Methylation of a MITE insertion in the MdRFNR1-1 promoter is positively associated with its allelic expression in apple in response to drought stress.

Miniature inverted-repeat transposable elements (MITEs) are widely distributed in the plant genome and can be methylated. However, whether DNA methylation of MITEs is associated with induced allelic expression and drought tolerance is unclear. Here, we identified the drought-inducible MdRFNR1 (root-type ferredoxin-NADP+ oxidoreductase) gene in apple (Malus domestica). MdRFNR1 plays a positive role in drought tolerance by regulating the redox system, including increasing NADP+ accumulation and catalase and peroxidase activities and decreasing NADPH levels. Sequence analysis identified a MITE insertion (MITE-MdRF1) in the promoter of MdRFNR1-1 but not the MdRFNR1-2 allele. MdRFNR1-1 but not MdRFNR1-2 expression was significantly induced by drought stress, which was positively associated with the MITE-MdRF1 insertion and its DNA methylation. The methylated MITE-MdRF1 is recognized by the transcriptional anti-silencing factors MdSUVH1 and MdSUVH3, which recruit the DNAJ domain-containing proteins MdDNAJ1, MdDNAJ2, and MdDNAJ5, thereby activating MdRFNR1-1 expression under drought stress. Finally, we showed that MdSUVH1 and MdDNAJ1 are positive regulators of drought tolerance. These findings illustrate the molecular roles of methylated MITE-MdRF1 (which is recognized by the MdSUVH-MdDNAJ complex) in induced MdRFNR1-1 expression as well as the drought response of apple and shed light on the molecular mechanisms of natural variation in perennial trees.

Exploring the impact of high-altitude de-acclimatization on renal function: The roles of oxidative and endoplasmic reticulum stress in rat models.

BACKGROUND: High-altitude de-acclimatization (HADA) significantly impacts physiological functions when individuals acclimatize to high altitudes return to lower altitudes. This study investigates HADA's effects on renal function and structure in rats, focusing on oxidative and endoplasmic reticulum stress as potential mechanisms of renal injury. OBJECTIVE: To elucidate the pathophysiological mechanisms of renal damage in HADA and evaluate the efficacy of antioxidants Vitamin C (Vit C) and tauroursodeoxycholic acid (TUDCA) in mitigating these effects. METHODS: 88 male Sprague-Dawley rats were randomly divided into a control group, a high-altitude (HA) group, a high-altitude de-acclimatization (HADA) group, and a treatment group. The control group was housed in a sea level environment (500 m), while the HA, HADA, and treatment groups were placed in a simulated high-altitude chamber (5000 m) for 90 days. After this period, the HA group completed the modeling phase; the HADA group was further subdivided into four subgroups, each continuing to be housed in a sea level environment for 3, 7, 14, and 30 days, respectively. The treatment group was split into the Vit C group, the TUDCA group, and two placebo groups, receiving medication for 3 consecutive days, once daily upon return to the sea level. The Vit C group received 100 mg/kg Vit C solution via intravenous injection, the TUDCA group received 250 mg/kg TUDCA solution via intraperitoneal injection, and the placebo groups received an equivalent volume of saline similarly. Serum, urine, and kidney tissues were collected immediately after the modeling phase. Renal function and oxidative stress levels were assessed using biochemical and ELISA methods. Renal histopathology was observed with H&E, Masson's trichrome, PAS, and PASM staining. Transmission electron microscopy was used to examine the ultrastructure of glomeruli and filtration barrier. TUNEL staining assessed cortical apoptosis in the kidneys. Metabolomics was employed for differential metabolite screening and pathway enrichment analysis. RESULTS: Compared to the control and HA groups, the HADA 3-day group (HADA-3D) exhibited elevated renal function indicators, significant pathological damage, observable ultrastructural alterations including endoplasmic reticulum expansion and apoptosis. TUNEL-positive cells significantly increased, indicating heightened oxidative stress levels. Various differential metabolites were enriched in pathways related to oxidative and endoplasmic reticulum stress. Early intervention with Vit C and TUDCA markedly alleviated renal injury in HADA rats, significantly reducing the number of apoptotic cells, mitigating endoplasmic reticulum stress, and substantially lowering oxidative stress levels. CONCLUSION: This study elucidates the pivotal roles of oxidative and endoplasmic reticulum stress in the early-stage renal injury in rats undergoing HADA. Early intervention with the Vit C and TUDCA significantly mitigates renal damage caused by HADA. These findings provide insights into the pathophysiological mechanisms of HADA and suggest potential therapeutic strategies for its future management.

Enhanced copper removal by magnesium modified biochar derived from Alternanthera philoxeroides.

Adsorption processes are being widely used by various researchers for the removal of heavy metals from waste streams and biochar has been frequently used as an adsorbent. In this study, a MgO-loaded biochar derived from Alternanthera philoxeroides (MAPB) was synthesized for the removal of Cu(II). Compared with other biochar absorbents, MAPB showed a relatively slow adsorption kinetics, but an effective removal of Cu(II) with a maximum sorption capacity of 1, 238 mg/g. The adsorption mechanism of Cu(II) by MAPB was mainly controlled by chemical precipitation as Cu2(OH)3NO3, complexation and ion replacement. Fixed bed column with MAPB packed in same dosage (1, 000 mg) and different bed depth (1.3, 2.6 and 3.9 cm) showed that the increased of bed depth by mixing MAPB with quartz sand could increase the removal of Cu(II). The fitted breakthrough (BT) models showed that mixing MAPB with support media could reduce the mass transfer rate, increase the dynamic adsorption capacity and BT time. Therefore, MAPB adsorbent act as a highly efficient long-term adsorbent for Cu(II) contaminated water treatment may have great ecological and environmental significance.

MdGH3.6 is targeted by MdMYB94 and plays a negative role in apple water-deficit stress tolerance.

Drought significantly limits apple fruit production and quality. Decoding the key genes involved in drought stress tolerance is important for breeding varieties with improved drought resistance. Here, we identified GRETCHEN HAGEN3.6 (GH3.6), an indole-3-acetic acid (IAA) conjugating enzyme, to be a negative regulator of water-deficit stress tolerance in apple. Overexpressing MdGH3.6 reduced IAA content, adventitious root number, root length and water-deficit stress tolerance, whereas knocking down MdGH3.6 and its close paralogs increased IAA content, adventitious root number, root length and water-deficit stress tolerance. Moreover, MdGH3.6 negatively regulated the expression of wax biosynthetic genes under water-deficit stress and thus negatively regulated cuticular wax content. Additionally, MdGH3.6 negatively regulated reactive oxygen species scavengers, including antioxidant enzymes and metabolites involved in the phenylpropanoid and flavonoid pathway in response to water-deficit stress. Further study revealed that the homolog of transcription factor AtMYB94, rather than AtMYB96, could bind to the MdGH3.6 promoter and negatively regulated its expression under water-deficit stress conditions in apple. Overall, our results identify a candidate gene for the improvement of drought resistance in fruit trees.

Primary resistance to integrase inhibitors in Shenzhen.

OBJECTIVES: In recent years, integrase strand transfer inhibitor (INSTI)-containing regimens have been increasingly adopted in treatment for HIV/AIDS and promoted as non-occupational post-exposure prophylaxis in China. This study aims to describe the prevalence of resistance to integrase and drug resistance mutations (DRMs) among ART-naive patients in Shenzhen, China. METHODS: Serum samples and demographic information were collected from newly reported ART-naive patients in Shenzhen in 2020. The study sequenced the coding sequence of the HIV-1 integrase gene and determined the DRMs.​. RESULTS: In this study, 1682 newly reported cases were included and 1071 of them were successfully sequenced finally. The prevalence of primary drug resistance was 1.77%, with 19 samples showing varying degrees of resistance to INSTIs. The study detected six major DRMs in 16 individuals and eight accessory DRMs in 24 individuals. The prevalence of transmitted drug resistance (TDR) mutations was 1.21%, with five transmitted mutations detected in 13 individuals. The prevalence of drug resistance to raltegravir and elvitegravir was statistically higher than to bictegravir, cabotegravir and dolutegravir. CONCLUSIONS: The prevalence of INSTI resistance in Shenzhen in 2020 was relatively high. ​Continued surveillance for resistance to INSTIs is recommended and treatment regimens should be adopted based on the pattern of resistance to INSTIs. ​Dolutegravir or bictegravir is first recommended when considering INSTIs as treatment regimens.

Immune characteristics analysis and construction of a four-gene prognostic signature for lung adenocarcinoma based on estrogen reactivity.

Lung adenocarcinoma (LUAD) is a common type of malignant tumor with poor prognosis and high mortality. In our previous studies, we found that estrogen is an important risk factor for LUAD, and different estrogen statuses can predict different prognoses. Therefore, in this study, we constructed a prognostic signature related to estrogen reactivity to determine the relationship between different estrogen reactivities and prognosis. We downloaded the LUAD dataset from The Cancer Genome Atlas (TCGA) database, calculated the estrogen reactivity of each sample, and divided them into a high-estrogen reactivity group and a low-estrogen reactivity group. The difference in overall survival between the groups was significant. We also analyzed the status of immune cell infiltration and immune checkpoint expression between the groups. We analyzed the differential gene expression between the groups and screened four key prognostic factors by the least absolute shrinkage and selection operator (LASSO) regression and univariable and multivariable Cox regression. Based on the four genes, a risk signature was established. To a certain extent, the receiver operating characteristic (ROC) curve showed the predictive ability of the risk signature, which was further verified using the GSE31210 dataset. We also determined the role of estrogen in LUAD using an orthotopic mouse model. Additionally, we developed a predictive nomogram combining the risk signature with other clinical characteristics. In conclusion, our four-gene prognostic signature based on estrogen reactivity had prognostic value and can provide new insights into the development of treatment strategies for LUAD.

Cu-Based Catalysts Supported on H3PO4-Activated Coffee Biochar for Selective Reduction of Nitroaromatics.

Selective reduction of nitroaromatics to the corresponding aromatic amines is extremely an attractive chemical process for both fundamental research and potential commercial applications. Herewith, we report that a highly dispersed Cu catalyst supported on H3PO4-activated coffee biochar and the resulting Cu/PBCR-600 catalyst show complete conversion of the nitroaromatics and >97.0% selectivity for the corresponding aromatic amines. The TOF of catalyzing the reduction of nitroaromatics (1.55-460.74 min-1) is approximately 2 to 15 times higher than those of previously reported non-noble and even noble metal catalysts. Additionally, Cu/PBCR-600 also shows high stability in catalytic recycles. Furthermore, it exhibits long-term catalytic stability (660 min) for practical application in a continuous-flow reactor. The characterizations and activity tests reveal that Cu0 existing in Cu/PBCR-600 acts as an active site in nitroaromatics reduction. Also, the further characterization by FTIR and UV-vis demonstrates that N, P co-doped coffee biochar could selectively adsorb and activate the nitro group of nitroaromatics.

First-line programmed death receptor-1 (PD-1) inhibitor and epidermal growth factor receptor (EGFR) blockade, combined with platinum-based chemotherapy, for stage IV penile cancer.

OBJECTIVES: To evaluate the anti-tumour activity and safety of anti-programmed death receptor-1 (PD-1) antibody plus epidermal growth factor receptor blockade combined with platinum-based chemotherapy (PEP) as first-line therapy for stage IV penile squamous cell carcinoma (PSCC). PATIENTS AND METHODS: We conducted a retrospective review of 17 patients with stage IV PSCC undergoing first-line PEP at Sun Yat-sen University Cancer Center between January 2018 and September 2021. Clinical responses were assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Of 17 patients who received first-line PEP, 13 were observed to have partial responses. Twelve patients subsequently received consolidated surgery. Nine of these achieved pN0 status, of whom six with locally advanced PSCC achieved pathological complete response. The median (range) follow-up time was 24.87 (3.63-29.40) months. Median PFS and median OS were not reached, with 2-year PFS and OS rates being 68.4% (95% confidence interval [CI] 48.7-96.1) and 62.9% (95% CI 41.6-95), respectively. Eight patients experienced Grade 3 or 4 treatment-related AEs. No Grade 5 AEs or death associated with treatment was observed. CONCLUSIONS: Anti-PD-1 antibody plus epidermal growth factor receptor blockade and platinum-based chemotherapy showed promising anti-tumour activity, acceptable toxicity, and satisfying long-term survival for stage IV PSCC. Larger clinical trials are needed to validate our findings.

Rare Pseudo-Chediak-Higashi Inclusions in Therapy-Related Acute Myeloid Leukemia with Myelodysplasia-Related Changes.

BACKGROUND: Defined as rare large azurophilic cytoplasmic inclusions, Pseudo-Chediak-Higashi granules mimic those in granulocytes cytoplasm of Chediak-Higashi syndrome. Rare cases of hematopoietic and lymphoid tissues tumors showed Pseudo-Chediak-Higashi inclusions in cytoplasm, some of which presented with unusual morphological characteristics. METHODS: Herein, we report the first case, in which rare pseudo-Chediak-Higashi inclusions were observed in therapy-related acute myeloid leukemia with myelodysplasia-related changes (t-AML-MRC). RESULTS: The rare pseudo-Chediak-Higashi inclusions may be positive for Sudan black, and some scholars think that these rare inclusions are a kind of dysgranulopoiesis. CONCLUSIONS: The case highlights the significance of an integrated diagnostic work-up, with an interesting effect for morphology.

Pregnancy Outcomes after Uterus-sparing Operative Treatment for Adenomyosis: A Systematic Review and Meta-analysis.

OBJECTIVE: A meta-analysis was conducted to evaluate the overall pregnancy outcomes after uterus-sparing operative treatment in patients with adenomyosis (AD). DATA SOURCES: We searched PubMed, Web of Science, Cochrane Library, and Embase for literature from January 2000 to January 2022. METHODS OF STUDY SELECTION: We included all studies reporting reproductive outcomes of uterine-sparing surgery for patients with AD with fertility requirements. Surgical treatment was classified as complete excision or incomplete removal of AD and nonexcisional techniques for induction of necrosis in AD. The latter included physically removing the tissue where pathology is present or disrupting the blood flow to the affected area, involving high-intensity focused ultrasound, microwave ablation, radiofrequency ablation, and uterine artery embolization. Two independent researchers performed study selection according to the screening criteria. TABULATION, INTEGRATION, AND RESULTS: A total of 13 studies with 1319 patients with AD were included in this study, comprising 795 women wishing fertility. Pooled estimates of pregnancy, miscarriage, and live-birth rates after excisional treatment for women attempting to conceive were 40% (95% confidence interval [CI], 29-52), 21% (95% CI, 16-27), and 70% (95% CI, 64-76), respectively, and corresponding rates after nonexcisional treatment were 51% (95% CI, 42-60), 22% (95% CI, 13-34), and 71% (95% CI, 57-83), respectively. The differences were not statistically significant. CONCLUSION: Excisional treatment could be a treatment consideration for patients with symptomatic AD and infertility for several years or repeated failure of assisted reproductive technology. Nonexcisional techniques may be considered probably for AD-related infertility.

CircRNA Circ_0000118 Regulates Malignancy of Cervical Cancer Cells by Regulating miR-211-5p/miR-377-3p/AKT2 Axis.

CircRNAs are implicated in the development of several cancers. Nevertheless, the involvement of circ_0000118 in the development of cervical cancer (CC) remains unclear. Circ_0000118 levels in tumor tissues and cells were examined by qRT-PCR. The function of circ_0000118 in regulating the malignancy of CC cells was investigated using functional assays, including CCK-8, colony formation, transwell, and tube formation experiments. The functional interaction between circ_0000118 and microRNAs were validated by dual-luciferase activity assay and RNA precipitation experiments. In vivo mouse model was employed to assess the effect of circ_0000118 in the tumorigenesis of CC cells. Circ_0000118 was overexpressed in CC cells and tissues. Loss-of-function experiments demonstrated that circ_0000118 knockdown impaired the proliferation and tumor sphere formation, as well as the angiogenic potential of CC cells. RNA interaction experiments confirmed that circ_0000118 sponged miR-211-5p and miR-377-3p. AKT2 was found to be a target gene negatively modulated by miR-211-5p and miR-377-3p. AKT2 overexpression rescued the inhibition of circ_0000118 downregulation on CC cells. Our study suggested that circ_0000118 functions as an oncogenic factor in progression of CC by maintaining AKT2 level through targeting miR-211-5p and miR-377-3p as a ceRNA (competitive endogenous RNA), which provides novel therapeutic target in the management of CC.

Toxicity interaction of polystyrene nanoplastics with sulfamethoxazole on the microalgae Chlamydomonas reinhardtii: A closer look at effect of light availability.

The coexistence of nanoplastics and antibiotics in the aquatic environment has raised a complicated risk for ecosystems and human health. How the environmental factors e.g., light, regulate the interaction between nanoplastics and antibiotics and the resulting combined toxicity is poorly understood. Here, we investigated the individual and combined toxicity of polystyrene nanoplastics (nPS, 100 mg L1) and sulfamethoxazole (SMX, 2.5 and 10 mg L-1) toward the microalgae Chlamydomonas reinhardtii under low (LL, 16 µmol m-2·s-1), normal (NL, 40 µmol m-2·s-1), and high light (HL, 150 µmol m-2·s-1) in terms of cellular responses. Results indicated that the joint toxicity of nPS and SMX commonly exhibited a strong antagonistic/mitigative effect under LL/NL at 24 h, and under NL at 72 h. nPS could adsorb more SMX under LL/NL at 24 h (1.90/1.33 mg g-1) and under NL at 72 h (1.01 mg g-1), thereby alleviating SMX toxicity to C. reinhardtii. However, the self-toxicity of nPS had a negative influence on the degree of antagonism between nPS and SMX. The experimental results coupled with computational chemistry further revealed that the adsorption capacity of SMX on nPS was stimulated by low pH under LL/NL at 24 h (∼7.5), while by less co-existing saline ions (0.83 ppt) and algae-derived dissolved organic matter (9.04 mg L-1) under NL at 72 h. nPS toxicity that was responsible for the toxic action modes was mainly attributed to the shading effect induced by hetero-aggregation and hindrance of light transmittance (>60%), as well as being regulated by additives leaching (0.49-1.07 mg L-1) and oxidative stress. Overall, these findings provided a critical basis for the risk assessment and management of multiple pollutants in the complex natural environment.

RITA1 drives the growth of bladder cancer cells by recruiting TRIM25 to facilitate the proteasomal degradation of RBPJ.

Bladder cancer (BC) is one of the most prevalent malignancies worldwide, but it lacks effective targeted therapy due to its elusive molecular mechanism. Therefore, it is important to further investigate the molecular mechanisms that mediate BC progression. By performing a tumor tissue-based gene microarray and shRNA library screening, we found that recombination signal binding protein for immunoglobulin kappa J region (RBPJ) interacting and tubulin associated 1 (RITA1) is crucial for the growth of BC cells. Moreover, RITA1 is aberrantly highly expressed in BC tissues and is also correlated with poor prognosis in patients with BC. Mechanistically, we determined that RITA1 recruits tripartite motif containing 25 (TRIM25) to ubiquitinate RBPJ to accelerate its degradation via proteasome, which leads to the transcriptional inhibition of Notch1 downstream targets. Our results suggest that aberrant high expression of RITA1 drives the growth of BC cells via the RITA1/TRIM25/RBPJ axis and RITA1 may serve as a promising therapeutic target for BC.

A genome-wide association study provides insights into fatty acid synthesis and metabolism in Malus fruits.

As a precursor of aromatic compounds, fatty acids play important roles in apple fruit quality; however, the genetic and molecular basis underlying fatty acid synthesis and metabolism is largely unknown. In this study, we conducted a genome-wide association study (GWAS) of seven fatty acids using genomic data of 149 Malus accessions and identified 232 significant signals (-log10P>5) associated with 99 genes from GWAS of four fatty acids across 2 years. Among these, a significant GWAS signal associated with linoleic acid was identified in the transcriptional regulator SUPERMAN-like (SUP) MD13G1209600 at chromosome 13 of M. × domestica. Transient overexpression of MdSUP increased the contents of linoleic and linolenic acids and of three aromatic components in the fruit. Our study provides genetic and molecular information for improving the flavor and nutritional value of apple.

Use of HIV Post-Exposure Prophylaxis Among Men Who Have Sex With Men in Shenzhen, China: A Serial Cross-Sectional Study.

HIV postexposure prophylaxis (PEP) has been prescribed to non-occupational people in recent years, but the implementation of PEP in China is still unclear. This study sought to examine the PEP use rate and factors associated with PEP in Men who have sex with men (MSM). We recruited HIV-negative MSM through offline methods from 2018 to 2020 in Shenzhen, China. Overall, PEP use increased from 3.92% to 2018, 5.73% in 2019, and 10.29% in 2020. Among 2833 participants who reported their most recent questionnaire, factors associated with PEP use included residence in Shenzhen less than 1 year, sexual intercourse with women, preferred way of finding sexual partners in MSM venues, multiple sexual partners (≥ 2), condom use, lubricant use, viagra use, less use of rush popper, HIV-related services and interest in initiating Pre-exposure prophylaxis (PrEP). The implementation of the PEP plan should focus on the groups that may be at risk of HIV infection and their continued risky behaviours. For the inappropriate use of PEP, PEP publicity should guide MSM to choose regular hospitals and strengthen HIV testing before and after PEP.

Cytoreductive prostate cryoablation and metronomic cyclophosphamide for metastatic hormone-sensitive prostate cancer.

Aim: This study reports the outcomes of cytoreductive prostate cryoablation and metronomic cyclophosphamide for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Methods: Patients with mHSPC from the authors' prostate cancer database who had received cytoreductive prostate cryoablation and metronomic cyclophosphamide were identified retrospectively. Results: Eight consecutive patients were enrolled in the study. All the patients tolerated combination therapy. The median metastatic castration-resistant prostate cancer-free survival was 62.5 months. Seven patients (87.5%) had a prostate-specific antigen nadir <0.1 ng/ml. Dysuria and hematuria before prostate cryoablation disappeared within 1 month after cryosurgery, and no incontinence was seen after prostate cryoablation. No local therapy was needed during follow-up. Conclusion: Cytoreductive prostate cryoablation and metronomic cyclophosphamide prove an effective and safe combination therapy for mHSPC.

A negative association between low-density lipoprotein cholesterol level and infection risk in elderly stage 5 chronic kidney disease patients.

BACKGROUND: To explore the relationship between low-density lipoprotein cholesterol (LDL-C) level and infection risk in elderly stage 5 kidney disease (CKD) patients. METHODS: This study retrospectively analyzed all 378 patients with grade 5 CKD over 60 years old treated in the Nephrology Department of our hospital from February 2014 to July 2019, including 286 cases with infection and 92 cases without. According to LDL-C levels, the patients were divided into three groups (Tertile 1-Tertile 3). Basic patient data and laboratory test results were collected for all three groups for analysis. RESULTS: The incidence of infection showed a gradually decreasing trend in the three groups (from 80.2, 78.6 to 68.3%), along with increasing LDL-C levels from Tertile 1 to Tertile 3, although the differences were not statistically significant (p = 0.075). After fully adjusting for confounding factors, the risk of infection was significantly reduced (OR = 0.646, 95% CI 0.420-0.993, p = 0.046) with increasing LDL-C levels. For the LDL-C levels of the three groups, the rising trend of LDL-C was significantly associated with the reduction in infection risk (OR = 0.545, 95% CI 0.317-0.937, p = 0.028). Curve fitting revealed that LDL-C levels were linearly negatively associated with the risk of infection, and the relationship between the two was not affected by the other factors (p for interaction: 0.567-1.000). CONCLUSIONS: LDL-C level is linearly negatively associated with the risk of infection in elderly patients with stage 5 CKD.

Living arrangement modifies the associations of loneliness with adverse health outcomes in older adults: evidence from the CLHLS.

BACKGROUND: Although it has been suggested that loneliness is a risk factor for adverse health outcomes, living arrangement may confound the association. This study aimed to investigate whether the associations of loneliness with adverse health outcomes differ in community-dwelling older adults according to different living arrangements. METHODS: In the 2008/2009 wave of Chinese Longitudinal Healthy Longevity Survey, 13,738 community-dwelling older adults (≥65 years) were included for analyses. Living arrangements and loneliness were assessed. Health outcomes including cognitive and physical functions were assessed using MMSE, ADL/IADL scales and Frailty Index in the 2008/2009 and 2011/2012 waves; mortality was assessed in the 3-year follow-up from 2008/2009 to 2011/2012. The effect modificaitons of loneliness on adverse health outcomes by living arrangements were estimated using logistic regression or Cox proportional hazards regression models. RESULTS: Living alone older adults were significantly more likely to be lonely at baseline (52% vs 29.5%, OR = 1.90, 95% CI = 1.67-2.16, P < 0.001), compared with those living with others. Loneliness in older adults was a significant risk factor for prevalent cognitive impairment and frailty, and 3-year mortality, especially among those who lived with others (OR = 1.32, 95% CI = 1.15-1.52, P < 0.001; OR = 1.39, 95% CI = 1.24-1.57, P < 0.001; HR = 1.14, 95% CI = 1.05-1.24, P = 0.002, respectively). In contrast, among the living alone older adults, loneliness was only significantly associated with higher prevalence of frailty (OR = 1.42, 95% CI = 1.07-1.90, P = 0.017). Living arrangement significantly modified the associations of loneliness with prevalent cognitive impairment and 3-year mortality (P values for interaction = 0.005 and 0.026, respectively). CONCLUSIONS: Living arrangement modifies the associations of loneliness with adverse health outcomes in community-dwelling older adults, and those who lived with others but felt lonely had worse cognitive and physical functions as well as higher mortality. Special attention should be paid to this population and more social services should be developed to reduce adverse health outcomes, in order to improve their quality of life and promote successful aging.

Association between squamous cell carcinoma antigen level and EGFR mutation status in Chinese lung adenocarcinoma patients.

BACKGROUND: To investigate the association between squamous cell carcinoma antigen (SCCAg) level and epidermal growth factor receptor (EGFR) mutation status in Chinese lung adenocarcinoma patients. METHODS: We retrospectively analyzed 293 patients with lung adenocarcinoma, divided into EGFR mutant group (n = 178) and EGFR wild-type group (n = 115). The general data and laboratory parameters of the two groups were compared. We used univariable and multivariable logistic regression to analyze the association between SCCAg level and EGFR mutation. Generalized additive model was used for curve fitting, and a hierarchical binary logistic regression model was used for interaction analysis. RESULTS: Squamous cell carcinoma antigen level in the EGFR wild-type group was significantly higher than that in the mutant group (p < 0.001). After adjusting for confounding factors, we found that elevated SCCAg was associated with a lower probability of EGFR mutation, with an OR of 0.717 (95% CI: 0.543-0.947, p = 0.019). For the tripartite SCCAg groups, the increasing trend of SCCAg was significantly associated with the decreasing probability of EGFR mutation (p for trend = 0.015), especially for Tertile 3 versus Tertile 1 (OR = 0.505; 95% CI: 0.258-0.986; p = 0.045). Curve fitting showed that there was an approximate linear negative relationship between continuous SCCAg and EGFR mutation probability (p = 0.020), which was first flattened and then decreased (p < 0.001). The association between the two was consistent among different subgroups, suggesting no interaction (all p > 0.05). CONCLUSION: There is a negative association between SCCAg level and EGFR mutation probability in Chinese lung adenocarcinoma patients.

[Analysis of a patient with severe Hemophilia A due to a large duplication of F8 gene].

OBJECTIVE: To report on a case with severe hemophilia A (HA) due to a large duplication of F8 gene. METHODS: Inversion detection, Sanger sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used to detect the mutation in the proband and his mother. RESULTS: The patient, a 7-year-old boy, was diagnosed with severe HA at 8 months. No inhibitor was developed over 150 exposure days. Intronic inversion detection and Sanger sequencing have failed to identify pathogenic variants, while MLPA revealed a large duplication [Ex 1_22 dup (2 copies)] in the proband, for which his mother was a carrier [Ex 1_22 dup (3 copies)]. Large duplications of the F8 gene have so far been found in 24 HA patients, all of whom had a severe phenotype, only one had a history of inhibitors. CONCLUSION: Large duplications of F8 gene are associated with severe HA. The diagnostic rate for HA may be increased by MLPA.