Computed tomography radiogenomics: A potential tool for prediction of molecular subtypes in gastric stromal tumor.

BACKGROUND: Preoperative knowledge of mutational status of gastrointestinal stromal tumors (GISTs) is essential to guide the individualized precision therapy. AIM: To develop a combined model that integrates clinical and contrast-enhanced computed tomography (CE-CT) features to predict gastric GISTs with specific genetic mutations, namely KIT exon 11 mutations or KIT exon 11 codons 557-558 deletions. METHODS: A total of 231 GIST patients with definitive genetic phenotypes were divided into a training dataset and a validation dataset in a 7:3 ratio. The models were constructed using selected clinical features, conventional CT features, and radiomics features extracted from abdominal CE-CT images. Three models were developed: ModelCT sign, modelCT sign + rad, and model CTsign + rad + clinic. The diagnostic performance of these models was evaluated using receiver operating characteristic (ROC) curve analysis and the Delong test. RESULTS: The ROC analyses revealed that in the training cohort, the area under the curve (AUC) values for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic for predicting KIT exon 11 mutation were 0.743, 0.818, and 0.915, respectively. In the validation cohort, the AUC values for the same models were 0.670, 0.781, and 0.811, respectively. For predicting KIT exon 11 codons 557-558 deletions, the AUC values in the training cohort were 0.667, 0.842, and 0.720 for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic, respectively. In the validation cohort, the AUC values for the same models were 0.610, 0.782, and 0.795, respectively. Based on the decision curve analysis, it was determined that the modelCT sign + rad + clinic had clinical significance and utility. CONCLUSION: Our findings demonstrate that the combined modelCT sign + rad + clinic effectively distinguishes GISTs with KIT exon 11 mutation and KIT exon 11 codons 557-558 deletions. This combined model has the potential to be valuable in assessing the genotype of GISTs.

Quantification and Functional Studies of Neutrophilic Cells Identifies Distinct Papilloma Phenotypes.

OBJECTIVES: To characterize the distribution of immune cell subsets within laryngeal papillomas and to study the function of potentially immunosuppressive neutrophilic and regulatory T cells (Tregs). METHODS: Fresh clinical papilloma specimens were collected at the time of surgery and studied with multiparameter flow cytometry. Papilloma infiltrating neutrophilic cells and Tregs were sorted and studied functionally with ex vivo T cell suppression assays. RESULTS: Flow cytometric analysis of fresh laryngeal papillomas samples from 18 adult patients with recurrent respiratory papillomatosis revealed patterns in immune constituency between patients. Clearly divergent phenotypes based primarily on the degree of neutrophilic and T cell infiltration were identified. Relative neutrophilic cell enrichment and T cell depletion were observed in 50% of samples and neutrophilic cell depletion and T cell enrichment were observed in the others. Greater papilloma neutrophilic cell enrichment was positively associated with the number of clinically indicated interventions required in the 12 months prior to sample collection, linking papilloma neutrophil inflammation to disease severity. Functional assays revealed the ability of both papilloma infiltrating neutrophilic and Tregs to suppress T cell function at roughly equal magnitudes, but substantially increased infiltration of neutrophilic cells compared to Tregs across samples. CONCLUSION: Neutrophilic cells are an important contributor to immunosuppression within the respiratory papilloma microenvironment. Given these data and the association between greater neutrophilic cell infiltration and lack of clinical response to therapeutic vaccination, additional study of strategies aimed at limiting neutrophilic cell infiltration or function within papillomas is warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 2024.

Pathogenicity classification of missense mutations based on deep generative model.

Missense mutations affect the function of human proteins and are closely associated with multiple acute and chronic diseases. The identification of disease-associated missense mutations and their classification for pathogenicity can provide insights into the genetic basis of disease and protein function. This paper proposes MLAE (Method based on LSTM-Ladder AutoEncoder), a deep learning classification model for identifying disease-associated missense mutations and classifying their pathogenicity based on the Variational AutoEncoder (VAE) framework. MLAE overcomes the limitations of the VAE framework by introducing the Ladder structure, combined with LSTM networks. This reduces the loss of original information during the transmission process, thereby making the model more effective in learning. In the experiment, MLAE classified all 27572 possible missense variants of the three input proteins with an average classification AUC of 0.941. This result provides evidence that MLAE is effective in predicting pathogenicity. Additionally, MLAE provides results for multi-label classification, with an average Hamming loss of 0.196, supporting the classification of complex variants. The proposed MLAE method provides an insightful approach to effectively capture amino acid sequence information and accurately predict the pathogenicity of mutations, thereby providing an analytical basis for the study and prevention of related diseases.

