Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Effects of biotin and coated cobalamin on lactation performance, nutrient digestion and rumen fermentation in Holstein dairy cows.

Biotin (BI) and cobalamin (CA) are essential for rumen propionate production and hepatic gluconeogenesis. The study evaluated the influence of BI or/and coated CA (CCA) on milk performance and nutrient digestion in cows. Sixty Holstein dairy cows were assigned in a 2 × 2 factorial arrangement and randomised block design to four groups. The factors were BI at 0 or 20 mg/day and CCA at 0 or 9 mg CA/day. Dry matter intake increased with BI addition but was unchanged with CCA supply. Addition of BI or CCA increased fat-corrected milk, milk fat and milk protein yields and feed efficiency. Moreover, lactose yield was increased by CCA addition. Dry matter, organic matter, crude protein and acid detergent fibre total-tract digestibility increased for BI or CCA supply. When CCA was supplemented, positive response of neutral detergent fibre digestibility to BI addition was enhanced. Supplementing BI did not affect pH, propionate content and acetate to propionate ratio, but increased total volatile fatty acids (VFA) and acetate contents. Supplementing CCA decreased pH and acetate to propionate ratio, but increased total VFA, acetate and propionate contents. Rumen protease and carboxymethyl-cellulase activities and fungi, bacteria and Butyrivibrio fibrisolvens numbers increased for BI or CCA supply. In addition, protozoa increased for BI addition, and protease activity and Prevotella ruminicola increased for CCA supply. When CCA was supplemented, positive responses of R. albus and Ruminobacter amylophilus numbers to BI addition were enhanced. Blood glucose concentration was unchanged with BI supply, but increased for CCA supply. Blood nonesterified fatty acids and ß-hydroxybutyrate contents reduced with BI or CCA supply. Supplementation with BI or CCA increased blood BI or CA content. The results showed that supplementing BI or/and CCA improved lactation performance and nutrient digestion, and CCA supply did not enhance the lactation performance response to BI supply.

Effects of Dietary Valine Chelated Zinc Supplementation on Growth Performance, Antioxidant Capacity, Immunity, and Intestine Health in Weaned Piglets.

This study was conducted to investigate the effects of dietary valine chelated zinc (ZnVal) supplementation on growth performance, antioxidant capacity, immunity, and intestine health in weaned piglets. A total of 240 healthy 35-day-old weaned piglets (Duroc × Landrace × Yorkshire, average weight 10.70 ± 0.14 kg) were randomly divided into five groups with six replicate pens and eight piglets per pen. Dietary treatments were a corn-soybean meal basal diet supplemented with 0, 25, 50, 75, and 100 mg/kg ZnVal, respectively. The experiment lasted for 28 days. Results showed that average daily gain (ADG) was increased (P < 0.05) by ZnVal with 75-100 mg/kg supplementation on days 15-28 and with 50-100 mg/kg supplementation on days 1-28. Supplementation of 25-100 mg/kg ZnVal reduced (P < 0.01) the diarrhea rate of weaned piglets on days 1 to 14 and 1 to 28. Dietary supplementation with 25-100 mg/kg ZnVal increased (P < 0.05) copper/zinc-superoxide dismutase (Cu/Zn-SOD) and decreased malonaldehyde (MDA) activities in the serum on day 14 and 28. Supplementation of 25-100 mg/kg ZnVal increased (P < 0.05) glutathione peroxidase (GSH-Px) activity in serum on day 14. Additionally, the supplementation of 75 mg/kg ZnVal significantly increased the activity of superoxide dismutase (SOD) and Cu/Zn-SOD in the liver (P < 0.05). Furthermore, the supplementation of 25-100 mg/kg ZnVal significantly increased the total antioxidant capacity (T-AOC) in the liver (P < 0.05). Higher (P < 0.05) concentrations of IgG in the serum were measured from piglets supplemented with 75-100 mg/kg ZnVal on day 14 and dietary supplementation with 25-100 mg/kg ZnVal increased the level of immunoglobulin G (IgG) in serum on day 28 (P < 0.05). In addition, higher (P < 0.05) concentrations of immunoglobulin A (IgA) in the duodenum and ileum were measured from piglets supplemented with 75 mg/kg ZnVal and the supplementation of 25-100 mg/kg ZnVal also showed a higher (P < 0.05) concentration of immunoglobulin G (IgG) in duodenum. Supplementation of 50-100 mg/kg ZnVal increased the villus height and villus height/crypt depth of jejunum (P < 0.05). Moreover, dietary supplementation with 75-100 mg/kg ZnVal showed a higher (P < 0.05) concentration of zinc in the liver and supplementation of 50-100 mg/kg ZnVal increased (P < 0.05) the concentration of zinc in the heart, spleen, and kidney. In conclusion, the present research showed that supplementation of ZnVal improves growth performance by increasing antioxidant capacity and immunity and regulating intestinal morphology and the optimal inclusion level of ZnVal was 65~80 mg/kg.

Effects of folic acid and riboflavin on growth performance, nutrient digestion and rumen fermentation in Angus bulls.

This study examined the influences of coated folic acid (CFA) and coated riboflavin (CRF) on bull performance, nutrients digestion and ruminal fermentation. Forty-eight Angus bulls based on a randomised block and 2 × 2 factorial design were assigned to four treatments. The CFA of 0 or 6 mg of folic acid/kg DM was supplemented in diets with CRF 0 or 60 mg riboflavin (RF)/kg DM. Supplementation of CRF in diets with CFA had greater increase in daily weight gain and feed efficiency than in diets without CFA. Supplementation with CFA or CRF enhanced digestibility of DM, organic matter, crude protein, neutral-detergent fibre and non-fibre carbohydrate. Ruminal pH and ammonia N content decreased and total volatile fatty acids concentration and acetate to propionate ratio elevated for CFA or CRF addition. Supplement of CFA or CRF increased the activities of fibrolytic enzymes and the numbers of total bacteria, protozoa, fungi, dominant fibrolytic bacteria and Prevotella ruminicola. The activities of α-amylase, protease and pectinase and the numbers of Butyrivibrio fibrisolvens and Ruminobacter amylophilus were increased by CFA but were unaffected by CRF. Blood concentration of folate elevated and homocysteine decreased for CFA addition. The CRF supplementation elevated blood concentrations of folate and RF. These findings suggested that CFA or CRF inclusion had facilitating effects on performance and ruminal fermentation, and combined addition of CFA and CRF had greater increase in performance than CFA or CRF addition alone in bulls.

Effects of Different Levels of Organic Trace Minerals on Oxidative Status and Intestinal Function in Weanling Piglets.

An experiment was conducted to compare the effects of replacing inorganic trace minerals (ITM) with different levels of complex organic trace minerals (OTM) on the growth performance, oxidative status, and intestinal function of piglets. Weanling piglets were assigned to five groups: a control group fed a basal diet supplemented with inorganic trace minerals and the other four groups fed basal diets supplemented with different levels of OTMs. The results showed that diets supplemented with 50 ppm Fe, 30 ppm Zn, 15 ppm Mn, and 0.2 ppm Se from OTM (L-OTM), or with 75 ppm Fe, 45 ppm Zn, 22.5 ppm Mn, and 0.3 ppm Se from OTM (M-OTM) significantly decreased the diarrhea ratio in the piglets compared with those supplemented with 100 ppm Fe, 90 ppm Zn, 40 ppm Mn, and 0.4 ppm Se from ITM. Compared with those in the ITM group, the piglets in the M-OTM group had significantly higher serum CuZnSOD, MnSOD, and GSH-Px levels. Moreover, piglets in the L-OTM and M-OTM groups had higher Sod and Gpx gene expression than those in the ITM group. Additionally, piglets in the L-OTM and M-OTM groups had significantly higher villus height than those in the ITM group, and the M-OTM group piglets had lower serum diamine oxidase content and higher ileal ZO-1 and occludin protein expression levels than those in the ITM group. These results indicate that replacing dietary ITMs with OTMs could decrease diarrhea occurrence and improve the oxidative status and intestinal barrier function in weanling piglets.

Effects of guanidinoacetic acid supplementation on lactation performance, nutrient digestion and rumen fermentation in Holstein dairy cows.

BACKGROUND: Considering the high energy demand of lactation and the potential of guanidinoacetic acid (GAA) addition on the increase in creatine supply for cows, the present study investigated the effects of 0, 0.3, 0.6 and 0.9 g kg-1 dry matter (DM) of GAA supplementation on lactation performance, nutrient digestion and ruminal fermentation in dairy cows. The study used 40 mid-lactation multiparous Holstein cows and the study duration was 100 days. RESULTS: DM intake was not affected, but milk and milk component yields and feed efficiency increased linearly with increasing GAA addition. The total-tract digestibility of DM, organic matter, neutral detergent fibre, acid detergent fibre and non-fibre carbohydrates increased linearly and that of crude protein increased quadratically with increasing GAA addition. When the addition level of GAA increased, ruminal pH, molar percentages of butyrate, isobutyrate and isovalerate and the acetate-to-propionate ratio decreased linearly, and the total volatile fatty acids concentration and propionate molar percentage also increased linearly, whereas the acetate molar percentage and ammonia-N concentration were unaltered. The activities of fibrolytic enzymes, α-amylase and protease increased linearly. The populations of total bacteria, fungi, Ruminococcus albus, Fibrobacter succinogenes, Ruminococcus flavefaciens, Ruminobacter amylophilus and Prevotella ruminicola increased linearly, whereas protozoa and methanogens decreased linearly with increasing GAA addition. As for the blood metabolites, concentrations of glucose, urea nitrogen and methionine were unchanged, total protein, albumin, creatine and homocysteine increased linearly, and folate decreased linearly with increasing GAA supply. CONCLUSION: The results of the present study indicate that supplementation of GAA improved milk performance and rumen fermentation in lactating dairy cows. © 2022 Society of Chemical Industry.

The association between maternal tea consumption and the risk of pregnancy induced hypertension: A retrospective cohort study in Lanzhou, China.

BACKGROUND: Existing evidence on the relationship between maternal tea consumption and pregnancy induced hypertension (PIH) is inconclusive. This study aimed to evaluate the association between maternal tea consumption and the risk of PIH. METHODS: This study analysed the data of women without chronic hypertension who participated in a retrospective birth cohort study conducted from 2010 to 2012 at the Gansu Provincial Maternity and Child Care Hospital in Lanzhou, China. Multivariable logistic regression models were used to estimate the association between tea consumption and the risk of PIH and its clinical subtypes by different tea exposure time windows. RESULTS: Among the 10,452 women included in this study, tea consumption during pregnancy was significantly associated with an increased risk of PIH (odds ratio [OR] = 1.44, 95 % confidence interval [CI]: 1.01, 2.05), gestational hypertension (OR = 1.86, 95 % CI: 1.07, 3.21), and early-onset preeclampsia (OR = 2.93, 95 % CI: 1.21, 7.09). This was especially the case with black tea (OR = 3.57, 95 % CI: 1.67, 7.62). CONCLUSIONS: Tea consumption during pregnancy might be associated with an increased risk of PIH, gestational hypertension, and early-onset preeclampsia. These findings have important implications for public health in reducing the PIH.

Effects of Benzo[a]pyrene-DNA adducts, dietary vitamins, folate, and carotene intakes on preterm birth: a nested case-control study from the birth cohort in China.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) and its DNA adducts has been suggested to increase the risk of preterm birth (PB). Yet, few studies have been conducted to investigate this association, and the role of dietary nutrients intakes including vitamins, folate, and carotene during pre- and post-conception on this association has not been studied. METHODS: Building upon a birth cohort in Taiyuan China, we conducted a nested case control study including 83 PB and 82 term births. Benzo[a]pyrene (BaP)-DNA adducts were measured by an improved LC-MC/MC analytic method. Dietary nutrient intakes were estimated from food frequency questionnaire using the Chinese Standard Tables of Food Consumption. Multivariable logistic regression model was used to examine the associations. RESULTS: Increased risk of PB was observed as per interquartile increase in maternal BaP-DNA adduct level (OR = 1.27, 95%CI 0.95-1.67). Compared to low level (below mean) of maternal adducts, high level (above mean) of adducts was associated with the risk of PB (OR = 2.05, 95%CI 1.05-4.01). After stratified by dietary nutrients intakes, high adducts levels were associated with approximately 2-fourfold times increases in risk of PB among women with low vitamin A, C, E, folate, and carotene intakes during pre- and/or post-conception. Stronger stratified associations were consistently seen during preconception. Similar patterns were observed after additional adjustment for supplementation. CONCLUSIONS: Our study supports the hypothesis that high level of maternal PAHs exposure was significantly associated with increased risk of PB, and provides the first evidence that dietary vitamins, carotene, and folate intake levels may modify this association during different pregnancy windows. Our findings are relevant to identify recommendation for environment management and prenatal nutrition regarding pregnant women and newborns. Further investigation in other populations is warranted.

Screening of genes related to breast cancer prognosis based on the DO-UniBIC method.

BACKGROUND: Early screening is the most effective way to control breast cancer. Due to the lack of accurate biomarkers, early diagnosis of breast cancer is still very difficult. Therefore, it is necessary to discover new candidate genes of breast cancer and improve the early diagnosis and prognosis. METHODS: A DO-UniBIC gene screening method was proposed. First, Disease Ontology (DO) analysis was used to screen out breast cancer related genes from differentially expressed genes, and then the UniBIC algorithm was used to find all gene clusters with the same changing trend based on the longest common subsequence. In addition, an eight-gene prognostic model was constructed to assess the prognostic risk of breast cancer patients. RESULTS: The prognostic analysis of the candidate genomes based on multivariate Cox proportional regression model revealed eight genes that were significantly related to prognosis. The eight genes were ACSL1, CD24, EMP1, JPH3, CAMK4, JUN, S100B and TP53AIP1. Among them, ACSL1 was a new potential breast cancer related gene screened by the DO-UniBIC method. CONCLUSIONS: More comprehensive cancer-related genes can be screened based on the DO-UniBIC method, which can be used as the candidate gene set for prognostic analysis.

Correlations of gestational hemoglobin level, placental trace elements content, and reproductive performances in pregnant sows.

The iron status of sows has a great influence on reproductive performance. Iron deficiency reduces reproductive performance and newborn piglet survival rate of sow. The hemoglobin is a potential predictor for the iron status of sows and is convenient for rapid detection in pig farms. However, the relationship between iron status, hemoglobin, placental trace elements, and reproductive performance remains unclear. In this study, the hemoglobin and reproductive performance of more than 500 sows with first to sixth parities at different gestation stages (25, 55, 75, 95, and 110 d of gestation) in two large-scale sow farms were collected, and the content of placental Fe, Zn, Mn, and Cu was analyzed. The results show that hemoglobin levels of sows during pregnancy (days 75, 95, and 110) decreased significantly (P < 0.001). As the parity increases, the hemoglobin levels of sows at days 25 and 55 of gestation and placental mineral element contents including Fe, Zn, Mn, and Cu at delivery decreased (P < 0.05), while the litter size, birth alive, and litter weights increased gradually (P < 0.001). Furthermore, hemoglobin during pregnancy had a negative linear correlation with litter weight and average weight (P < 0.05), and higher hemoglobin at day 25 of gestation may reduce the number of stillbirths (P = 0.05), but higher hemoglobin at day 110 of gestation may tend to be a benefit for the birth (P = 0.01). And there was a significant positive linear correlation between hemoglobin at day 110 of gestation and placental Fe and Mn levels (P = 0.002, P = 0.013). There was also a significant positive linear correlation among Fe, Zn, Mn, and Cu in the placenta (P < 0.001). The levels of Fe, Zn, and Mn in the placental at delivery were positively related to the average weight of the fetus (P = 0.048, P = 0.027, P = 0.047), and placental Cu was linearly correlated with litter size (P = 0.029). Our research revealed that the requirements for iron during gestation were varied in different gestation periods and parities. The feeds should be adjusted according to the gestation periods, parities, or iron status to meet the iron requirements of sows and fetal pigs.

Iron deficiency and iron excess may cause adverse outcomes during pregnancy. In sows' feed, iron is added as ferrous sulfate, ferrous glycine, or other forms to improve their reproductive performance and prevent iron-deficiency anemia in their offspring. However, it is always ineffective and iron-deficiency anemia often occurs in piglets. To explore the iron requirements in pregnant sows, we conducted a large-scale farm study to track the hemoglobin levels, placental trace element content, and reproductive performances of hundreds of sows. The correlation between the hemoglobin levels, placental trace element content, and reproductive performance indicators of sows during pregnancy at different parities was analyzed. We found that pregnancy hemoglobin level of sows decreases during the gestation and varies at different parities. The hemoglobin level of sows during pregnancy was linearly negatively correlated with reproductive performance. The content of iron, zinc, manganese, and copper in the placenta was linearly positively correlated. Our results revealed that iron deficiency or excess in sows' feed may not be conducive to the improvement of reproductive performance, and the optimal iron supplementation dose during pregnancy may depend on the iron status and number of fetuses of sow.

Ailanthus Altissima-derived Ailanthone enhances Gastric Cancer Cell Apoptosis by Inducing the Repression of Base Excision Repair by Downregulating p23 Expression.

Chemotherapy plays an irreplaceable role in the treatment of GC, but currently available chemotherapeutic drugs are not ideal. The application of medicinal plants is an important direction for new drug discovery. Through drug screening of GC organoids, we determined that ailanthone has an anticancer effect on GC cells in vitro and in vivo. We also found that AIL can induce DNA damage and apoptosis in GC cells. Further transcriptome sequencing of PDX tissue indicated that AIL inhibited the expression of XRCC1, which plays an important role in DNA damage repair, and the results were also confirmed by western blotting. In addition, we found that AIL inhibited the expression of P23 and that inhibition of P23 decreased the expression of XRCC1, indicating that AIL can regulate XRCC1 via P23. The results of coimmunoprecipitation showed that AIL can inhibit the binding of P23 and XRCC1 to HSP90. These findings indicate that AIL can induce DNA damage and apoptosis in GC cells. Meanwhile, AIL can decrease XRCC1 activity by downregulating P23 expression to inhibit DNA damage repair. The present study sheds light on the potential application of new drugs isolated from natural medicinal plants for GC therapy.

Manganese methionine hydroxy analog chelated affects growth performance, trace element deposition and expression of related transporters of broilers.

The present study aimed to evaluate the effects of manganese methionine hydroxyl analog chelated (Mn-MHAC) as a manganese (Mn) source on growth performance and trace element deposition in broilers. A total of 432 Arbor Acres commercial female broilers were fed a basal corn-soybean diet containing Mn at 25.64 mg/kg diet for 10 d. They were then randomly assigned to 6 groups, including a control group (the basal diet), a Mn sulfate group (the basal diet supplemented with Mn at 100 mg/kg diet), and 4 Mn-MHAC groups (the basal diet supplemented with Mn-MHAC at 25, 50, 75 and 100 mg Mn/kg diet, respectively). The results showed that compared with the control group, groups supplemented with Mn-MHAC had a positive effect on BW (quadratic, P = 0.017) and ADG (quadratic, P = 0.017). Moreover, the Mn-MHAC (50 mg Mn/kg diet) group had significantly greater BW and ADG (P < 0.05) compared with the other Mn-MHAC groups. Trace element deposition results also showed that tibial Mn increased (linear or quadratic, P = 0.002 and 0.009, respectively) in groups fed diets with increased levels of Mn-MHAC. In contrast, Fe deposition decreased both in the heart (linear, P = 0.020) and tibia (P < 0.05). In addition, the Mn-MHAC supplement noticeably lowered serum Mn-SOD activity (linear or quadratic, P = 0.048 and 0.019, respectively). The relative mRNA levels of divalent metal transporter 1 (DMT1) (P = 0.024), ferroportin 1 (FPN1) (P = 0.049), and Cu transporter-1(CTR1) (P < 0.001) in the duodenum, as well as CTR1 in the jejunum and ileum (P = 0.040 and 0.011, respectively) were higher in the Mn-supplemented group than in the control group. Furthermore, the relative mRNA level of DMT1 in the jejunum and ileum of broilers in the Mn-MHAC group (50 mg Mn/kg diet) did not differ from those in the control group, but was lower than those in the Mn sulfate group (P < 0.05). In conclusion, Mn-MHAC dietary supplementation improved the growth performance and trace element deposition in broilers. From this study, we recommend the optimum Mn-MHAC level to meet the Mn requirement of broilers is 50 to 75 mg Mn/kg diet.

Phytoestrogens and Thyroid Cancer Risk: A Population-Based Case-Control Study in Connecticut.

BACKGROUND: Very few previous studies have examined the relationship between thyroid cancer risk and intake of phytoestrogens (PE); furthermore, these studies have reached inconsistent results. METHODS: We analyzed data from a population-based case-control study in Connecticut from 2010 to 2011, including 387 histologically confirmed thyroid cancer cases and 433 population-based controls, with compound data available concerning specific PEs. Multivariate unconditional logistic regression models were used to estimate the associations between specific PEs and the risk of thyroid cancer, adjusting for potential confounders. RESULTS: An elevated risk of thyroid cancer was associated with moderate to high levels of coumestrol intake [OR = 2.48, 95% confidence interval (CI), 1.39-4.43 for 40-80 µg/day; OR = 2.41, 95% CI, 1.32-4.40 for 80-130 µg/day; and OR = 2.38, 95% CI, 1.26-4.50 for >200 µg/day compared with <40 µg/day], and the main elevation in risk appeared among microcarcinomas (≤1 cm). A decreased risk of papillary macrocarcinomas (>1 cm; OR = 0.26, 95% CI, 0.08-0.85 for 1,860-3,110 µg/day compared with <760 µg/day) was associated with moderate genistein intake among women. CONCLUSIONS: Our study suggests that high coumestrol intake increases the risk of thyroid cancer, especially microcarcinomas, whereas moderate amounts of genistein intake appear to be protective for females with thyroid macrocarcinomas. IMPACT: The study highlights the importance of distinguishing between microcarcinomas and macrocarcinomas in future research on the etiology of thyroid cancer.

Folic acid supplementation, dietary folate intake and risk of small for gestational age in China.

OBJECTIVE: To investigate the hypothesis that folic acid supplementation and dietary folate intake before conception and during pregnancy reduce the risk of small for gestational age (SGA) and to examine the joint effect of folic acid supplementation and dietary folate intake on the risk of SGA. DESIGN: Participants were interviewed by trained study interviewers using a standardized and structured questionnaire. Information on birth outcomes and maternal complications was abstracted from medical records and dietary information was collected via a semi-quantitative FFQ before conception and during pregnancy. SETTING: A birth cohort data analysis using the 2010-2012 Gansu Provincial Maternity and Child Care Hospital. PARTICIPANTS: Women (n 8758) and their children enrolled in the study. RESULTS: Folic acid supplementation was associated with a reduced risk of SGA (OR = 0·72, 95 % CI 0·60, 0·86), with the reduced risk seen mainly for SGA at ≥37 weeks of gestational age (OR = 0·70, 95 % CI 0·58, 0·85) and nulliparous SGA (OR = 0·67, 95 % CI 0·54, 0·84). There was no significant association between dietary folate intake and SGA risk. CONCLUSIONS: Our study suggested that folic acid supplementation was associated with a reduced risk of SGA and the risk varied by preterm status and parity.

Practice Patterns and Guideline Non-Adherence in Surgical Management of Appendiceal Carcinoid Tumors.

BACKGROUND: Surgical management of appendiceal carcinoid tumors is heavily debated, despite National Comprehensive Cancer Network guidelines recommending aggressive resection of tumors >2 cm. We investigated national practice patterns and the predictors and impact of guideline non-adherence. STUDY DESIGN: The National Cancer Database was queried for cases of appendiceal carcinoids diagnosed from 2004 to 2015 treated with either appendectomy or hemicolectomy. Multivariable logistic regression, adjusted for demographic and clinical factors, identified associations with the procedure type among patients stratified by tumor size ≤2 cm and >2 cm. Cox Proportional Hazards then identified associations with overall survival among stratified patient groups. RESULTS: Of 3,198 cases of appendiceal carcinoids, 1,893 appendectomies and 1,305 hemicolectomies were identified. Contrary to National Comprehensive Cancer Network guidelines, 32.4% of tumors ≤2 cm were treated with hemicolectomy and 31.3% of tumors >2 cm were treated with definitive appendectomy. Hemicolectomy for small tumors was associated with age 65 years and older (odds ratio [OR] 2.4; 95% CI 1.7 to 3.3; reference group age 18 to 39 years), history of malignancy (OR 2.0; 95% CI 1.6 to 2.6), tumor size 1.1 to 2 cm (OR 2.8; 95% CI 2.3 to 3.4; reference group size ≤1 cm), and lymphovascular invasion (OR 2.2; 95% CI 1.6 to 3.2); appendectomy for large tumors was associated with age 65 years and older only (OR 2.2; 95% CI 1.1 to 4.2). Procedure type was not associated with survival for small or large tumors (hazard ratio 1.0; 95% CI 0.7 to 1.4 and hazard ratio 1.1; 95% CI 0.6 to 2.0, respectively). CONCLUSIONS: Despite well-known size-based treatment guidelines for appendiceal carcinoids, one-third of patients in the US undergo hemicolectomy for small tumors and appendectomy for large tumors. Guideline non-adherence, however, is not associated with overall survival. Reasons for these practice patterns should be explored, and guidelines revisited.

Isorhamnetin, Hispidulin, and Cirsimaritin Identified in Tamarix ramosissima Barks from Southern Xinjiang and Their Antioxidant and Antimicrobial Activities.

As a natural potential resource, Tamarix ramosissima has been widely used as barbecue skewers for a good taste and unique flavor. The polyphenolics in the branch bark play a key role in the quality improvement. The purposes of the present work were to explore the polyphenolic composition of T. ramosissima bark extract and assess their potential antioxidant and antimicrobial activities. Hispidulin and cirsimaritin from T. ramosissima bark extract were first identified in the Tamarix genus reported with UPLC-MS analysis. Isorhamnetin (36.91 µg/mg extract), hispidulin (28.79 µg/mg extract) and cirsimaritin (13.35 µg/mg extract) are rich in the bark extract. The extract exhibited promising antioxidant activity with IC50 values of 117.05 µg/mL for 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 151.57 µg/mL for hydroxyl radical scavenging activities, as well as excellent reducing power with an EC50 of 93.77 µg/mL. The bark extract showed appreciable antibacterial properties against foodborne pathogens. Listeria monocytogenes was the most sensitive microorganism with the lowest minimum inhibitory concentration (MIC) value of 5 mg/mL and minimum bactericidal concentration (MBC) value of 10 mg/mL followed by S. castellani and S. aureus among the tested bacteria. The T. ramosissima bark extract showed significantly stronger inhibitory activity against Gram-positive than Gram-negative bacteria. Nevertheless, this extract failed to show any activity against tested fungi. Overall, these results suggested that T. ramosissima shows potential in improving food quality due to its highly efficacious antioxidant and antibacterial properties.

Retrospective Observational Study from a Chinese Network of the Impact of Combination Therapy versus Monotherapy on Mortality from Carbapenem-Resistant Enterobacteriaceae Bacteremia.

Data for a total of 164 bloodstream infection cases due to carbapenem-resistant Enterobacteriaceae (CRE) from 2013 to 2017 were retrospectively collected from 36 tertiary hospitals in 19 provinces in China to evaluate the outcomes and risk factors for mortality by univariable and multivariable analysis. The most frequent infecting species was Klebsiella pneumoniae (69.5%, 114/164). The overall in-hospital and 14-day mortality rates were 32.9% (54/164) and 31.1% (42/135), respectively. Multivariable analysis revealed that septic shock (adjusted odds ratio [aOR], 6.339; 95% confidence interval [CI], 1.586 to 25.332; P = 0.009), the Pitt bacteremia score (aOR, 1.300; 95% CI, 1.009 to 1.676; P = 0.042), and the Charlson comorbidity index (aOR, 1.392; 95% CI, 1.104 to 1.755; P = 0.005) were independently associated with a hazard effect on mortality. Combination therapy, especially tigecycline-based combination therapy, resulted in relatively low rates of in-hospital mortality and failure in clearance of CRE infection. Survival analysis revealed that appropriate therapy was associated with a lower 14-day mortality rate than inappropriate therapy (including nonactive therapy; P = 0.022), that combination therapy was superior to monotherapy (P = 0.036), that metallo-ß-lactamase producers were associated with a lower 14-day mortality than strains without carbapenemases or KPC-2 producers (P = 0.009), and that strains with MICs of >8 mg/liter for meropenem were associated with a higher 14-day mortality rate than those with MICs of ≤8 mg/liter (P = 0.037). Collectively, the severity of illness, meropenem MICs of >8 mg/liter, and carbapenemase-producing types were associated with the clinical outcome. Early detection of the carbapenemase type and initiation of appropriate combination therapy within 96 h might be helpful for improving survival.

Effects of Different Selenium Sources on Laying Performance, Egg Selenium Concentration, and Antioxidant Capacity in Laying Hens.

Supplementation of selenium (Se) is a common practice in the poultry industry via sodium selenite (SS) and selenium yeast (SY), while the effects of nano-selenium (NS) on laying hens are poorly known. This study aimed to compare the effects of NS, SS, and SY on productivity; selenium (Se) deposition in eggs; and antioxidant capacity in laying hens. A total of 288 30-week-old Brown Hy-line laying hens were randomly assigned into four dietary treatments, which included corn-soybean meal basal diet (Con) without Se sources and basal diets supplemented with 0.3 mg Se/kg as SS, SY, or NS, respectively. The results exhibited that Se-supplemented treatments achieved greater egg production, egg weight, and daily egg mass, also better feed conversion ratio than Con group (p < 0.05). Se supplementation significant increased egg Se concentration and decreased the egg Se deposition efficiency (p < 0.05), while SY or NS supplementation had higher Se deposition efficiency than SS group at 35 days (p < 0.05). Moreover, serum glutathione peroxidase (GSH-Px) activity increased in SS or NS group compared to Con group (p < 0.05). The glutathione peroxidase 4 (GPX-4) mRNA levels in liver were significantly higher (p < 0.05) in SS or SY group than in NS group, and mRNA levels of the methionine (Met) metabolism gene glycine N-methyltranserfase (GNMT) were markedly upregulated (p < 0.05) in SY group compared to SS or NS group. Taken together, the results revealed Se from SY is deposited into eggs more efficiently than Se from NS or SS, probably via enhancing the route of Met metabolism. Meanwhile, it might be concluded that SS or SY supplementation directly regulated GSH-Px activity via enhancing GPx4 level, whereas NS via GPx1, thus affecting body oxidation and development.

Maternal folic acid supplementation and dietary folate intake and congenital heart defects.

BACKGROUND: It has been reported that folic acid supplementation before and/or during pregnancy could reduce the risk of congenital heart defects (CHDs). However, the results from limited epidemiologic studies have been inconclusive. We investigated the associations between maternal folic acid supplementation, dietary folate intake, and the risk of CHDs. METHODS: A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. After exclusion of stillbirths and multiple births, a total of 94 births were identified with congenital heart defects, and 9,993 births without any birth defects. Unconditional logistic regression was used to estimate the associations. RESULTS: Compared to non-users, folic acid supplement users before pregnancy had a reduced risk of overall CHDs (OR: 0.42, 95% CI: 0.21-0.86, Ptrend = 0.025) after adjusted for potential confounders. A protective effect was observed for certain subtypes of CHDs (OR: 0.37, 95% CI: 0.16-0.85 for malformation of great arteries; 0.26, 0.10-0.68 for malformation of cardiac septa; 0.34, 0.13-0.93 for Atrial septal defect). A similar protective effect was also seen for multiple CHDs (OR: 0.49, 95% CI: 0.26-0.93, Ptrend = 0.004). Compared with the middle quartiles of dietary folate intake, lower dietary folate intake (<149.88 µg/day) during pregnancy were associated with increased risk of overall CHDs (OR: 1.63, 95% CI: 1.01-2.62) and patent ductus arteriosus (OR: 1.85, 95% CI: 1.03-3.32). Women who were non-user folic acid supplement and lower dietary folate intake have almost 2-fold increased CHDs risk in their offspring. CONCLUSIONS: Our study suggested that folic acid supplementation before pregnancy was associated with a reduced risk of CHDs, lower dietary folate intake during pregnancy was associated with increased risk. The observed associations varied by CHD subtypes. A synergistic effect of dietary folate intake and folic acid supplementation was also observed.

Molecular epidemiology of colistin-resistant Enterobacteriaceae in inpatient and avian isolates from China: high prevalence of mcr-negative Klebsiella pneumoniae.

Whether chromosomal and transmissible mechanisms contribute simultaneously to colistin resistance in Klebsiella pneumoniae and Escherichia coli remains unknown. This study aims to identify the underlying mechanisms of colistin resistance in inpatient and avian K. pneumoniae and E. coli in China. We retrospectively screened 2353 Enterobacteriaceae isolates from inpatients at multiple centers during 2011-2014, and 168 avian isolates from one slaughterhouse in 2013 for the presence of MCR-1/MCR-2. Mutations and transcriptional levels of the chromosomal RamA, PhoPQ, and PmrAB genes were determined by PCR and RT-qPCR. The transferability and genetic characteristics of the underlying colistin-resistance genes were detected by conjugation and whole-genome sequencing. The MIC90 for colistin in colistin-resistant K. pneumoniae (ColRKP, 128 mg/L, N = 17) was 16-fold higher than in colistin-resistant E. coli (ColREC, 8 mg/L, N = 33). The dominant sequence types of ColRKP were ST2018 and ST37, whereas ColREC displayed diversity. The chromosomal genes ramA, pmrB, and phoQ were not associated with colistin resistance in ColRKP. The transcriptional levels of PmrB in ColREC were 7.5-fold greater than in colistin-susceptible isolates. The carrying rates of MCR-1 in ColREC and ColRKP were 100% (33/33) and 23.5% (4/17), respectively. Plasmid IncI2 (~60 kb) carrying MCR-1 could be transferred to recipient E. coli EC600 with frequencies ranging from 8.74 × 10-6 to 1.31 × 10-4. No transferable genes were identified in mcr-1-negative ColRKP. MCR-1 combined with upregulated PmrB was associated with low-level colistin resistance in ColREC. However, two-thirds of the ColRKP isolates were mcr-negative and need to be studied further.