A c-di-GMP signaling module controls responses to iron in Pseudomonas aeruginosa.

Cyclic dimeric guanosine monophosphate (c-di-GMP) serves as a bacterial second messenger that modulates various processes including biofilm formation, motility, and host-microbe symbiosis. Numerous studies have conducted comprehensive analysis of c-di-GMP. However, the mechanisms by which certain environmental signals such as iron control intracellular c-di-GMP levels are unclear. Here, we show that iron regulates c-di-GMP levels in Pseudomonas aeruginosa by modulating the interaction between an iron-sensing protein, IsmP, and a diguanylate cyclase, ImcA. Binding of iron to the CHASE4 domain of IsmP inhibits the IsmP-ImcA interaction, which leads to increased c-di-GMP synthesis by ImcA, thus promoting biofilm formation and reducing bacterial motility. Structural characterization of the apo-CHASE4 domain and its binding to iron allows us to pinpoint residues defining its specificity. In addition, the cryo-electron microscopy structure of ImcA in complex with a c-di-GMP analog (GMPCPP) suggests a unique conformation in which the compound binds to the catalytic pockets and to the membrane-proximal side located at the cytoplasm. Thus, our results indicate that a CHASE4 domain directly senses iron and modulates the crosstalk between c-di-GMP metabolic enzymes.

Influence of protonic acid on the structure and properties of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) in oxidation polymerization.

Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is widely used because of its excellent performance. We report the synthesis of two PEDOT:PSS dispersions. The two dispersions differ by the addition of additional protonic acid in the oxidative polymerization system. Although there are examples of the introduction of acids into the polymerization system, the effects of acid on the structure and properties of these materials, in particular their mechanisms of action, have not been elucidated. We describe the chemical structure and molecular weight of two PEDOT polymers using Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, UV-vis-NIR spectroscopy, and density functional theory calculations. The carrier concentration, carrier mobility, and surface morphology of the composites are characterized by UV-vis-NIR spectroscopy, electron spin resonance, Raman spectra, Hall effect measurements, and atomic force microscopy. The crystallinity of PEDOT:PSS was measured by X-ray diffraction patterns. We show that the addition of a proper amount of protonic acid to the oxidative polymerization system can effectively reduce the formation of the terminal carbonyl group of PEDOT chains, which is conducive to the growth of polymer chains, and further improve the carrier concentration, which leads to an improvement of conductivity. Our results highlight the optimization of the chemical structure of PEDOT in order to increase its molecular weight and ultimately its conductivity.

Association between serum total bilirubin and diabetic kidney disease in US diabetic patients.

Background: Bilirubin has been widely reported to be a protective factor against diabetic kidney disease (DKD) in Asian populations. However, few large-sample analyses have been conducted in American populations. This study aimed to investigate the association between serum total bilirubin (STB) level and DKD in a US diabetic cohort. Methods: This cross-sectional study enrolled participants from the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Univariate and multivariate logistic regression analyses were performed to assess the association between STB level and DKD. Three models were conducted to control the potential confounding factors. Subgroup analysis was carried out for further validation. Results: Among the 5,355 participants, the median age [interquartile range (IQR)] was 62 [52-71] years; 2,836 (52.96%) were male, and 1,576 (29.43%) were diagnosed with DKD. In the entire cohort, no significant association between STB level and DKD was observed in any logistic regression models (p > 0.05). Subgroup analysis revealed that, in U.S. diabetic males, STB levels > 11.98 µmol/L were associated with a nearly 30% lower risk of DKD than STB levels ≤ 8.55 µmol/L. Additionally, a moderate STB level (8.56-11.98 µmol/L) was found associated with a nearly 25% lower risk of DKD in U.S. diabetic patients over 65 years old. Conclusion: The association of STB level with DKD may depict differences across diverse populations, among which the impact of race, sex, and age requires thorough consideration and relevant inferences should be interpreted cautiously.

Relationship Between Retinal Layer Thickness and Genetic Susceptibility to Age-Related Macular Degeneration in Asian Populations.

Purpose: For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility. Design: Genetic association study. Participants: A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included. Methods: Spectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRSAMD). Main Outcome Measures: Associations of individual SNPs, overall PRSAMD, and pathway-specific PRSAMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield. Results: CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers (P < 1.67 × 10-3), all at the central subfield. The overall PRSAMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (ß = -0.63 µm; P = 5.45 × 10-9). Pathway-specific PRSAMD for the complement cascade (ß = -0.53 µm; P = 9.42 × 10-7) and lipoprotein metabolism (ß = -0.05 µm; P = 0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRSAMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (ß = -1.00 µm; P = 2.91 × 10-7; R2 = 5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous. Conclusions: Overall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Contribution of common and rare variants to Asian neovascular age-related macular degeneration subtypes.

Neovascular age-related macular degeneration (nAMD), along with its clinical subtype known as polypoidal choroidal vasculopathy (PCV), are among the leading causes of vision loss in elderly Asians. In a genome-wide association study (GWAS) comprising 3,128 nAMD (1,555 PCV and 1,573 typical nAMD), and 5,493 controls of East Asian ancestry, we identify twelve loci, of which four are novel ([Formula: see text]). Substantial genetic sharing between PCV and typical nAMD is noted (rg = 0.666), whereas collagen extracellular matrix and fibrosis-related pathways are more pronounced for PCV. Whole-exome sequencing in 259 PCV patients revealed functional rare variants burden in collagen type I alpha 1 chain gene (COL1A1; [Formula: see text]) and potential enrichment of functional rare mutations at AMD-associated loci. At the GATA binding protein 5 (GATA5) locus, the most significant GWAS novel loci, the expressions of genes including laminin subunit alpha 5 (Lama5), mitochondrial ribosome associated GTPase 2 (Mtg2), and collagen type IX alpha 3 chain (Col9A3), are significantly induced during retinal angiogenesis and subretinal fibrosis in murine models. Furthermore, retinoic acid increased the expression of LAMA5 and MTG2 in vitro. Taken together, our data provide insights into the genetic basis of AMD pathogenesis in the Asian population.

A multiethnic genome-wide analysis of 19,420 individuals identifies novel loci associated with axial length and shared genetic influences with refractive error and myopia.

Introduction: Long axial length (AL) is a risk factor for myopia. Although family studies indicate that AL has an important genetic component with heritability estimates up to 0.94, there have been few reports of AL-associated loci. Methods: Here, we conducted a multiethnic genome-wide association study (GWAS) of AL in 19,420 adults of European, Latino, Asian, and African ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, with replication in a subset of the Consortium for Refractive Error and Myopia (CREAM) cohorts of European or Asian ancestry. We further examined the effect of the identified loci on the mean spherical equivalent (MSE) within the GERA cohort. We also performed genome-wide genetic correlation analyses to quantify the genetic overlap between AL and MSE or myopia risk in the GERA European ancestry sample. Results: Our multiethnic GWA analysis of AL identified a total of 16 genomic loci, of which 5 are novel. We found that all AL-associated loci were significantly associated with MSE after Bonferroni correction. We also found that AL was genetically correlated with MSE (rg = -0.83; SE, 0.04; p = 1.95 × 10-89) and myopia (rg = 0.80; SE, 0.05; p = 2.84 × 10-55). Finally, we estimated the array heritability for AL in the GERA European ancestry sample using LD score regression, and found an overall heritability estimate of 0.37 (s.e. = 0.04). Discussion: In this large and multiethnic study, we identified novel loci, associated with AL at a genome-wide significance level, increasing substantially our understanding of the etiology of AL variation. Our results also demonstrate an association between AL-associated loci and MSE and a shared genetic basis between AL and myopia risk.

Genetic Variability of Complement Factor H Has Ethnicity-Specific Associations With Choroidal Thickness.