Clinical application of regional citrate anticoagulation for membrane-based therapeutic plasma exchange in children with liver failure.

Background: Regional citrate anticoagulation (RCA) is being used more commonly in children for continuous renal replacement therapy. Few reports describe the application of membrane-based therapeutic plasma exchange (mTPE) with RCA in children with liver failure (LF). Aims: To explore the application of RCA-mTPE in children with LF. Methods: We retrospectively analyzed data from children with LF who underwent RCA-mTPE in the Children's Hospital of Chongqing Medical University's pediatric intensive care unit. We used the total to ionized calcium ratio (T/iCa) > 2.5 as the diagnostic criteria for citrate accumulation (CA). The patients were divided into two groups according to the occureence of CA at the end of RCA-mTPE (CA group: T/iCa > 2.5; NCA group: T/iCa ≤ 2.5). To evaluate the clinical safety and efficacy of RCA-mTPE, the following data from medical records were assessed and compared between groups: clinical characteristics, reasons for LF, RCA-mTPE parameters and duration, laboratory findings, and complications. Results: In total, 92 RCA-mTPE treatments were administered to 21 children with LF over 3.8 ± 0.9 h. The following mean values were determined: blood flow rate (QB) = 2.8 ml/kg/min, 4% sodium citrate dose/blood flow rate ratio (QCi/QB) = 1.1(QCi,ml/kg/h); plasma dose/body weight ratio(QP/BW) = 18.5 (QP, ml/kg/h); 10% calcium gluconate dose/blood flow rate ratio (QCa/QB) = 0.2(QCa, ml/kg/h). The mean concentration of iCa in vitro was 0.38 ± 0.07 mmol/L. Citrate accumulation was recorded after 34 (37%) treatments. Hypocalcemia occurred in 11 (12%) and 7 (7.6%) treatments, during and after mTPE, respectively. Three hypotensive and one convulsive events, related to hypocalcemia, and two clotting events occurred during RCA-mTPE. After RCA-mTPE, the patients' pH, HCO3- and Na+ levels, and T/iCa were significantly increased and the total bilirubin (TB), conjugated bilirubin (DB), prothrombin time (PT), activated partial thromboplastin time (APTT), alanine aminotransferase (ALT), aspartate aminotransferase (AST),and ammonia levels were significantly decreased. The TB, DB, and lactic acid levels, before RCA-mTPE, were significantly higher in the CA group than in the NCA group, but there were no significance between the two groups in QB/BW, QCi/QB, and QP/BW, mTPE duration, and estimated amount of citrate metabolized. Conclusions: Children with LF undergoing RCA-mTPE are at risk of hypocalcemia. With proper protocol adjustment, however, RCA-mTPE can be used safely and effectively in these patients.

Functional to structural plasticity in unilateral sudden sensorineural hearing loss: neuroimaging evidence.

A cortical plasticity after long-duration single side deafness (SSD) is advocated with neuroimaging evidence while little is known about the short-duration SSDs. In this case-cohort study, we recruited unilateral sudden sensorineural hearing loss (SSNHL) patients and age-, gender-matched health controls (HC), followed by comprehensive neuroimaging analyses. The primary outcome measures were temporal alterations of varied dynamic functional network connectivity (dFNC) states, neurovascular coupling (NVC) and brain region volume at different stages of SSNHL. The secondary outcome measures were pure-tone audiograms of SSNHL patients before and after treatment. A total of 38 SSNHL patients (21 [55%] male; mean [standard deviation] age, 45.05 [15.83] years) and 44 HC (28 [64%] male; mean [standard deviation] age, 43.55 [12.80] years) were enrolled. SSNHL patients were categorized into subgroups based on the time from disease onset to the initial magnetic resonance imaging scan: early- (n = 16; 1-6 days), intermediate- (n = 9; 7-13 days), and late- stage (n = 13; 14-30 days) groups. We first identified slow state transitions between varied dFNC states at early-stage SSNHL, then revealed the decreased NVC restricted to the auditory cortex at the intermediate- and late-stage SSNHL. Finally, a significantly decreased volume of the left medial superior frontal gyrus (SFGmed) was observed only in the late-stage SSNHL cohort. Furthermore, the volume of the left SFGmed is robustly correlated with both disease duration and patient prognosis. Our study offered neuroimaging evidence for the evolvement from functional to structural brain alterations of SSNHL patients with disease duration less than 1 month, which may explain, from a neuroimaging perspective, why early-stage SSNHL patients have better therapeutic responses and hearing recovery.

The tumor microenvironment state associates with response to HPV therapeutic vaccination in patients with respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a rare, debilitating neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11 and characterized by growth of papillomas in the upper aerodigestive tract. There is no approved medical therapy, and patients require repeated debulking procedures to maintain voice and airway function. PRGN-2012 is a gorilla adenovirus immune-therapeutic capable of enhancing HPV 6/11-specific T cell immunity. This first-in-human, phase 1 study (NCT04724980) of adjuvant PRGN-2012 treatment in adult patients with severe, aggressive RRP demonstrates the overall safety and clinically meaningful benefit observed with PRGN-2012, with a 50% complete response rate in patients treated at the highest dose. Responders demonstrate greater expansion of peripheral HPV-specific T cells compared with nonresponders. Additional correlative studies identify an association between reduced baseline papilloma HPV gene expression, greater interferon responses and expression of CXCL9 and CXCL10, and greater papilloma T cell infiltration in responders. Conversely, nonresponders were characterized by greater HPV and CXCL8 gene expression, increased neutrophilic cell infiltration, and reduced T cell papilloma infiltration. These results suggest that papilloma HPV gene expression may regulate interferon signaling and chemokine expression profiles within the tumor microenvironment that cooperate to govern clinical response to therapeutic HPV vaccination in patients with respiratory papillomatosis.

Novel blood product transfusion regimen to prevent clotting and citrate accumulation during continuous renal replacement therapy with regional citrate anticoagulation in children.

Objective: Introduce a novel protocol to prevent clotting and citrate accumulation (CA) from blood product transfusion (BPT) during continuous renal replacement therapy (CRRT) with regional citrate anticoagulation (RCA) in children. Methods: We prospectively compared fresh frozen plasma (FFP) and platelet transfusions between the two BPT protocols, direct transfusion protocol (DTP) and partial replacement of citrate transfusion protocol (PRCTP), in terms of the risks of clotting, citric accumulation (CA), and hypocalcemia. For DTP, blood products were directly transfused without any adjustment to the original RCA-CRRT regimen. For PRCTP, the blood products were infused into the CRRT circulation near the sodium citrate infusion point, and the dosage of 4% sodium citrate was reduced depending on the dosage of sodium citrate in the blood products. Basic information and clinical data were recorded for all children. Heart rate, blood pressure, ionized calcium (iCa) and various pressure parameters were recorded before, during and after BPT, as well as coagulation indicators, electrolytes, and blood cell counts before and after BPT. Results: Twenty-six children received 44 PRCTPs and 15 children received 20 DTPs. The two groups had similar in vitro ionized calcium (iCa) concentrations (PRCTP: 0.33 ± 0.06 mmol/L, DTP: 0.31 ± 0.04 mmol/L), total filter lifespan (PRCTP: 49.33 ± 18.58, DTP: 50.65 ± 13.57 h), and filter lifespan after BPT (PRCTP: 25.31 ± 13.87, DTP: 23.39 ± 11.34 h). There was no visible filter clotting during BPT in any of the two groups. The two groups had no significant differences in arterial pressure, venous pressure, and transmembrane pressure before, during, or after BPT. Neither treatment led to significant decreases in WBC, RBC, or hemoglobin. The platelet transfusion group and the FFP group each had no significant decrease in platelets, and no significant increases in PT, APTT, and D-dimer. The most clinically significant changes were in the DTP group, in which the ratio of total calcium to ionized calcium (T/iCa) increased from 2.06 ± 0.19 to 2.52 ± 0.35, the percentage of patients with T/iCa above 2.5 increased from 5.0% to 45%, and the level of in vivo iCa increased from 1.02 ± 0.11 to 1.06 ± 0.09 mmol/L (all p < 0.05). Changes in these three indicators were not significant in the PRCTP group. Conclusion: Neither protocol was associated with filter clotting during RCA-CRRT. However, PRCTP was superior to DTP because it did not increase the risk of CA and hypocalcemia.

