A novel machine learning-based imputation strategy for missing data in step-stress accelerated degradation test.

The presence of missing data is a significant data quality issue that negatively impacts the accuracy and reliability of data analysis. This issue is especially relevant in the context of accelerated tests, particularly for step-stress accelerated degradation tests. While missing data can occur due to objective factors or human error, high missing rate is an inevitable pattern of missing data that will occur during the conversion process of accelerated test data. This type of missing data manifests as a degradation dataset with unequal measuring intervals. Therefore, developing a more appropriate imputation method for accelerated test data is essential. In this study, we propose a novel hybrid imputation method that combines the LSSVM and RBF models to address missing data problems. A comparison is conducted between the proposed model and various traditional and machine learning imputation methods using simulation data, to justify the advantages of the proposed model over the existing methods. Finally, the proposed model is implemented on real degradation datasets of the super-luminescent diode (SLD) to validate its performance and effectiveness in dealing with missing data in step-stress accelerated degradation test. Additionally, due to the generalizability of the proposed method, it is expected to be applicable in other scenarios with high missing data rates.

Efficient removal of U(VI) from aqueous solution using poly(amidoxime-hydroxamic acid) functionalized graphene oxide.

The efficient development of selective materials for uranium recovery from wastewater and seawater is crucial for the utilization of uranium resources and environmental protection. The potential of graphene oxide (GO) as an effective adsorbent for the removal of environmental contaminants has been extensively investigated. Further modification of the functional groups on the basal surface of GO can significantly enhance its adsorption performance. In this study, a novel poly(amidoxime-hydroxamic acid) functionalized graphene oxide (pAHA-GO) was synthesized via free radical polymerization followed by an oximation reaction, aiming to enhance its adsorption efficiency for U(VI). A variety of characterization techniques, including SEM, Raman spectroscopy, FT-IR, and XPS, were employed to demonstrate the successful decoration of amidoxime and hydroxamic acid functional groups onto GO. Meanwhile, the adsorption of U(VI) on pAHA-GO was studied as a function of contact time, adsorbent dosage, pH, ionic strength, initial U(VI) concentration, and interfering ions by batch-type experiments. The results indicated that the pAHA-GO exhibited excellent reuse capability, high stability, and anti-interference ability. Specially, the U(VI) adsorption reactions were consistent with pseudo-second-order and Langmuir isothermal adsorption models. The maximum U(VI) adsorption capacity was evaluated to be 178.7 mg/g at pH 3.6, displaying a higher U(VI) removal efficiency compared with other GO-based adsorbents in similar conditions. Regeneration of pAHA-GO did not significantly influence the adsorption towards U(VI) for up to four sequential cycles. In addition, pAHA-GO demonstrated good adsorption capacity stability when it was immersed in HNO3 solution at different concentrations (0.1-1.0 mol/L) for 72 h. pAHA-GO was also found to have anti-interference ability for U(VI) adsorption in seawater with high salt content at near-neutral pH condition. In simulated seawater, the adsorption efficiency was above 94% for U(VI) across various initial concentrations. The comprehensive characterization results demonstrated the involvement of oxygen- and nitrogen-containing functional groups in pAHA-GO in the adsorption process of U(VI). Overall, these findings demonstrate the feasibility of the pAHA-GO composite used for the capture of U(VI) from aqueous solutions.

Mediastinal Cryobiopsy for Pathological Diagnosis of Fibrosing Mediastinitis-Associated Pulmonary Hypertension.

INTRODUCTION: Fibrosing mediastinitis is a benign but fatal disorder characterized by the proliferation of fibrous tissue in the mediastinum, causing encasement of mediastinal organs and extrinsic compression of adjacent bronchovascular structures. FM-associated pulmonary hypertension (FM-PH) is a serious complication of FM, resulting from the external compression of lung vessels. Pathologic assessment is important for etiologic diagnosis and effective treatment of this disease. CASE PRESENTATION: A 59-year-old male patient presented at our hospital and was diagnosed with FM-PH. He declined surgical biopsy that is the reference standard for pathologic assessment, in consideration of the potential risks. Therefore, an endobronchial ultrasound examination was performed, which identified the subcarinal lesion. Under ultrasound guidance, four needle aspirations were carried out, followed by one cryobiopsy. Histopathological examination of transbronchial needle aspiration specimens was inconclusive, while samples from cryobiopsy suggested a diagnosis of idiopathic FM. Further immunophenotyping demonstrated the infiltration of lymphocytes, macrophages, and FOXP3-positive cells in FM-PH. CONCLUSION: Mediastinal cryobiopsy might be a novel and safe option for FM-PH patients who are unwilling or unsuitable for surgical procedure.