Purpose: To identify genetic alleles associated with differences in choroidal thickness (CT) in a population-based multiethnic Asian cohort. Methods: A population-based multiethnic Asian cohort without retinal pathology was subjected to spectral-domain OCT (SD-OCT) and genotyping of risk alleles in CFH, VIPR2, ARMS2, and CETP. Subfoveal choroidal thickness (SFCT) values were assessed from SD-OCT, and associations with the risk alleles were determined for each cohort. Results: A total of 1045 healthy Asian individuals (550 Chinese, 147 Indians, 348 Malays) were prospectively enrolled in the study. Several CFH alleles (rs800292, rs1061170, and rs1329428) were associated with increased SFCT in Indians (+18.7 to +31.7 µm; P = 0.001-0.038) and marginally associated with decreased SFCT in Malays (-12.7 to -20.6 µm; P = 0.014-0.022). Haplotype analysis of CFH revealed variable associations with SFCT among races, with the H6 haplotype being associated with a 29.08-µm reduction in SFCT in the Chinese cohort (P = 0.02) but a 35.2-µm increase in SFCT in the Indian cohort (P < 0.001). Finally, subfield analysis of the Chinese cohort identified associations between the CFH risk allele rs1061170 and reduced CT in the nasal and superior sectors (-20.2 to -25.8 µm; P = 0.003-0.027). Conclusions: CFH variants are variably associated with CT among Asian ethnic groups. This has broad implications for the pathogenesis of common diseases such as age-related macular degeneration and central serous choroidopathy, the pathogenesis of which is associated with CT.

Mendelian Randomization Implicates Bidirectional Association between Myopia and Primary Open-Angle Glaucoma or Intraocular Pressure.

PURPOSE: Observational studies suggest that myopic eyes carry a greater risk of primary open-angle glaucoma (POAG); however, the evidence for this association is inconsistent. This may be the result of confounding factors that arise from myopia that complicate clinical tests for glaucoma. This study used Mendelian randomization (MR) analysis to determine genetic causal associations among myopia, glaucoma, and glaucoma-related traits that overcome the effects of external confounders. DESIGN: Bidirectional genetic associations between myopia and refractive spherical equivalent (RSE), POAG, and POAG endophenotypes were investigated. PARTICIPANTS: Data from the largest publicly available genetic banks (n = 216,257-542,934) were analyzed. METHODS: Multiple MR models and multivariate genomic structural modeling to identify significant mediators for the relationship between myopia and POAG. MAIN OUTCOME MEASURES: Genetic causal associations between myopia and POAG and POAG endophenotypes. RESULTS: We found consistent bidirectional genetic associations between myopia and POAG and between myopia and intraocular pressure (IOP) using multiple MR models at Bonferroni-corrected levels of significance. Intraocular pressure showed the most significant mediation effect on RSE and POAG (Sobel test, 0.13; 95% confidence interval, 0.09-0.17; P = 1.37 × 10-8). CONCLUSIONS: A strong bidirectional genetic causal link exists between myopia and POAG that is mediated mainly by IOP. Our findings suggest that IOP-lowering treatment for glaucoma may be beneficial in myopic eyes, despite the challenges of establishing a clear clinical diagnosis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Characterization of keystone taxa and microbial metabolic potentials in copper tailing soils.

Copper mining has caused serious soil contamination and threaten the balance of underground ecosystem. Effects of metal contamination on the soil microbial community assembly and their multifunctionality are still unclear. In this study, the keystone taxa and microbial metabolic potential of soil microorganisms surrounding a typical copper tailing were investigated. Results showed that pH and metal contents of adjacent soil in copper tailing increased, which largely reduced soil microbial communities' diversity. Metal contaminated soils enriched a group of keystone taxa with metal-tolerance such as Bacteroidota (20-54%) and Firmicutes (24-48%), which were distinct from the uncontaminated background soils that dominated by Proteobacteria (19-24%) and Actinobacteria (13-24%). In the contaminated soils, these keystone taxa were identified as Alistipes, Bacteroides, and Faecalibacterium, suggesting their adaptation to the metal-rich environment. Co-occurrence network analysis showed that the microbial community was loosely connected in the metal contaminated soils with a lower number of nodes and links. Co-occurrence networks further revealed that the dynamics of keystone taxa significantly correlated with copper content. Functional gene analysis of soil microorganisms indicated that metal contamination might inhibit important microbial metabolic potentials, such as secondary metabolites biosynthesis, carbon fixation, and nitrogen fixation. Results also found the flexible adaptation strategies of soil microbial communities to metal-rich environments with metal-resistance or bio-transformation, such as efflux (CusB/CusF/CzsB and pcoB/copB) and oxidation (aoxAB). These findings provide insight into the interaction between keystone taxa and soil environment, which is helpful to reveal the microbial metabolic potential and physiological characteristics in tailing contaminated soils.