Assessment of firefighter-training effectiveness in China based on human-factor parameters and machine learning.

BACKGROUND: The emergency rescue ability of firefighters is particularly important in the event of major disasters or accidents. Therefore, an assessment of the firefighter-training effectiveness is necessary. OBJECTIVE: This paper aims to achieve a scientific and effective assessment of the firefighter-training effectiveness in China. An assessment method based on human factor parameters and machine learning was proposed. METHOD: The model is constructed by collecting the corresponding human factor parameters such as electrocardiographic signals, electroencephalographic signals, surface electromyographic signals, and photoplethysmographic signals through wireless sensors and using them as constraint indicators. For the problems of weak human factor parameters and high noise proportion, an improved flexible analytic wavelet transform algorithm is used to denoise and extract the corresponding feature values. To overcome the limitations of traditional assessment methods, improved machine learning algorithms are used to comprehensively assess the training effectiveness of firefighters and provide targeted training suggestions. RESULTS: The effectiveness of this study's evaluation method is verified by comparing it with the expert scoring method and considering firefighters from a special fire station in Xhongmen, Daxing District, Beijing, as an example. CONCLUSION: This study can effectively guide the scientific training of firefighters and the method is more objective and accurate than the traditional method.

Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer.

Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8+ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-ß and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-ß-driven CD103 expression on CD8+ T cells is reversed following TGF-ß neutralization in vitro, implicating TGF-ß in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying T cell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of T cell tissue retention as a promising neoadjuvant treatment strategy.

Regional citrate anticoagulation for continuous renal replacement therapy in newborns.

Background: Regional citrate anticoagulant (RCA) is recommended as the preferred anticoagulant regimen for continuous renal replacement therapy (CRRT) in adults; however, it is rarely reported in neonates due to concerns associated with their immature liver. Few studies have reported on the use of RCA to evaluate the safety and efficacy of RCA-CRRT in neonates. Method: In this retrospective observational study, we reviewed the clinical records of neonates who underwent RCA-CRRT at our pediatric intensive care unit between September 2015 to January 2021. Results: A total of 23 neonates underwent 57 sessions of RCA-CRRT. Their mean age was 10.1 ± 6.9 days and mean weight was 3.0 ± 0.7 kg (range, 0.95-4 kg). The mean filter life was 31.54 ± 19.58 h (range, 3.3-72.5 h). Compared to pretreatment values, the total-to-ionized calcium ratio (T/iCa) on RCA-CRRT increased (2.00 ± 34 0.36 vs. 2.19 ± 0.40, P = 0.056) as did the incidence of T/iCa levels >2.5 (11.4 vs. 14.3, P = 0.477), albeit not significantly. Using a post-treatment T/iCa threshold of 2.5, we divided all the cases into citrate accumulation (CA) and non-CA (NCA) groups. Compared with the NCA group, the CA group had significantly higher body weight (3.64 ± 0.32 kg vs. 2.95 ± 0.41 kg, P = 0.033) and significantly lower blood flow rate per body weight ml/kg/min (3.08 ± 0.08 vs. 4.07 ± 0.71, P = 0.027); however, there was no significant difference between the two groups in terms of age, corrected gestational age, the PRISM-III score, and biochemical tests. Conclusion: RCA-CRRT is safe and effective for neonates. After appropriate adjustments of the RCA-CRRT parameters, the incidence of CA was not higher in neonates than in children or adults, and CA was not found to be significantly correlated with age or corrected gestational age.

Multiscale Visual-Attribute Co-Attention for Zero-Shot Image Recognition.

