Circulating micronutrient levels and their association with sepsis susceptibility and severity: a Mendelian randomization study.

Background: Sepsis, a global health challenge, necessitates a nuanced understanding of modifiable factors for effective prevention and intervention. The role of trace micronutrients in sepsis pathogenesis remains unclear, and their potential connection, especially with genetic influences, warrants exploration. Methods: We employed Mendelian randomization (MR) analyses to assess the causal relationship between genetically predicted blood levels of nine micronutrients (calcium, ß-carotene, iron, magnesium, phosphorus, vitamin C, vitamin B6, vitamin D, and zinc) and sepsis susceptibility, severity, and subtypes. The instrumental variables for circulating micronutrients were derived from nine published genome-wide association studies (GWAS). In the primary MR analysis, we utilized summary statistics for sepsis from two independent databases (UK Biobank and FinnGen consortium), for initial and replication analyses. Subsequently, a meta-analysis was conducted to merge the results. In secondary MR analyses, we assessed the causal effects of micronutrients on five sepsis-related outcomes (severe sepsis, sepsis-related death within 28 days, severe sepsis-related death within 28 days, streptococcal septicaemia, and puerperal sepsis), incorporating multiple sensitivity analyses and multivariable MR to address potential heterogeneity and pleiotropy. Results: The study revealed a significant causal link between genetically forecasted zinc levels and reduced risk of severe sepsis-related death within 28 days (odds ratio [OR] = 0.450; 95% confidence interval [CI]: 0.263, 0.770; p = 3.58 × 10-3). Additionally, suggestive associations were found for iron (increased risk of sepsis), ß-carotene (reduced risk of sepsis death) and vitamin C (decreased risk of puerperal sepsis). No significant connections were observed for other micronutrients. Conclusion: Our study highlighted that zinc may emerges as a potential protective factor against severe sepsis-related death within 28 days, providing theoretical support for supplementing zinc in high-risk critically ill sepsis patients. In the future, larger-scale data are needed to validate our findings.

[Comparison of Functional Status Between Diabetic Patients With and Without Nephropathy Based on the International Classification of Functioning,Disability and Health Rehabilitation Set].

Objective To compare the functional status of diabetic patients with and without nephropathy and identify the items that diabetic patients with nephropathy are more likely to develop dysfunction than diabetic patients without nephropathy based on the international classification of functioning,disability and health rehabilitation set(ICF-RS).Methods A cross-sectional study was conducted.A total of 320 diabetic patients hospitalized in Guangdong Provincial Hospital of Chinese Medicine from August 2021 to February 2022 were selected and assigned into a group with nephropathy and a group without nephropathy.The general characteristics,clinical examination,and laboratory findings were compared by the t test,rank sum test,and Chi-squared test.The functional status of the patients was compared between the two groups by the t test based on the ICF-RS.Logistic regression was employed to control interferential factors between the two groups and identify the association between nephropathy and ICF-RS problematic items among diabetic patients.Results The diabetic patients with nephropathy had more problematic items in ICF-RS(P<0.001),the body function dimension(P=0.003),the activity dimension(P<0.001),and the participation dimension(P<0.001)than those without nephropathy.Moreover,the diabetic patients with nephropathy experienced severer problems in 5 body function items(energy and drive functions,sleep functions,sexual functions,exercise tolerance functions,and muscle power functions),10 activity items(transferring oneself,walking,moving around using equipment,moving around,washing oneself,caring for body parts,toileting,dressing,doing housework,and looking after one's health),and 4 participation items(using transportation,assisting others,basic interpersonal interactions,and recreation and leisure)(all P<0.05).The Logistic regression results showed that compared with the diabetic patients without nephropathy,the diabetic patients with nephropathy were more likely to develop problems in energy and drive functions(aOR=4.35,95%CI=1.28-14.79,P=0.019),emotional functions(aOR=1.88,95%CI=1.06-3.34,P=0.031),sexual functions(aOR=3.39,95%CI=1.82-6.34,P<0.001),moving around(aOR=3.11,95%CI=1.76-5.52,P<0.001),doing housework(aOR=17.48,95%CI=3.57-85.60,P<0.001),looking after one's health(aOR=1.97,95%CI=1.13-3.43,P=0.017),using transportation(aOR=2.59,95%CI=1.38-4.88,P=0.003),and recreation and leisure(aOR=2.52,95%CI=1.46-4.35,P<0.001).Conclusion Compared with the diabetic patients without nephropathy,the patients with nephropathy suffer more ICF-RS problematic items and are more likely to develop dysfunction in certain items in all the three dimensions.

Analysis of coexisting pathogens in nasopharyngeal swabs from COVID-19.

Background: The impact of COVID-19 on the world is still ongoing, and it is currently under regular management. Although most infected people have flu-like symptoms and can cure themselves, coexisting pathogens in COVID-19 patients should not be taken lightly. The present study sought to investigate the coexisting pathogens in SARS-CoV-2 infected patients and identify the variety and abundance of dangerous microbes to guide treatment strategies with a better understanding of the untested factors. Methods: We extracted total DNA and RNA in COVID-19 patient specimens from nasopharyngeal swabs to construct a metagenomic library and utilize Next Generation Sequencing (NGS) to discover chief bacteria, fungi, and viruses in the body of patients. High-throughput sequencing data from Illumina Hiseq 4000 were analyzed using Krona taxonomic methodology for species diversity. Results: We studied 56 samples to detect SARS-CoV-2 and other pathogens and analyzed the species diversity and community composition of these samples after sequencing. Our results showed some threatening pathogens such as Mycoplasma pneumoniae, Klebsiella pneumoniae, Streptococcus pneumoniae, and some previously reported pathogens. SARS-CoV-2 combined with bacterial infection is more common. The results of heat map analysis showed that the abundance of bacteria was mostly more than 1000 and that of viruses was generally less than 500. The pathogens most likely to cause SARS-CoV-2 coinfection or superinfection include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoniae, and Human gammaherpesvirus 4. Conclusions: The current coinfection and superinfection status is not optimistic. Bacteria are the major threat group that increases the risk of complications and death in COVID-19 patients and attention should be paid to the use and control of antibiotics. Our study investigated the main types of respiratory pathogens prone to coexisting or superinfection in COVID-19 patients, which is valuable for identifying and treating SARS-CoV-2.

Effects of the salbutamol bronchodilator response on measurements of fractional exhaled nitric oxide in children with asthma: a prospective, observational study.

Background: Salbutamol bronchodilator response (BDR) test and fractional exhaled nitric oxide (FeNO) have been recommended for the diagnosis of asthma in children, but FeNO levels is affected by many factors. Nonetheless, data of the effect on the FeNO values throughout the bronchodilator test and the differences in FeNO values between BDR positive (BDR+) and negative (BDR-) children with asthma are still limited. We aimed to evaluate the effect of the BDR test on FeNO and the differences in FeNO levels between BDR+ and BDR- children with asthma. Methods: This was a prospective, observational study performed over a 5-month period (December 2018 to April 2019) and involved 57 children with asthma. The FeNO levels at pre-spirometry, post-spirometry, and post-salbutamol BDR testing were estimated. Finally, the children were divided into two groups i.e., BDR+ and BDR-, and differences in the FeNO levels were compared between the two groups. Results: The spirometry results were normal in 2 patients (3.5%). There were 53 (93%) patients with obstructive lung disease, including 40 (70.2%), 11 (19.3%), and 2 (3.5%) patients with mild, moderate, and severe obstruction, respectively. The remaining two patients had mixed lesions (3.5%), none of which were restrictive. The baseline median FeNO levels were significantly higher in the BDR+ group than in the BDR- group [33.00 (23.78, 46.73) vs. 23.00 (9.80, 37.80), (P=0.048)]. Following spirometry, there was a statistically significant decrease in median FeNO levels from baseline to post-spirometry (P=0.002). However, there was no significant difference between the median FeNO levels at baseline and following the BDR test (P=0.976). The impact of spirometry on FeNO was not statistically different in BDR+ versus BDR- children (Z=-0.186, P=0.853); however, the impact of bronchodilators on FeNO exhibited a statistically significant difference between the two groups (Z=3.160, P=0.002). Conclusions: This study revealed dynamic changes in the FeNO levels during the BDR test. The use of a bronchodilator results in a statistically significant difference in FeNO levels between BDR+ and BDR- children with asthma. Moreover, spirometry leads to a marked decrease in the FeNO levels. Our results will allow clinicians to better interpret FeNO, BDR and pulmonary function outcomes and better develop clinical protocols.

A stochastic SIR epidemic model with Lévy jump and media coverage.

A stochastic susceptible-infectious-recovered epidemic model with temporary immunity and media coverage is proposed. The effects of Lévy jumps on the dynamics of the model are considered. A unique global positive solution for the epidemic model is obtained. Sufficient conditions are derived to guarantee that the epidemic disease is extinct and persistent in the mean. The threshold behavior is discussed. Numerical simulations are given to verify our theoretical results.

A 2-year step-down withdrawal from inhaled corticosteroids in asthmatic children receiving immunotherapy.

BACKGROUND: Inhaled corticosteroids (ICSs) for treating asthma are controversial because of their negative effects on the growth of asthmatic children and without clearly defined withdrawal strategy. A 2-year ICS step-down and withdrawal strategy has been developed for asthmatic children receiving 3-year subcutaneous immunotherapy (SCIT). METHODS: Eleven children were included into the SCIT group and 13 children into the ICS group. ICSs were discontinued when children met the following criteria: requiring only 1 puffper day, with good control, for at least 6 months; having a forced expiratory volume in 1 second (FEV1)/forced vital capacity ≥80%; and SCIT discontinued for ≥24 months. The main endpoints were the results of both the childhood asthma control test (C-CAT) and the methacholine bronchial provocation test. RESULTS: In the SCIT group, all the 11 children had ICS discontinued, with one child developed asthma attack after pneumonia and received ICS again after completion of SCIT. In the ICS group, five children discontinued ICS and developed asthma attacks later and received ICS again; the other eight children developed severe symptoms during ICS step-down. Thus, the discontinuation of ICS was only achieved in the SCIT group. The dose of methacholine that caused a decrease of 20% in FEV1 continued to improve after discontinuation of ICS for the SCIT group and presented better results than the ICS group (P=0.050). After completion of SCIT, the C-CAT had improved significantly after 30 months of treatment compared with the ICS group (P<0.05). CONCLUSIONS: In the present study, we developed a 2-year step-down and withdrawal strategy from ICSs strategy for allergic asthma children receiving SCIT; the strategy was efficacious and safe.

Interleukin-8 induces the endothelial cell migration through the activation of phosphoinositide 3-kinase-Rac1/RhoA pathway.

Endothelial cell migration is essential for tumor angiogenesis, and interleukin-8 (IL-8) has been shown to play an important role in tumor growth, angiogenesis, and metastasis. This study aimed to investigate the molecular mechanism of IL-8 induced endothelial cell migration. Our results indicated that IL-8 induced a rapid rearrangement of the actin cytoskeleton in EA.Hy926 cells, generating extensions resembling membrane ruffling and stress fibers. These processes required parallel upregulation of the small GTPases Rac1 and RhoA. Moreover, we demonstrated that IL-8 activated PI3K following the same kinetics observed from IL-8 induction of cytoskeletal rearrangement, suggesting the participation of PI3K in these processes. Taken together, our study demonstrates that PI3K-Rac1/RhoA signaling pathway plays a vital role in IL-8 induced endothelial cell migration, and provides new insight into the molecular mechanisms by which IL-8 contributes to tumor angiogenesis and metastasis.

Anticancer potency of cytotoxic drugs after exposure to high-intensity focused ultrasound in the presence of microbubbles and hematoporphyrin.

Chemotherapy is undertaken perioperatively to improve the efficacy of high-intensity focused ultrasound (HIFU) for solid tumors. HIFU at a sufficient intensity for tissue ablation has recently been applied for drug delivery; ultrasonic cavitation plays an important part in HIFU and drug delivery. Hematoporphyrin and microbubbles are adjuncts because they aid cavitation. The effect of HIFU (1.0 MHz; 12,999 W/cm(2) in continuous waves), in the presence of hematoporphyrin and/or microbubbles, on the anticancer potency of 5-fluorouracil, cisplatin, paclitaxel, mitomycin C or adriamycin, was investigated. Insonated adriamycin resulted in a lower death rate of human cancer cells HO-8910 (45.85 ± 2.65% vs 34.84 ± 1.21%, p < 0.05), which was exacerbated when employing hematoporphyrin (34.84 ± 1.21% vs 23.09 ± 7.82%, p < 0.05) or hematoporphyrin combined with microbubbles (34.84 ± 1.21% vs. 8.79 ± 3.69%, p < 0.05); the therapeutic activity was not affected when adding microbubbles alone. High-performance liquid chromatography detected a smaller peak area after subjecting adriamycin to HIFU with the use of hematoporphyrin alone or combined with microbubbles. The other drugs were not affected. Hematoporphyrin, microbubbles and adriamycin increased the throughput of hydroxyl radicals resulting from cavitation as determined by iodine and methylene blue assays. These data suggested that the anticancer activity of a drug may be decreased by HIFU exposure (particularly in the presence of hematoporphyrin and microbubbles). Cavitation produced reactive species that attacked drug molecules, thereby decreasing their antitumor potency; this process was enhanced if the drug itself generated free radicals under insonation.

[Effects of medroxyprogesterone acetate on endothelial progenitor cell].

UNLABELLED: This experiment was aimed to study the effects of different concentrations of medroxyprogesterone acetate (MPA) on proliferation, migration and apoptosis of endothelial progenitor cells (EPCs) in vitro and to provide experimental evidence for the use of MPA as anti-angiogenesis drug. We separated EPCs from bone marrow of a beagle dog and identified the expression of progesterone receptor (PR) in EPCs by immunocytochemistry. Proliferation tests (MTT analysis) were performed with EPCs in response to different concentration of MPA every 24 h for 7 consecutive days, the growth curve of these EPCs was obtained then. The inhibition rates were also obtained from MTT assay performed with EPCs exposed to different concentration of MPA. The migration tests were performed with EPCs in response to different concentrations of MPA. The cell cycle and apoptosis of EPCs exposed to different concentrations of MPA were analyzed by use of flow cytometry. RESULTS: Immunohistochemical staining showed that EPCs were positive to PR. High concentration of MPA had significant inhibition effect on the growth of EPCs. This effect was time- and dose-dependent. But the low concentration of MPA had not have such effect, EPCs exposed to high concentration of MPA were found arrested in S phase, and the apoptosis rate increased. The migration ability of EPCs exposed to high concentration of MPA was also damaged. CONCLUSION: High concentration of MPA can induce EPCs' apoptosis and inhibit their growth and migration. All these biological effects of MPA may be achieved through PR on EPCs.

[Effects of fluid shear stress on bone resorption in rat osteoclasts].

This study was aimed to assess the effects of fluid shear stress on the bone resorption in rat osteoclasts. The osteoclasts were derived from the lumbar vertebrae marrow cells which were isolated from the 6-month-old female Sprague Dawley rats, cultured on the slide at 1 x 10(6) cell/ml, and induced with 1, 25 (OH)2 Dihydroxyvitamin D3. The slide containing osteoclasts was taken out on day 7 after culture and then put into the flow chamber. The loads of fluid shear stress applied to the osteoclasts were 5.97, 11.36, 16.08 and 20.54 dyne/cm2, respectively, for 30 minutes. The osteoclasts unloading fluid shear stress were used as control. The bone resorptive pits were studied by light microscopy and scanning electron microscopy. The tartrate-resistant acid phosphatase (TRAP) secreted by osteoclasts was detected with ultraviolet spectrophotometry. The results showed that fluid shear stress can increase the activity of TRAP and significantly increase the number and area of bone resorptive pits made by osteoclasts,and the effect of fluid shear stress on the bone resorption of osteoclasts is the same as that on the activity of TRAP. The reaction of the osteoclasts to the fluid shear stress in this study also suggested that the bone resorption of osteoclasts be increased in a magnitude of fluid shear stress-dependent manner, and that the changes of TRAP activity be closely related to the changes of the number and area of resorptive pits of the osteoclasts.