Patient's care bundle benefits to prevent stroke associated pneumonia: A meta-analysis with trial sequential analysis.

Background: Patient's care bundle has been found to have a beneficial effect on refractory diseases, but the preventive effect of this strategy on stroke-associated pneumonia (SAP) remains unclear. The purpose of this meta-analysis was to determine the role of the patient's care bundle in the prevention of SAP. Methods: A systematic search was conducted in five electronic databases to identify randomized controlled trials (RCTs) published before January 31, 2022. The incidence of SAP and aspiration and the length of hospital stay were assessed. Random pair-wise meta-analysis was conducted using Review Manager 5.4, and trial sequential analysis (TSA) was also performed. Results: Twenty eligible RCTs involving 1916 patients were included for data analysis. Pooled results suggested that patient's care bundle was associated with significantly lower incidence of SAP (risk ratio [RR], 0.37; 95% CI, 0.29-0.46; p < 0.001; I2 = 0%) and aspiration (RR, 0.23; 95% CI, 0.15-0.35; p < 0.001; I2 = 0%). Meanwhile, patient's care bundle also significantly shortened the length of hospital stay for general patients (mean difference [MD], -3.10; 95% CI, -3.83 to -2.37; p < 0.001; I2 = 16%) and the length of intensive care unit (ICU) stay for patients with severe stoke (MD, -4.85; 95% CI, -5.86-3.84; p < 0.001; I2 = 0%). Results of TSA confirmed that none of the findings could be significantly reversed by future studies. Conclusions: The patient's care bundle effectively prevents the occurrence of SAP and aspiration and shortens the hospital stay of stroke patients. However, it is necessary to design more high-quality studies to further validate our findings and investigate their applicability in other geographical regions.

Single-Cell Transcriptome of Wet AMD Patient-Derived Endothelial Cells in Angiogenic Sprouting.

Age-related macular degeneration (AMD) is a global leading cause of visual impairment in older populations. 'Wet' AMD, the most common subtype of this disease, occurs when pathological angiogenesis infiltrates the subretinal space (choroidal neovascularization), causing hemorrhage and retinal damage. Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our 'activated' BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome has been created to facilitate further discovery research.

Hemodynamics of transcatheter tricuspid valve replacement with Lux-Valve.

Objective: Transcatheter tricuspid valve intervention (TTVI) has emerged as an alternative treatment option for high-risk and inoperable patients with symptomatic tricuspid regurgitation (TR). However, scarce data in hemodynamic profiles were available on TTVI. In this paper, we attempt to report the hemodynamic profiles of LuX-Valve. Methods: 30 patients from July 2020 to July 2021 were enrolled in this study. The patient was diagnosed with severe symptomatic TR. The clinical, invasive hemodynamic, and echocardiographic data were collected. Results: The surgical success rate was 100%. The cardiac index and stroke volume increased sharply from 2.42(2.27, 2.85) and 47.8(43.6, 62.0) to 3.04 ± 0.63 and 57.2 ± 14.7, respectively. With the elimination of TR and the increase of forward blood flow of the tricuspid valve, the extravascular lung water [798.0 (673.0, 1147.0) vs. 850.3 ± 376.1, P < 0.01] increased subsequently. The peak right atrium pressure decreased after Lux-Valve implantation (21.0 ± 6.4 vs. 19.4 ± 6.5, P < 0.05). On the contrary, the nadir right atrium pressure increased [10.0(8.0, 15.0) vs. 12.0(10.0, 17.0), P < 0.01]. Notably, the right atrium pressure difference dropped sharply from 9.0(5.0, 13.0) to 5.0(4.0, 8.0) after Lux-Valve implantation. There was no significant change in the pulmonary artery pressure. The right atrium volume decreased from 128(83, 188) to 91(67, 167) mL at 1 month and 107(66,157) mL at 6 months. With the remolding of the right heart chamber, the tricuspid annulus diameter shrank significantly from 42.5 ± 5.6 to 36.6 ± 6.3 mm at 1 month and 36.0 (33.0, 38.0) at 6 months. Conclusion: Invasive right atrium pressure may act as a potential candidate for TR evaluation and procedural guidance. Elimination of TR by LuX-Valve implantation improves the cardiac output and right atrium pressure and has no significant effect on the pulmonary artery pressure even with the increment of forward blood flow, suggesting the hemodynamic superiority of transcatheter tricuspid valve replacement but needs further study.