Zero-shot image recognition aims to classify data from unseen classes, by exploring the association between visual features and the semantic representations of each class. Most existing approaches focus on learning a shared single-scale embedding space (often at the output layer of the network) for both visual and semantic features, ignoring a fact that different-scale visual features exhibit different semantics. In this article, we propose a multi-scale visual-attribute co-attention (mVACA) model, considering both visual-semantic alignment and visual discrimination at multiple scales. At each scale, a hybrid visual attention is realized by attribute-related attention and visual self-attention. The attribute-related attention is guided by a pseudo attribute vector inferred via a mutual information regularization (MIR). The visual self-attentive features further influence the attribute attention to emphasize visual-associated attributes. Leveraging multiscale visual discrimination, mVACA unifies standard zero-shot learning (ZSL) and generalized ZSL tasks in one framework, achieving state-of-the-art or competitive performance on several commonly used benchmarks of both setups. To better understand the interaction between images and attributes in mVACA, we also provide visualized analysis.

Comparative study on the treatment of rhegmatogenous retinal detachment between foldable capsular body and scleral buckling / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To compare the effectiveness and complications of treating rhegmatogenous retinal detachment(RRD)with foldable capsule body(FCB)and scleral buckling(SB).METHODS: The clinical data of 81 patients(82 eyes)with RRD who underwent surgery at our hospital from March 2019 to April 2022 were retrospectively analyzed. The differences in retinal reattachment rate, best-corrected visual acuity, the absorption of subretinal fluid, postoperative discomfort and incidence of complications between the two treatments were compared.RESULTS: The retinal reattachment rate was 96% in the FCB group and 92% in the SB group, with no significant difference between the two groups(P&#x003E;0.05). The best corrected visual acuity of the affected macular eyes was different in the both groups(P&#x003C;0.01). Both groups effectively promoted the absorption of subretinal fluid. The operation time of FCB group was 16.50(12.75, 25.00)min, while it was 38.00(36.25, 41.75)min in the SB group(P&#x003C;0.001). Patients in the FCB group also had significantly lower eyelid swelling and pain symptoms than those in the SB group(P&#x003C;0.001). The visual analogue scale(VAS)score at 1d after operation was 1.00(0.00, 2.00)in the FCB group and 3.00(2.00, 3.00)in the SB group(P&#x003C;0.001).CONCLUSION: FCB is a safe and effective surgical method to treat RRD that can alleviate patient's pain. Furthermore, FCB has a significantly shorter operation time and milder postoperative adverse reactions than SB.

A soft microrobot with highly deformable 3D actuators for climbing and transitioning complex surfaces.

The climbing microrobots have attracted growing attention due to their promising applications in exploration and monitoring of complex, unstructured environments. Soft climbing microrobots based on muscle-like actuators could offer excellent flexibility, adaptability, and mechanical robustness. Despite the remarkable progress in this area, the development of soft microrobots capable of climbing on flat/curved surfaces and transitioning between two different surfaces remains elusive, especially in open spaces. In this study, we address these challenges by developing voltage-driven soft small-scale actuators with customized 3D configurations and active stiffness adjusting. Combination of programmed strain distributions in liquid crystal elastomers (LCEs) and buckling-driven 3D assembly, guided by mechanics modeling, allows for voltage-driven, complex 3D-to-3D shape morphing (bending angle > 200°) at millimeter scales (from 1 to 10 mm), which is unachievable previously. These soft actuators enable development of morphable electroadhesive footpads that can conform to different curved surfaces and stiffness-variable smart joints that allow different locomotion gaits in a single microrobot. By integrating such morphable footpads and smart joints with a deformable body, we report a multigait, soft microrobot (length from 6 to 90 mm, and mass from 0.2 to 3 g) capable of climbing on surfaces with diverse shapes (e.g., flat plane, cylinder, wavy surface, wedge-shaped groove, and sphere) and transitioning between two distinct surfaces. We demonstrate that the microrobot could navigate from one surface to another, recording two corresponding ceilings when carrying an integrated microcamera. The developed soft microrobot can also flip over a barrier, survive extreme compression, and climb bamboo and leaf.

Clinical application of regional citrate anticoagulation for continuous renal replacement therapy in children with liver injury.

