuracy. APPROACH: In DoFPs-CRMMM, to improve the measurement speed, we applied the dual DoFP polarimeters design on the collinear reflection system for the first time to achieve fast imaging in about 2 s. To improve the measurement accuracy, we improved the double-pass eigenvalue calibration method (dp-ECM) by background light correction, and explored the optimization of the set of reference samples. RESULTS: DoFPs-CRMMM was applied to measure the standard polarization samples and monitor the tissue optical clearing process of an artificial layered bulk tissue. Results show that the system has satisfactory performance which can capture the variation of polarization properties during the dynamic process. CONCLUSIONS: We present the establishment and demo application of DoFPs-CRMMM. The measurement speed can be further accelerated for potential applications in monitoring dynamic processes or living biomedical systems.

Win ratio approach for analyzing composite time-to-event endpoint with opposite treatment effects in its components.

There is an increasing interest in the use of win ratio with composite time-to-event due to its flexibility in combining component endpoints. Exploring this flexibility further, one interesting question is in assessing the impact when there is a difference in treatment effect in the component endpoints. For example, the active treatment may prolong the time to occurrence of the negative event such as death or ventilation; meanwhile, the treatment effect may also shorten the time to achieving positive events, such as recovery or improvement. Notably, this portrays a situation where the treatment effect on time to recovery is in a different direction of benefit compared to the time to ventilation or death. Under such circumstances, if a single endpoint is used, the benefit gained for other individual outcomes is not counted and is diminished. As consequence, the study may need a larger sample size to detect a significant effect of treatment. Such a scenario can be handled by win ratio in a novel way by ranking component events, which is different from the usual composite endpoint approach such as time-to-first event. To evaluate how the different directions of treatment effect on component endpoints will impact the win ratio analysis, we use a Clayton copula-based bivariate survival simulation to investigate the correlation of component time-to-event. Through simulation, we found that compared to the marginal model using single endpoints, the win ratio analysis on composite endpoint performs better, especially when the correlation between two events is weak. Then, we applied the methodology to an infectious disease progression simulated study motivated by COVID-19. The application demonstrates that the win ratio approach offers advantages in empirical power compared to the traditional Cox proportional hazard approach when there is a difference in treatment effect in the marginal events.

Dynamic incorporation of real world evidence within the framework of adaptive design.

For the clinical studies in rare diseases or small patient populations, having an adequately powered randomized controlled trial is further complicated by variability. As such, sample size re-estimation can be a useful tool if at an interim look the trial sample size needs to be increased to achieve adequate power to reject the null hypothesis. Meanwhile, borrowing or extrapolating information from real-world data or real-world evidence has gained increasing use in trial design and analysis since 2014. Combining these two strategies, high-quality real-world data, if leveraged properly, has the potential to generate real-world evidence that can assist interim decision-making, lower enrollment burden, and reduce study timeline and costs. With proper borrowing from historical control, some of the challenges in these high unmet medical need studies could be resolved considerably. We examine the incorporation of real-world evidence within the framework of adaptive design strategy in pediatric type II diabetes trials where recruitment has been challenging and the completion is hardly on time. Simulations under various scenarios are conducted to assess the borrowing strategy, i.e., the matching method in combination of sample size re-estimation. Comparisons of performance metrics are presented to showcase the advantages of proposed method.

Rapidly Measuring Scattered Polarization Parameters of the Individual Suspended Particle with Continuously Large Angular Range.

Suspended particles play a vital role in aquatic environments. We propose a method to rapidly measure the scattered polarization parameters of individual suspended particles with continuously large angular range (PCLAR), from 60° to 120° in one shot. A conceptual setup is built to measure PCLAR with 20 kHz; to verify the setup, 10 µm-diameter silica microspheres suspended in water, whose PCLAR are consistent with those simulated by Mie theory, are measured. PCLAR of 6 categories of particles are measured, which enables high-accuracy classification with the help of a convolutional neural network algorithm. PCLAR of different mixtures of Cyclotella stelligera and silica microspheres are measured to successfully identify particulate components. Furthermore, classification ability comparisons of different angular-selection strategies show that PCLAR enables the best classification beyond the single angle, discrete angles and small-ranged angles. Simulated PCLAR of particles with different size, refractive index, and structure show explicit discriminations between them. Inversely, the measured PCLAR are able to estimate the effective size and refractive index of individual Cyclotella cells. Results demonstrate the method's power, which intrinsically takes the advantage of the optical polarization and the angular coverage. Future prototypes based on this concept would be a promising biosensor for particles in environmental monitoring.