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Purpose To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Background Optimal nutrition therapy has not yet been established for the acute phase of severe coronavirus disease 2019 (COVID-19) infection. Objectives To examine the effects of nutrition delivery in the acute phase on the mortality and long-term outcomes of post-intensive care syndrome (PICS). Methods A multicenter prospective study was conducted on adult patients with COVID-19 infection requiring mechanical ventilation during an intensive care unit (ICU) stay. Daily total energy (kcal/kg) and protein (g/kg) deliveries in the first week of the ICU stay were calculated. The questionnaire for the PICS evaluation was mailed within a median of 6 months after hospital discharge. The primary outcome was in-hospital mortality, and secondary outcomes were PICS components of physical, cognitive dysfunction and mental illness. Results Among 414 eligible patients, 297 who received mechanical ventilation for 7 days or longer were examined. PICS was evaluated in 175 patients among them. High protein delivery on days 4–7 correlated with a low in-hospital mortality rate. In contrast, high protein delivery on days 1–3 correlated with physical impairment. A multivariate logistic regression analysis adjusted for age, sex, body mass index, and severity revealed that average energy and protein deliveries on days 4–7 correlated with decreased in-hospital mortality; odds ratio 0.94 (95%CI 0.89,0.99) (P = 0.013) and 0.40 (95%CI 0.17,0.93) (P = 0.031), respectively. Nutrition delivery did not correlate with PICS outcomes after adjustments. In the multivariate regression using restricted cubic spline model, in-hospital mortality monotonically decreased with increases in average nutrition delivery on days 4–7. Conclusions In patents with COVID-19 on mechanical ventilation ≥ 7 days, nutrition delivery in the late period of the acute phase was monotonically associated with a decrease in in-hospital mortality. Adequate protein delivery is needed on days 4–7.

To characterize the IgG and IgA responses to different SARS-CoV-2 proteins, we investigated the antibody responses to SARS-CoV-2 following natural infection and following a single dose of AZD1222 (Covishield), in Sri Lankan individuals. The IgG and IgA responses were assessed to S1, S2, RBD, and N proteins in patients at 4 weeks and 12 weeks since the onset of illness or following vaccination. Antibodies to the receptor-binding domain of SARS-CoV-2 wild type (WT), α, β, and λ and ACE2 (Angiotensin Converting Enzyme 2) receptor blocking antibodies were also assessed in these cohorts. For those with mild illness and in vaccines, the IgG responses to S1, S2, RBD, and N protein increased from 4 weeks to 12 weeks, while it remained unchanged in those with moderate/severe illness. In the vaccines, IgG antibodies to the S2 subunit had the highest significant rise (P < 0.0001). Vaccines had several-fold lower IgA antibodies to all the SARS-CoV-2 proteins tested than those with natural infection. At 12 weeks, the haemagglutination test (HAT) titres were significantly lower to the α in vaccines and significantly lower in those with mild illness and in vaccines to β and for λ. No such difference was seen in those with moderate/severe illness. Vaccines had significantly less IgA to SARS-CoV-2, but comparable IgG responses those with natural infection. However, following a single dose vaccines had reduced antibody levels to the VOCs, which further declined with time, suggesting the need to reduce the gap between the two doses, in countries experiencing outbreaks due to VOCs.

Background Carbohydrate restriction shows promise for diabetes, but concerns regarding high saturated fat content of low-carbohydrate diets limit widespread adoption. Objectives This preplanned ancillary study aimed to determine how diets varying widely in carbohydrate and saturated fat affect cardiovascular disease (CVD) risk factors during weight-loss maintenance. Methods After 10–14% weight loss on a run-in diet, 164 participants (70% female; BMI = 32.4 ± 4.8 kg/m2) were randomly assigned to 3 weight-loss maintenance diets for 20 wk. The prepared diets contained 20% protein and differed 3-fold in carbohydrate (Carb) and saturated fat as a proportion of energy (Low-Carb: 20% carbohydrate, 21% saturated fat; Moderate-Carb: 40%, 14%; High-Carb: 60%, 7%). Fasting plasma samples were collected prerandomization and at 20 wk. Lipoprotein insulin resistance (LPIR) score was calculated from triglyceride-rich, high-density, and low-density lipoprotein particle (TRL-P, HDL-P, LDL-P) sizes and subfraction concentrations (large/very large TRL-P, large HDL-P, small LDL-P). Other outcomes included lipoprotein(a), triglycerides, HDL cholesterol, LDL cholesterol, adiponectin, and inflammatory markers. Repeated measures ANOVA was used for intention-to-treat analysis. Results Retention was 90%. Mean change in LPIR (scale 0–100) differed by diet in a dose-dependent fashion: Low-Carb (–5.3; 95% CI: –9.2, –1.5), Moderate-Carb (–0.02; 95% CI: –4.1, 4.1), High-Carb (3.6; 95% CI: –0.6, 7.7), P = 0.009. Low-Carb also favorably affected lipoprotein(a) [–14.7% (95% CI: –19.5, –9.5), –2.1 (95% CI: –8.2, 4.3), and 0.2 (95% CI: –6.0, 6.8), respectively; P = 0.0005], triglycerides, HDL cholesterol, large/very large TRL-P, large HDL-P, and adiponectin. LDL cholesterol, LDL-P, and inflammatory markers did not differ by diet. Conclusions A low-carbohydrate diet, high in saturated fat, improved insulin-resistant dyslipoproteinemia and lipoprotein(a), without adverse effect on LDL cholesterol. Carbohydrate restriction might lower CVD risk independently of body weight, a possibility that warrants study in major multicentered trials powered on hard outcomes. The registry is available through ClinicialTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02068885.

Background A large proportion of infants in low- and middle-income countries are stunted. These infants are often fed complementary foods that are low-quality, primarily in terms of protein and micronutrients. Objectives We aimed to test 2 milk–cereal mixes supplemented with modest and high amounts of protein during 6–12 mo of age, compared with no supplementation, for their effect on length-for-age z score (LAZ) at 12 mo of age. Methods Eligible infants (6 mo plus ≤29 d) were randomly assigned to either of the 2 interventions (modest- and high-protein) or a no supplement group. The milk–cereal mixes provided ∼125 kcal, 30%–45% energy from fats, and 80%–100% RDA of multiple micronutrients (MMN). The modest-protein group received 2.5 g protein [protein energy ratio (PER): 8%; 0.75 g from milk source] and the high-protein group received 5.6 g protein (PER: 18%, 1.68 g from milk source). One packet was given daily for 180 d. Counseling on continued breastfeeding and optimal infant-care practices was provided to all. Results We enrolled 1548 infants (high-protein: n = 512; modest-protein: n = 519; and no supplement: n = 517). Compared with the no supplement group, there was an improvement in LAZ [adjusted mean difference (MD): 0.08; 95% CI: 0.01, 0.15], weight-for-age z score (MD: 0.12; 95% CI: 0.06, 0.19), weight-for-length z score (MD: 0.11; 95% CI: 0.02, 0.19), and midupper arm circumference z score (MD: 0.10; 95% CI: 0.02, 0.18) in the high-protein group at 12 mo of age. No significant differences for these anthropometric indicators were noted between the modest-protein and no supplement groups or between the high- and modest-protein groups. Conclusions Cereal mixes with higher amounts of milk-based protein and MMN may lead to improvement in linear growth and other anthropometric indexes in infants, compared with no supplementation. This trial was registered at ctri.nic.in as CTRI/2018/04/012932.

Impairment of antigen-presenting functions is a key mechanism contributing to sepsis-induced immunosuppression. Recently, γδ T cells have been demonstrated as professional antigen-presenting cells (APCs); however, their role in sepsis remains unknown. In this in vitro study, the APC function of human peripheral γδ T cells was assessed using samples collected from 42 patients with sepsis and 27 age-matched healthy controls. The APC-related markers HLA-DR, CD27, CD80, and CCR7 on fresh γδT cells were significantly higher in patients with sepsis compared with matched controls; however, they responded poorly to 4-hydroxy-3-methyl-2-butenyl pyrophosphate (HMBPP) stimulation, characterized by the deactivation of these APC markers and impaired proliferation. Furthermore, the adhesion function of γδ T cells, essential for antigen presentation, was greatly reduced in patients with sepsis; for instance, in co-cultures with green fluorescent protein-expressing Escherichia coli, HMBPP-activated γδT cells from healthy individuals adhered to E. coli efficiently, whereas no such phenomenon was observed with respect to γδT cells from patients with sepsis. In line with these results, in co-cultures with isolated CD4+ αβ T cells, HMBPP-activated γδT cells of healthy individuals promoted the efficient proliferation of CD4+ αβ T cells, whereas γδT cells from patients with sepsis did not do so. In conclusion, our findings show that the antigen-presenting function of γδT cells is severely impaired in patients with sepsis and the mechanisms behind need further study., The APC-related markers on fresh γδT cells were significantly higher in patients with sepsis compared with matched controls; however, they responded poorly to 4-hydroxy-3-methyl-2-butenyl pyrophosphate (HMBPP) stimulation, characterized by the deactivation of these APC markers and impaired proliferation. HMBPP-activated γδT cells from healthy individuals adhered to E. coliefficiently and promoted the efficient proliferation of CD4+ aß T cells, whereas γδT cells from patients with sepsis did not do so. In conclusion, our findings show that the antigen-presenting function of γδT cells is severely impaired in patients with sepsis., Graphical Abstract Graphical Abstract