Background: Regional citrate anticoagulation (RCA) is increasingly used for continuous renal replacement therapy (CRRT) in children, but it is rarely used in children with liver injury, especially liver failure (LF). We analyze this issue through the following research. Methods: We retrospectively analyzed 75 children with liver injury who underwent RCA-CRRT in the Pediatric Intensive Care Unit (PICU) of Children's Hospital of Chongqing Medical University. The patients were divided into the LF group and liver dysfunction (LD) group. The two groups were compared to evaluate the clinical safety and efficacy of RCA-CRRT in children with liver injury and to explore RCA-CRRT management strategies, in terms of the following indicators: the incidence of bleeding, clotting, citrate accumulation (CA), acid-base imbalance, and electrolyte disturbance, as well as filter lifespans, changes in biochemical indicators, and CRRT parameters adjustment. Results: The total incidence of CA (TCA) and persistent CA (PCA) in the LF group were significantly higher than those in the LD group (38.6 vs. 16.2%, p < 0.001; 8.4 vs. 1.5%, p < 0.001); and the CA incidence was significantly reduced after adjustment both in the LF (38.6 vs. 8.4%, p < 0.001) and LD groups (16.2 vs. 1.5%, p < 0.001). The incidence of hypocalcemia was significantly higher in the LF group than in the LD group either before (34.9 vs. 8.8%, p < 0.001) or after treatment (12.0 vs. 0%, p < 0.001). The speed of the blood and citrate pumps after adjustment was lower than the initial setting values in both the LF and LD groups. The dialysis speed plus replacement speed were higher than the initial settings parameters. Conclusion: For children undergoing RCA-CRRT, the risks of CA and hypocalcemia are significantly higher in children with liver failure than those with liver dysfunction, but through the proper adjustment of the protocol, RCA-CRRT can still be safely and effectively approached for children with LD and even LF.

Assembly of complex 3D structures and electronics on curved surfaces.

Electronic devices with engineered three-dimensional (3D) architectures are indispensable for frictional-force sensing, wide-field optical imaging, and flow velocity measurement. Recent advances in mechanically guided assembly established deterministic routes to 3D structures in high-performance materials, through controlled rolling/folding/buckling deformations. The resulting 3D structures are, however, mostly formed on planar substrates and cannot be transferred directly onto another curved substrate. Here, we introduce an ordered assembly strategy to allow transformation of 2D thin films into sophisticated 3D structures on diverse curved surfaces. The strategy leverages predefined mechanical loadings that deform curved elastomer substrates into flat/cylindrical configurations, followed by an additional uniaxial/biaxial prestretch to drive buckling-guided assembly. Release of predefined loadings results in an ordered assembly that can be accurately captured by mechanics modeling, as illustrated by dozens of complex 3D structures assembled on curved substrates. Demonstrated applications include tunable dipole antennas, flow sensors inside a tube, and integrated electronic systems capable of conformal integration with the heart.

Durable response in a patient with recurrent respiratory papillomatosis treated with immune checkpoint blockade.

BACKGROUND: Immune checkpoint blockade can provide clinical benefit for patients with advanced cancer. Here, we report durable disease control over many years following PD-L1 blockade through induction of a viral antigen-specific T cell response in an adult patient with recurrent respiratory papillomatosis. METHODS: Antigen-specific T cell response assays, single cell RNA-sequencing, and RNA-scope was used to study clinical tissues. RESULTS: An HPV6 E2-specific T cell clone restricted to HLA-B*55, present at low frequency in the pre-treatment papilloma, significantly expanded after six doses of PD-L1 blockade and remained present and functional at the site of initial response in the larynx as a tissue resident memory T cell for 4 years. An associated reduction in E2 target gene was observed following treatment. CONCLUSIONS: Although demonstrated in a single exceptional responder, these results highlight that immune checkpoint blockade may induce durable, viral antigen-specific immunity of sufficient magnitude to control disease in patients with nonmalignant disorders.

Clinical Application Value of Pharmacokinetic Parameters of Vancomycin in Children Treated in the Pediatric Intensive Care Unit.

