Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results.

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 .

COVID-19 school closures and Chinese children's school readiness: Results from the natural experimental data.

AIMS: To determine the associations between COVID-19 school closures and school readiness skills for Chinese kindergarteners. DESIGN: We utilized the natural experimental condition created by local COVID-19 outbreaks in 2022 (Study 1) to compare school readiness skills of children whose kindergartens were closed for 5 months (Group 1) with children whose kindergartens stayed open (Group 2). We further compared the school readiness skills of one pre-COVID-19 cohort (Cohort 2019) with one COVID-19 cohort (Cohort 2021) from a fifth kindergarten (Study 2). SAMPLES: For Study 1, Group 1 included 445 children and Group 2 included 584 children aged 4-6 years. For Study 2, Cohort 2019 included 156 children and Cohort 2021 included 228 children aged 3-6 years. MEASURES: For both studies, survey data on four school readiness skills were collected from parents. Additionally, Study 1 collected parental locus of control data from parents. RESULTS: Controlling for covariates, Study 1 revealed that Group 1 and Group 2 did not differ in terms of language and emergent literacy or approaches to learning. However, Group 1 scored lower than Group 2 on health and well-being and arts and imagination. Study 2 revealed that Cohort 2021 scored higher than Cohort 2019 on language and emergent literacy but lower on the other three skills. CONCLUSIONS: The associations of COVID-19 school closures with Chinese children's school readiness skills were not uniform, with a positive relation with language and emergent literacy and negative associations with health and well-being, approaches to learning, as well as arts and imagination.

New-Style Logic Operation and Neuromorphic Computing Enabled by Optoelectronic Artificial Synapses in an MXene/Y:HfO2 Ferroelectric Memristor.

Today's computing systems, to meet the enormous demands of information processing, have driven the development of brain-inspired neuromorphic systems. However, there are relatively few optoelectronic devices in most brain-inspired neuromorphic systems that can simultaneously regulate the conductivity through both optical and electrical signals. In this work, the Au/MXene/Y:HfO2/FTO ferroelectric memristor as an optoelectronic artificial synaptic device exhibited both digital and analog resistance switching (RS) behaviors under different voltages with a good switching ratio (>103). Under optoelectronic conditions, optimal weight update parameters and an enhanced algorithm achieved 97.1% recognition accuracy in convolutional neural networks. A new logic gate circuit specifically designed for optoelectronic inputs was established. Furthermore, the device integrates the impact of relative humidity to develop an innovative three-person voting mechanism with a veto power. These results provide a feasible approach for integrating optoelectronic artificial synapses with logic-based computing devices.

Swelling of Thin Graphene Oxide Film in Water Vapor Studied by In Situ Spectroscopic Ellipsometry.

Graphene oxide (GO) is obtained by the chemical treatment of graphene sheets, resulting in decoration with oxygen-containing functional groups. In the work presented here, we examined marked changes that occur in a thin film of parallel aligned GO sheets when exposed to water vapor at various pressures. It was found that exceptionally fast and substantial water uptake and release occur that is accompanied by major changes in GO interlayer spacing. These characteristics were obtained in situ with spectroscopic ellipsometry. At 99% relative humidity (RH) and 25 °C, the interlayer spacing became 1.41 nm, which recovers to ∼0.8 nm within 30 s when exposed to 10% RH. Besides layer thickness values, uniaxial optical constants for the GO vs RH were derived from the ellipsometry data. Molar refraction theory was applied that indicated monolayer water formation at ∼91% RH at 25 °C upon water adsorption. Our findings contribute to the understanding of the interaction between GO and its environment. The very outspoken effect of external water vapor pressure on GO water content, interlayer spacing, and optical properties can be utilized in sensing and separation devices, subnanometer positioning, chemical switches, and environmentally aware materials.

Knockout of integrin αvß6 protects against renal inflammation in chronic kidney disease by reduction of pro-inflammatory macrophages.

Integrin αvß6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvß6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvß6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvß6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvß6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvß6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvß6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvß6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvß6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvß6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvß6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvß6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvß6 in renal inflammation, providing a solid rationale for the use of αvß6 inhibition to treat kidney inflammation and fibrosis.

Enhancing the Stability, Solubility, and Antioxidant Activity of Cinchonine through Pharmaceutical Cocrystallization.

PURPOSE: Cinchoninze hydrochloride solves the problem of the low solubility of cinchonine, but it is unstable and susceptible to deliquescence. In this study, we designed and prepared cinchonine cocrystal salts or cinchonine salts with better stability, solubility and antioxidant activity than cinchonine. METHOD: We successfully synthesized and characterized three cinchonine salts, namely, cinchonine-fumaric acid, cinchonine-isoferulic acid, and cinchonine-malic acid. The high humidity (92.5% RH) and high temperature (60°C) tests were conducted to determine the physical stability and hygroscopicity of cinchonine hydrochloride, cinchonine and three cinchonine salts. And the ultraviolet spectrophotometry was conducted to determine the equilibrium solubility and intrinsic dissolution rate of cinchonine and salts. Moreover, the DPPH, ABTS, and FRAP assays determined the antioxidant activity of cinchonine and salts. RESULT: Compared with cinchonine hydrochloride and cinchonine, all three cinchonine salts exhibited good physical stability over 15 days under high humidity (92.5% RH) and high temperature (60°C) conditions. While cinchonine and cinchonine hydrochloride are categorized as hygroscopic and deliquescent, respectively, three cinchonine salts are classified as slightly hygroscopic, meaning that they have a lower hygroscopicity than cinchonine and cinchonine hydrochloride. And three cinchonine salts had higher equilibrium solubility, faster intrinsic dissolution rates, and higher antioxidant activity in comparison to cinchonine. Moreover, they showed a "spring and parachute" pattern in the phosphate buffer (pH = 6.8). CONCLUSION: Cocrystallization technology is a viable option for improving cinchonine's poor physicochemical qualities.

Can a nomogram predict apical prostate cancer pathology upgrade from fusion biopsy to final pathology? A multicenter study.

BACKGROUND: This study evaluates the efficacy of a nomogram for predicting the pathology upgrade of apical prostate cancer (PCa). METHODS: A total of 754 eligible patients were diagnosed with apical PCa through combined systematic and magnetic resonance imaging (MRI)-targeted prostate biopsy followed by radical prostatectomy (RP) were retrospectively identified from two hospitals (training: 754, internal validation: 182, internal-external validation: 148). A nomogram for the identification of apical tumors in high-risk pathology upgrades through comparing the results of biopsy and RP was established incorporating statistically significant risk factors based on univariable and multivariable logistic regression. The nomogram's performance was assessed via the receiver operating characteristic (ROC) curve, calibration plots, and decision curve analysis (DCA). RESULTS: Univariable and multivariable analysis identified age, targeted biopsy, number of targeted cores, TNM stage, and the prostate imaging-reporting and data system score as significant predictors of apical tumor pathological progression. Our nomogram, based on these variables, demonstrated ROC curves for pathology upgrade with values of 0.883 (95% CI, 0.847-0.929), 0.865 (95% CI, 0.790-0.945), and 0.840 (95% CI, 0.742-0.904) for the training, internal validation and internal-external validation cohorts respectively. Calibration curves showed good consistency between the predicted and actual outcomes. The validation groups also showed great generalizability with the calibration curves. DCA results also demonstrated excellent performance for our nomogram with positive benefit across a threshold probability range of 0-0.9 for the training and internal validation group, and 0-0.6 for the internal-external validation group. CONCLUSION: The nomogram, integrating clinical, radiological, and pathological data, effectively predicts the risk of pathology upgrade in apical PCa tumors. It holds significant potential to guide clinicians in optimizing the surgical management of these patients.

Gasdermin D deficiency aborts myeloid calcium influx to drive granulopoiesis in lupus nephritis.