Antigen-specific T cells can serve as a response biomarker in non-clinical or clinical immunotherapy studies in autoimmune disease. There are protocols with optimized multimer staining methods to detect peptide (p)MHCII+ CD4+ T cells, and some qualified and validated protocols for pMHCI+ CD8+ T cells. However, no protocol is fully or partially qualified to enumerate and characterize antigen-specific pMHCII+ CD4+ T cells from patient samples. Implementing such an assay requires a desired level of specificity and precision, in terms of assay repeatability and reproducibility. In transgenic type II collagen (CII)-immunized HLA-DR1/DR4 humanized mouse models of collagen-induced arthritis (CIA), CII259-273-specific T cells dominantly expand. Therefore antigen-specific T cells recognizing this epitope presented by rheumatoid arthritis (RA)-associated risk HLA-DR allomorphs are of interest to understand disease progression and responses to immunotherapy in RA patients. Using HLA-DRB1∗04:01 or ∗01:01-collagen type II (CII)259–273 tetramers, we evaluated parameters influencing precision and reproducibility of an optimized flow cytometry–based method for antigen-specific CD4+ T cells and eight specific subpopulations with and without tetramer positivity. We evaluated specificity, precision, and reproducibility for research environments and non-regulated laboratories. The assay has excellent overall precision with %CV

Background Effects of soy foods on cerebral blood flow (CBF)-a marker of cerebrovascular function-may contribute to the beneficial effects of plant-based diets on cognitive performance. Objectives We aimed to investigate longer-term effects of soy nut consumption on CBF in older adults. Changes in 3 different domains of cognitive performance were also studied. Methods Twenty-three healthy participants (age: 60-70 y; BMI: 20-30 kg/m(2)) participated in a randomized, controlled, single-blinded crossover trial with an intervention (67 g/d of soy nuts providing similar to 25.5 g protein and 174 mg isoflavones) and control period (no nuts) of 16 wk, separated by an 8-wk washout period. Adults followed the Dutch food-based dietary guidelines. At the end of each period, CBF was assessed with arterial spin labeling MRI. Psychomotor speed, executive function, and memory were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Results No serious adverse events were reported, and soy nut intake was well tolerated. Body weights remained stable during the study. Serum isoflavone concentrations increased (daidzein mean difference +/- SD: 128 +/- 113 ng/mL, P < 0.001; genistein: 454 +/- 256 ng/mL, P < 0.001), indicating excellent compliance. Regional CBF increased in 4 brain clusters located in the left occipital and temporal lobes (mean +/- SD increase: 11.1 +/- 12.4 mL center dot 100 g(-1) center dot min(-1), volume: 11,296 mm(3), P < 0.001), bilateral occipital lobe (12.1 +/- 15.0 mL center dot 100 g(-1) center dot min(-1), volume: 2632 mm(3), P = 0.002), right occipital and parietal lobes (12.7 +/- 14.3 mL center dot 100 g(-1) center dot min(-1), volume: 2280 mm(3), P = 0.005), and left frontal lobe (12.4 +/- 14.5 mL center dot 100 g(-1) center dot min(-1), volume: 2120 mm(3), P = 0.009) which is part of the ventral network. These 4 regions are involved in psychomotor speed performance, which improved as the movement time reduced by (mean +/- SD) 20 +/- 37 ms (P = 0.005). Executive function and memory did not change. Conclusions Longer-term soy nut consumption may improve cerebrovascular function of older adults, because regional CBF increased. Effects may underlie observed improvements in psychomotor speed. This trial was registered at clinicaltrials.gov as NCT03627637.

