Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over : a randomised controlled trial

Background: Observational studies have frequently reported an association between cognitive function and nutrition in later life but randomised trials of B vitamins and antioxidant supplements have mostly found no beneficial effect. We examined the effect of daily supplementation with 11 vitamins and 5 minerals on cognitive function in older adults to assess the possibility that this could help to prevent cognitive decline. Methods: The study was carried out as part of a randomised double blind placebo controlled trial of micronutrient supplementation based in six primary care health centres in North East Scotland. 910 men and women aged 65 years and over living in the community were recruited and randomised: 456 to active treatment and 454 to placebo. The active treatment consisted of a single tablet containing eleven vitamins and five minerals in amounts ranging from 50–210 % of the UK Reference Nutrient Intake or matching placebo tablet taken daily for 12 months. Digit span forward and verbal fluency tests, which assess immediate memory and executive functioning respectively, were conducted at the start and end of the intervention period. Risk of micronutrient deficiency at baseline was assessed by a simple risk questionnaire. Results: For digit span forward there was no evidence of an effect of supplements in all participants or in sub-groups defined by age or risk of deficiency. For verbal fluency there was no evidence of a beneficial effect in the whole study population but there was weak evidence for a beneficial effect of supplementation in the two pre-specified subgroups: in those aged 75 years and over (n 290; mean difference between supplemented and placebo groups 2.8 (95% CI -0.6, 6.2) units) and in those at increased risk of micronutrient deficiency assessed by the risk questionnaire (n 260; mean difference between supplemented and placebo groups 2.5 (95% CI -1.0, 6.1) units). Conclusion: The results provide no evidence for a beneficial effect of daily multivitamin and multimineral supplements on these domains of cognitive function in community-living people over 65 years. However, the possibility of beneficial effects in older people and those at greater risk of nutritional deficiency deserves further attention.Peer reviewedPublisher PD

Dynamical description of the breakup of one-neutron halo nuclei 11Be and 19C

We investigate the breakup of the one-neutron halo nuclei 11Be and 19C within a dynamical model of the continuum excitation of the projectile. The time evolution of the projectile in coordinate space is described by solving the three-dimensional time dependent Schroedinger equation, treating the projectile-target (both Coulomb and nuclear) interaction as a time dependent external perturbation. The pure Coulomb breakup dominates the relative energy spectra of the fragments in the peak region, while the nuclear breakup is important at higher relative energies. The coherent sum of the two contributions provides a good overall description of the experimental spectra. Cross sections of the first order perturbation theory are derived as a limit of our dynamical model. The dynamical effects are found to be of the order of 10-15% for the beam energies in the range of 60 - 80 MeV/nucleon. A comparison of our results with those of a post form distorted wave Born approximation shows that the magnitudes of the higher order effects are dependent on the theoretical model.Comment: 15 pages, ReVTeX, 5 figures, typos corrected, accepted for publication in Physical Review

Resource Planning for Neglected Tropical Disease (NTD) Control Programs: Feasibility Study of the Tool for Integrated Planning and Costing (TIPAC).

<p>Resource Planning for Neglected Tropical Disease (NTD) Control Programs: Feasibility Study of the Tool for Integrated Planning and Costing (TIPAC)</p

Predictors of 30-Day Mortality Among Dutch Patients Undergoing Colorectal Cancer Surgery, 2011-2016

