Associations of perfluoroalkyl substances with metabolic-associated fatty liver disease and non-alcoholic fatty liver disease: NHANES 2017-2018.

OBJECTIVES: This study investigated the potential effects of perfluoroalkyl substance (PFAS) in serum on MAFLD, NAFLD, and liver fibrosis. METHODS: Our sample included 696 participants (≥ 18 years) from the 2017-2018 NHANES study with available serum PFASs, covariates, and outcomes. Using the first quartile of PFAS as the reference group, we used weighted binary logistic regression and multiple ordered logistic regression used to analyze the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and multiple ordinal logistic regression to investigate the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and calculated the odds ratio (OR) and 95% confidence interval for each chemical. Finally, stratified analysis and sensitivity analysis were performed according to gender, age, BMI, and serum cotinine concentration. RESULTS: A total of 696 study subjects were included, including 212 NAFLD patients (weighted 27.03%) and 253 MAFLD patients (weighted 32.65%). The quartile 2 of serum PFOA was positively correlated with MAFLD and NAFLD (MAFLD, OR 2.29, 95% CI 1.05-4.98; NAFLD, OR 2.37, 95% CI 1.03-5.47). PFAS were not significantly associated with liver fibrosis after adjusting for potential confounders in MAFLD and NAFLD. Stratified analysis showed that PFOA was strongly associated with MAFLD, NAFLD, and liver fibrosis in males and obese subjects. In women over 60 years old, PFHxS was also correlated with MAFLD, NAFLD, and liver fibrosis. CONCLUSION: The serum PFOA was positively associated with MAFLD and NAFLD in US adults. After stratified analysis, the serum PFHxS was correlated with MFALD, NAFLD, and liver fibrosis.

Association between plasma trans fatty acids and serum α-klotho levels in adults in the United States of America: an analysis of the NHANES 2009-2010 datasets.

BACKGROUND: This study aimed to explore the potential associations between trans fatty acid (TFA) and α-klotho levels. METHODS: Datasets from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) were analysed for this study. Multivariable linear regression and restricted cubic spline (RCS) analyses were performed to examine the relationships between plasma TFA and serum α-klotho levels. RESULTS: A total of 1,205 participants were included, with a geometric mean (GM) of 803.60 (95% CI: 787.45, 820.00) pg/mL for serum α-klotho levels. RCS analysis revealed L-shaped relationships between TFA and α-klotho levels. The inflection points for palmitelaidic acid (PA), vaccinic acid (VA), elaidic acid (EA), and total TFA levels were 4.55, 20.50, 18.70, and 46.40 µmol/L, respectively. Before reaching the inflection point, serum α-klotho levels were negatively correlated with plasma PA, VA, EA and total TFA levels, with ß values (95% CI) of -0.15 (-0.24, -0.06), -0.16 (-0.23, -0.09), -0.14 (-0.22, -0.05) and - 0.19 (-0.27, -0.11), respectively. Linolelaidic acid (LA) levels exhibited an inverse and linear association with α-klotho levels ( Pnonlinearity=0.167, Poverall<0.001). L-shaped relationships between TFA and α-klotho levels were also observed in the subgroups of participants who were aged < 65 years, were male, did not exercise, were ex-smokers, and were overweight/obese. CONCLUSIONS: L-shaped correlations between plasma PA, VA, EA, and total TFA levels and serum α-klotho levels were observed among adults in the United States.

The association of metabolic profile of folate with diabetic kidney disease: evidence from 2011-2020 cycles of the NHANES.

AIMS: Diabetic kidney disease (DKD) develops in approximately 40% of patients with type 2 diabetes mellitus (T2DM). The role of folate metabolites in the progression from T2DM to DKD has not been clearly articulated. Our aim was to assess the association of folate metabolites with DKD. METHODS: We conducted a cross-sectional study sourced from the U.S. National Health and Nutrition Examination Survey from 2011 to 2020. Several forms of folate were measured. DKD was defined as diabetes with albuminuria or impaired glomerular filtration rate. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: Of the 3,461 diabetes patients, 1,349 (38.98%) were diagnosed with DKD. Serum total folate and 5-Methyl-THF were negatively associated with DKD, the OR for comparing extreme quintile were both 0.73 (0.57-0.94). However, a positive association of RBC folate, UMFA, Non-5-Methyl-THF, and MeFox with DKD was observed with extreme quintile OR of 1.41 (1.10-1.82), 1.60 (1.24-2.07), 1.53 (1.20-1.96), and 3.45 (2.65-4.50). Furthermore, the ratio of UMFA to 5-Methyl-THF exhibited a positive association with DKD, with extreme quintile OR of 1.94 (1.50-2.50). CONCLUSIONS: Our findings suggested that guidelines and interventions highlighting the importance of promoting 5-Methyl-THF and reducing UMFA might have significant benefit for the management of patients with diabetes.

Of 3,461 diabetes patients, 1,349 (38.98%) were diagnosed with diabetic kidney disease (DKD).Serum total folate, 5-Methy-THF and the risk of DKD exhibited a negative association, characterized by a U-shaped relationship.RBC folate, serum non-5-methyl-THF and MeFox were positively associated with DKD, without a safety threshold.

Evaluation of the Role of Tanshinone I in an In Vitro System of Charcot-Marie-Tooth Disease Type 2N.

Charcot-Marie-Tooth disease type 2N (CMT2N) is an inherited nerve disorder caused by mutations in the alanyl-tRNA synthetase (AlaRS) gene, resulting in muscle weakness and sensory issues. Currently, there is no cure for CMT2N. Here, we found that all five AlaRS mutations in the aminoacylation domain can interact with neuropilin-1 (Nrp1), which is consistent with our previous findings. Interestingly, three of these mutations did not affect alanine activation activity. We then performed a high-throughput screen of 2000 small molecules targeting the prevalent R329H mutant. Using thermal stability assays (TSA), biolayer interferometry (BLI), ATP consumption, and proteolysis assays, we identified Tanshinone I as a compound that binds to and modifies the conformation of the R329H mutant and other CMT-related AlaRS mutants interacting with Nrp1. Molecular docking and dynamic simulation studies further clarified Tanshinone I's binding mode, indicating its potential against various AlaRS mutants. Furthermore, co-immunoprecipitation (Co-IP) and pull-down assays showed that Tanshinone I significantly reduces the binding of AlaRS mutants to Nrp1. Collectively, these findings suggest that Tanshinone I, by altering the conformation of mutant proteins, disrupts the pathological interaction between AlaRS CMT mutants and Nrp1, potentially restoring normal Nrp1 function. This makes Tanshinone I a promising therapeutic candidate for CMT2N.

Competitive Inhibition of Okanin against Plasmodium falciparum Tyrosyl-tRNA Synthetase.

Malaria is a severe disease that presents a significant threat to human health. As resistance to current drugs continues to increase, there is an urgent need for new antimalarial medications. Aminoacyl-tRNA synthetases (aaRSs) represent promising targets for drug development. In this study, we identified Plasmodium falciparum tyrosyl-tRNA synthetase (PfTyrRS) as a potential target for antimalarial drug development through a comparative analysis of the amino acid sequences and three-dimensional structures of human and plasmodium TyrRS, with particular emphasis on differences in key amino acids at the aminoacylation site. A total of 2141 bioactive compounds were screened using a high-throughput thermal shift assay (TSA). Okanin, known as an inhibitor of LPS-induced TLR4 expression, exhibited potent inhibitory activity against PfTyrRS, while showing limited inhibition of human TyrRS. Furthermore, bio-layer interferometry (BLI) confirmed the high affinity of okanin for PfTyrRS. Molecular dynamics (MD) simulations highlighted the stable conformation of okanin within PfTyrRS and its sustained binding to the enzyme. A molecular docking analysis revealed that okanin binds to both the tyrosine and partial ATP binding sites of the enzyme, preventing substrate binding. In addition, the compound inhibited the production of Plasmodium falciparum in the blood stage and had little cytotoxicity. Thus, okanin is a promising lead compound for the treatment of malaria caused by P. falciparum.

A qualitative study of head nurses' experience in China: forced growth during patient safety incidents.

BACKGROUND: In patient safety accidents, nurse managers are indirectly victimized by the pressures from many aspects and become the second victim. This study delves into the experiences of nurse managers in China, aiming to uncover their cognition and provide reference for relevant managers. METHODS: A descriptive phenomenological approach was used to gain insight into the inner reality of nurse leaders' experiences and management perceptions of experiencing patient safety incidents. The data of 15 nurse leaders who experienced patient safety incidents in Bethune Hospital, Shanxi Province, China, were collected via face‒to‒face semi-structured interviews, and the data were analyzed via the 7-step analysis method of Colaizzi. RESULTS: On the basis of the content of the interviews, three themes were identified, the emotional experience of experiencing patient safety events, role dilemmas, the obstruction and conceptual reshaping of nursing management. Eight subthemes as follows: physical and mental health-related symptoms due to passive coping and life and work disorder, self-relief, playing multiple roles with lack of role adjustment ability, blurred role positioning and initial signs of job burnout, event replay is impeded, Inaccurate analysis of safety incidents, subversion and remolding of the nursing management concept. Finally, it can be abstracted as "forced growth in patient safety events". CONCLUSION: Patient safety incidents can lead to negative impacts, role dilemmas, and management confusion for head nurses, but they also promote purposeful rumination, meditation, and growth. Medical institutions should pay attention to special groups that are second victims of head nurses and construct a safety event support system for nurse leaders to improve the post-training and education system for nurse leaders, help them better adapt to their roles, break through their role dilemmas, improve their post-competence, and construct an effective safety event management system.

AtPRMT5-mediated AtLCD methylation improves Cd2+ tolerance via increased H2S production in Arabidopsis.

Arabidopsis (Arabidopsis thaliana) PROTEIN ARGININE METHYLTRANSFERASE5 (PRMT5), a highly conserved arginine (Arg) methyltransferase protein, regulates multiple aspects of the growth, development, and environmental stress responses by methylating Arg in histones and some mRNA splicing-related proteins in plants. Hydrogen sulfide (H2S) is a recently characterized gasotransmitter that also regulates various important physiological processes. l-cysteine desulfhydrase (LCD) is a key enzyme of endogenous H2S production. However, our understanding of the upstream regulatory mechanisms of endogenous H2S production is limited in plant cells. Here, we confirmed that AtPRMT5 increases the enzymatic activity of AtLCD through methylation modifications during stress responses. Both atprmt5 and atlcd mutants were sensitive to cadmium (Cd2+), whereas the overexpression (OE) of AtPRMT5 or AtLCD enhanced the Cd2+ tolerance of plants. AtPRMT5 methylated AtLCD at Arg-83, leading to a significant increase in AtLCD enzymatic activity. The Cd2+ sensitivity of atprmt5-2 atlcd double mutants was consistent with that of atlcd plants. When AtPRMT5 was overexpressed in the atlcd mutant, the Cd2+ tolerance of plants was significantly lower than that of AtPRMT5-OE plants in the wild-type background. These results were confirmed in pharmacological experiments. Thus, AtPRMT5 methylation of AtLCD increases its enzymatic activity, thereby strengthening the endogenous H2S signal and ultimately improving plant tolerance to Cd2+ stress. These findings provide further insights into the substrates of AtPRMT5 and increase our understanding of the regulatory mechanism upstream of H2S signals.

[Sleep patterns of infants and young children and their association with breastfeeding: a study based on K-means clustering]. / 基于K-meansèšç±»åˆ†æžçš„å©´å¹¼å„¿ç¡çœ æ¨¡å¼åŠä¸Žæ¯ä¹³å–‚å »å ³ç³»çš„ç ”ç©¶.

OBJECTIVES: To investigate the sleep patterns and characteristics of infants and young children and the association between sleep patterns and breastfeeding. METHODS: A general information questionnaire, Brief Infant Sleep Questionnaire (BISQ), and a questionnaire on feeding were used to investigate the sleep quality and feeding patterns of 1 148 infants and young children aged 7-35 months. The K-means clustering method was used to identify sleep patterns and characteristics. A multivariate logistic regression analysis was used to investigate the association between sleep patterns and breastfeeding. RESULTS: Three typical sleep patterns were identified for the 1 148 infants and young children aged 7-35 months: early bedtime and long sleep time; short sleep latency and moderate sleep time; late bedtime, prolonged sleep latency, and insufficient sleep time. The third pattern showed sleep disorders. The multivariate logistic regression analysis showed that compared with formula feeding, exclusive breastfeeding within 6 months after birth reduced the risk of sleep disorder patterns by 69% (OR=0.31, 95%CI: 0.11-0.81). The risk of sleep disorder patterns was reduced by 40% (OR=0.60, 95%CI: 0.38-0.96) in the infants receiving breastfeeding for 4-6 months compared with those receiving breastfeeding for 1-3 months. CONCLUSIONS: There are different sleep patterns in infants and young children, and breastfeeding can reduce the development of sleep disorder patterns.

A PK/PD study comparing twice-daily to once-daily dosing regimens of ertugliflozin in healthy subjects
.

OBJECTIVE: Ertugliflozin is approved in the US and European Union as a stand-alone product for adults with type 2 diabetes mellitus as once daily (QD) dosing. The approved fixed-dose combination (FDC) of ertugliflozin and immediate-release metformin is dosed twice daily (BID). This study assessed steady-state pharmacokinetics (PK; area under the concentration-time curve over 24 hours (AUC24)) and pharmacodynamics (PD; urinary glucose excretion over 24 hours (UGE24)) for ertugliflozin 5 and 15 mg total daily doses administered BID or QD. MATERIALS AND METHODS: In this open-label, two-cohort, randomized, multiple-dose, crossover study, healthy subjects received ertugliflozin 2.5 mg BID and 5 mg QD (n = 28) or ertugliflozin 7.5 mg BID and 15 mg QD (n = 22) for 6 days. Plasma and urine samples were collected for 24 hour post morning dose on day 6 in each period. RESULTS: The geometric mean ratio (GMR) (90% CI) of ertugliflozin AUC24 was 100.8% (98.8%, 102.8%) for 2.5 mg BID vs. 5 mg QD, and 99.7% (97.1%, 102.5%) for 7.5 mg BID vs. 15 mg QD. GMR (90% CI) of UGE24 for BID vs. QD administration was 110.2% (103.0%, 117.9%) at a total daily dose of 5 mg, and 102.8% (97.7%, 108.1%) at 15 mg. The 90% CIs of the GMR of AUC24 and UGE24 for BID vs. QD dosing were within the acceptance range for equivalence (80 - 125%) and the prespecified criterion for similarity (70 - 143%), respectively. All treatments were well tolerated. CONCLUSION: There are no clinically meaningful differences in steady-state PK or PD between ertugliflozin BID and QD regimens at total daily doses of 5 and 15 mg, supporting BID administration of ertugliflozin as a component of the ertugliflozin/metformin (immediate-release) FDC.

The Ca2+ /calmodulin2-binding transcription factor TGA3 elevates LCD expression and H2 S production to bolster Cr6+ tolerance in Arabidopsis.

Heavy metal (HM) contamination on agricultural land not only reduces crop yield but also causes human health concerns. As a plant gasotransmitter, hydrogen sulfide (H2 S) can trigger various defense responses and help reduce accumulation of HMs in plants; however, little is known about the regulatory mechanisms of H2 S signaling. Here, we provide evidence to answer the long-standing question about how H2 S production is elevated in the defense of plants against HM stress. During the response of Arabidopsis to chromium (Cr6+ ) stress, the transcription of L-cysteine desulfhydrase (LCD), the key enzyme for H2 S production, was enhanced through a calcium (Ca2+ )/calmodulin2 (CaM2)-mediated pathway. Biochemistry and molecular biology studies demonstrated that Ca2+ /CaM2 physically interacts with the bZIP transcription factor TGA3, a member of the 'TGACG'-binding factor family, to enhance binding of TGA3 to the LCD promoter and increase LCD transcription, which then promotes the generation of H2 S. Consistent with the roles of TGA3 and CaM2 in activating LCD expression, both cam2 and tga3 loss-of-function mutants have reduced LCD abundance and exhibit increased sensitivity to Cr6+ stress. Accordingly, this study proposes a regulatory pathway for endogenous H2 S generation, indicating that plants respond to Cr6+ stress by adjusting the binding affinity of TGA3 to the LCD promoter, which increases LCD expression and promotes H2 S production. This suggests that manipulation of the endogenous H2 S level through genetic engineering could improve the tolerance of grains to HM stress and increase agricultural production on soil contaminated with HMs.

Metabolism, excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration.

1. The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100 mg/100 µCi [14C]glasdegib to six healthy male volunteers (NCT02110342). 2. The peak concentrations of glasdegib (890.3 ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75 hours post-dose. The AUCinf were 8469 ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity. 3. Mean recovery of [14C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0-120 hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites. 4. Elimination of [14C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.

Influence of Different Lengths of Rubber Tube on Patients After Esophageal Stent Implantation Using a Silk Thread.

Our objective was to compare the efficacy of different lengths of rubber tube (6 French) on patients with esophageal stent implantation performed using a silk thread. We measured the effects in terms of pain and foreign body sensation felt in the pharynx and esophageal mucosa of the patients. A retrospective analysis was conducted using records of 65 patients who were divided into 3 groups. Group A had 20 cases with the distal end of the tube toward the nasal cavity, Group B had 21 cases with the distal end of the tube reaching the nasopharynx without exceeding the soft palate, and Group C had 24 cases with the distal end of the tube toward the upper end of the stent. Follow-up was performed on 1 day, 2 days, 1 week, 2 weeks, 4 weeks, 6 weeks, and 8 weeks postoperatively. During each period, the pain scores for Groups B and C were lower than those for Group A (p < .05), whereas no difference was observed when Groups B and C were compared. Although no variations were seen between the 3 groups in terms of the proportion of patients with foreign body sensation on the first day (p > .05), Groups A and B had a lower proportion than Group C (p < .05) at those periods. No difference was observed when Groups A and B were compared. In conclusion, the Group B method was successful in alleviating the side effects caused by the silk thread.

Minimization of CYP2D6 Polymorphic Differences and Improved Bioavailability via Transdermal Administration: Latrepirdine Example.

PURPOSE: Transdermal delivery has the potential to offer improved bioavailability by circumventing first-pass gut and hepatic metabolism. This study evaluated the pharmacokinetics of oral immediate release and transdermal latrepirdine in extensive and poor CYP2D6 metabolizers (EM/PM). METHODS: Latrepirdine transdermal solution was prepared extemporaneously. The solution was applied with occlusive dressing to upper or middle back for 24 h. Each subject received a single dose of 8.14 mg oral, 5 mg transdermal, and 10 mg transdermal (EMs only) latrepirdine free base in a fixed sequence. RESULTS: Twelve EMs and 7 PMs (50-79 years) enrolled and completed the study. Latrepirdine was well tolerated following both routes of administration. Dose-normalized latrepirdine total exposures were approximately 11-fold and 1.5-fold higher in EMs and PMs, respectively following administration of transdermal relative to oral. Differences between EM and PM latrepirdine exposures were decreased, with PMs having 1.9- and 2.7-fold higher peak and total exposures, respectively, following transdermal administration compared to 11- and 20-fold higher exposures, respectively, following oral administration. CONCLUSION: Transdermal delivery can potentially mitigate the large intersubject differences observed with compounds metabolized primarily by CYP2D6. Transdermal delivery was readily accomplished in the clinic using an extemporaneously prepared solution [NCT00990613].

Investigation of the impact of hepatic impairment on the pharmacokinetics of dacomitinib.

Dacomitinib (PF-00299804) is a small-molecule inhibitor of the tyrosine kinases human epidermal growth factor receptor-1 (HER1; epidermal growth factor receptor, EGFR), HER2, and HER4 currently being developed for the treatment of lung cancer with sensitizing mutations in EGFR or refractory to EGFR-directed treatment. Dacomitinib is largely metabolized by the liver through oxidative and conjugative metabolism; therefore, determination of the impact of varying degrees of hepatic impairment on the pharmacokinetics (PK) of dacomitinib was warranted to ensure patient safety. In this phase I, open-label, parallel-group study, a single dose of dacomitinib was administered to healthy volunteers and to subjects with mild or moderate liver dysfunction, as determined by Child-Pugh classification. The primary goal of this study was to evaluate the effects of mild and moderate hepatic impairment on the single-dose PK profile of dacomitinib, as well as to assess the safety and tolerability in these subjects. Plasma protein binding and impact of hepatic function on the PK of the active metabolite PF-05199265 was also investigated. Twenty-five male subjects received dacomitinib 30 mg, with 8 subjects in the healthy- and mild-impairment cohorts and 9 subjects in the moderate-impairment cohort. Compared with healthy volunteers, there was no significant change in dacomitinib exposure in subjects with mild or moderate liver dysfunction and no observed alteration in plasma protein binding. No serious treatment-related adverse events were reported in any group, and dacomitinib was well tolerated. A dose adjustment does not appear necessary when administering dacomitinib to patients with mild or moderate hepatic impairment.

Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study.

AIMS: The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM). METHODS: T2DM subjects (glycosylated haemoglobin: 7.0-10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5-200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride - an early marker of drug activity. RESULTS: No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5-7.7 h and 66.5- 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups. CONCLUSIONS: Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.

Open-label, 2-period sequential drug interaction study to evaluate the effect of a 100-mg dose of desvenlafaxine on the pharmacokinetics of tamoxifen when coadministered in healthy postmenopausal female subjects.

BACKGROUND: Potential drugdrug interactions are a concern for patients taking tamoxifen. OBJECTIVE: This study was designed to determine the effect of coadministering desvenlafaxine on tamoxifen pharmacokinetics. MATERIALS AND METHODS: This open-label, 2-period inpatient and outpatient study enrolled healthy, postmenopausal women. Period 1, day 1, subjects were administered tamoxifen 40 mg followed by 23 days of blood sampling for pharmacokinetic analyses. During period 2, subjects received desvenlafaxine 100 mg/d for 28 days; a single dose of tamoxifen 40 mg was administered with desvenlafaxine 100 mg on day 7, followed by 23 days of blood sampling. Pharmacokinetics of tamoxifen and its metabolites (AUC over infinite time (AUC(inf)), AUC to the last measurable concentration (AUC(last)), peak plasma concentration (C(max)) were compared for monotherapy vs. combination therapy using the ratio of adjusted mean differences. A superposition method was used in the statistical analysis of N-desmethyl-tamoxifen and endoxifen to address the carry-over observed for those metabolites. The test for interaction was considered negative if the 90% confidence intervals (CIs) for the ratios were within 80 - 125%. RESULTS: Coadministration of tamoxifen with steady-state desvenlafaxine did not alter tamoxifen AUC(inf), AUC(last), and C(max), as reflected by the ratio of adjusted geometric means (90% CIs) of 100.7% (96.7%, 104.9%), 103.5% (100.2%, 106.9%), and 99.4% (94.0%, 105.2%), respectively. Similarly, coadministration did not alter 4-hydroxy- tamoxifen and N-desmethyl-amoxifen pharmacokinetics. The 11.8% (88.2% (82.6%, 94.2%)) and 8.0% (92.0% (84.7%, 100.0%)) decreases in endoxifen AUC(last) and C(max), respectively, were not significant (90% CIs fell wholly within the prespecified acceptance range). CONCLUSIONS: Steady-state desvenlafaxine 100 mg did not affect tamoxifen pharmacokinetics. For women treated with tamoxifen, desvenlafaxine may represent a safe and effective treatment unlikely to alter tamoxifen efficacy.

The Impact of Abusive Supervision on Nurses' Organizational Silence: The Multiple Linear Mediation of Psychological Capital and Fear.

Purpose: To assess abusive supervision and organizational silence among nurses and investigate the mediating influence of psychological capital and fear. Background: Since the end of 2019, China's National Development and Reform Commission (NDRC) department has decided to start the construction of regional medical centers in Shanxi, reducing cross-provincial and cross-regional medical care. In order to improve the overall standard of care in a hospital in a short period of time, health care leadership decision makers may adopt various effective leadership management practices to achieve the set goals and have high work pressure at the same time. In this case, abusive management may occur. Methods: A cross-sectional survey design was employed. In January -March 2024, a convenience sampling method was used to collect data from 470 nurses in a total of 5 hospitals in Shanxi province they were required to complete the questionnaires online anonymously. The chain mediation model was tested using the PROCESS macro program in the SPSS software and multiple linear regression model was used to verify the mediating effect. Results: Psychological capital and fear mediate the relationship between abusive supervision and nurses' organizational silence, playing indirect mediating roles. Abusive supervision was positively associated with nurses' organizational silence. Additionally, psychological capital plays a negative mediating role, accounting for 48.48% of the indirect effect, and fear plays a positive mediating role, accounting for 45.83% of the indirect effect. They form a chain intermediary, accounting for 5.69% of the indirect effect. Conclusion: Psychological capital and fear mediate the impact of abusive supervision on nurses' organizational silence. Positive leadership training should be conducted to help reducing the level of head nurses' abusive supervision behaviors, while also fostering actions that elevate nurses' psychological capital levels.

Association between dietary choline intake and asthma and pulmonary inflammation and lung function: NHANES analysis 2009-2018.

BACKGROUND: Asthma is a chronic inflammatory condition, and choline may alleviate airway inflammation and oxidative stress but studies on the association between dietary choline and asthma remain limited. The purpose of this study is to investigate the associations between dietary choline intake and asthma, as well as pulmonary inflammation and lung function in children and adults. METHODS: In our research, we employed the data of the National Health and Nutrition Examination Survey (NHANES) from 2009 to 2018, including 7,104 children and 16,580 adults. We used fractional exhaled nitric oxide (FENO) to assess pulmonary inflammation and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), the FEV1/FVC ratio, peak expiratory flow rate (PEF), predicted FEV1% and predicted FVC% to assess lung function. Binary logistic regression, linear regression, and the restricted cubic splines were used to analyze the associations between dietary choline intake and asthma and pulmonary inflammation and lung function. RESULTS: In children, we observed the positive associations between the natural logarithmic transformation of choline (ln-choline) and ln-FEV1 [ ß:0.011; 95%CI: (0.004,0.018)] and ln-FVC [ ß:0.009; 95%CI: (0.002,0.016)]. In adult males, the ln-choline was positively associated with ln-FEV1[ ß:0.018; 95%CI: (0.011,0.024)], ln-FVC [ ß:0.020; 95%CI: (0.014,0.026)], ln-PEF [ ß:0.014; 95%CI: (0.007,0.022)], ln-predicted FEV1% [ ß: 0.007; 95%CI: (0.001, 0.013)] and ln-predicted FVC%[ ß: 0.010; 95%CI: (0.005, 0.015)] and negatively associated with FENO [ ß: -0.029; 95%CI: (-0.049, -0.009)]. In unadjusted and partially adjusted models, adult females with ln-choline in the highest quartile had 25.2% (95%CI:9.4-38.3%) and 23.8% (95%CI:7.6-37.1%) decreased odds of asthma compared to those with the lowest quartile group. In the dose-response relationships of dietary choline and pulmonary inflammation and lung function indicators in adults, there existed threshold and saturation effects. CONCLUSION: The associations between dietary choline and lung function indicators such as FEV1 and FVC are positive in children and adults. The association between dietary choline and pulmonary inflammation is negative only in adults.

Associations of co-exposure to polycyclic aromatic hydrocarbons and heavy metals with sex steroid hormones among children aged 6-19 years.

Introduction Polycyclic aromatic hydrocarbons (PAHs) and heavy metals (HMs) are endocrine-disrupting chemicals (EDCs) that may have a combined effect on sex hormone levels in children. This study investigated the correlations between co-exposure to PAHs and HMs and levels of sex steroid hormones in children. Methods We employed the data from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016, including 1,167 participants aged 6-19 years. Sex hormone indicators include testosterone (TT), estradiol (E2), sex hormone-binding globulin (SHBG), free androgen index (FAI), and the TT/E2 ratio. Weighted multivariate linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were used to analyze the associations between co-exposure to PAHs and HMs and sex steroid hormone levels. Results Co-exposure to PAHs and HMs was associated with a 16.2% reduction [95%CI (-0.321, -0.004)] in SHBG level among prepubertal males and a 16% reduction [95%CI (-0.30, -0.03)] in E2 level among pubertal males by the weighted quantile sum (WQS) regression, and cadmium (Cd) and mercury (Hg) contributed the highest weight respectively. In the Bayesian kernel machine regression (BKMR) model, co-exposure to PAHs and HMs was positively associated with TT/ E2 in pubertal males and negatively correlated with FAI in pubertal females, and 1-hydroxypyrene (1-PYR) and Cd were the most important components respectively. Conclusions Co-exposure to PAHs and HMs was associated with sex hormone levels in children. These findings highlight the necessity for preventing the effects of these chemicals on sex hormones.

Dietary calcium is inversely associated with hepatitis B virus infection: an analysis of US National Health and Nutrition Examination Survey (NHANES) 2007-2020.

BACKGROUND: There have been studies on the relationship between hepatitis B virus (HBV) infection and diet. We hypothesized HBV infection is related to dietary calcium intake, but the evidence is limited. This study aimed to examine whether dietary calcium intake is independently related to HBV infection in the United States population. METHODS: A total of 20,488 participants aged over 20 years from the National Health and Nutrition Examination Survey (NHANES), conducted from 2007 to 2020, were included in this study. Pearson correlation was used to test the association between dietary calcium and serum calcium. The relationships of HBV infection with dietary calcium and serum calcium were assessed by logistic regression models. RESULTS: There was a weak correlation between dietary calcium and serum calcium (r = 0.048). Logistic regression models indicated that HBV infection had a linear negative correlation with dietary calcium (OR 0.37; 95%CI 0.19, 0.76). For each additional 10 mg dietary calcium, the possibility of HBV infection was reduced by 63%. Hepatitis B positive participants had lower serum calcium content than negative participants. Stratified analysis shown the linear relationship between calcium and HBV infection varied among sex, race/ethnicity, and body mass index. CONCLUSION: Our findings demonstrated HBV infection was linearly and inversely correlated with dietary calcium. The current study is expected to offer a fresh perspective on reducing HBV infection.