Objective: To explore the efficacy and safety of vancomycin as measured by pharmacokinetic/pharmacodynamic parameters in children with severe infection in the Pediatric Intensive Care Unit (PICU) and to determine the appropriate threshold for avoiding nephrotoxicity. Methods: The medical records of hospitalized children with severe infection treated with vancomycin in the PICU of a tertiary pediatric hospital from September 2018 to January 2021 were retrospectively collected. Univariate analysis was used to assess the correlation between vancomycin pharmacokinetic/pharmacodynamic parameters and therapeutic efficacy or vancomycin-related nephrotoxicity. Binary logistic regression was used to analyze the risk factors for vancomycin-related nephrotoxicity. The vancomycin area under the concentration-time curve over 24 h (AUC0-24) threshold was determined by receiver operating characteristic (ROC) curve analysis. Results: One hundred and 10 patients were included in this study. Seventy-six patients (69.1%) exhibited clinically effective response, while the rest exhibited clinically ineffective response. There were no significant differences in APACHE II score, steady-state trough concentration, peak concentration or AUC0-24 of vancomycin between the effective and ineffective groups. Among the 110 patients, vancomycin-related nephrotoxicity occurred in 15 patients (13.6%). Multivariate analysis showed that vancomycin treatment duration, trough concentration, and AUC0-24 were risk factors for vancomycin-related nephrotoxicity. The ROC curve indicated that AUC0-24 < 537.18 mg.h/L was a suitable cutoff point for predicting vancomycin-related nephrotoxicity. Conclusion: No significant correlations were found between the trough concentration or AUC0-24 of vancomycin and therapeutic efficacy when the daily dose of vancomycin was approximately 40 mg/kg d, while the trough concentration and AUC0-24 were both closely related to vancomycin-related nephrotoxicity. The combination of AUC0-24 and trough concentration for therapeutic drug monitoring may reduce the risk of nephrotoxicity.

Highly-integrated, miniaturized, stretchable electronic systems based on stacked multilayer network materials.

Elastic stretchability and function density represent two key figures of merits for stretchable inorganic electronics. Various design strategies have been reported to provide both high levels of stretchability and function density, but the function densities are mostly below 80%. While the stacked device layout can overcome this limitation, the soft elastomers used in previous studies could highly restrict the deformation of stretchable interconnects. Here, we introduce stacked multilayer network materials as a general platform to incorporate individual components and stretchable interconnects, without posing any essential constraint to their deformations. Quantitative analyses show a substantial enhancement (e.g., by ~7.5 times) of elastic stretchability of serpentine interconnects as compared to that based on stacked soft elastomers. The proposed strategy allows demonstration of a miniaturized electronic system (11 mm by 10 mm), with a moderate elastic stretchability (~20%) and an unprecedented areal coverage (~110%), which can serve as compass display, somatosensory mouse, and physiological-signal monitor.

Determining if T cell antigens are naturally processed and presented on HLA class I molecules.

BACKGROUND: Determining T cell responses to naturally processed and presented antigens is a critical immune correlate to determine efficacy of an investigational immunotherapeutic in clinical trials. In most cases, minimal epitopes and HLA restriction elements are unknown. RESULTS: Here, we detail the experimental use of ex vivo expanded autologous B cells as antigen presenting cells to overcome the limitation of unknown HLA restriction, and the use of electroporated full length mRNA encoding full length parental proteins to ensure that any observed T cell responses are specific for antigens that are naturally processed and presented. CONCLUSIONS: This technique can serve as useful experimental approach to determine the induction or enhancement of specific responses to naturally processed and presented antigens on HLA class I molecules in peripheral blood or tumor infiltrating T cells.

Comprehensive multiomic characterization of human papillomavirus-driven recurrent respiratory papillomatosis reveals distinct molecular subtypes.

Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Patients with severe RRP can require hundreds of lifetime surgeries to control their disease and pulmonary papillomatosis can be fatal. Here we report the comprehensive genomic and transcriptomic characterization of respiratory papillomas. We discovered and characterized distinct subtypes with transcriptional resemblance to either a basal or differentiated cell state that associate with disease aggressiveness and differ in key molecular, immune and APOBEC mutagenesis profiles. Through integrated comparison with high-risk HPV-associated head and neck squamous cell carcinoma, our analysis revealed divergent molecular and immune papilloma subtypes that form independent of underlying genomic alterations. Cumulatively our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies.