Brainstem inhibitory neurons enhance behavioral feature selectivity by sharpening the tuning of excitatory neurons.

The brainstem is a hub for sensorimotor integration, which mediates crucial innate behaviors. This brain region is characterized by a rich population of GABAergic inhibitory neurons, required for the proper expression of these innate behaviors. However, what roles these inhibitory neurons play in innate behaviors and how they function are still not fully understood. Here, we show that inhibitory neurons in the nucleus of the optic tract and dorsal-terminal nuclei (NOT-DTN) of the mouse can modulate the innate eye movement optokinetic reflex (OKR) by shaping the tuning properties of excitatory NOT-DTN neurons. Specifically, we demonstrate that although these inhibitory neurons do not directly induce OKR, they enhance the visual feature selectivity of OKR behavior, which is mediated by the activity of excitatory NOT-DTN neurons. Moreover, consistent with the sharpening role of inhibitory neurons in OKR behavior, they have broader tuning relative to excitatory neurons. Last, we demonstrate that inhibitory NOT-DTN neurons directly provide synaptic inhibition to nearby excitatory neurons and sharpen their tuning in a sustained manner, accounting for the enhanced feature selectivity of OKR behavior. In summary, our findings uncover a fundamental principle underlying the computational role of inhibitory neurons in brainstem sensorimotor circuits.

Acupuncture Provides Short-Term Functional Improvements and Pain Relief for Patients After Knee Replacement Surgery: A Systematic Review and Meta-analysis.

The impact of acupuncture on knee function and pain intensity following knee replacement remains controversial. Therefore, we categorized the postsurgery recovery period into 3 phases: short-term (≤2 weeks), intermediate-term (2 weeks-3 months), and long-term (>3 months), and then assessed the effectiveness of acupuncture in improving function and alleviating pain at different stages following knee replacement. This meta-analysis included randomized controlled trials that compared acupuncture intervention with either no treatment or a sham group after knee replacement. Six databases were searched from inception to December 31, 2023, including PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and 2 Chinese databases (Chinese National Knowledge Infrastructure and WanFang Data). A total of 23 studies comprising 1,464 participants were included. Significant improvement of active range of motion was observed on day 7 and week 2 after operation. Lower pain intensity at rest was noted in patients receiving acupuncture in short-term periods after operation (12 hours, day 1, day 2, day 5, and week 2). A reduction in pain intensity during movement with acupuncture was observed on postoperative day 1 and day 7. Auricular acupuncture did not show not significant effectiveness in improving range of motion and pain intensity. For conventional acupuncture, the combination of distal and local point selection was found to be the most effective. Early application of acupuncture, in conjunction with physical therapy, starting before postoperative day 1 or day 2, was recommended. Further high-quality researches are warranted to validate the findings in this meta-analysis. PERSPECTIVE: This article demonstrates that acupuncture has short-term effects (≤2 weeks) on improving active range of motion and reducing pain during rest and during movement following knee replacement surgery. The findings support the early application of acupuncture in hospital settings after knee replacement. REGISTRATION ID: The study was registered on PROSPERO (CRD42024503479).

Decimeter-depth and polarization addressable color 3D meta-holography.

Fueled by the rapid advancement of nanofabrication, metasurface has provided unprecedented opportunities for 3D holography. Large depth 3D meta-holography not only greatly increases information storage capacity, but also enables distinguishing of the relative spatial relationship of 3D objects, which has important applications in fields like optical information storage and medical diagnosis. Although the methods based on Fresnel diffraction theory can reconstruct the real depth information of 3D objects, the maximum depth is only 2 mm. Here, we develop a 3D meta-holography based on angular spectrum diffraction theory to break through the depth limit. By developing the angular spectrum diffraction theory into meta-holography, the metasurface structure with independent polarization control is used to create a polarization multiplexing 3D meta-hologram. The fabricated amorphous silicon metasurface increases the depth range by 47.5 times and realizes 0.95 dm depth reconstruction for polarization independent and different color 3D meta-hologram in visible. Such polarization controlled large-depth color meta-holography is expected to open avenue for data storage, display, information security and virtual reality.

Lipids, lipid-lowering drugs and lateral epicondylitis of the humerus: a drug-targeted Mendelian randomization study.