Gasdermin D (GSDMD) is emerging as an important player in autoimmune diseases, but its exact role in lupus nephritis (LN) remains controversial. Here, we identified markedly elevated GSDMD in human and mouse LN kidneys, predominantly in CD11b+ myeloid cells. Global or myeloid-conditional deletion of GSDMD was shown to exacerbate systemic autoimmunity and renal injury in lupus mice with both chronic graft-versus-host (cGVH) disease and nephrotoxic serum (NTS) nephritis. Interestingly, RNA sequencing and flow cytometry revealed that myeloid GSDMD deficiency enhanced granulopoiesis at the hematopoietic sites in LN mice, exhibiting remarkable enrichment of neutrophil-related genes, significant increases in total and immature neutrophils as well as granulocyte/macrophage progenitors (GMPs). GSDMD-deficient GMPs and all-trans-retinoic acid (ATRA)-stimulated human promyelocytes NB4 were further demonstrated to possess enhanced clonogenic and differentiation abilities compared with controls. Mechanistically, GSDMD knockdown promoted self-renewal and granulocyte differentiation by restricting calcium influx, contributing to granulopoiesis. Functionally, GSDMD deficiency led to increased pathogenic neutrophil extracellular traps (NETs) in lupus peripheral blood and bone marrow-derived neutrophils. Taken together, our data establish that GSDMD deletion accelerates LN development by promoting granulopoiesis in a calcium influx-regulated manner, unraveling its unrecognized critical role in LN pathogenesis.

A Rare Neurilemmoma of the Nasal Vestibule: A Case With the Review of Literature.

A variety of diseases can affect the nasal vestibule. It might be challenging to diagnose and treat a nasal vestibular tumor due to the anatomical characteristics of the nasal vestibule. Neurilemmoma is a tumor derived from Schwann cells of the nerve sheath. Less than 4% of these tumors invade the nasal cavity and sinuses. Nasal vestibule neurilemmoma is rare, it is often overlooked when a mass discovered. The diagnosis of it is mainly based on clinical symptoms, nasal endoscopy, and imaging, The mainstay of treatment is complete resection surgery. Pathological examination provides the final diagnosis. We present a patient with nasal vestibule neurilemmoma who underwent a successful endoscopic surgery without cosmetic deformity, and discuss the clinical manifestations, histological features, imaging features, differential diagnosis, treatment options, then reviewed relevant literature of this rare benign lesion.

One-step solvothermal synthesis of full-color fluorescent carbon dots for information encryption and anti-counterfeiting applications.

Multicolor fluorescent carbon dots (CDs) have received extensive attention due to their excellent fluorescence tunable performance. In this study, multicolor CDs with color tunable and high fluorescence quantum yields (QYs) were successfully prepared under the same conditions by a one-step solvothermal method using 2-aminoterephthalic acid (ATA) and Nile Blue A (NBA) as reaction reagents, achieving a wide color field coverage. Detailed studies on the relevant mechanisms have been carried out for blue, green and red CDs, indicating that the regulating mechanism of multicolor luminescence is determined by the size of the sp2 conjugated domains, which is due to the increase of particle size that causes an increase in the size of the sp2 conjugated domains, resulting in the narrowing of the band gap and the red-shift of the emission wavelength. It was found that the CDs have the advantages of simple preparation, high photostability and high quantum yield. They were used as fluorescent ink and mixed with polyvinyl alcohol (PVA) to form CD/PVA composites, which were successfully applied in the field of information encryption and anti-counterfeiting. This work provides a new strategy for the synthesis of panchromatic tunable fluorescent CDs and their application in the field of information encryption and anti-counterfeiting.

Elimination of Intragrain Defect to Enhance the Performance of FAPbI3 Perovskite Solar Cells by Ionic Liquid.

Ionic liquids have been widely used to improve the efficiency and stability of perovskite solar cells (PSCs), and are generally believed to passivate defects on the grain boundaries of perovskites. However, few studies have focused on the relevant effects of ionic liquids on intragrain defects in perovskites which have been shown to be critical for the performance of PSCs. In this work, the effect of ionic liquid 1-hexyl-3-methylimidazolium iodide (HMII) on intragrain defects of formamidinium lead iodide (FAPbI3) perovskite is investigated. Abundant {111}c intragrain planar defects in pure FAPbI3 grains are found to be significantly reduced by the addition of the ionic liquid HMII, shown by using ultra-low-dose selected area electron diffraction. As a result, longer charge carrier lifetimes, higher photoluminescence quantum yield, better charge carrier transport properties, lower Urbach energy, and current-voltage hysteresis are achieved, and the champion power conversion efficiency of 24.09% is demonstrated. These observations suggest that ionic liquids significantly improve device performance resulting from the elimination of {111}c intragrain planar defects.

A Novel "Microscrew With Tie-Down Sutures" Technique for FGG Anchorage: A Case Report.

The most challenging and time-consuming step in the free gingival graft (FGG) for keratinized mucosa augmentation is the compression suture anchoring the FGG to the periosteum. This article proposed a novel "microscrew with tie-down sutures" technique to anchor the FGG to the recipient site without the traditional trans-periosteum suture. This patient's keratinized mucosa width (KMW) around the healing abutments of teeth #29 and #30 was less than 1 mm. After an apically positioned flap (AFP) was prepared, 2 microscrews were placed at the buccal plate of the alveolar ridge bone, which is the coronal margin of the AFP. Then, the sutures winded between the microscrews and the healing abutments to anchor the FGG. In conclusion, the "microscrew with tie-down sutures" technique offers a feasible and straightforward alternative for the trans-periosteum compression suture, mainly when the periosteum is fragile, thin, or injured.

Distribution and Severity of Cervical Intraepithelial Neoplasia in Women With Different Human Papillomavirus: An Analysis From Liaoning Province of Northeastern China.

OBJECTIVE: Persistent infection with high-risk human papillomavirus (HPV) is a key contributor to cervical intraepithelial neoplasia (CIN), but the relation between high-risk HPV genotypes and the location of CIN lesions remains unclear. The aims of this study were to investigate the most frequent biopsy site of CIN lesions in women with different HPV infection and to analyze the biopsy times, CIN frequency, and the clustering of CIN frequency based on 12-o'clock sites and cervical quadrant locations. MATERIALS AND METHOD: We conducted a retrospective study of HPV detection and genotyping at the virology department of our hospital. Colposcopy exams were performed by specialists according to a standardized protocol, and all visually abnormal areas were further biopsied. Pearson chi-squared tests and cluster analyses were implemented to analyze the data. RESULTS: Among 1,381 women enrolled in this study, 933 cases infected with HPV. HPV16, HPV58, and HPV18 were the most common genotypes. The most frequent biopsy site was the 6 o'clock position. The highest frequency of high-grade CIN findings in single-genotype HPV groups was the 6 o'clock position and that for multiple-genotype HPV group was the 12 o'clock location. All CIN clusters were found in the 6 and 12 o'clock biopsy sites, except in the HPV18 group. Quadrant 2 and 4 were clustered in most groups. CONCLUSIONS: The 6 and 12 o'clock sites in cervical quadrant 2 and 4 should be targeted during cervical biopsy procedures. These findings can provide clinicians with specific recommendations on the optimal site for CIN biopsy when considering the HPV genotype.

Heat-Insulated Regenerated Fibers with UV Resistance: Silk Fibroin/Al2O3 Nanoparticles.

The various wastes generated by silkworm silk textiles that are no longer in use are increasing, which is causing considerable waste and contamination. This issue has attracted widespread attention in countries that use a lot of silk. Therefore, enhancing the mechanical properties of regenerated silk fibroin (RSF) and enriching the function of silk are important directions to expand the comprehensive utilization of silk products. In this paper, the preparation of RSF/Al2O3 nanoparticles (NPs) hybrid fiber with different Al2O3 NPs contents by wet spinning and its novel performance are reported. It was found that the RSF/Al2O3 NPs hybrid fiber was a multifunctional fiber material with thermal insulation and UV resistance. Natural light tests showed that the temperature rise rate of RSF/Al2O3 NPs hybrid fibers was slower than that of RSF fibers, and the average temperature rose from 29.1 °C to about 35.4 °C in 15 min, while RSF fibers could rise to about 40.1 °C. UV absorption tests showed that the hybrid fiber was resistant to UV radiation. Furthermore, the addition of Al2O3 NPs may improve the mechanical properties of the hybrid fibers. This was because the blending of Al2O3 NPs promoted the self-assembly of ß-sheets in the RSF reaction mixture in a dose-dependent manner, which was manifested as the RSF/Al2O3 NPs hybrid fibers had more ß-sheets, crystallinity, and a smaller crystal size. In addition, RSF/Al2O3 NPs hybrid fibers had good biocompatibility and durability in micro-alkaline sweat environments. The above performance makes the RSF/Al2O3 NPs hybrid fibers promising candidates for application in heat-insulating and UV-resistant fabrics as well as military clothing.

Identifying optimal surgical approach among T1N2-3M0 non-small cell lung cancer patients: a population-based analysis.

Background: Whether stage T1N2-3M0 non-small cell lung cancer (NSCLC) patients could benefit from surgery and the optimal surgical procedure have remained controversial and unclear. This study aimed to investigate whether stage T1N2-3M0 NSCLC can benefit from different surgery types and develop a tool for survival prediction. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with stage T1N2-3M0 NSCLC between 2000 and 2015. A 1:1 propensity score-matched (PSM) analysis was used to balance the distribution of clinical characteristics. Survival analyses were performed by using the Kaplan-Meier (KM) curves and Cox proportional hazards regression. All patients were randomly split at a ratio of 7:3 into training and validation cohorts. The nomogram was constructed by integrating all independent predictors for overall survival (OS) and cancer-specific survival (CSS). The model's performance was evaluated by discrimination, calibration ability, and risk stratification ability. Results: A total of 4,671 patients were enrolled. After 1:1 PSM, the distribution proportions of clinical characteristics in 1,146 patients were balanced (all P>0.05). The non-surgical approach was associated with worse survival compared with sublobectomy and lobectomy in the unmatched and matched cohorts. The multivariate Cox analysis showed that sublobectomy and lobectomy were both related to better OS and CSS rates compared with no surgery (P<0.001). Moreover, the results of subgroup analyses based on age, N stage, and radiotherapy or chemotherapy strategy were consistent. A total of 801 patients were included in the training cohort and 345 cases constituted the validation cohort. The nomogram constructed for the 1-, 3-, and 5-year OS and CSS prediction showed good discrimination, performance, and calibration both in the training and validation sets. Significant distinctions in survival curves between different risk groups stratified by prognostic scores were also observed (all P<0.001). Conclusions: Stage T1N2-3M0 NSCLC patients could benefit from sublobectomy or lobectomy, and lobectomy provides better survival benefits. We developed and validated nomograms, which could offer clinicians instructions for strategy making.

Dynamics of respiratory infectious diseases under rapid urbanization and COVID-19 pandemic in the subcenter of Beijing during 2014-2022.

Objective: The study analyzed the impact of urbanization on epidemiological characteristics of respiratory infectious disease in Tongzhou District, Beijing during 2014-2022 to provide reference for prevention and control priorities of respiratory infectious diseases during the innovative urbanization process in China. Methods: The incidence data of notifiable respiratory infectious diseases (NRIDs) in Tongzhou Beijing during 2014-2022 were summarized. The trend of incidence rate was analyzed by Joinpoint regression model, and entropy method was performed to construct the comprehensive index of urbanization (CIU) and generalized linear model was used to analyze the influence of CIU on the incidence rate of respiratory infectious diseases. Results: Totally 72616 NRIDs cases were reported in Tongzhou District during 2014-2022, and the incidence rate of NRIDs was higher during 2017-2019 (153/100 000) than during 2014-2016 (930/100 000) and during 2020-2022 (371/100 000), respectively (both P < 0.001). The CIU constantly increased with slight fluctuation in 2016 and 2018, respectively. The incidence rate of NRIDs showed an increase along with the CIU during 2014-2019 (r = 0.95, P = 0.004), while the incidence rate's tendency was interrupted by COVID-19 during 2020 with slight decrease in 2020-2021 and rebounded in 2022. For the patients aged <15 years, the incidence rate of NRIDs revealed a very sharp rise at the urbanization period without COVID-19 pandemic compared with that under pre-urbanization period (RR = 7.93, 95 % CI 7.63-8.24), and dropped off to the similar level as of pre-urbanization period when COVID-19 pandemic spread. Conclusions: Urbanization process may increase the incidence of NRIDs but constrained by COVID-19. Certain measures should be taken to prevent and control the effects by urbanization process, such as good natural environment with less population density, ecological environment with good air quality, promoted hand hygiene, mask wearing, keeping interpersonal distance, vaccination, media publicity for NRIDs' prevention and control.

Use of pressure muscle index to predict the contribution of patient's inspiratory effort during pressure support ventilation: a prospective physiological study.

Background: The successful implementation of assisted ventilation depends on matching the patient's effort with the ventilator support. Pressure muscle index (PMI), an airway pressure based measurement, has been used as noninvasive monitoring to assess the patient's inspiratory effort. The authors aimed to evaluate the feasibility of pressure support adjustment according to the PMI target and the diagnostic performance of PMI to predict the contribution of the patient's effort during ventilator support. Methods: In this prospective physiological study, 22 adult patients undergoing pressure support ventilation were enrolled. After an end-inspiratory airway occlusion, airway pressure reached a plateau, and the magnitude of change in plateau from peak airway pressure was defined as PMI. Pressure support was adjusted to obtain the PMI which was closest to -1, 0, +1, +2, and + 3 cm H2O. Each pressure support level was maintained for 20 min. Esophageal pressure was monitored. Pressure-time products of respiratory muscle and ventilator insufflation were measured, and the fraction of pressure generated by the patient was calculated to represent the contribution of the patient's inspiratory effort. Results: A total of 105 datasets were collected at different PMI-targeted pressure support levels. The differences in PMI between the target and the obtained value were all within ±1 cm H2O. As targeted PMI increased, pressure support settings decreased significantly from a median (interquartile range) of 11 (10-12) to 5 (4-6) cm H2O (p < 0.001), which resulted in a significant increase in pressure-time products of respiratory muscle [from 2.9 (2.1-5.0) to 6.8 (5.3-8.1) cm H2O•s] and the fraction of pressure generated by the patient [from 25% (19-31%) to 72% (62-87%)] (p < 0.001). The area under receiver operating characteristic curves for PMI to predict 30 and 70% contribution of patient's effort were 0.93 and 0.95, respectively. High sensitivity (all 1.00), specificity (0.86 and 0.78), and negative predictive value (all 1.00), but low positive predictive value (0.61 and 0.43) were obtained to predict either high or low contribution of patient's effort. Conclusion: Our results preliminarily suggested the feasibility of pressure support adjustment according to the PMI target from the ventilator screen. PMI could reliably predict the high and low contribution of a patient's effort during assisted ventilation.Clinical trial registration: ClinicalTrials.gov, identifier NCT05970393.

Screening, identification and evaluation of an acidophilic strain of Bacillus velezensis B4-7 for the biocontrol of tobacco bacterial wilt.