IMPORTANCE Quality improvement programs for colorectal cancer surgery have been introduced with benchmarking based on quality indicators, such as mortality. Detailed (pre)operative characteristics may offer relevant information for proper case-mix correction. OBJECTIVE To investigate the added value of machine learning to predict quality indicators for colorectal cancer surgery and identify previously unrecognized predictors of 30-day mortality based on a large, nationwide colorectal cancer registry that collected extensive data on comorbidities. DESIGN, SETTING, AND PARTICIPANTS All patients who underwent resection for primary colorectal cancer registered in the Dutch ColoRectal Audit between January 1, 2011, and December 31, 2016, were included. Multiple machine learning models (multivariable logistic regression, elastic net regression, support vector machine, random forest, and gradient boosting) were made to predict quality indicators. Model performance was compared with conventionally used scores. Risk factors were identified by logistic regression analyses and Shapley additive explanations (ie, SHAP values). Statistical analysis was performed between March 1 and September 30, 2020. MAIN OUTCOMES AND MEASURES The primary outcome of this cohort study was 30-day mortality. Prediction models were trained on a training set by performing 5-fold cross-validation, and outcomes were measured by the area under the receiver operating characteristic curve on the test set. Machine learning was further used to identify risk factors, measured by odds ratios and SHAP values. RESULTS This cohort study included 62 501 records, most patients were male (35 116 [56.2%]), were aged 61 to 80 years (41 560 [66.5%]), and had an American Society of Anesthesiology score of II (35 679 [57.1%]). A 30-day mortality rate of 2.7% (n = 1693) was found. The area under the curve of the best machine learning model for 30-day mortality (0.82; 95% CI, 0.79-0.85) was significantly higher than the American Society of Anesthesiology score (0.74; 95% CI, 0.71-0.77; P &lt; .001), Charlson Comorbidity Index (0.66; 95% CI, 0.63-0.70; P &lt; .001), and preoperative score to predict postoperative mortality (0.73; 95% CI, 0.70-0.77; P &lt; .001). Hypertension, myocardial infarction, chronic obstructive pulmonary disease, and asthma were comorbidities with a high risk for increased mortality. Machine learning identified specific risk factors for a complicated course, intensive care unit admission, prolonged hospital stay, and readmission. Laparoscopic surgery was associated with a decreased risk for all adverse outcomes. CONCLUSIONS AND RELEVANCE This study found that machine learning methods outperformed conventional scores to predict 30-day mortality after colorectal cancer surgery, identified specific patient groups at risk for adverse outcomes, and provided directions to optimize benchmarking in clinical audits.</p

Preclinical Strategies to Identify Off-Target Toxicity of High-Affinity TCRs

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Self-sufficient primary natural killer cells engineered to express T cell receptors and interleukin-15 exhibit improved effector function and persistence

BackgroundNK cells can be genetically engineered to express a transgenic T-cell receptor (TCR). This approach offers an alternative strategy to target heterogenous tumors, as NK:TCR cells can eradicate both tumor cells with high expression of HLA class I and antigen of interest or HLA class I negative tumors. Expansion and survival of NK cells relies on the presence of IL-15. Therefore, autonomous production of IL-15 by NK:TCR cells might improve functional persistence of NK cells. Here we present an optimized NK:TCR product harnessed with a construct encoding for soluble IL-15 (NK:TCR/IL-15), to support their proliferation, persistence and cytotoxic capabilities.MethodsExpression of tumor-specific TCRs in peripheral blood derived NK-cells was achieved following retroviral transduction. NK:TCR/IL-15 cells were compared with NK:TCR cells for autonomous cytokine production, proliferation and survival. NK:BOB1-TCR/IL-15 cells, expressing a HLA-B*07:02-restricted TCR against BOB1, a B-cell lineage specific transcription factor highly expressed in all B-cell malignancies, were compared with control NK:BOB1-TCR and NK:CMV-TCR/IL-15 cells for effector function against TCR antigen positive malignant B-cell lines in vitro and in vivo.ResultsViral incorporation of the interleukin-15 gene into engineered NK:TCR cells was feasible and high expression of the TCR was maintained, resulting in pure NK:TCR/IL-15 cell products generated from peripheral blood of multiple donors. Self-sufficient secretion of IL-15 by NK:TCR cells enables engineered NK cells to proliferate in vitro without addition of extra cytokines. NK:TCR/IL-15 demonstrated a marked enhancement of TCR-mediated cytotoxicity as well as enhanced NK-mediated cytotoxicity resulting in improved persistence and performance of NK:BOB1-TCR/IL-15 cells in an orthotopic multiple myeloma mouse model. However, in contrast to prolonged anti-tumor reactivity by NK:BOB1-TCR/IL-15, we observed in one of the experiments an accumulation of NK:BOB1-TCR/IL-15 cells in several organs of treated mice, leading to unexpected death 30 days post-NK infusion.ConclusionThis study showed that NK:TCR/IL-15 cells secrete low levels of IL-15 and can proliferate in an environment lacking cytokines. Repeated in vitro and in vivo experiments confirmed the effectiveness and target specificity of our product, in which addition of IL-15 supports TCR- and NK-mediated cytotoxicity

Dietary strategies can increase cloacal endotoxin levels and modulate the resident microbiota in broiler chickens

Endotoxins released from poultry feces have been associated with impaired human health. Because endotoxins are released from gram-negative intestinal bacteria, it was hypothesized that dietary strategies may influence endotoxin excretion via modulation of gut microbiota. We therefore tested dietary strategies that could potentially reduce cloacal endotoxin levels in broiler chickens. One-day-old male Ross 308 (N = 1,344) broilers were housed in 48 pens (N = 8 pens/treatment, 28 chickens per pen) and fed 1 of 6 diets for 35 days (d) in a 3-phase feeding program: a basic diet (CON) that served as the reference diet, or basic diet supplemented with butyrate (BUT), inulin (INU), medium-chain fatty acids (MCFA) or Original XPC™LS (XPC), or a high-fiber-low-protein (HF-LP) diet. A significant (P < 0.05) increase in cloacal endotoxin concentration at d 35 was observed in BUT as compared to CON. Analysis of cloacal microbiota showed a trend (P < 0.07) for a higher gram-negative/gram-positive ratio and for a higher relative abundance of gram-negative bacteria at d 35 (P ≤ 0.08) in BUT and HF-LP as compared to CON. A significant (P < 0.05) increase in average daily gain (ADG) and improved feed conversion ratio (P < 0.05) were observed in MCFA during the grower phase (d 14-28), and a significant (P < 0.05) increase in average daily feed intake (ADFI) was observed in MCFA during d 0 to 28. Broilers fed HF-LP had a significantly (P < 0.05) higher FCR and lower ADG throughout the rearing period. No treatment effects were found on footpad dermatitis, but BUT had worst hock burn scores at d 35 (P < 0.01) and MCFA had worst cleanliness scores at d 21 but not at d 35 (treatment*age P < 0.05), while INU had better cleanliness as compared to CON at d 35 (P < 0.05). In conclusion, especially BUT and HF-LP were able to modulate resident microbiota and BUT also increased cloacal endotoxin levels, which was opposite to our hypothesis. The present study indicates that cloacal endotoxin release can be affected by the diet but further study is needed to find dietary treatments that can reduce cloacal endotoxin release

Comparing CAR and TCR engineered T cell performance as a function of tumor cell exposure

Chimeric antigen receptor (CAR) T cell therapies have resulted in profound clinical responses in the treatment of CD19-positive hematological malignancies, but a significant proportion of patients do not respond or relapse eventually. As an alternative to CAR T cells, T cells can be engineered to express a tumor-targeting T cell receptor (TCR). Due to HLA restriction of TCRs, CARs have emerged as a preferred treatment moiety when targeting surface antigens, despite the fact that functional differences between engineered TCR (eTCR) T and CAR T cells remain ill-defined. Here, we compared the activity of CAR T cells versus engineered TCR T cells in targeting the B cell malignancy-associated antigen CD20 as a function of antigen exposure. We found CAR T cells to be more potent effector cells, producing higher levels of cytokines and killing more efficiently than eTCR T cells in a short time frame. However, we revealed that the increase of antigen exposure significantly impaired CAR T cell expansion, a phenotype defined by high expression of coinhibitory molecules and effector differentiation. In contrast, eTCR T cells expanded better than CAR T cells under high antigenic pressure, with lower expression of coinhibitory molecules and maintenance of an early differentiation phenotype, and comparable clearance of tumor cells

Glutathione-S-transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2

Background: Interleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. Methods: We used house dust mite (HDM) or interleukin-1β in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1β and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. Results: Ablation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1β-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1β-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. Conclusions: GSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes