Liraglutide improved the reproductive function of obese mice by upregulating the testicular AC3/cAMP/PKA pathway.

BACKGROUND: The incidence of male reproductive dysfunction is increasing annually, and many studies have shown that obesity can cause severe harm to male reproductive function. The mechanism of male reproductive dysfunction caused by obesity is unclear, and there is no ideal treatment. Identification of effective therapeutic drugs and elucidation of the molecular mechanism involved in male reproductive health are meaningful. In this study, we investigated the effects of the GLP-1 receptor agonist liraglutide on sex hormones, semen quality, and testicular AC3/cAMP/PKA levels in high-fat-diet-induced obese mice. METHODS: Obese mice and their lean littermates were treated with liraglutide or saline for 12 weeks. Body weight was measured weekly. Fasting blood glucose (FBG) was measured using a blood glucose test strip. The serum levels of insulin (INS), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), free testosterone (F-TESTO), estradiol (E2), and sex hormone binding globulin (SHBG) were detected using ELISA. The sperm morphology and sperm count were observed after Pap staining. The mRNA and protein expression levels of testicular GLP-1R and AC3 were measured by RT-qPCR and Western blot, respectively. Testicular cAMP levels and PKA activity were detected using ELISA. RESULTS: Liraglutide treatment can decrease body weight, FBG, INS, HOMA-IR, E2 and SHBG levels; increase LH, FSH, T, and F-TESTO levels; increase sperm count; decrease the sperm abnormality rate; and increase GLP-1R and AC3 expression levels and cAMP levels and PKA activity in testicular tissue. CONCLUSIONS: Liraglutide can improve the sex hormone levels and semen quality of obese male mice. In addition to its weight loss effect, liraglutide can improve the reproductive function of obese male mice, which may also be related to the upregulation of AC3/cAMP/PKA pathway in the testis. This work lays the groundwork for future clinical studies.

Triglyceride-glucose index is strongly associated with all-cause mortality in elderly females with diabetic foot ulcers: A 9-year follow-up study.

This study aims to explore the association between the triglyceride-glucose (TyG) index and all-cause mortality in patients with diabetic foot ulcers (DFUs) through an ambispective cohort study. A total of 555 inpatients with DFUs were qualified to participate in the trial study from 2013 to 2022. Throughout a median 63-month period, all subjects were followed up every 6 months. According to the three quantiles of the TyG index, participants were divided into three groups: low-level (≤8.75, n = 185), moderate-level (8.76-9.33, n = 185) and high-level (≥9.34, n = 185). The association between the TyG index and all-cause mortality in patients with DFUs was then assessed. During the follow-up period, out of 555 patients with DFUs, 116 died (20.9%). After adjusting for confounding factors, the TyG index was positively associated with all-cause mortality in patients with DFUs (HR = 1.733; 95% CI = 1.341-2.241; p < 0.001). Compared with the low-level TyG index, the moderate-level TyG index (HR = 1.685; 95% CI = 1.011-2.810; p = 0.045) and the high-level TyG index (HR = 2.769; 95% CI = 1.678-4.568; p < 0.001) were positively correlated with all-cause mortality in patients with DFUs. Additionally, in subgroup analysis, both females (HR = 1.905; 95% CI = 1.250-2.904; p = 0.003), males (HR = 1.729; 95% CI = 1.240-2.409; p = 0.001), younger (<65 years old) (HR = 1.467; 95% CI = 1.008-2.135; p = 0.046) and elderly (≥ 65) (HR = 1.933; 95% CI = 1.339-2.791; p < 0.001) showed a positive correlation between TyG index and all-cause mortality rate in patients with DFUs. Furthermore, in the high-level TyG index group compared, males (HR = 2.699; 95% CI = 1.457-4.998) and participants aged <65 years (HR = 2.031; 95% CI = 0.972-4.242), with the TyG index level increase by 1.0, the risk for all-cause mortality increased 3.277-fold in females (HR = 4.277; 95% CI = 1.645-11.124) and 1.909-fold in elderly aged ≥65 years (HR = 2.909; 95% CI = 1.486-5.695), respectively. Kaplan-Meier survival curve analysis showed that the higher the TyG index level, the higher risk of all-cause mortality in patients with DFUs (log-rank, all p < 0.001). Briefly, this study implies a strong positive correlation between the TyG index and all-cause mortality in patients with DFUs, especially in older women. Therefore, special attention should be paid to elderly females with DFUs because they have a higher TyG index level and risk of all-cause mortality than other populations in daily clinical practice.

Metabolic dysfunction-associated fatty liver disease in the elderly with diabetic foot ulcers: A longitudinal cohort study.

This study aimed to explore the association between metabolic-associated fatty liver disease (MAFLD) and ulcer recurrence risk in patients with diabetic foot ulcers (DFUs) through an ambispective longitudinal cohort. From December 2013 to December 2022, a total of 482 inpatients with DFUs (PEDIS grade 3 and above with a severe infection) were eligible for inclusion in this study. This was an ambispective longitudinal cohort study. All participants were followed up every 6 months for 9 years with a median of 36 months. According to whether having MAFLD or not, all subjects were placed into two groups: non-MAFLD (n = 351) and MAFLD (n = 131). The association between MAFLD and ulcer recurrence in patients with DFUs was then evaluated through multivariate Cox regression analysis, stratified analyses and Kaplan-Meier survival analysis. Throughout the follow-up period, out of 482 subjects with DFUs, 68 had ulcer recurrence (14.1%). Three Cox regression models were established for data analyses. In the model I (unadjusted), MAFLD was significantly associated with the ulcer recurrence rate in patients with DFUs (HR = 1.79; 95% CI = 1.097-2.92; p = 0.02). Model II (adjusted model I with gender and age) (HR = 1.781; 95% CI = 1.09-2.912; p = 0.021) and model III (adjusted model II with CVD, duration of diabetes and Cr.) (HR = 1.743; 95% CI = 1.065-2.855; p = 0.027) also showed that MAFLD was significantly related to the ulcer recurrence risk in patients with DFUs, respectively. Stratified analysis indicated that subjects aged ≥60 had a greater risk of ulcer recurrence in MAFLD than in non-MAFLD (HR = 2.31; 95% CI = 1.268-4.206; p = 0.006). Kaplan-Meier survival curve analysis showed that ulcer recurrence rate had a significant association with MAFLD (log-rank, p = 0.018). This study indicated a close association between ulcer recurrence risk and MAFLD in patients with DFUs, especially in the elderly (aged ≥60). Therefore, special attention should be paid to the elderly with both DFUs and MAFLD because they have a higher ulcer recurrence rate than other general populations in routine clinical practice.

The triglyceride glucose index as a sensitive predictor for the risk of MACCEs in patients with diabetic foot ulcers: An ambispective longitudinal cohort study.

The triglyceride glucose (TyG) index has been confirmed a predictive value for type 2 diabetes mellitus (T2DM). However, no research has yet confirmed whether there is a linear correlation between the TyG index and MACCEs in DFUs. The present study aimed to delve into the association between the TyG index and the risk of MACCEs in patients with DFUs. A total of 960 inpatients with DFUs were recruited. All participants were followed up every 6 months for 11 years with a median of 83 months. According to the cut-off value of the TyG index acquired from receiver operating characteristic (ROC) analysis, the subjects were divided into two groups: low-level (<9.12, n = 480) and high-level (≥9.12, n = 480). The relationship between the TyG index and MACCEs was evaluated by the multivariable Cox regression model, restricted cubic spline (RCS) model, stratified analysis and the Kaplan-Meier survival analysis. Out of 960 participants, 271 experienced MACCEs (28.22%), of whom 79 (29.15%) died. ROC analysis got the optimal TyG index cut-off value of 9.12. Multivariable Cox regression analysis combined with the RCS model showed that the TyG index was positively associated with MACCEs in an S-shaped non-linear dose-dependent manner within the range of TyG index 7.5-9.5 (p < 0.001). The Kaplan-Meier survival analysis indicated the higher the TyG index, the greater the cumulative incidence of MACCEs (log-rank, p < 0.001). The study first confirmed an S-shaped non-linear dose-dependent positive relationship between the TyG index and the risk of MACCEs in DFUs. Consequently, lowering the TyG index level aids in improving the prognosis of patients with DFUs.

Autologous wound margin point columnar full-thickness skin grafting combined with negative pressure wound therapy improves wound healing in refractory diabetic foot ulcers.

Diabetic lower extremity ulcers (DLEUs) are a severe complication of diabetes mellitus (DM) and are difficult to heal. This study aimed to explore the efficacy of autologous point columnar full-thickness skin graft taken from the ulcer wound margin combined with negative pressure wound therapy (NPWT) in refractory DLEUs. This is a prospective cohort study. A total of 40 inpatients with refractory DLEUs were recruited in the Diabetes Foot Center of Guangxi Zhuang Autonomous Region People's Hospital from October 2019 to November 2021. According to the doctors' professional suggestions and the patients' personal wishes, these enrolled patients were divided into two groups based on different topical wound management: the graft group (n = 18) and the conventional wound therapeutic (CWT) group (n = 22). The efficacy evaluations included the time to complete re-epithelialization of the wound and healing speed within 14 days of graft treatment or after 14 days of graft treatment in the two groups. Before the treatment, the graft group had a significantly larger ulcer area than the CWT group [27.22 (15.28, 46.59) versus 10.92 (7.00, 24.93) cm2 , P < .01]. However, the time to complete wound re-epithelialization in the graft group was shorter than in the CWT group [58.22 ± 30.60 versus 86.09 ± 49.54 d, P < .05]. Meanwhile, the healing speed in graft group was markedly faster than in CWT group, whether within 14 days [0.60 (0.40, 0.92) versus 0.16 (0.07, 0.34) cm2 /d, P < .01] or after 14 days of graft treatment [0.57 (0.45, 0.91) versus 0.13 (0.08, 0.27) cm2 /d, P < .01]. However, the total treatment cost in the graft group was lower than in the CWT group [419.59 ± 137.20 versus 663.97 ± 497.02 $, P < .05]. The novel treatment modality of autologous full-thickness skin graft taken from the ulcer wound margin combined with NPWT has hereby proposed for the first time, and is a safe, effective, and reliable method with a good performance-to-cost ratio to promote wound healing and shorten the healing time for DLEUs.

Risk factors for foot ulcer recurrence in patients with comorbid diabetic foot osteomyelitis and diabetic nephropathy: A 3-year follow-up study.

This study aimed to explore the risk factors for foot ulcer recurrence in patients with comorbid diabetic foot osteomyelitis (DFO) and diabetic nephropathy (DN). This is a prospective cohort study. Between May 2018 and May 2021, we selected 120 inpatients with comorbid severe diabetic foot infection (PEDIS Grade 3 or above) and DN for inclusion in our study. All cases were followed up for 36 months. The study outcomes were whether foot ulcer recurred and the time to recurrence. The risk factors of ulcer recurrence were analysed by comparing the data of the three groups. According to the recurrence of foot ulcer, the participants were divided into three groups: Group A (no foot ulcer recurrence, n = 89), Group B (foot ulcer recurrence within 12-36 months, n = 19) and Group C (foot ulcer recurrence within 6-12 months, n = 12). The multivariate Cox regression analysis showed that urine albumin-creatinine ratio (UACR) (HR: 1.008, 95% CI: 1.005-1.011, P < .001) and vibration perception threshold (VPT) (HR: 1.064, 95% CI: 1.032-1.096, P < .001) were identified as independent risk factors. Kaplan-Meier curves showed a significant positive association between UACR or VPT and the risk of foot ulcer recurrence (log rank, all P < .05). Areas under the ROC curves for UACR, VPT and the combination of UACR and VPT were 0.802, 0.799 and 0.842, respectively. The best cut-off values of UACR and VPT were 281.51 mg/g and 25.12 V, respectively. In summary, elevated UACR and VPT were independent risk factors. The best clinical cut-off values of UACR and VPT for prediction of foot ulcer recurrence were 281.51 mg/g and 25.12 V, respectively. Besides, our results suggested that microcirculation disorders rather than macrovascular complications play a major role in the recurrence of foot ulcer in patients with comorbid DFO and DN.

Rhodamine-based chemosensor for Sn2+ detection and its application in nanofibrous film and bioimaging.

A simple rhodamine-based compound CK was designed and synthesized as a fluorescent chemosensor for Sn2+ based on Sn2+-mediated cyclization. The optical investigation indicated that the probe could quantitatively detect Sn2+ in a concentration range of 10-30 µM, with a detection limit of 118 nM. Moreover, probe CK, with low cytotoxicity, was successfully applied for imaging of Sn2+ in HeLa cells and mice, exhibiting excellent biocompatibility and cell membrane permeability. For on-site monitoring, CK-hybridized polymethyl methacrylate (PMMA) nanofibers were prepared by electrospinning and successfully employed for the visual detection of Sn2+ in actual samples. All the results demonstrated that the chemosensor could be a promising tool for the detection of Sn2+ in vitro and in vivo.

Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels.

Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation.

Preparation of Silica/Reduced Graphene Oxide Nanosheet Composites for Removal of Organic Contaminants from Water.

Graphene-based composites open up new opportunities as effective adsorbents for the removal of organic contaminants from water. In this article, we report a novel and facile process to synthesize well-dispersed silica/reduced graphene oxide (SiO2/RGO) nanosheet composites. The SiO2/RGO nanosheet composites are prepared through a modified sol-gel process with in situ hydrolysis of tetraethoxysilane (TEOS) on graphene oxide (GO) nanosheet, followed by reduction of GO to graphene. In comparison with the RGO nanosheets, the as-prepared SiO2/RGO nanosheet composites have a larger surface area and good aqueous disperse ability. In addition, the application of SiO2/RGO nanosheet composites was demonstrated on removing organic dyes from water. The SiO2/RGO nanosheet composites show rapid and stable adsorption performance on removal of Methylene Blue (MB) and thionine (TH) from water. It is indicated that the resulting SiO2/RGO composites can be utilized as efficient adsorbents for the removal of organic contaminants from water.

A novel MVK missense mutation in one Chinese family with disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is a severe chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. mevalonate kinase, (MVK) a gene know to play an important role in regulation of calcium-induced keratinocyte differentiation and proliferation, has recently been suggested as the disease-causing gene for DSAP. Here we report a direct sequencing analysis of this gene in 3 DSAP families, 6 sporadic cases, and 100 unrelated healthy controls. We detected a heterozygous T to A transition at nucleotide 205 in exon 3 of MVK gene in one familial case. This mutation will result in an amino acid change at codon 69 (P.Ser69Thr), which is from a serine codon (TCA) to a threonine codon (ACA). No such mutation was detected in the unaffected family members or the 100 unrelated healthy controls. Our results demonstrated a novel missense mutation in MVK gene. This will be valuable for the diagnosis of DSAP as well as for genetic counseling and prenatal diagnosis of affected families.

Reactivation Risk of Latent Tuberculosis or Inactive Hepatitis B Virus Infection and Effectiveness of Ustekinumab in Chinese Plaque Psoriasis Patients: A 28-Week Retrospective, Observational Study.

Introduction: This study observed the effectiveness of ustekinumab and reactivation risk of concurrent latent tuberculosis infection (LTBI) and inactive hepatitis B virus (HBV) infection in Chinese mainland psoriasis patients on ustekinumab treatment. Methods: This retrospective, multicenter, observational study was conducted in three centers in China. Adult patients with moderate to severe plaque psoriasis were treated with ustekinumab for 28 weeks. The effectiveness endpoint included 75% and 90% improvement in Psoriasis Area Severity Index (PASI75/90) response rate, percentage of PASI improvement, change of absolute PASI score and body surface area involvement (BSA) score, absolute PASI ≤1/3 and Physicians' Global Assessment (PGA)=0/1, as well as Dermatology life quality index (DLQI)=0/1 response rate at week 4, 16 and 28. Screening of tuberculosis and hepatitis were performed at baseline and week 28. Results: A total of 82 patients were enrolled between March 2021 and May 2023 and the number of patients combined with LTBI and inactive HBV infection was 20 and 21 respectively. The PASI75 and PASI90 response rate at week 28 was 95.1% and 81.7% respectively. The mean PASI score decreased from 14.93 ± 12.07 at baseline to 0.78 ± 1.86 at week 28, and the mean BSA score decreased from 21% ± 18% at baseline to 1% ± 2% at week 28 (both P<0.001 compared with baseline). DLQI 0/1 response rate at week 28 was 73.2%. No reactivation of LTBI and inactive HBV infection and also no new-onset tuberculosis and hepatitis B occurred in patients without LTBI and inactive HBV infection at baseline. Conclusion: Ustekinumab demonstrated great effectiveness in Chinese plaque psoriasis patients and good safety in psoriasis concurrent with LTBI and inactive HBV infection under the real-world setting.

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and MACCEs in Patients with Diabetic Foot Ulcers: An Ambispective Longitudinal Cohort Study.

Aim: Metabolic dysfunction-related fatty liver disease (MAFLD) is closely related to metabolic disorders. However, the relationship between MAFLD and the prognosis in diabetic foot ulcers (DFUs) remains unclear. This study aimed to explore the association between MAFLD and the risk of major adverse cardiac and cerebral events (MACCEs) in patients with DFUs. Methods: 889 inpatients with DFUs (PEDIS/TEXAS mild and above) were included in this study from 2013 to 2023. All participants were placed into non-MAFLD (n = 643) and MAFLD (n = 246) groups and followed up every 6 months for 10.9 years with a median of 63 months through in-person outpatient interviews and family fixed-line telephone visits. The association between MAFLD and the risk of MACCEs was evaluated through Multivariate Cox regression analyses, Stratified analyses and Kaplan-Meier survival analyses. Results: Of the 889 subjects, 214 (24.07%) experienced MACCEs. Multivariate Cox regression analysis showed that MAFLD was independently associated with MACCEs (P < 0.001), of which with non-fatal myocardial infarction (P = 0.04), non-fatal stroke (P = 0.047), coronary artery revascularization (P = 0.002), heart failure (P = 0.029), and all-cause mortality (P = 0.021), respectively. The stratified analysis revealed that compared with non-MAFLD (HR=1), DFUs with MAFLD had a 2.64-fold increased risk for MACCEs (P <0.001; P for interaction = 0.001) in peripheral arterial disease (PAD) subgroup. Kaplan-Meier analysis evidenced that the MAFLD group had a higher cumulative incidence of MACCEs (log-rank, all P < 0.05). Conclusion: MAFLD is a high-risk factor for MACCEs in patients with DFUs. The findings will remind clinicians to pay more attention to MAFLD in patients with DFUs, especially in patients with DFUs combined with PAD as early as possible in clinical practice and adopt timely effective intervention strategies to prevent the occurrence of MACCEs to improve the clinical prognosis in patients with DFUs.

The Ratio of Red Blood Cell Distribution Width to Albumin as a Predictor for Rehospitalization Risk and Rehospitalization All-Cause Mortality in Middle-Aged and Elderly Survivors with Sepsis: An Ambispective ICU Cohort Study.

Objective: To explore the relationship between red blood cell distribution width to albumin (RDW/ALB) ratio (RAR) and the risk of rehospitalization and rehospitalization all-cause mortality in middle-aged and elderly survivors with sepsis based on an ambispective longitudinal cohort from the Intensive Care Unit (ICU). Methods: Between 2017 and 2022, 455 adults who survived the first-episode severe sepsis without recurrence for at least 3 months were included in this study. All participants were followed up every 4 weeks for 12 months. According to the tertiles of RAR, participants were divided into three groups: low-level (≤0.36, n = 152), moderate-level (0.37-0.44, n = 152), and high-level (≥0.45, n = 151). The relationship between RAR and the risk of rehospitalization and rehospitalization all-cause mortality was evaluated. Results: Out of 455 participants, 156 experienced rehospitalization (34.3%), of which 44 (28.2%) died. Receiver operating characteristic (ROC) analysis showed that the RAR cut-off values for rehospitalization and rehospitalization all-cause mortality were 0.4251 and 0.4743, respectively. Multivariate Cox regression analysis indicated that the RAR was positively associated with rehospitalization (P = 0.011) and all-cause mortality (P = 0.006). Compared with the low-level, the high-level RAR presented a higher dose-dependent rehospitalization risk (P = 0.02) and rehospitalization all-cause mortality (P = 0.044). The stratified analysis displayed that compared to the low-level, with the RAR increasing by 1.0, the risk for rehospitalization increased 3.602-fold in aged <65 patients (P = 0.002) and 1.721-fold in female patients (P = 0.014). Kaplan-Meier survival analysis implied a significant positive association between the RAR and the cumulative incidence of rehospitalization and rehospitalization all-cause mortality (log-rank, all P < 0.001). Conclusion: RAR has a reliable predictive value for the risk of rehospitalization and rehospitalization all-cause mortality in patients with sepsis. Consequently, monitoring RAR for at least 1 year after surviving sepsis in female patients aged <65 in clinical practice is critical.

Radioactive Iodine-131 Therapy Reduced the Risk of MACEs and All-Cause Mortality in Elderly with Hyperthyroidism Combined with Type 2 Diabetes.

Aim: This study aimed to assess the efficacy of antithyroid drugs (ATDs) and radioactive iodine-131 (RAI) therapies in reducing the risk of major adverse cardiovascular events (MACEs) and all-cause mortality in patients with hyperthyroidism complicated with type 2 diabetes mellitus (T2DM). Methods: Between January 2013 and December 2021, 540 subjects were included in the analysis. All participants were followed up for 9 years, with a median of 54 months (2451 person-years). The subjects were categorized into two groups: the ATDs group (n = 414) and the RAI group (n = 126). According to the free triiodothyronine (FT3) tertiles, the patients receiving RAI were further grouped as follows: low-level (≤ 4.70 pmol/L, n = 42), moderate-level (4.70-12.98 pmol/L, n = 42), and high-level (≥ 12.98 pmol/L, n = 42). The efficacy of ATDs and RAI therapies in reducing the risk of MACEs and all-cause mortality was assessed. Results: Of the 540 participants, 163 experienced MACEs (30.19%), 25 (15.34%) of whom died. Multivariate Cox regression analyses revealed that RAI was associated with a 38.5% lower risk of MACEs (P = 0.016) and a 77.1% lower risk of all-cause mortality (P = 0.046). Stratified analyses indicated that RAI had a protective effect on MACEs in patients aged ≥ 60 years (P = 0.001, P for interaction = 0.031) and patients with a duration of diabetes mellitus ≥ 6 years (P = 0.013, P for interaction = 0.002). Kaplan‒Meier analysis revealed a lower cumulative incidence of MACEs and all-cause mortality in the RAI group (log-rank, all P < 0.05). Moreover, the ROC curve suggested an optimal FT3 cut-off value of 5.4 pmol/mL for MACE (P < 0.001). Conclusion: Our findings suggested that RAI therapy effectively reduced the risk of MACEs and all-cause mortality in elderly patients with hyperthyroidism combined with T2DM.

Geriatric nutritional risk index as a predictor for fragility fracture risk in elderly with type 2 diabetes mellitus: A 9-year ambispective longitudinal cohort study.

BACKGROUND & AIMS: The elderly are prone to fragility fractures, especially those suffering from type 2 diabetes mellitus (T2DM) combined with osteoporosis. Although studies have confirmed the association between GNRI and the prevalence of osteoporosis, the relationship between GNRI and fragility fracture risk and the individualized 10-year probability of osteoporotic fragility fractures estimated by FRAX remains unclear. This study aims to delve into the association between the GNRI and a fragility fracture and the 10-year probability of hip fracture (HF) and major osteoporotic fracture (MOF) evaluated by FRAX in elderly with T2DM. METHODS: A total of 580 patients with T2DM aged ≥60 were recruited in the study from 2014 to 2023. This research is an ambispective longitudinal cohort study. All participants were followed up every 6 months for 9 years with a median of 3.8 years through outpatient services, medical records, and home fixed-line telephone interviews. According to the tertiles of GNRI, all subjects were divided into three groups: low-level (59.72-94.56, n = 194), moderate-level (94.56-100.22, n = 193), and high-level (100.22-116.45, n = 193). The relationship between GNRI and a fragility fracture and the 10-year probability of HF and MOF calculated by FRAX was assessed by receiver operating characteristic (ROC) analysis, Spearman correlation analyses, restricted cubic spline (RCS) analyses, multivariable Cox regression analyses, stratified analyses, and Kaplan-Meier survival analysis. RESULTS: Of 580 participants, 102 experienced fragile fracture events (17.59%). ROC analysis demonstrated that the optimal GNRI cut-off value was 98.58 with a sensitivity of 75.49% and a specificity of 47.49%, respectively. Spearman partial correlation analyses revealed that GNRI was positively related to 25-hydroxy vitamin D [25-(OH) D] (r = 0.165, P < 0.001) and bone mineral density (BMD) [lumbar spine (LS), r = 0.088, P = 0.034; femoral neck (FN), r = 0.167, P < 0.001; total hip (TH), r = 0.171, P < 0.001]; negatively correlated with MOF (r = -0.105, P = 0.012) and HF (r = -0.154, P < 0.001). RCS analyses showed that GNRI was inversely S-shaped dose-dependent with a fragility fracture event (P < 0.001) and was Z-shaped with the 10-year MOF (P = 0.03) and HF (P = 0.01) risk assessed by FRAX, respectively. Multivariate Cox regression analysis demonstrated that compared with high-level GNRI, moderate-level [hazard ratio (HR) = 1.950; 95% confidence interval (CI) = 1.076-3.535; P = 0.028] and low-level (HR = 2.538; 95% CI = 1.378-4.672; P = 0.003) had an increased risk of fragility fracture. Stratified analysis exhibited that GNRI was negatively correlated with the risk of fragility fracture, which the stratification factors presented in the forest plot were not confounding factors and did not affect the prediction effect of GNRI on the fragility fracture events in this overall cohort population (P for interaction > 0.05), despite elderly females aged ≥70, with body mass index (BMI) ≥24, hypertension, and with or without anemia (all P < 0.05). Kaplan-Meier survival analysis identified that the lower-level GNRI group had a higher cumulative incidence of fragility fractures (log-rank, all P < 0.001). CONCLUSION: This study confirms for the first time that GNRI is negatively related to a fragility fracture and the 10-year probability of osteoporotic fragility fractures assessed by FRAX in an inverse S-shaped and Z-shaped dose-dependent pattern in elderly with T2DM, respectively. GNRI may serve as a valuable predictor for fragility fracture risk in elderly with T2DM. Therefore, in routine clinical practice, paying attention to the nutritional status of the elderly with T2DM and giving appropriate dietary guidance may help prevent a fragility fracture event.

Efficacy of Morning Versus Evening Latanoprost/Timolol Fixed Combination for Open-Angle Glaucoma and Ocular Hypertension: A Randomized Clinical Trial.

Purpose: To compare the efficacy of morning and evening latanoprost/timolol fixed-combination (LTFC) dosing in patients with primary open-angle glaucoma (POAG) and ocular hypertension. Methods: In this double-blind, randomized clinical trial, 63 untreated Chinese patients with POAG and ocular hypertension were enrolled. All patients received LTFC and were randomized (1:1) to group 1, morning (8 AM) dosing, or group 2, evening (8 PM) dosing. Vehicle drops were used in the morning or evening, accordingly, to preserve masking. Patients were treated for 4 weeks. Outcomes included mean reduction of the 24-hour intraocular pressure (IOP) and IOP fluctuation from baseline after a 4-week treatment. Results: Fifty-six patients were included in the final analysis. In both groups, the posttreatment IOP values were significantly lower than those at baseline at each 24-hour measuring time point. A significant difference between the groups in IOP reduction from baseline was observed at the 9:30 AM time point (4.01 ± 2.62 vs. 2.42 ± 3.23 mm Hg, evening dosing versus morning dosing group; P = 0.048). Both groups showed decreased IOP fluctuation after treatment. However, the morning dosing group had a significantly greater decrease in diurnal IOP fluctuation than that of the evening dosing group (2.04 ± 2.32 mm Hg vs. 0.50 ± 1.70 mm Hg, respectively; P = 0.012). Conclusions: Both morning and evening LTFC dosing can effectively reduce 24-hour IOP and IOP fluctuation. Morning dosing is more likely to effectively control diurnal IOP fluctuations. Translational Relevance: This multicenter, double-blind, randomized clinical trial generates robust evidence on the optimal LTFC dosing regimen to help clinical decision-making in the treatment of raised IOP.

One novel susceptibility locus associate with systemic lupus erythematosus in Chinese Han population.

The aim of the study is to explore additional susceptibility factors for systemic lupus erythematosus (SLE) in Chinese Hans. Based on our previous GWAS of SLE, we performed a multistage replication study involving 3,152 cases and 7,050 controls from China to identify additional susceptibility loci for SLE by using the Sequenom MassArray system. All Chinese Han samples used in this study were obtained from doctors through collaboration with multiple hospitals in two geographic regions (central and southern China). Single-marker association analyses were performed using logistic regression with gender as a covariate in each case-control cohort. The joint analysis of all combined samples was performed using logistic regression with gender and sample cohorts as covariates. The significant association evidence for rs906868 (OR = 1.14, 95% CI 1.08-1.20, P combined = 7.71 × 10(-10)) and rs7579944 (OR = 1.13, 95% CI 1.07-1.19, P combined = 5.55 × 10(-9)) was observed, which located at 2p23.1. In this region, limb bud and heart development homolog (LBH) was the only gene indicated, suggesting LBH might be a susceptibility gene for SLE, although its function was still unknown. The results indicated that the SNP rs7579944, rs906868 at 2p23.1 showed significant association with SLE. The genes LBH which located in this loci might be the predisposing genes of SLE.

Potential adverse actions of prenatal exposure of acetaminophen to offspring.

Acetaminophen (APAP) is a widely used as analgesic and antipyretic drug. APAP is also added as an active ingredient in various medications to relieve pain and reduce fever. APAP has been widely used in pregnant women in the past decades because it is considered a relatively safe drug with recommended dose in different countries. However, an increasing number of epidemiological and experimental studies have shown that APAP exposure during pregnancy may increase the risk of inducing reproductive and neurobehavior dysfunctions, hepatotoxicity in offspring. This review aims to assess the potential effects of prenatal APAP exposure on offspring growth and development.

Low Molecular Weight Hydrogel for Wound Healing.

Octadecylazanediyl dipropionic acid (C18ADPA) is a zwitterionic amphiphile with a dendritic headgroup. C18ADPA self-assembles to lamellar networks, which encompasses water and forms a low-molecular-weight hydrogel (LMWG). In this study, we use the C18ADPA hydrogel as a drug carrier for the in vivo delivery of a copper salt for wound healing in a mouse model. A structural transition was observed based on cryo-scanning electron microscope (cryo-SEM) images after drug loading. The C18ADPA hydrogel, which had a layered structure, transformed into a self-assembled fibrillar network (SAFiN). The mechanical strength of the LMWG has always been an important issue in its applications. However, due to the structural transition, both the storage and loss moduli increased. In vivo tests showed that wound closure was faster after applying the hydrogel formulation compared with the Vaseline formulation. For the first time, we have also provided histological evidence of these effects on skin tissue. The hydrogel formulation exhibited clear advantages in regenerating tissue structure over traditional delivery formulations.

Triglyceride Glucose Index is Strongly Associated with a Fragility Fracture in Postmenopausal Elderly Females with Type 2 Diabetes Mellitus Combined with Osteoporosis: A 6-Year Follow-Up Study.

Purpose: The triglyceride glucose (TyG) index serves as an indicator of insulin resistance (IR), which is also associated with bone metabolism. However, research on the relationship between the TyG index and a fragility fracture in individuals with type 2 diabetes mellitus (T2DM) or osteoporosis (OP) remains sparse. This study aims to explore the association between the TyG index and fragility fracture risk in postmenopausal elderly females with T2DM combined with OP based on an ambispective cohort study. Patients and Methods: A total of 220 postmenopausal women hospitalized with T2DM combined with OP between January 2015 and December 2020 were eligible for inclusion in this study. All participants were followed up every 6 months for 6 years with a median of 42 months. According to the tertiles of the TyG index, participants were divided into three groups: low-level (≤ 8.79, n =73), moderate-level (8.80-9.32, n=73), and high-level (≥ 9.33, n=74). The association between the TyG index and fragility fracture risk was then assessed. Results: Out of 220 patients, 46 experienced fragility fracture events (20.9%). Multivariate Cox regression analysis showed that the TyG index was positively associated with a fragility fracture in postmenopausal women with T2DM combined with OP. Furthermore, compared to the low-level group, with the TyG index level increase by 1.0, the risk for fragility fracture increased 1.293-fold in the high-level group (HR=2.293, 95% CI=1.007-5.221, P < 0.05). Kaplan-Meier survival analysis indicated that fragility fractures were more likely to occur in patients with high levels of TyG index (log-rank, all P < 0.05). Conclusion: Our study showed that the TyG index was strongly associated with a fragility fracture in postmenopausal women with T2DM combined with OP. Therefore, special attention should be paid to postmenopausal elderly females with T2DM combined with OP in routine clinical practice.