Higher affinities of fibers with cell receptors increase the infection capacity and virulence of human adenovirus type 7 and type 55 compared to type 3.

IMPORTANCE: HAdV-3, -7, and -55 are the predominant types causing acute respiratory disease outbreaks and can lead to severe and fatal pneumonia in children and adults. In recent years, emerging or re-emerging strains of HAdV-7 and HAdV-55 have caused multiple outbreaks globally in both civilian and military populations, drawing increased attention. Clinical studies have reported that HAdV-7 and HAdV-55 cause more severe pneumonia than HAdV-3. This study aimed to investigate the mechanisms explaining the higher severity of HAdV-7 and HAdV-55 infection compared to HAdV-3 infection. Our findings provided evidence linking the receptor-binding protein fiber to stronger infectivity of the strains mentioned above by comparing several fiber-chimeric or fiber-replaced adenoviruses. Our study improves our understanding of adenovirus infection and highlights potential implications, including in novel vector and vaccine development.

Molecular mechanisms of drought resistance using genome-wide association mapping in maize (Zea mays L.).

BACKGROUND: Drought is a critical abiotic stress that influences maize yield and reduces grain yield when it occurs at the flowering or filling stage. To dissect the genetic architecture of grain yield under drought stress (DS), a genome-wide association analysis was conducted in a maize population composed of diverse inbred lines from five locations under well-watered and DS conditions at flowering in 2019 and 2020. RESULTS: Using a fixed and random model circulating probability unification model, a total of 147 loci associated with grain yield or the drought resistance index (DRI) were identified, of which 54 loci were associated with a DRI with an average phenotypic variation explanation of 4.03%. Further, 10 of these loci explained more than 10% of the phenotypic variation. By integrating two public transcriptome datasets, 22 differentially expressed genes were considered as candidate genes, including the cloned gene ZmNAC49, which responds to drought by regulating stomatal density. Enrichment and protein interaction network showed that signaling pathways responded to drought resistance, including jasmonic acid and salicylic acid, mitogen-activated protein kinase, and abscisic acid-activated. Additionally, several transcription factors involved in DS were identified, including basic leucine zipper (GRMZM2G370026), NAC (GRMZM2G347043), and ethylene-responsive element binding protein (GRMZM2G169654). CONCLUSIONS: In this study, we nominated several genes as candidate genes for drought resistance by intergrating association maping and transcription analysis. These results provide valuable information for understanding the genetic basis of drought tolerance at the mature stage and for designing drought-tolerant maize breeding.

Brainmask: an ultrasoft and moist micro-electrocorticography electrode for accurate positioning and long-lasting recordings.

Bacterial cellulose (BC), a natural biomaterial synthesized by bacteria, has a unique structure of a cellulose nanofiber-weaved three-dimensional reticulated network. BC films can be ultrasoft with sufficient mechanical strength, strong water absorption and moisture retention and have been widely used in facial masks. These films have the potential to be applied to implantable neural interfaces due to their conformality and moisture, which are two critical issues for traditional polymer or silicone electrodes. In this work, we propose a micro-electrocorticography (micro-ECoG) electrode named "Brainmask", which comprises a BC film as the substrate and separated multichannel parylene-C microelectrodes bonded on the top surface. Brainmask can not only guarantee the precise position of microelectrode sites attached to any nonplanar epidural surface but also improve the long-lasting signal quality during acute implantation with an exposed cranial window for at least one hour, as well as the in vivo recording validated for one week. This novel ultrasoft and moist device stands as a next-generation neural interface regardless of complex surface or time of duration.

SARS-CoV-2 mRNA vaccine requires signal peptide to induce antibody responses.

New SARS-CoV-2 variants continue to prevail worldwide, and effective vaccines are needed to prevent an epidemic. mRNA vaccines are gradually being applied to the prevention and control of infectious diseases with significant safety and effectiveness. The spike (S) protein of SARS-CoV-2 is the main target of mRNA vaccine design, but the impact of the signal peptide (SP), transmembrane region (TM), and cytoplasmic tail (CT) on mRNA vaccine remains unclear. In this study, we constructed three forms of mRNA vaccines related to the S protein: full-length, deletion of the TM and CT, and simultaneous deletion of the SP, TM and CT, and compared their immunogenicity. Our experimental data show that full-length S protein and deletion of the TM and CT could effectively induce neutralizing antibody production in mice, while S protein without the SP and TM could not. This indicates that the S protein SP is necessary for the design of mRNA vaccine.

OsPML2, a chloroplast envelope localized transporter is involved in manganese homeostasis in rice.

Manganese (Mn), a vital element, plays crucial roles in various biochemical and physiological processes by serving as an essential cofactor for numerous enzymes and acting as a catalytically active metal within biological clusters. In this study, we investigate the role of PHOTOSYNTHESIS-AFFECTED MUTANT 71-LIKE 2 (OsPML2), a member of the UNCHARACTERIZED PROTEIN FAMILY 0016 (UPF0016) family, in regulating Mn homeostasis in rice. OsPML2 was highly expressed in young leaves, ovaries, and stigmas. Cross sections from young leaves revealed that OsPML2 was mainly expressed in the phloem region and mesophyll cells. Furthermore, heterologous expression of OsPML2 restored the growth of Mn uptake-defective yeast strain Δsmf1 under Mn-limited conditions. Subcellular localization analysis demonstrated that OsPML2 was specifically localized in the chloroplast envelope. Knockdown of OsPML2 resulted in reduced chloroplast Mn content, significantly affecting plant growth under Mn deficiency. Furthermore, analysis of isolated thylakoid membranes using blue native gels indicated a compromised accumulation of photosystem II (PSII) complexes in OsPML2 knockdown lines. Additionally, grain yield, grain length, and width were significantly reduced in OsPML2 knockdown plants. Collectively, our findings provide insights into the transport function of OsPML2, which facilitates Mn transport from the cytosol to chloroplast stroma and influences the accumulation of PSII complexes in rice.

Differential proteomics argues against a general role for CD9, CD81 or CD63 in the sorting of proteins into extracellular vesicles.

The tetraspanins CD9, CD81 and CD63 are major components of extracellular vesicles (EVs). Yet, their impact on EV composition remains under-investigated. In the MCF7 breast cancer cell line CD63 was as expected predominantly intracellular. In contrast CD9 and CD81 strongly colocalized at the plasma membrane, albeit with different ratios at different sites, which may explain a higher enrichment of CD81 in EVs. Absence of these tetraspanins had little impact on the EV protein composition as analysed by quantitative mass spectrometry. We also analysed the effect of concomitant knock-out of CD9 and CD81 because these two tetraspanins play similar roles in several cellular processes and associate directly with two Ig domain proteins, CD9P-1/EWI-F/PTGFRN and EWI-2/IGSF8. These were the sole proteins significantly decreased in the EVs of double CD9- and CD81-deficient cells. In the case of EWI-2, this is primarily a consequence of a decreased cell expression level. In conclusion, this study shows that CD9, CD81 and CD63, commonly used as EV protein markers, play a marginal role in determining the protein composition of EVs released by MCF7 cells and highlights a regulation of the expression level and/or trafficking of CD9P-1 and EWI-2 by CD9 and CD81.

Morphological Effects of Au Nanoparticles on Electrochemical Sensing Platforms for Nitrite Detection.

Au nanoparticles were synthesized in a soft template of pseudo-polyanions composed of polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) by the in situ reduction of chloroauric acid (HAuCl4) with PVP. The particle sizes and morphologies of the Au nanoparticles were regulated with concentrations of PVP or SDS at room temperature. Distinguished from the Au nanoparticles with various shapes, Au nanoflowers (AuNFs) with rich protrusion on the surface were obtained at the low final concentration of SDS and PVP. The typical AuNF synthesized in the PVP (50 g·L-1)-SDS (5 mmol·L-1)-HAuCl4 (0.25 mmol·L-1) solution exhibited a face-centered cubic structure dominated by a {111} crystal plane with an average equivalent particle size of 197 nm and an average protrusion height of 19 nm. Au nanoparticles with four different shapes, nanodendritic, nanoflower, 2D nanoflower, and nanoplate, were synthesized and used to modify the bare glassy carbon electrode (GCE) to obtain Au/GCEs, which were assigned as AuND/GCE, AuNF/GCE, 2D-AuNF/GCE, and AuNP/GCE, respectively. Electrochemical sensing platforms for nitrite detection were constructed by these Au/GCEs, which presented different detection sensitivity for nitrites. The results of cyclic voltammetry (CV) demonstrated that the AuNF/GCE exhibited the best detection sensitivity for nitrites, and the surface area of the AuNF/GCE was 1.838 times of the bare GCE, providing a linear c(NO2-) detection range of 0.01-5.00 µmol·L-1 with a limit of detection of 0.01 µmol·L-1. In addition, the AuNF/GCE exhibited good reproducibility, stability, and high anti-interference, providing potential for application in electrochemical sensing platforms.