Background: Clinical observations indicate that blood lipids may be risk factors for lateral epicondylitis (LE) of the humerus, and lipid-lowering drugs are also used for the prevention and treatment of tendon diseases, but these lack high-quality clinical trial evidence and remain inconclusive. Mendelian randomization (MR) analyses can overcome biases in traditional observational studies and offer more accurate inference of causal relationships. Therefore, we employed this approach to investigate whether blood lipids are risk factors for LE and if lipid-lowering drugs can prevent it. Methods: Genetic variations associated with lipid traits, including low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), were obtained from the UK Biobank and the Global Lipids Genetics Consortium (GLGC). Data on genetic variation in LE were sourced from FinnGen, including 24,061 patients and 275,212 controls. Subsequently, MR analyses were conducted to assess the potential correlation between lipid traits and LE. Additionally, drug-target Mendelian randomization analyses were performed on 10 drug targets relevant to LE. For those drug targets that yielded significant results, further analysis was conducted using colocalization techniques. Results: No correlation was found between three blood lipid traits and LE. Lipoprotein lipase (LPL) enhancement is significantly associated with a decreased risk of LE (OR = 0.76, [95% CI, 0.65-0.90], p = 0.001). The expression of LPL in the blood is associated with LE and shares a single causal variant (12.07%), greatly exceeding the probability of different causal variations (1.93%), with a colocalization probability of 86.2%. Conclusion: The three lipid traits are not risk factors for lateral epicondylitis. LPL is a potential drug target for the prevention and treatment of LE.

Leveraging cfDNA fragmentomic features in a stacked ensemble model for early detection of esophageal squamous cell carcinoma.

In this study, we develop a stacked ensemble model that utilizes cell-free DNA (cfDNA) fragmentomics for the early detection of esophageal squamous cell carcinoma (ESCC). This model incorporates four distinct fragmentomics features derived from whole-genome sequencing (WGS) and advanced machine learning algorithms for robust analysis. It is validated across both an independent validation cohort and an external cohort to ensure its generalizability and effectiveness. Notably, the model maintains its robustness in low-coverage sequencing environments, demonstrating its potentials in clinical settings with limited sequencing resources. With its remarkable sensitivity and specificity, this approach promises to significantly improve the early diagnosis and management of ESCC. This study represents a substantial step forward in the application of cfDNA fragmentomics in cancer diagnostics, emphasizing the need for further research to fully establish its clinical efficacy.

Establishment and performance analysis of a new multiplex detection method for influenza an and B virus antigen.

BACKGROUND: Influenza A and B virus detection is pivotal in epidemiological surveillance and disease management. Rapid and accurate diagnostic techniques are crucial for timely clinical intervention and outbreak prevention. Quantum dot-encoded microspheres have been widely used in immunodetection. The integration of quantum dot-encoded microspheres with flow cytometry is a well-established technique that enables rapid analysis. Thus, establishing a multiplex detection method for influenza A and B virus antigens based on flow cytometry quantum dot microspheres will help in disease diagnosis. AIM: To establish a codetection method of influenza A and B virus antigens based on flow cytometry quantum dot-encoded microsphere technology, which forms the foundation for the assays of multiple respiratory virus biomarkers. METHODS: Different quantum dot-encoded microspheres were used to couple the monoclonal antibodies against influenza A and B. The known influenza A and B antigens were detected both separately and simultaneously on a flow cytometer, and the detection conditions were optimized to establish the influenza A and B antigen codetection method, which was utilized for their detection in clinical samples. The results were compared with the fluorescence quantitative polymerase chain reaction (PCR) method to validate the clinical performance of this method. RESULTS: The limits of detection of this method were 26.1 and 10.7 pg/mL for influenza A and B antigens, respectively, which both ranged from 15.6 to 250000 pg/mL. In the clinical sample evaluation, the proposed method well correlated with the fluorescent quantitative PCR method, with positive, negative, and overall compliance rates of 57.4%, 100%, and 71.6%, respectively. CONCLUSION: A multiplex assay for quantitative detection of influenza A and B virus antigens has been established, which is characterized by high sensitivity, good specificity, and a wide detection range and is promising for clinical applications.

Ultra-efficient and parameter-free computation of submicron thermal transport with phonon Boltzmann transport equation.

Understanding thermal transport at the submicron scale is crucial for engineering applications, especially in the thermal management of electronics and tailoring the thermal conductivity of thermoelectric materials. At the submicron scale, the macroscopic heat diffusion equation is no longer valid and the phonon Boltzmann transport equation (BTE) becomes the governing equation for thermal transport. However, previous thermal simulations based on the phonon BTE have two main limitations: relying on empirical parameters and prohibitive computational costs. Therefore, the phonon BTE is commonly used for qualitatively studying the non-Fourier thermal transport phenomena of toy problems. In this work, we demonstrate an ultra-efficient and parameter-free computational method of the phonon BTE to achieve quantitatively accurate thermal simulation for realistic materials and devices. By properly integrating the phonon properties from first-principles calculations, our method does not rely on empirical material properties input. It can be generally applicable for different materials and the predicted results can match well with experimental results. Moreover, by developing a suitable ensemble of advanced numerical algorithms, our method exhibits superior numerical efficiency. The full-scale (from ballistic to diffusive) thermal simulation of a 3-dimensional fin field-effect transistor with 13 million degrees of freedom, which is prohibitive for existing phonon BTE solvers even on supercomputers, can now be completed within two hours on a single personal computer. Our method makes it possible to achieve the predictive design of realistic nanostructures for the desired thermal conductivity. It also enables accurately resolving the temperature profiles at the transistor level, which helps in better understanding the self-heating effect of electronics.

Multidimensional Fragmentomics Enables Early and Accurate Detection of Colorectal Cancer.

Colorectal cancer is frequently diagnosed in advanced stages, highlighting the need for developing approaches for early detection. Liquid biopsy using cell-free DNA (cfDNA) fragmentomics is a promising approach, but the clinical application is hindered by complexity and cost. This study aimed to develop an integrated model using cfDNA fragmentomics for accurate, cost-effective early-stage colorectal cancer detection. Plasma cfDNA was extracted and sequenced from a training cohort of 360 participants, including 176 patients with colorectal cancer and 184 healthy controls. An ensemble stacked model comprising five machine learning models was employed to distinguish patients with colorectal cancer from healthy controls using five cfDNA fragmentomic features. The model was validated in an independent cohort of 236 participants (117 patients with colorectal cancer and 119 controls) and a prospective cohort of 242 participants (129 patients with colorectal cancer and 113 controls). The ensemble stacked model showed remarkable discriminatory power between patients with colorectal cancer and controls, outperforming all base models and achieving a high area under the receiver operating characteristic curve of 0.986 in the validation cohort. It reached 94.88% sensitivity and 98% specificity for detecting colorectal cancer in the validation cohort, with sensitivity increasing as the cancer progressed. The model also demonstrated consistently high accuracy in within-run and between-run tests and across various conditions in healthy individuals. In the prospective cohort, it achieved 91.47% sensitivity and 95.58% specificity. This integrated model capitalizes on the multiplex nature of cfDNA fragmentomics to achieve high sensitivity and robustness, offering significant promise for early colorectal cancer detection and broad patient benefit. Significance: The development of a minimally invasive, efficient approach for early colorectal cancer detection using advanced machine learning to analyze cfDNA fragment patterns could expedite diagnosis and improve treatment outcomes for patients. See related commentary by Rolfo and Russo, p. 3128.

Early change of plasma Epstein-Barr virus DNA load and the viral lytic genome level could positively predict clinical outcome in recurrent or metastatic nasopharyngeal carcinoma receiving anti-programmed cell death 1 monotherapy.

PURPOSE: Patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) have proven benefit from anti-programmed cell death 1 (anti-PD-1) monotherapy. Here, we retrospectively analyze the association of plasma Epstein-Barr virus (EBV) DNA load and tumor viral lytic genome with clinical outcome from 2 registered phase I trials. METHODS: Patients with RM-NPC from Checkmate 077 (nivolumab phase I trial in China) and Camrelizumab phase I trial between March 2016 and January 2018 were enrolled. Baseline EBV DNA titers were tested in 68 patients and EBV assessment was performed in 60 patients who had at least 3 post-baseline timepoints of EBV data and at least 1 post-baseline timepoint of radiographic assessment. We defined "EBV response" as 3 consecutive timepoints of load below 50% of baseline, and "EBV progression" as 3 consecutive timepoints of load above 150% of baseline. Whole-exome sequencing was performed in 60 patients with available tumor samples. RESULTS: We found that the baseline EBV DNA load was positively correlated with tumor size (spearman p < 0.001). Both partial response (PR) and stable disease (SD) patients had significantly lower EBV load than progression disease (PD) patients. EBV assessment was highly consistent with radiographic evaluation. Patients with EBV response had significantly improved overall survival (OS) than patients with EBV progression (log-rank p = 0.004, HR = 0.351 [95% CI: 0.171-0.720], median 22.5 vs. 11.9 months). The median time to initial EBV response and progression were 25 and 36 days prior to initial radiographic response and progression, respectively. Patients with high levels of EBV lytic genomes at baseline, including BKRF2, BKRF3 and BKRF4, had better progression-free survival (PFS) and OS. CONCLUSION: In summary, early clearance of plasma EBV DNA load and high levels of lytic EBV genes were associated with better clinical outcome in patients with RM-NPC receiving anti-PD-1 monotherapy.

Cross-linked Sodium Hyaluronate Gel with PLLA-b-PEG Microsphere for Facial Contouring in Chinese: A Retrospective Study.

BACKGROUND: In Asia, the demand for cosmetic facial treatments has surged due to technological advancements, increased social acceptability, and affordability. Poly-L-lactic acid (PLLA) fillers, known for their biocompatibility and biodegradability, have emerged as a popular choice for facial contouring, yet studies specifically addressing their use in Asian populations are scarce. METHODS: This retrospective study examined 30 Chinese patients who underwent facial contouring with PLLA fillers, focusing on product composition, injection techniques, and safety measures. A comprehensive clinical evaluation was performed, including the Global Aesthetic Improvement Scale (GAIS) and Global Impression of Change Scale (GICS) for effectiveness and patient satisfaction, respectively. RESULTS: No significant difference in GAIS scores was observed between injectors and blinded evaluators over a 12-month period, indicating consistent effectiveness. Patient satisfaction remained high, with GICS scores reflecting positive outcomes. The safety profile was favorable, with no serious adverse events reported. The study highlighted the importance of anatomical knowledge to avoid complications, particularly in areas prone to blindness. CONCLUSIONS: PLLA fillers offer a safe, effective option for facial contour correction in the Asian population, achieving high patient satisfaction and maintaining results over time. The study underscores the need for tailored approaches in cosmetic procedures for Asians, considering their unique facial structures and aesthetic goals. Further research with larger, multicenter cohorts is recommended to validate these findings and explore long-term effects. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Analytical Impact-Excitation Theory of Er/O/B Codoped Si Light-Emitting Diodes.

Er doped Si light-emitting diodes may find important applications in silicon photonics and optical quantum computing. These diodes exhibit an emission efficiency 2 orders of magnitude higher at reverse bias than forward bias due to impact excitation. However, physics of impact excitation in these devices remains largely unexplored. In this work, we fabricated an Er/O/B codoped Si light-emitting diode which exhibits a strong electroluminescence by the impact excitation of electrons inelastically colliding the Er ions. An analytical impact-excitation theory was established to predict the electroluminescence intensity and internal quantum efficiency which fit well with the experimental data. From the fittings, we find that the excitable Er ions reach a record concentration of 1.8×10^{19} cm^{-3} and up to 45% of them is in an excitation state by impact excitation. This work has important implications for developing efficient classical and quantum light sources based on rare earth elements in semiconductors.

Diagnoses and Treatment of Acquired Undescended Testes: A Review.

Acquired undescended testes were once considered a sporadic disease. In recent years, reports suggest that they are not uncommon, with an incidence rate about 3 times that of congenital undescended testes. The etiology of acquired undescended testes remains inconclusive, clinical diagnostic standards are unclear, and treatment approaches are still controversial. There is ongoing debate about the mechanism of testicular ascent. The prevailing view is that acquired undescended testes occur due to the partial absorption of the gubernaculum, which forms part of the parietal peritoneum. The residual gubernacular fibers continuously pull on the spermatic cord, preventing the spermatic cord from elongating proportionately to somatic growth, leading to a re-ascent of the testis. Acquired undescended testes may increase the risk of testicular cancer, but this is still debated. The preferred treatment method is also controversial. However, surgical fixation has an immediate effect; no studies have proven that early surgery improves fertility in patients. The etiology of acquired undescended testes is closely related to the continuous pull of the residual gubernacular fibers on the spermatic cord, which prevents the cord from extending proportionately to body growth. There are no clear diagnostic standards for acquired undescended testes yet, and spontaneous descent is possible, so testicular fixation surgery may not be the preferred treatment method.

Early detection of uterine corpus endometrial carcinoma utilizing plasma cfDNA fragmentomics.

BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is a prevalent gynecologic malignancy with a favorable prognosis if detected early. However, there is a lack of accurate and reliable early detection tests for UCEC. This study aims to develop a precise and non-invasive diagnostic method for UCEC using circulating cell-free DNA (cfDNA) fragmentomics. METHODS: Peripheral blood samples were collected from all participants, and cfDNA was extracted for analysis. Low-coverage whole-genome sequencing was performed to obtain cfDNA fragmentomics data. A robust machine learning model was developed using these features to differentiate between UCEC and healthy conditions. RESULTS: The cfDNA fragmentomics-based model showed high predictive power for UCEC detection in training (n = 133; AUC 0.991) and validation cohorts (n = 89; AUC 0.994). The model manifested a specificity of 95.5% and a sensitivity of 98.5% in the training cohort, and a specificity of 95.5% and a sensitivity of 97.8% in the validation cohort. Physiological variables and preanalytical procedures had no significant impact on the classifier's outcomes. In terms of clinical benefit, our model would identify 99% of Chinese UCEC patients at stage I, compared to 21% under standard care, potentially raising the 5-year survival rate from 84 to 95%. CONCLUSION: This study presents a novel approach for the early detection of UCEC using cfDNA fragmentomics and machine learning showing promising sensitivity and specificity. Using this model in clinical practice could significantly improve UCEC management and control, enabling early intervention and better patient outcomes. Further optimization and validation of this approach are warranted to establish its clinical utility.

Phase unwrapping algorithm based on phase diversity wavefront reconstruction and virtual Hartmann-Shack technology.

Phase unwrapping (PU) algorithms play a crucial role in various phase measurement techniques. Traditional algorithms cannot work well in strong noise environments, which makes it very difficult to obtain the accurate absolute phase from the noisy wrapped phase. In this Letter, we introduce a novel, to the best of our knowledge, phase unwrapping algorithm named PD-VHS. This algorithm innovatively employs point spread function (PSF) filtering to eliminate noise from the wrapped phase. Furthermore, it combines a phase diversity (PD) wavefront reconstruction technology with a virtual Hartmann-Shack (VHS) technology for phase reconstruction and phase unwrapping of the filtered PSFs. In simulations, hundreds of random noise wrapped phases, containing the first 45 Zernike polynomials (excluding piston and the two tilt terms) and the wavefront RMS = 0.5λ and 1λ, are used to compare the classical quality-map guided algorithm, the VHS algorithm with decent noise immunity, with our PD-VHS algorithm. When signal-to-noise ratio (SNR) drops to just 2 dB, the mean root mean square errors (RMSEs) of the residual wavefront between the unwrapped result and the absolute phase of the quality-map guided algorithm and the VHS algorithm are up to 3.99λ, 0.44λ, 4.29λ, and 0.85λ, respectively; however, our algorithm RMSEs are low: 0.11λ and 0.17λ. Simulation results demonstrated that the PD-VHS algorithm significantly outperforms the quality-map guided algorithm and the VHS algorithm under large-scale noise conditions.

Stabilizing High-Valence Copper(I) Sites with Cu-Ni Interfaces Enhances Electroreduction of CO2 to C2+ Products.

In this study, the copper-nickel (Cu-Ni) bimetallic electrocatalysts for electrochemical CO2 reduction reaction(CO2RR) are fabricated by taking the finely designed poly(ionic liquids) (PIL) containing abundant Salen and imidazolium chelating sites as the surficial layer, wherein Cu-Ni, PIL-Cu and PIL-Ni interaction can be readily regulated by different synthetic scheme. As a proof of concept, Cu@Salen-PIL@Ni(NO3)2 and Cu@Salen-PIL(Ni) hybrids differ significantly in the types and distribution of Ni species and Cu species at the surface, thereby delivering distinct Cu-Ni cooperation fashion for the CO2RR. Remarkably, Cu@Salen-PIL@Ni(NO3)2 provides a C2+ faradaic efficiency (FEC2+) of 80.9% with partial current density (jC 2+) of 262.9 mA cm-2 at -0.80 V (versus reversible hydrogen electrode, RHE) in 1 m KOH in a flow cell, while Cu@Salen-PIL(Ni) delivers the optimal FEC2+ of 63.8% at jC2+ of 146.7 mA cm-2 at -0.78 V. Mechanistic studies indicates that the presence of Cu-Ni interfaces in Cu@Salen-PIL@Ni(NO3)2 accounts for the preserve of high-valence Cu(I) species under CO2RR conditions. It results in a high activity of both CO2-to-CO conversion and C-C coupling while inhibition of the competitive HER.

Multi-dimensional cell-free DNA-based liquid biopsy for sensitive early detection of gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. METHODS: We collected a prospective study cohort of 110 stage I-II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. RESULTS: Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942-0.982) in the study cohort, 0.972 (95% CI: 0.953-0.992) in the first validation cohort and 0.937 (95% CI: 0.890-0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. CONCLUSIONS: We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

Molecular landscape and multi-omic measurements of heterogeneity in fetal adenocarcinoma of the lung.

Fetal adenocarcinoma of the lung (FLAC) is a rare form of lung adenocarcinoma and was divided into high-grade (H-FLAC) and low-grade (L-FLAC) subtypes. Despite the existence of some small case series studies, a comprehensive multi-omics study of FLAC has yet to be undertaken. In this study, we depicted the multi-omics landscapes of this rare lung cancer type by performing multi-regional sampling on 20 FLAC cases. A comparison of multi-omics profiles revealed significant differences between H-FLAC and L-FLAC in a multi-omic landscape. Two subtypes also showed distinct relationships between multi-layer intratumor heterogeneity (ITH). We discovered that a lower genetic ITH was significantly associated with worse recurrence-free survival and overall survival in FLAC patients, whereas higher methylation ITH in H-FLAC patients suggested a short survival. Our findings highlight the complex interplay between genetic and transcriptional heterogeneity in FLAC and suggest that different types of ITH may have distinct implications for patient prognosis.

The Effect of Process Parameters on the Microstructure, Stability, and Sensorial Properties of an Emulsion Cream Formulation.

A classical emulsion formulation based on petrolatum and mineral oil as the internal phase with emulsifier wax as a typical topical emulsion cream was investigated for the effect of process parameters on drug product quality and performance attributes. The Initial Design of Experiment (DoE) suggested that an oil phase above 15%, coupled with less than 10% emulsifying wax, resulted in less stable emulsions. Different processing parameters such as homogenization speed, duration, cooling rate, and final temperature showed minimal influence on properties and failed to improve stability. The final DoE suggested that the optimal emulsion stability was achieved by introducing a holding period midway through the cooling stage after solvent addition. Within the studied holding temperature range (25-35 °C), a higher holding temperature correlated with increased emulsion stability. However, the application of shear during the holding period, using a paddle mixer, adversely affected stability by disrupting the emulsion microstructure. IVRT studies revealed that the release of lidocaine was higher in the most stable emulsion produced at a holding temperature of 35 °C compared to the least stable emulsion produced at a holding temperature of 25 °C. This suggests that a holding temperature of 35 °C improves both the stability and active release performance. It appears that a slightly higher holding temperature, 35 °C, allows a more flexible and stable emulsifying agent film around the droplets facilitating stabilization of the emulsion. This study offers valuable insights into the relationship between process parameters at various stages of manufacture, microstructure, and various quality attributes of emulsion cream systems. The knowledge gained will facilitate improved design and optimization of robust manufacturing processes, ensuring the production of the formulations with the desired critical quality attributes.

The long-term efficacy of eltrombopag in children with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is the most common autoimmune disorder characterized by decreased platelet counts and impaired platelet production. Eltrombopag has been demonstrated to be safe and effective for children with ITP. It is reported eltrombopag can achieve a sustained response off treatment. However, data on its overall efficacy and safety profile are scarce in children. This study aimed to investigate the long-term efficacy of eltrombopag in children with ITP. Treatment overall response (OR), complete response (CR), response (R), durable response (DR), no response (NR), treatment free remission (TFR), and relapse rate, were assessed in 103 children with ITP during eltrombopag therapy. The OR rate, CR rate, R rate, DR rate, NR rate, TFR rate, and relapse rate were 67.0%, 55.3%, 11.7%, 56.3%, 33.0%, 60%, 36.2%, respectively. Importantly, we discovered that newly diagnosed ITP patients showed a higher DR rate, TFR rate and lower relapse rate compared to persistent and chronic ITP patients. Furthermore, the CR rate, DR rate, and TFR rate of 5 patients under six months were 100%. None of them suffered relapse. The most common adverse event (AEs) was hepatotoxicity (7.77%). Our study highlighted the critical role of eltrombopag as the second-line treatment in children with ITP who were intolerant to first-line therapy.