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The global pandemic of coronavirus disease 2019 (COVID-19) has brought great challenges to the traditional medical model. During the outbreak of COVID-19 in Shanghai, China, from March to May, 2022, there was a significant increase in the number of pediatric cases due to high transmissibility, immune escape, and vaccine breakthrough capacity of Omicron variants. The designated hospitals for children with COVID-19 served as a connecting link between children's specialized hospitals and mobile cabin hospitals. From April 7 to June 2, 2022, a total of 871 children with COVID-19 were admitted to Renji Hospital, Shanghai Jiao Tong University School of Medicine (South Branch), a designated hospital for children with COVID-19. Among these patients, 568 (65.2%) were children under 3 years old, 870 (99.9%) were mild or moderate, and 1 was severe. This article reports the experience in the management of pediatric cases in this designated hospital, which included the following aspects: establishing an optimal case-admission process; strengthening multidisciplinary standardized diagnosis and treatment; optimizing the management, warning, and rescue system for severe COVID-19; implementing family-centered nursing care; formulating an individualized traditional Chinese medicine treatment regimen; optimizing the discharge process and strengthening bed turnover; implementing strict whole-process control to reduce the risk of nosocomial infection; constructing a structured medical record system and using information platforms to adapt to the work mode of large-volume cases; conducting scientific research and sharing the experience in diagnosis and treatment.

Constitutive androstane receptor (CAR) mediates pyrene-induced inflammatory responses in mouse liver, with increased serum amyloid A proteins and Th17 cells.

BACKGROUND AND PURPOSE: The constitutive androstane receptor (CAR), a known xenobiotic sensor, plays an important role in drug metabolism by regulating numerous genes. The polycyclic aromatic hydrocarbon pyrene, an environmental pollutant, is a CAR activator and induces mouse hepatotoxicity via CAR. Here, we investigate the molecular mechanisms of the inflammatory response in pyrene-caused mice liver injury. EXPERIMENTAL APPROACH: Effects of pyrene on the liver were investigated in wild-type and CAR knockout (KO) mice. Levels of pyrene and its urinary metabolite were analysed by high performance liquid chromatography (HPLC). Inflammatory responses were measured by qRT-PCR, western blotting, and ELISA for cytokines. KEY RESULTS: Serum amyloid A proteins (SAAs) were markedly increased in the liver and serum of pyrene-exposed wild-type mice. IL-17-producing helper T cells (Th17 cells) and IL-17 levels were increased in the liver of pyrene-exposed wild-type mice. Hepatic mRNA levels of inflammatory cytokines including IL-1ß, IL-6 and TNFα, and serum IL-6 levels were significantly elevated in pyrene-treated wild-type mice. However, these changes were not observed in CAR KO mice. CONCLUSION AND IMPLICATIONS: CAR plays a crucial role in pyrene-caused mice liver inflammatory response with increased SAAs and Th17 cells. Our results suggest that serum SAAs may be a convenient biomarker for early diagnosis of liver inflammatory response caused by polycyclic aromatic hydrocarbons, including pyrene. CAR and Th17 cells may be potential targets for novel therapeutic strategies for xenobiotic-induced liver inflammation.

Genetic basis of job attainment characteristics and the genetic sharing with other SES indices and well-being.

Job attainment is an important component of socioeconomic status (SES). There is currently a paucity of genomic research on an individual's job attainment, as well as how it is related to other SES variables and overall well-being at the whole genome level. By incorporating O*NET occupational information into the UK Biobank database, we performed GWAS analyses of six major job attainment characteristics-job complexity, autonomy, innovation, information demands, emotional demands, and physical demands-on 219,483 individuals of European ancestry. The job attainment characteristics had moderate to high pairwise genetic correlations, manifested by three latent factors: cognitive, emotional, and physical requirements. The latent factor of overall job requirement underlying the job attainment traits represented a critical genetic path from educational attainment to income (P < 0.001). Job attainment characteristics were genetically positively correlated with positive health and well-being outcomes (i.e., subject well-being, overall health rating, number of non-cancer illnesses etc. (|rg|: 0.14-0.51), similar to other SES indices; however, the genetic correlations exhibited opposite directions for physical demands (|rg|: 0.14-0.51) and were largely negligible for emotional demands. By adopting a finer-grained approach to capture specific job attainment phenotypes, our study represents an important step forward in understanding the shared genetic architecture among job attainment characteristics, other SES indices, and potential role in health and well-being outcomes.

The effectiveness of Tuina in managing chronic non-specific low back pain: A protocol of a multicenter international randomized controlled trial.

BACKGROUND: Chronic non-specific low back pain (CNLBP) is a common complaint about medical care and carries a heavy social burden. The efficacy of Tuina (TN) or physiotherapy (PT) for CNLBP has been evaluated in previous systematic reviews. However, there is no high-quality evidence to support the efficacy of Tuina. Therefore, this study aims to conduct a large-scale, multicenter, high-quality clinical trial to provide evidence for Tuina to treat CNLBP. METHODS: This is a multicenter, assessor-, and analyst-blinded, randomized controlled trial with 3 parallel arms: TN, PT, and TN combined with PT (Tuina combined with physiotherapy) group. Six hundred twelve eligible CNLBP patients will be randomly assigned to the groups in a 1:1:1 ratio in 3 centers. The TN intervention includes 9-step routine techniques, while the PT intervention includes a physiotherapy treatment plan based on a patient's symptoms. The interventions for both groups will last for 30 minutes and will be carried out for 6 sessions in 8 weeks. The primary outcome will be the visual analog scale pain score. And the secondary outcomes will include the Oswestry Disability Index, spinal range of motion, 36-item short-form health survey. Safety evaluation will be recorded during the whole study. All data in this randomized controlled trial will be analyzed by SAS 9.4. DISCUSSION: The results of this trial will provide evidence to evaluate the efficacy of Tuina's value as a treatment for CNLBP. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2000040288, November 27, 2020).

Parameter Optimization of Asynchronous Cyclic Waterflooding for Horizontal-Vertical Well Patterns in Tight Oil Reservoirs.

Tight oil resources in China are mainly exploited by staged-fractured horizontal wells; horizontal wells face the problems of the rapid decline rate and low primary oil recovery. Pilot tests on the asynchronous cyclic waterflooding for the horizontal-vertical well pattern were carried out in recent years and achieved good performance. However, there are few studies on the influencing factors and parameter optimization of asynchronous cyclic waterflooding, which limits its wide application. This work took the tight oil reservoir in Yanchang formation, Fuxian area, Ordos Basin as its object, and the oil recovery mechanisms of asynchronous cyclic waterflooding for the horizontal-vertical well pattern were analyzed first. Then, the operation parameters of asynchronous cyclic waterflooding were optimized by the numerical simulation method. Among them, the injection proportion was optimized by the fuzzy synthetic evaluation method. Finally, the oilfield test was carried out based on the optimized parameters. The results showed that pressure disturbance and streamline deviation are the main oil recovery mechanisms of asynchronous cyclic waterflooding. The asynchronous mode of the diagonal well row is better than other asynchronous modes. For the injection time interval, injection-production ratio, and the injection and shut-in time, the cumulative oil production all show the trend of increasing first and then decreasing with the increase in these parameters. The optimal injection time interval and injection-production ratio are 0.5 T and 1, respectively. The optimal injection and shut-in time can be calculated by empirical formulas. Ultimately, the fuzzy synthetic evaluation model was established to optimize the injection proportion. Field practices showed that the average daily oil production of horizontal wells was increased from 1.7 to 3.0 m3 with the optimized parameters, which further verified the accuracy of the optimized parameters. This research can provide theoretical support for the effective development of tight oil reservoirs.

Genetics, leadership position, and well-being: An investigation with a large-scale GWAS.

SignificanceOur study presents the largest whole-genome investigation of leadership phenotypes to date. We identified genome-wide significant loci for leadership phenotypes, which are overlapped with top hits for bipolar disorder, schizophrenia, and intelligence. Our study demonstrated the polygenetic nature of leadership, the positive genetic correlations between leadership traits and a broad range of well-being indicators, and the unique association of leadership with well-being after accounting for genetic influences related to other socioeconomic status measures. Our findings offer insights into the biological underpinnings of leadership.