Tobacco (Nicotiana tabacum L.) bacterial wilt, caused by Ralstonia solanacearum, is indeed a highly destructive plant disease, leading to substantial damage in tobacco production. While biological control is considered an effective measure for managing bacterial wilt, related research in this area has been relatively limited compared to other control methods. In order to discover new potential antagonistic bacteria with high biocontrol efficacy against tobacco bacterial wilt, we conducted an analysis of the microbial composition differences between disease-suppressive and disease-conducive soils using Illumina sequencing. As a result, we successfully isolated six strains from the disease-suppressive soil that exhibited antibacterial activity against Ralstonia solanacearum. Among these strains, B4-7 showed the strongest antibacterial activity, even at acidic conditions with a pH of 4.0. Based on genome analysis using Average Nucleotide Identity (ANI), B4-7 was identified as Bacillus velezensis. In greenhouse and field trials, strain B4-7 significantly reduced the disease index of tobacco bacterial wilt, with control efficiencies reaching 74.03% and 46.88% respectively. Additionally, B4-7 exhibited plant-promoting abilities that led to a 35.27% increase in tobacco production in field conditions. Quantitative real-time (qPCR) analysis demonstrated that strain B4-7 effectively reduced the abundance of R. solanacearum in the rhizosphere. Genome sequencing and Liquid Chromatography-Mass Spectrometry (LC-MS) analysis revealed that strain B4-7 potentially produces various lipopeptide metabolites, such as microlactin, bacillaene, difficidin, bacilysin, and surfactin. Furthermore, B4-7 influenced the structure of the rhizosphere soil microbial community, increasing bacterial abundance and fungal diversity, while also promoting the growth of different beneficial microorganisms. In addition, B4-7 enhanced tobacco's resistance to R. solanacearum by increasing the activities of defense enzymes, including superoxide dismutase (SOD), phenylalanine ammonia-lyase (PAL), peroxidase (POD), catalase (CAT), and polyphenol oxidase (PPO). Collectively, these findings suggest that B. velezensis B4-7 holds significant biocontrol potential and can be considered a promising candidate strain for eco-friendly management of tobacco bacterial wilt.

The relationship between diabetes and the dementia risk: a meta-analysis.

BACKGROUND: The link between diabetes and dementia risk is not well understood. This study evaluates the factors linking diabetes to dementia onset, providing guidance for preventing dementia in diabetic patients. METHODS: This analysis utilized databases such as PubMed, Embase, Web of Science, and the Cochrane Library to review literature from January 31, 2012, to March 5, 2023. Articles were rigorously assessed using specific inclusion and exclusion criteria. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the studies. Data analysis was performed with STATA 15.0. RESULTS: The study analyzed 15 articles, covering 10,103,868 patients, with 8,821,516 diagnosed with diabetes. The meta-analysis reveals a substantial association between diabetes and an increased risk of dementia [RR: 1.59, 95%CI (1.40-1.80), P < 0.01, I²=96.4%]. A diabetes duration of less than five years is linked to a higher dementia risk [RR: 1.29, 95%CI (1.20-1.39), P < 0.01, I²=92.6%]. Additionally, hypoglycemia significantly raises dementia risk [RR: 1.56, 95%CI (1.13-2.16), P < 0.01, I²=51.5%]. Analyses of blood sugar control, glycated hemoglobin, and fasting blood sugar indicated no significant effects on the onset of dementia. CONCLUSION: Diabetes notably increases dementia risk, particularly where diabetes duration is under five years or hypoglycemia is present. REGISTRATION: The research protocol was registered with PROSPERO and assigned the registration number CRD42023394942.

Massively parallel CRISPR-assisted homologous recombination enables saturation editing of full-length endogenous genes in yeast.

Performing saturation editing of chromosomal genes will enable the study of genetic variants in situ and facilitate protein and cell engineering. However, current in vivo editing of endogenous genes either lacks flexibility or is limited to discrete codons and short gene fragments, preventing a comprehensive exploration of genotype-phenotype relationships. To enable facile saturation editing of full-length genes, we used a protospacer adjacent motif-relaxed Cas9 variant and homology-directed repair to achieve above 60% user-defined codon replacement efficiencies in Saccharomyces cerevisiae genome. Coupled with massively parallel DNA design and synthesis, we developed a saturation gene editing method termed CRISPR-Cas9- and homology-directed repair-assisted saturation editing (CHASE) and achieved highly saturated codon swapping of long genomic regions. By applying CHASE to massively edit a well-studied global transcription factor gene, we found known and unreported genetic variants affecting an industrially relevant microbial trait. The user-defined codon editing capability and wide targeting windows of CHASE substantially expand the scope of saturation gene editing.