Enhanced polygenic risk score incorporating gene-environment interaction suggests the association of major depressive disorder with cardiac and lung function.

BACKGROUND: Depression has been linked to an increased risk of cardiovascular and respiratory diseases; however, its impact on cardiac and lung function remains unclear, especially when accounting for potential gene-environment interactions. METHODS: We developed a novel polygenic and gene-environment interaction risk score (PGIRS) integrating the major genetic effect and gene-environment interaction effect of depression-associated loci. The single nucleotide polymorphisms (SNPs) demonstrating major genetic effect or environmental interaction effect were obtained from genome-wide SNP association and SNP-environment interaction analyses of depression. We then calculated the depression PGIRS for non-depressed individuals, using smoking and alcohol consumption as environmental factors. Using linear regression analysis, we assessed the associations of PGIRS and conventional polygenic risk score (PRS) with lung function (N = 42 886) and cardiac function (N = 1791) in the subjects with or without exposing to smoking and alcohol drinking. RESULTS: We detected significant associations of depression PGIRS with cardiac and lung function, contrary to conventional depression PRS. Among smokers, forced vital capacity exhibited a negative association with PGIRS (ß = -0.037, FDR = 1.00 × 10-8), contrasting with no significant association with PRS (ß = -0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (ß = 0.088, FDR = 0.010), whereas no such association was found with PRS (ß = 0.040, FDR = 0.265). Notably, in individuals who both smoked and drank, forced expiratory volume in 1-second demonstrated a negative association with PGIRS (ß = -0.042, FDR = 6.30 × 10-9), but not with PRS (ß = -0.003, FDR = 0.857). CONCLUSIONS: Our findings underscore the profound impact of depression on cardiac and lung function, highlighting the enhanced efficacy of considering gene-environment interactions in PRS-based studies.

Association between white matter hyperintensity and anxiety/depression.

Although previous studies have explored the associations of white matter hyperintensity with psychiatric disorders, the sample size is small and the conclusions are inconsistent. The present study aimed to further systematically explore the association in a larger sample. All data were extracted from the UK Biobank. First, general linear regression models and logistic regression models were used to assess the association between white matter hyperintensity volume and anxiety/depression. White matter hyperintensity has been classified into periventricular white matter hyperintensity and deep white matter hyperintensity. Anxiety was determined by General Anxiety Disorder-7 score (n = 17,221) and self-reported anxiety (n = 15,333), depression was determined by Patient Health Questionnaire-9 score (n = 17,175), and self-reported depression (n = 14,519). Moreover, we employed Cox proportional hazard models to explore the association between white matter hyperintensity volume and anxiety/depression. The covariates included in fully adjusted model are age, gender, body mass index, Townsend deprivation index, healthy physical activity, cigarette consumption, alcohol consumption, educational attainment, diabetes, hypertension, and coronary heart disease. The results of the fully adjusted model showed that white matter hyperintensity volume was significantly associated with General Anxiety Disorder-7 score (periventricular white matter hyperintensity: ß = 0.152, deep white matter hyperintensity: ß = 0.094) and Patient Health Questionnaire-9 score (periventricular white matter hyperintensity: ß = 0.168). Logistic regression analysis results indicated that periventricular white matter hyperintensity volume (odds ratio = 1.153) was significantly associated with self-reported anxiety. After applying the Cox proportional hazard models, we found that larger white matter hyperintensity volume was associated with increased risk of depression (periventricular white matter hyperintensity: hazard ratio = 1.589, deep white matter hyperintensity: hazard ratio = 1.200), but not anxiety. In summary, our findings support a positive association between white matter hyperintensity volume and depression.

Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

Sodium oligomannate's amelioration of reproductive and metabolic phenotypes in a letrozole-induced PCOS-like mouse model depends on the gut microbiome.

It has been well-established that there is a connection between polycystic ovary syndrome (PCOS) pathology and gut microbiome dysbiosis. A marine-derived oligosaccharide, GV-971, has been reported to alter gut microbiota and alleviate Aß amyloidosis. In this study, the effects of GV-971 on PCOS-like mice were explored. Mice were randomly assigned into four groups: control, letrozole, letrozole + GV-971, control + GV-971. Glucose metabolism in PCOS-like mice was ameliorated by GV-971, while the reproductive endocrine disorder of PCOS-like mice was partially reversed. The messenger ribonucleic acid levels of steroidogenic enzymes in ovaries of PCOS-like mice were improved. GV-971 restored the fertility of PCOS-like mice and significantly increase the number of litters. Furthermore, GV-971 treatment effectively mitigated abnormal bile acid metabolism. Notably, after GV-971 intervention, gut microbiota alpha-diversity was considerably raised and the relative abundance of Firmicutes was reduced. In conclusion, the hyperinsulinemia and hyperandrogenemia of PCOS-like mice were alleviated by GV-971 intervention, which was associated with mitigating bile acid metabolism and modulating gut microbiota.

Genetic and prognostic analysis of blastoid and pleomorphic mantle cell lymphoma: a multicenter analysis in China.

Blastoid or pleomorphic mantle cell lymphoma (B/P-MCL) is characterized by high invasiveness and unfavorable outcomes, which is still a challenge for treating MCL. This retrospective study was performed to comprehensively analyze the clinical, genomic characteristics and treatment options of patients with B/PMCL from multicenter in China. Data were obtained from 693 patients with B/PMCL from three centers in China between April 1999 and December 2019. Seventy-four patients with BMCL (n = 43) or PMCL (n = 31) were included in the analysis. The median age of the cohort was 60.0 years with a male-to-female ratio of 2.89:1. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 44.1% and 46.0%, respectively. Mutations of TP53, ATM, NOTCH1, NOTCH2, NSD2, SMARCA4, CREBBP, KMT2D, FAT1, and TRAF2 genes were the most common genetic changes in B/P-MCL. Progression of disease within 12 months (POD12) could independently predict the poor prognosis of patients with blastoid and pleomorphic variants. Patients with POD12 carried a distinct mutation profile (TP53, SMARCA4, NSD2, NOTCH2, KMT2D, PTPRD, CREBBP, and CDKN2A mutations) compared to patients with non-POD12. First-line high-dose cytosine arabinoside exposure obtained survival benefits in these populations, and BTKi combination therapy as the front-line treatment had somewhat improvement in survival with no significant difference in the statistic. In conclusion, B/P-MCL had inferior outcomes and a distinct genomic profile. Patients with POD12 displayed a distinct mutation profile and a poor prognosis. New therapeutic drugs and clinical trials for B/P-MCL need to be further explored.

Rapid detection of human adenovirus subgroup B using recombinase polymerase amplification assay.

Human adenovirus subgroup B (HAdV B) is one of the major pathogens of human respiratory virus infections, which has considerable transmission and morbidity in a variety of populations. Therefore, rapid and specific detection of HAdV B in clinical samples is essential for diagnosis. This study aimed to develop a product for rapid nucleic acid detection of HAdV B using recombinase polymerase amplification assay (RPA) and validate the performance of this method by using clinical samples. Results showed that this method achieved a lower limit of detection (LOD) of 10 copies/µL and had no cross-reactivity with other adenovirus subgroups or respiratory pathogens. In addition to high sensitivity, it can be completed within 30 min at 40 °C. There is no need to perform nucleic acid extraction on clinical samples. Taking qPCR as the gold standard, the RPA assay possessed a high concordance (Cohen's kappa, 0.896; 95% CI 0.808-0.984; P < 0.001), with a sensitivity of 87.80% and a specificity of 100.00%. The RPA assay developed in this study provided a simple and highly specific method, making it an important tool for rapid adenovirus nucleic acid detection and facilitating large-scale population screening in resource-limited settings.

Development and clinical application of loop-mediated isothermal amplification combined with lateral flow assay for rapid diagnosis of SARS-CoV-2.

BACKGROUND: The diagnostic assay leveraging multiple reverse transcription loop-mediated isothermal amplification (RT-LAMP) could meet the requirements for rapid nucleic acid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: The devised assay merged the lateral flow assay with the RT-LAMP technology and designed specific primers for the simultaneous detection of the target and human-derived internal reference genes within a single reaction. An inquiry into the assay's limit of detection (LOD), sensitivity, and specificity was carried out. The effectiveness of this assay was validated using 498 clinical specimens. RESULTS: This LOD of the assay was determined to be 500 copies/mL, and there was no observed cross-reaction with other respiratory pathogens. The detection results derived from clinical specimens showed substantial concordance with those from real-time reverse transcription-polymerase chain reaction (RT-qPCR) (Cohen's kappa, 0.876; 95% CI: 0.833-0.919; p<0.005). The diagnostic sensitivity and specificity were 87.1% and 100%, respectively. CONCLUSION: The RT-LAMP assay, paired with a straightforward and disposable lateral immunochromatographic strip, achieves visual detection of dual targets for SARS-CoV-2 immediatly. Moreover, the entire procedure abstains from nucleic acids extraction. The samples are lysed at room temperature and subsequently proceed directly to the RT-LAMP reaction, which can be executed within 30 minutes at a constant temperature of 60-65°C. Then, the RT-LAMP amplification products are visualized using colloidal gold test strips. TRIAL REGISTRATION: This study was registered at the Chinese Clinical Trial Registry (Registration number: ChiCTR2200060495, Date of registration 2022-06-03).

Identifying novel chemical-related susceptibility genes for five psychiatric disorders through integrating genome-wide association study and tissue-specific 3'aQTL annotation datasets.

The establishment of 3'aQTLs comprehensive database provides an opportunity to help explore the functional interpretation from the genome-wide association study (GWAS) data of psychiatric disorders. In this study, we aim to search novel susceptibility genes, pathways, and related chemicals of five psychiatric disorders via GWAS and 3'aQTLs datasets. The GWAS datasets of five psychiatric disorders were collected from the open platform of Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc/ ) and iPSYCH ( https://ipsych.dk/ ) (Demontis et al. in Nat Genet 51(1):63-75, 2019; Grove et al. in Nat Genet 51:431-444, 2019; Genomic Dissection of Bipolar Disorder and Schizophrenia in Cell 173: 1705-1715.e1716, 2018; Mullins et al. in Nat Genet 53: 817-829; Howard et al. in Nat Neurosci 22: 343-352, 2019). The 3'untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) summary datasets of 12 brain regions were obtained from another public platform ( https://wlcb.oit.uci.edu/3aQTLatlas/ ) (Cui et al. in Nucleic Acids Res 50: D39-D45, 2022). First, we aligned the GWAS-associated SNPs of psychiatric disorders and datasets of 3'aQTLs, and then, the GWAS-associated 3'aQTLs were identified from the overlap. Second, gene ontology (GO) and pathway analysis was applied to investigate the potential biological functions of matching genes based on the methods provided by MAGMA. Finally, chemical-related gene-set analysis (GSA) was also conducted by MAGMA to explore the potential interaction of GWAS-associated 3'aQTLs and multiple chemicals in the mechanism of psychiatric disorders. A number of susceptibility genes with 3'aQTLs were found to be associated with psychiatric disorders and some of them had brain-region specificity. For schizophrenia (SCZ), HLA-A showed associated with psychiatric disorders in all 12 brain regions, such as cerebellar hemisphere (P = 1.58 × 10-36) and cortex (P = 1.58 × 10-36). GO and pathway analysis identified several associated pathways, such as Phenylpropanoid Metabolic Process (GO:0009698, P = 6.24 × 10-7 for SCZ). Chemical-related GSA detected several chemical-related gene sets associated with psychiatric disorders. For example, gene sets of Ferulic Acid (P = 6.24 × 10-7), Morin (P = 4.47 × 10-2) and Vanillic Acid (P = 6.24 × 10-7) were found to be associated with SCZ. By integrating the functional information from 3'aQTLs, we identified several susceptibility genes and associated pathways especially chemical-related gene sets for five psychiatric disorders. Our results provided new insights to understand the etiology and mechanism of psychiatric disorders.

Assessing the effect of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes.

Longitudinal changes in brain structure and lifestyle can affect sleep phenotypes. However, the influence of the interaction between longitudinal changes in brain structure and lifestyle on sleep phenotypes remains unclear. Genome-wide association study dataset of longitudinal changes in brain structure was obtained from published study. Phenotypic data of lifestyles and sleep phenotypes were obtained from UK Biobank cohort. Using genotype data from UK Biobank, we calculated polygenetic risk scores of longitudinal changes in brain structure phenotypes. Linear/logistic regression analysis was conducted to evaluate interactions between longitudinal changes in brain structure and lifestyles on sleep duration, chronotype, insomnia, snoring and daytime dozing. Multiple lifestyle × longitudinal changes in brain structure interactions were detected for 5 sleep phenotypes, such as physical activity×caudate_age2 for daytime dozing (OR = 1.0389, P = 8.84 × 10-3) in total samples, coffee intake×cerebellar white matter volume_age2 for daytime dozing (OR = 0.9652, P = 1.13 × 10-4) in females. Besides, we found 4 overlapping interactions in different sleep phenotypes. We conducted sex stratification analysis and identified one overlapping interaction between female and male. Our results support the moderate effects of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes, and deepen our understanding of the pathogenesis of sleep disorders.

Assessing the association of coffee consumption on the relationship of chronic pain with depression and anxiety.

BACKGROUND: A bidirectional relationship between chronic pain (CP) and mental disorders has been reported, and coffee was believed to be associated with both. However, the association of coffee in this bidirectional relationship remains unclear. We aim to analyze the association of coffee consumption on the relationship of CP with depression and anxiety. METHODS: A total of 376,813 participants from UK Biobank were included. We collected data on anxiety, depression and CP from objects of our study population. The association of coffee consumption on the relationship of CP with depression and anxiety was assessed through logistic/linear regression models. Moreover, seemingly unrelated estimation test (SUEST) was used to compare whether the coefficients differed in two different groups. RESULTS: We observed significant associations of coffee consumption in the interaction of CP with depression and anxiety, such as the association of multisite chronic pain (MCP) on self-reported depression (ßcoffee = 0.421, ßnon-coffee = 0.488, PSUEST = 0.001), and the association of MCP on generalized anxiety disorder-7 (GAD-7) scores (ßcoffee = 0.561, ßnon-coffee = 0.678, PSUEST = 0.004) were significantly different between coffee drinking and non-coffee drinking groups. Furthermore, in analysis stratified by gender, we found headache (ßmale = 0.392, ßfemale = 0.214, PSUEST = 0.022) and hip pain (ßmale = 0.480, ßfemale = 0.191, PSUEST = 0.021) had significant associations with self-reported depression between males and females groups in coffee drinkers. CONCLUSIONS: Our results suggested that coffee consumption has a significant association on the relationship of CP with depression and anxiety.

Coffee consumption and risk of kidney function decline in a Dutch population-based cohort.

BACKGROUND AND AIMS: Whether coffee consumption is associated with changes in estimated glomerular filtration rate (eGFR) is unknown. We investigated the relationship between coffee consumption and annual eGFR change in a large Dutch population-based study. METHODS AND RESULTS: This study was performed in 78,346 participants without chronic kidney disease (CKD) in the population-based Lifelines Cohort Study. Coffee consumption was assessed at baseline using food frequency questionnaires. Outcomes were annual eGFR change and a composite kidney outcome (defined as eGFR <60 mL/min per 1.73 m2 or >20 % eGFR decline). Multivariable linear and logistic regression analyses were used to evaluate the associations of coffee consumption (categories and cups/day) with kidney outcomes. Overall, 90 % of the participants drank coffee daily and 36 % drank >2-4 cups/day. Unadjusted mean ± SD annual eGFR change ranged from -2.86 ± 2.96 (for non-coffee drinkers) to -2.35 ± 2.62 (for participants consuming >6 cups/day) mL/min per 1.73 m2. During 3.6 ± 0.9 years follow-up, 11.1 % of participants reached the composite kidney outcome. As compared to non-coffee drinkers, higher coffee consumption was associated with less annual eGFR decline in multivariable models (ß [95 % CIs] ranged from 0.15 [0.07, 0.22] for >0-2 cups/day to 0.29 [0.20, 0.38] for >6 cups/day, P-trend <0.001). Consumption of one more cup of coffee per day was associated with a 3 % lower risk of the composite kidney outcome (OR [95%CI], 0.97 [0.96, 0.99]). The inverse association was more pronounced in a subgroup of individuals with diabetes. CONCLUSION: Coffee consumption was inversely associated with annual eGFR change and CKD risk in a large Dutch population-based cohort.

[Mechanism of Xinshubao Tablets in exerting anti-inflammatory, vasodilation, and cardioprotective effects based on network pharmacology].

This study aims to explore the anti-inflammatory, vasodilation, and cardioprotective effects of the intestinal absorption liquids containing Xinshubao Tablets or single herbs, and to elucidate the potential mechanism based on network pharmacology. Western blot was then conducted to validate the expression changes of core proteins. Lipopolysaccharide(LPS)-stimulated RAW264.7 cells were used to observe the anti-inflammatory effect. The vasodilation activity was examined by the microvessel relaxation assay in vitro. Oxygen-glucose deprivation(OGD)-induced H9c2 cells were used to investigate the cardioprotective effect. The chemical components were retrieved from Herb databases and composition of Xinshubao Tablets drug-containing intestinal absorption solution. Drug targets were retrieved from SwissTargetPrediction databases. GeneCards was searched for the targets associated with the anti-inflammatory, vasodilation, and cardioprotective effects. The common targets shared by the drug and the effects were used to establish the protein-protein interaction(PPI) network, from which the core targets were obtained. Finally, the core targets were imported into Cytoscape 3.9.1 for Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) analyses. The anti-inflammatory experiment showed that both Xinshubao Tablets and the single herbs constituting this formula had anti-inflammatory effects. Curcumae Radix had the strongest inhibitory effect on the production of tumor necrosis factor-α(TNF-α), and Salviae Miltiorrhizae Radix et Rhizoma had the strongest inhibitory effect on the generation of interleukin-6(IL-6). Xinshubao Tablets, Curcumae Radix, and Crataegi Fructus had vasodilation effect, and Crataegi Fructus had the strongest effect. Xinshubao Tablets, Salviae Miltiorrhizae Radix et Rhizoma, Acanthopanacis Senticosi Radix et Rhizoma seu Caulis, and Paeoniae Radix Alba had cardioprotective effects, and Salviae Miltiorrhizae Radix et Rhizoma had the strongest cardioprotective effect. Network pharmacology results demonstrated that except the whole formula, Salviae Miltiorrhizae Radix et Rhizoma had the most components with anti-inflammatory effect, and Curcumae Radix had the most components with vasodilation and cardioprotective effects, followed by Salviae Miltiorrhizae Radix et Rhizoma. The nitric oxide synthase 3(NOS3) was predicted as the core target for the anti-inflammatory, vasodilation, and cardioprotective effects. Western blot results showed that Xinshubao Tablets significantly up-regulated the expression of NOS3 in OGD-induced H9c2 cells. GO enrichment analysis showed that the effects were mainly related to lipid exported from cell, regulation of blood pressure, and inflammatory response. KEGG pathway enrichment predicted AGE-RAGE and HIF-1 signaling pathways as the key pathways.

Treatment patterns and clinical outcomes of mantle cell lymphoma: A retrospective cohort study by CHOICE.

Regimens based on Bruton's tyrosine kinase inhibitors (BTKi) have been increasingly used to treat mantle cell lymphoma (MCL). A real-world multicenter study was conducted to characterize treatment patterns and outcomes in patients with newly diagnosed MCL by Chinese Hematologist and Oncologist Innovation Cooperation of the Excellent (CHOICE). The final analysis included 1261 patients. Immunochemotherapy was the most common first-line treatment, including R-CHOP in 34%, cytarabine-containing regimens in 21% and BR in 3% of the patients. Eleven percent (n = 145) of the patients received BTKi-based frontline therapy. Seventeen percent of the patients received maintenance rituximab. Autologous hematopoietic stem cell transplantation (AHCT) was conducted in 12% of the younger (<65 years) patients. In younger patients, propensity score matching analysis did not show significant difference in 2-year progression-free survival and 5-year overall survival rate in patients receiving standard high-dose immunochemotherapy followed by AHCT than induction therapy with BTKi-based regimens without subsequent AHCT (72% vs 70%, P = .476 and 91% vs 84%, P = .255). In older patients, BTKi combined with bendamustine plus rituximab (BR) was associated with the lowest POD24 rate (17%) compared with BR and other BTKi-containing regimens. In patients with resolved hepatitis B at the baseline, HBV reactivation rate was 2.3% vs 5.3% in those receiving anti-HBV prophylaxis vs not; BTKi treatment was not associated with higher risk of HBV reactivation. In conclusion, non-HD-AraC chemotherapy combined with BTKi may be a viable therapeutic strategy for younger patients. Anti-HBV prophylaxis should be implemented in patients with resolved hepatitis B.

Effect the accumulation of bioactive constituents of a medicinal plant (Salvia Miltiorrhiza Bge.) by arbuscular mycorrhizal fungi community.

BACKGROUND: Arbuscular mycorrhizal fungi (AMF) form symbiotic relationships with various terrestrial plants and have attracted considerable interest as biofertilizers for improving the quality and yield of medicinal plants. Despite the widespread distribution of AMFs in Salvia miltiorrhiza Bunge's roots, research on the impact of multiple AMFs on biomass and active ingredient accumulations has not been conducted. In this study, the effects of five native AMFs (Glomus formosanum, Septoglomus constrictum, Rhizophagus manihotis, Acaulospora laevis, and Ambispora gerdemannii) and twenty-six communities on the root biomass and active ingredient concentrations of S. miltiorrhiza were assessed using the total factor design method. RESULTS: Thirty-one treatment groups formed symbiotic relationships with S. miltiorrhiza based on the pot culture results, and the colonization rate ranged from 54.83% to 89.97%. AMF communities had higher colonization rates and total phenolic acid concentration than single AMF, and communities also appeared to have higher root fresh weight, dry weight, and total phenolic acid concentration than single inoculations. As AMF richness increased, there was a rising trend in root biomass and total tanshinone accumulations (ATTS), while total phenolic acid accumulations (ATP) showed a decreasing trend. This suggests that plant productivity was influenced by the AMF richness, with higher inoculation benefits observed when the communities contained three or four AMFs. Additionally, the affinities of AMF members were also connected to plant productivity. The inoculation effect of closely related AMFs within the same family, such as G. formosanum, S. constrictum, and R. manihotis, consistently yielded lower than that of mono-inoculation when any combinations were applied. The co-inoculation of S. miltiorrhiza with nearby or distant AMFs from two families, such as G. formosanum, R. manihotis, and Ac. laevis or Am. gerdemannii resulted in an increase of ATP and ATTS by more than 50%. AMF communities appear to be more beneficial to the yield of bioactive constituents than the single AMF, but overall community inoculation effects are related to the composition of AMFs and the relationship between members. CONCLUSION: This study reveals that the AMF community has great potential to improve the productivity and the accumulation of bioactive constituents in S. miltiorrhiza, indicating that it is an effective way to achieve sustainable agricultural development through using the AMF community.

Anlotinib as a third-line or further treatment for recurrent or metastatic nasopharyngeal carcinoma: a single-arm, phase 2 clinical trial.

BACKGROUND: Treatment options beyond the first-line setting for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC) are limited. The role of the multitarget tyrosine kinase inhibitor anlotinib in RM-NPC is unclear. METHODS: In this prospective, single-arm, phase 2 trial, patients with histologically confirmed RM-NPC and failure of at least two lines of prior systemic treatments were eligible. Anlotinib was given at 12 mg once daily on days 1-14 every 3 weeks until disease progression or intolerable toxicities. The primary end point was disease control rate, defined as the percentage of patients achieving complete response, partial response, or stable disease by RECIST criteria. RESULTS: From April 2019 to March 2021, 39 patients were enrolled and received a median of 4 cycles (range, 0.5-20) of anlotinib treatment. Partial response and stable disease were observed in 8 and 20 patients, respectively. The disease control rate was 71.8%, and objective response rate was 20.5%. With a median follow-up of 17.2 months, the median progression-free survival was 5.7 months. The 12-month overall survival was 58.3%, and the median overall survival was not reached. The most frequent grade 3/4 treatment-related adverse events were hand-foot syndrome (23.7%), oral mucositis (21.0%), hypertension (7.9%), and triglyceride elevation (7.9%). Hemorrhage, all grade 1 or 2, occurred in 34.2% of the patients. CONCLUSIONS: Anlotinib monotherapy exhibited promising anti-tumor activities and disease control for heavily pretreated RM-NPC patients with a tolerable toxicity profile. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03906058.

Combined effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression: A cross-sectional study based on UK Biobank.

Infection-induced perturbation of immune homeostasis could promote psychopathology. Psychiatric sequelae have been observed after previous coronavirus outbreaks. However, limited studies were conducted to explore the potential interaction effects of inflammation and coronavirus disease 2019 (COVID-19) on the risks of anxiety and depression. In this study, first, polygenic risk scores (PRS) were calculated for eight COVID-19 clinical phenotypes using individual-level genotype data from the UK Biobank. Then, linear regression models were developed to assess the effects of COVID-19 PRS, C-reactive protein (CRP), systemic immune inflammation index (SII), and their interaction effects on the Generalized Anxiety Disorder-7 (GAD-7, 104 783 individuals) score and the Patient Health Questionnaire-9 (PHQ-9, 104 346 individuals) score. Several suggestive interactions between inflammation factors and COVID-19 clinical phenotypes were detected for PHQ-9 score, such as CRP/SII × Hospitalized/Not_Hospitalized in women group and CRP × Hospitalized/Unscreened in age >65 years group. For GAD-7 score, we also found several suggestive interactions, such as CRP × Positive/Unscreened in the age ≤65 years group. Our results suggest that not only COVID-19 and inflammation have important effects on anxiety and depression but also the interactions of COVID-19 and inflammation have serious risks for anxiety and depression.

A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma.

Current prognostic scoring systems based on clinicopathologic variables are inadequate in predicting the survival and treatment response of extranodal natural killer/T-cell lymphoma (ENKTL) patients undergoing nonanthracyline-based treatment. We aimed to construct a classifier based on single-nucleotide polymorphisms (SNPs) for improving predictive accuracy and guiding clinical decision making. Data from 722 patients with ENKTL from international centers were analyzed. A 7-SNP-based classifier was constructed using LASSO Cox regression in the training cohort (n = 336) and further validated in the internal testing cohort (n = 144) and in 2 external validation cohorts (n = 142 and n = 100). The 7-SNP-based classifier showed good prognostic predictive efficacy in the training cohort and the 3 validation cohorts. Patients with high- and low-risk scores calculated by the classifier exhibited significantly different progression-free survival (PFS) and overall survival (OS) (all P < .001). The 7-SNP-based classifier was further proved to be an independent prognostic factor by multivariate analysis, and its predictive accuracy was significantly better than clinicopathological risk variables. Application of the 7-SNP-based classifier was not affected by sample types. Notably, chemotherapy combined with radiotherapy significantly improved PFS and OS vs radiotherapy alone in high-risk Ann Arbor stage I patients, whereas there was no statistical difference between the 2 therapeutic modalities among low-risk patients. A nomogram was constructed comprising the classifier and clinicopathological variables; it showed remarkably better predictive accuracy than either variable alone. The 7-SNP-based classifier is a complement to existing risk-stratification systems in ENKTL, which could have significant implications for clinical decision making for patients with ENKTL.

A longitudinal genome-wide association study of bone mineral density mean and variability in the UK Biobank.

Bone mineral density (BMD) is an essential predictor of osteoporosis and fracture. We conducted a genome-wide trajectory analysis of BMD and analyzed the BMD change. PURPOSE: This study aimed to identify the genetic architecture and potential biomarkers of BMD. METHODS: Our analysis included 141,261 white participants from the UK Biobank with heel BMD phenotype data. We used a genome-wide trajectory analysis tool, TrajGWAS, to conduct a genome-wide association study (GWAS) of BMD. Then, we validated our findings in previously reported BMD genetic associations and performed replication analysis in the Asian participants. Finally, gene-set enrichment analysis (GSEA) of the identified candidate genes was conducted using the FUMA platform. RESULTS: A total of 52 genes associated with BMD trajectory mean were identified, of which the top three significant genes were WNT16 (P = 1.31 × 10-126), FAM3C (P = 4.18 × 10-108), and CPED1 (P = 8.48 × 10-106). In addition, 114 genes associated with BMD within-subject variability were also identified, such as AC092079.1 (P = 2.72 × 10-13) and RGS7 (P = 4.72 × 10-10). The associations for these candidate genes were confirmed in the previous GWASs and replicated successfully in the Asian participants. GSEA results of BMD change identified multiple GO terms related to skeletal development, such as SKELETAL SYSTEM DEVELOPMENT (Padjusted = 2.45 × 10-3) and REGULATION OF OSSIFICATION (Padjusted = 2.45 × 10-3). KEGG enrichment analysis showed that these genes were mainly enriched in WNT SIGNALING PATHWAY. CONCLUSIONS: Our findings indicated that the CPED1-WNT16-FAM3C locus plays a significant role in BMD mean trajectories and identified several novel candidate genes contributing to BMD within-subject variability, facilitating the understanding of the genetic architecture of BMD.

Appraisal of guidelines for managing contrast medium in patients with metformin: consensuses, controversies, and gaps.

OBJECTIVES: The current guidelines contain substantial inconsistency regarding the use of metformin concomitantly with contrast media. The objective of this study is to appraise the guidelines and summarize the agreements and differences among recommendations. METHODS: Our search focused on English language guidelines published between 2018 and 2021. Guidelines for the management of contrast media in patients with continuous metformin were included. Guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation II instrument. RESULTS: Six guidelines out of 1134 fulfilled the inclusion criteria with an AGREE II score of 79.2% (IQR 72.7 to 85.1%). There was good overall quality of the guidelines, with six considered "strongly recommended." CPGs scored poorly in "Clarity of Presentation" and "Applicability," with scores of 75.9% and 76.4%, respectively. The intraclass correlation coefficients were excellent in each domain. There are some guidelines (33.3%) that recommend discontinuation of metformin in patients with an eGFR of < 30 mL/min/1.73 m2, while some guidelines (16.7%) suggest the threshold of renal function should be eGFR < 40 mL/min/1.73 m2. CONCLUSIONS: Most guidelines recommend withdrawing metformin before using contrast agents in diabetic patients with severely impaired kidney function but disagree on the renal function thresholds. Furthermore, the gaps regarding discontinuing metformin with moderate renal impairment (30 mL/min/1.73 m2 < eGFR < 60 mL/min/1.73 m2) must be considered in future studies. KEY POINTS: • Guidelines involving metformin and contrast agents are reliable and optimal. • Most guidelines advocate discontinuing metformin before using contrast agents in diabetic patients with advanced renal failure, but there are controversial suggestions regarding kidney function thresholds. • The gaps regarding the time of discontinuation of the metformin with moderate renal impairment (30 mL/min/1.73 m2 < eGFR < 60 mL/min/1.73 m2) must be considered in the extensive RCT studies.

Epidemiological and clinical characteristics of psittacosis among cases with complicated or atypical pulmonary infection using metagenomic next-generation sequencing: a multi-center observational study in China.

BACKGROUND: Chlamydia psittaci (C. psittaci) causes parrot fever in humans. Development of metagenomic next-generation sequencing (mNGS) enables the identification of C. psittaci. METHODS: This study aimed to determine the epidemiological and clinical characteristics of parrot fever cases in China. A multi-center observational study was conducted in 44 tertiary and secondary hospitals across 14 provinces and municipalities between April 2019 and October 2021. RESULTS: A total of 4545 patients with complicated or atypical pulmonary infection were included in the study, among which the prevalence of C. psittaci was determined to be 2.1% using mNGS. The prevalence of C. psittaci was further determined across demographic groups and types of specimens. It was significantly higher in patients with senior age (2.6% in those > 50 years), winter-spring (3.6%; particularly in December, January, and February), and southwestern (3.4%) and central and southern China (2.7%) (each P < 0.001). Moreover, the prevalence was the highest in bronchoalveolar lavage fluid (BALF) (2.9%), compared with sputum (1.1%) and peripheral blood specimens (0.9%). Additionally, co-infection of principal microorganisms was compared. Certain microorganisms were more likely to co-infect in parrot fever cases, such as Candida albicans in BALF (26.7%) and peripheral blood (6.3%), compared with non-parrot fever cases (19.7% and 1.3%); however, they did not significantly differ (each P > 0.05). CONCLUSION: Parrot fever remains low in patients with complicated or atypical pulmonary infection. It is likely to occur in winter-spring and southwestern region in China. BALF may be the optimal specimen in the application of mNGS. Co-infection of multiple microorganisms should be further considered.