Identification of conserved linear epitopes in the SARS-CoV-2 receptor-binding region using monoclonal antibodies.

The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused millions of cases of infections, leading to a global health emergency. The SARS-CoV-2 spike (S) protein plays the most important role in viral infection, and S1 subunit and its receptor-binding domain (RBD) are widely considered the most attractive vaccine targets. The RBD is highly immunogenic and its linear epitopes are important for vaccine development and therapy, but linear epitopes on the RBD have rarely been reported. In this study, 151 mouse monoclonal antibodies (mAbs) against the SARS-CoV-2 S1 protein were characterized and used to identify epitopes. Fifty-one mAbs reacted with eukaryotic SARS-CoV-2 RBD. Sixty-nine mAbs reacted with the S proteins of Omicron variants B.1.1.529 and BA.5, indicating their potential as rapid diagnostic materials. Three novel linear epitopes of RBD, R6 (391CFTNVYADSFVIRGD405), R12 (463PFERDISTEIYQAGS477), and R16 (510VVVLSFELLHAPAT523), were identified; these were highly conserved in SARS-CoV-2 variants of concern and could be detected in the convalescent serum of COVID-19 patients. From pseudovirus neutralization assays, some mAbs including one detecting R12 were found to possess neutralizing activity. Together, from the reaction of mAbs with eukaryotic RBD (N501Y), RBD (E484K), and S1 (D614G), we found that a single amino acid mutation in the SARS-CoV-2 S protein may cause a structural alteration, exerting substantial impact on mAb recognition. Our results could, therefore, help us better understand the function of the SARS-CoV-2 S protein and develop diagnostic tools for COVID-19.

Efficacy and safety of vaginal electrical stimulation as an alternative or adjunct treatment for overactive bladder syndrome in women: a meta-analysis of randomized controlled trials.

INTRODUCTION AND HYPOTHESIS: The objective was to evaluate the efficacy and safety of vaginal electrical stimulation (VES) as an alternative or adjunct treatment for overactive bladder (OAB) syndrome in women. METHODS: Five English-language databases and four Chinese-language databases were searched to identify relevant studies. Studies comparing VES (VES alone or VES plus other interventions) with other interventions (medicines, bladder training, or PFMT) were included. Voiding diary, quality of life (QoL), and adverse events were extracted from the included studies for comparison. RESULTS: Seven trials with 601 patients in total were reviewed. The results showed that when compared with other interventions, VES alone significantly improved urgency episodes (p = 0.0008) and voiding frequency (p = 0.01), but did not significantly reduce nocturia (p = 0.85), urinary incontinence episodes (p = 0.90) and number of pads (p = 0.87). When VES plus other interventions was compared with other interventions, the former significantly improved voiding frequency (p < 0.00001), nocturia (p < 0.00001), and number of pads (p = 0.03), but it did not significantly reduce urinary incontinence episodes (p = 0.24). Both VES alone (p < 0.00001) and VES plus other interventions (p = 0.003) showed significant benefit on QoL. CONCLUSIONS: This study demonstrated that VES alone decreased urgency episodes and QoL better than other therapies. Although VES alone reduced voiding frequency better and VES plus other therapies decreased nocturia, number of pads, urgency episodes, and QoL better than other therapies, the results should be interpreted with caution for clinical practice because some of the RCTs included were of low quality and because of the small number of studies included.

SMARCA4-Deficient Undifferentiated Tumor Achieved by Transbronchial Mediastinal Cryobiopsy Additional to Needle Aspiration.

Lung cancer is the leading cause of deaths from malignant neoplasms worldwide, and a satisfactory biopsy that allows for histological and other analyses is critical for its diagnosis. Guidelines have recommended endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as the reference standard for the staging of lung cancer. However, the relatively limited sample volume retrieved by needle aspiration might restrict the diagnostic capacity of EBUS-TBNA in other uncommon thoracic tumors. Transbronchial mediastinal cryobiopsy is a recently developed sampling strategy for mediastinal lesions, which demonstrates added diagnostic value to conventional needle aspiration. Here, we present a case of thoracic SMARCA4-deficient undifferentiated tumor successfully diagnosed by mediastinal cryobiopsy additional to EBUS-TBNA.

Online/Offline MA-CP-ABE with Cryptographic Reverse Firewalls for IoT.

Devices in the Internet of Things (IoT) usually use cloud storage and cloud computing to save storage and computing cost. Therefore, the efficient realization of one-to-many communication of data on the premise of ensuring the security of cloud storage data is a challenge. Ciphertext-Policy Attribute-Based Encryption (CP-ABE) can not only protect the security of data in the cloud and achieve one-to-many communication but also achieve fine-grained access control for data. However, the single-authority CP-ABE faces the crisis of single point of failure. In order to improve security, the Multi-Authority CP-ABE (MA-CP-ABE) is adopted. Although there are provably-secure MA-CP-ABE schemes, Edward Snowden's research shows that provably-secure cryptographic schemes are vulnerable to backdoor attacks, resulting in secret disclosure, and thus threatening security. In addition, ABE requires huge computational overhead in key generation, encryption and decryption, which increase with the increase in the number of attributes and the complexity of the access structure, and there are a large number of resource-constrained devices in the IoT. To mitigate this issue, we construct the Online/Offline MA-CP-ABE with Cryptographic Reverse Firewalls (OO-MA-CP-ABE-CRFs) scheme. This scheme not only uses Cryptographic Reverse Firewall (CRF) to resist backdoor attacks but also uses online/offline key generation, online/offline encryption and outsourcing encryption technology to optimize the efficiency of the MA-CP-ABE scheme with reverse firewall, reducing the storage and computing cost of users. Finally, the security of the OO-MA-CP-ABE-CRFs scheme is proved, and the experimental results indicate that the scheme is efficient and practical.

3D-Printed Thermoplastic Polyurethane Electrodes for Customizable, Flexible Lithium-Ion Batteries with an Ultra-Long Lifetime.

3D printing technology has demonstrated great potential in fabricating flexible and customizable high-performance batteries, which are highly desired in the forthcoming intelligent and ubiquitous energy era. However, a significant performance gap, especially in cycling stability, still exists between the 3D-printed and conventional electrodes, seriously limiting the practical applications of 3D-printed batteries. Here, for the first time, a series of thermoplastic polyurethane (TPU)-based 3D-printed electrodes is developed via fused deposition modeling for flexible and customizable high-performance lithium-ion batteries. The TPU-based electrode filaments in kilogram order are prepared via a facile extrusion method. As a result, the electrodes are well-printed with high dimensional accuracy, flexibility, and mechanical stability. Notably, 3D-printed TPU-LFP electrodes exhibit a capacity retention of 100% after 300 cycles at 1C, which is among the best cycling performance of all the reported 3D-printed electrodes. Such excellent performance is associated with the superb stress cushioning properties of the TPU-based electrodes that can accommodate the volume change during the cycling and thus significantly prevent the collapse of 3D-printed electrode structures. The findings not only provide a new avenue to achieve customizable and flexible batteries but also guide a promising way to erase the performance gap between 3D-printed and conventional lithium-ion batteries.

Comparative Efficacy of Neuromodulation Technologies for Overactive Bladder in Adults: A Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The aim of this study was to investigate the comparative efficacy of neuromodulation technologies for overactive bladder (OAB) syndrome in adults. DATA SOURCES: A computerized search was conducted of Cochrane Library, EMBASE, MEDLINE (via PubMed), Web of Science, CNKI, Wan Fang Data, and ClinicalTrials.gov up to April 21, 2022. STUDY SELECTION: The search selected clinical trials with random allocation to percutaneous tibial nerve stimulation (PTNS), transcutaneous tibial nerve stimulation (TTNS), vaginal electrical stimulation (VES), sacral neuromodulation (SNM), parasacral stimulation (PS), pudendal neuromodulation, or placebo. DATA EXTRACTION: The main outcomes were the voiding diary, OAB-related quality of life, and positive response rate. The Cochrane Risk of Bias tool (RoB 2.0) was used to assess the risk of bias of each included study, and the Grading of Recommendations Assessment, Development, and Evaluation tool was used to evaluate the overall evidence quality of key outcomes. DATA SYNTHESIS: The study included 21 randomized controlled trials involving 1433 participants, and all trials were used for the meta-analysis. In the network meta-analyses, five of six neuromodulation technologies, including PTNS, TTNS, VES, SNM, and PS, were related to higher efficacy than the placebo. Ranking probability showed that SNM was the most efficacious therapy for improving OAB-related quality of life, urinary episodes, and urinary frequency. For urgency incontinence episodes and the number of pads, PTNS and TTNS were the most efficacious modalities, respectively. CONCLUSION: Neuromodulation technologies, including PTNS, TTNS, VES, SNM, and PS, may be effective and safe solutions for OAB syndrome in adults. Moreover, SNM is the most efficacious regimen for OAB-related quality of life, urinary episodes, and urinary frequency. PTNS and TTNS are the most efficacious modalities for reducing urgency incontinence episodes and the number of pads, respectively. Future studies should pay more attention to the quality of study design and report, patients who may benefit the most from neuromodulation, and the long-term effect, cost-effectiveness, and satisfaction of neuromodulation.

Will the economic growth benefit public health? Health vulnerability, urbanization and COVID-19 in the USA.

Economic growth has a significant impact on health vulnerability primarily through the process of urbanization. This paper conducts a pioneer study by analyzing the impact of regional economic growth and urbanization on the public health vulnerability in the 51 states and territories of the USA from 2011 to 2018 with a fixed-effect panel data regression model. We construct an epidemiological vulnerability index (EVI) using regional smoking, diabetes, obesity, and hypertension, collect CDC social vulnerability index (SVI) as state-level public health vulnerability status, and use COVID-19 to test the actual effect of health vulnerability. The preliminary results show that higher regional economic growth is related to lower EVI and SVI, while urbanization is positively associated with regional health vulnerability and the severity of COVID-19 from case rate and death rate. Robustness check with unemployment shows the same result. We conclude that economic growth is related to lower public health vulnerability, and urbanization has negative public health benefits. Our finding indicates an urgent need to balance the externalities generated by economic development and urbanization trends on public health vulnerability by promoting reasonable medical resource distribution, health practices and safety, improving social and environmental justice, and other health management measures. Supplementary Information: The online version contains supplementary material available at 10.1007/s00168-021-01103-9.

Skeletal muscle abnormalities in heart failure with preserved ejection fraction.

Almost half of all heart failure (HF) disease burden is due to HF with preserved ejection fraction (HFpEF). The primary symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance and is associated with their reduced quality of life. Recently, studies showed that HFpEF patients have multiple skeletal muscle (SM) abnormalities, and these are associated with decreased exercise intolerance. The SM abnormalities are likely intrinsic to the HFpEF syndrome, not a secondary consequence of an epiphenomenon. These abnormalities are decreased muscle mass, reduced type I (oxidative) muscle fibers, and reduced type I-to-type II fiber ratio as well as a reduced capillary-to-fiber ratio, abnormal fat infiltration into the thigh SM, increased levels of atrophy genes and proteins, reduction in mitochondrial content, and rapid depletion of high-energy phosphate during exercise with markedly delayed repletion of high-energy phosphate during recovery in mitochondria. In addition, patients with HFpEF have impaired nitric oxide bioavailability, particularly in the microvasculature. These SM abnormalities may be responsible for impaired diffusive oxygen transport and/or impaired SM oxygen extraction. To date, exercise training (ET) and caloric restriction are some of the interventions shown to improve outcomes in HFpEF patients. Improvements in exercise tolerance following aerobic ET are largely mediated through peripheral SM adaptations with minimal change in central hemodynamics and highlight the importance of targeting SM to improve exercise intolerance in HFpEF. Focusing on the abnormalities mentioned above may improve the clinical condition of patients with HFpEF.

Transbronchial needle aspiration combined with cryobiopsy in the diagnosis of mediastinal diseases: a multicentre, open-label, randomised trial.

BACKGROUND: Transbronchial mediastinal cryobiopsy is a novel sampling technique for mediastinal disease. Despite the possibility of lung cancer misdiagnosis, the improved diagnostic yield of this approach for non-lung-cancer lesions compared with standard endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) highlights its diagnostic potential as a complementary technique to conventional biopsy. We aimed to evaluate the safety profile and added value of the combined use of transbronchial mediastinal cryobiopsy and standard EBUS-TBNA for the diagnosis of mediastinal diseases. METHODS: We conducted an open-label, randomised trial at three hospital sites in Europe and Asia. Eligible patients were aged 15 years or older, with at least one mediastinal lesion of 1 cm or longer in the short axis that required diagnostic bronchoscopy. Participants were randomly assigned (1:1) using a block randomisation scheme generated by a computer (block size of four participants based on a random table from an independent statistician) to the combined use of EBUS-TBNA and transbronchial mediastinal cryobiopsy (combined group) or EBUS-TBNA alone (control group). Because of the nature of the intervention, neither participants nor investigators were masked to group assignment. The coprimary outcomes were differences in procedure-related complications and diagnostic yield (defined as the proportion of participants for whom mediastinal biopsy led to a definitive diagnosis), assessed in the full analysis set, including all the patients who met the eligibility criteria and had a biopsy. A fully paired, intraindividual diagnostic analysis in participants who had both needle aspiration and mediastinal cryobiopsy was conducted, in addition to interindividual comparisons. This trial is now complete and is registered with ClinicalTrials.gov, NCT04572984. FINDINGS: Between Oct 12, 2020, and Sept 9, 2021, 297 consecutive patients were assessed for eligibility and 271 were enrolled and randomly assigned to the combined group (n=136) or the control group (n=135). The addition of cryobiopsy to standard sampling significantly increased the overall diagnostic yield for mediastinal lesions, as shown by both interindividual (126 [93%] of 136 participants in the combined group vs 109 [81%] of 135 in the control group; risk ratio [RR] 1·15 [95% CI 1·04-1·26]; p=0·0039) and intraindividual (126 [94%] of 134 vs 110 [82%] of 134; RR 1·15 [95% CI 1·05-1·25]; p=0·0026) analyses. In subgroup analyses in the intraindividual population, diagnostic yields were similar for mediastinal metastasis (68 [99%] of 69 participants in the combined group vs 68 [99%] of 69 in the control group; RR 1·00 [95% CI 0·96-1·04]; p=1·00), whereas the combined approach was more sensitive than standard needle aspiration in benign disorders (45 [94%] of 48 vs 32 [67%] of 48; RR 1·41 [95% CI 1·14-1·74]; p=0·0009). The combined approach also resulted in an improved suitability of tissue samples for molecular and immunological analyses of non-small-cell lung cancer. The incidence of adverse events related to the biopsy procedure did not differ between trial groups, as grade 3-4 airway bleeding occurred in three (2%) patients in the combined group and two (1%) in the control group (RR 0·67 [95% CI 0·11-3·96]; p=1·00). There were no severe complications causing death or disability. INTERPRETATION: The addition of mediastinal cryobiopsy to standard EBUS-TBNA resulted in a significant improvement in diagnostic yield for mediastinal lesions, with a good safety profile. These data suggest that this combined approach is a valid first-line diagnostic tool for mediastinal diseases. FUNDING: National Natural Science Foundation of China.

Characterization and application of a series of monoclonal antibodies against SARS-CoV-2 nucleocapsid protein.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has a significant global social and economic impact, and the emergence of new and more destructive mutant strains highlights the need for accurate virus detection. Here, 90 monoclonal antibodies (MAbs) that exclusively reacted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (NP) were generated. These MAbs did not cross-react with NPs of common human coronaviruses (HCoVs, i.e., 229E, OC43, HKU1, and NL63) and Middle East Respiratory Syndrome Coronavirus. Subsequently, overlapped peptides in individual fragments (N1-N4) of NP were synthesized. N1-3 (25-GSNQNGERSGARSKQ-39), N3-1 (217-AALALLLLDRLNQL-230), and N4-8 (393-TLLPAADLDDFSKQL-407) were identified as major epitopes using enzyme-linked immunoassay (ELISA) and recognized by 47, 1, and 18 MAbs, respectively. The 24 remaining MAbs exhibited no reactivity with all synthetic peptides. Among MAb-epitope pairs, only MAbs targeting epitope N1-3 displayed no cross-reaction with NPs of SARS-CoV-1 and other SARS-related CoVs. All Omicron variants contained a three-amino acid deletion (31ERS33) in the N1-3 region. Thus, MAbs targeting N1-3 failed to recognize these variants. Furthermore, a double-antibody sandwich ELISA for antigen detection was established using the optimal MAbs. Overall, a series of MAbs targeting SARS-CoV-2 NP was prepared, characterized with epitope mapping, and applied for the detection of SARS-CoV-2 antigens, and some novel B-cell epitopes of the viral NP were identified.