Human B cells and their expressed antibodies are crucial in conferring immune protection. Identifying pathogen-specific antibodies following infection is possible due to enhanced humoral immunity against well-described molecules on the pathogen surface. However, screening for cancer-reactive antibodies remains challenging since target antigens are often not identified a priori and the frequency of circulating B cells recognizing cancer cells is likely very low. We investigated whether combined ex vivo culture of human B cells with three innate stimuli, interleukin-17 (IL-17), B-cell activation factor (BAFF), and the toll-like receptor 9 (TLR-9) agonist DNA motif CpG ODN 2006 (CpG), each known to activate B cells through different signalling pathways, promote cell activation, proliferation, and antibody production. Combined IL-17+BAFF+CpG prolonged B-cell survival and increased proliferation compared with single stimuli. IL-17+BAFF+CpG triggered higher IgG secretion, likely by activating differentiated, memory and class-switched CD19+CD20+CD27+IgD- B cells. Regardless of anti-FOLR antibody seropositive status, IL-17+BAFF+CpG combined with a monovalent tumour-associated antigen (folate receptor alpha [FOLR]) led to secreted antibodies recognizing the antigen and the antigen-expressing IGROV1 cancer cells. In a seropositive individual, FOLR stimulation favoured class-switched memory B-cell precursors (CD27-CD38-IgD-), class-switched memory B cells and anti-FOLR antibody production, while IL-17+BAFF+CpG combined with FOLR, promoted class-switched memory B-cell precursors and antibody-secreting (CD138+IgD-) plasma cells. Furthermore, IL-17+BAFF+CpG stimulation of peripheral blood B cells from patients with melanoma revealed tumour cell-reactive antibodies in culture supernatants. These findings suggest that innate signals stimulate B-cell survival and antibody production and may help identify low-frequency antigen-reactive humoral responses.

Epidermal melanocyte loss in vitiligo, triggered by stresses ranging from trauma to emotional stress, chemical exposure or metabolite imbalance, to the unknown, can stimulate oxidative stress in pigment cells, which secrete damage-associated molecular patterns that then initiate innate immune responses. Antigen presentation to melanocytes leads to stimulation of autoreactive T-cell responses, with further targeting of pigment cells. Studies show a pathogenic basis for cellular stress, innate immune responses and adaptive immunity in vitiligo. Improved understanding of the aetiological mechanisms in vitiligo has already resulted in successful use of the Jak inhibitors in vitiligo. In this review, we outline the current understanding of the pathological mechanisms in vitiligo and locate loci to which therapeutic attack might be directed.

B-cell-depleting agents are among the most commonly used drugs to treat haemato-oncological and autoimmune diseases. They rapidly induce a state of peripheral B-cell aplasia with the potential to interfere with nascent vaccine responses, particularly to novel antigens. We have examined the relationship between B-cell reconstitution and SARS-CoV-2 vaccine responses in two cohorts of patients previously exposed to B-cell-depleting agents: a cohort of patients treated for haematological B-cell malignancy and another treated for rheumatological disease. B-cell depletion severely impairs vaccine responsiveness in the first 6 months after administration: SARS-CoV-2 antibody seroprevalence was 42.2% and 33.3% in the haemato-oncological patients and rheumatology patients, respectively and 22.7% in patients vaccinated while actively receiving anti-lymphoma chemotherapy. After the first 6 months, vaccine responsiveness significantly improved during early B-cell reconstitution; however, the kinetics of reconstitution was significantly faster in haemato-oncology patients. The AstraZeneca ChAdOx1 nCoV-19 vaccine and the Pfizer BioNTech 162b vaccine induced equivalent vaccine responses; however, shorter intervals between vaccine doses (36 m previously), vaccine non-responsiveness was independent of peripheral B-cell reconstitution. The findings have important implications for primary vaccination and booster vaccination strategies in individuals clinically vulnerable to SARS-CoV-2., B cell depleting drugs including rituximab are commonly used to treat haematological malignancy and autoimmune diseases but may impair the immunological response to vaccination. This study investigates SARS-CoV-2 vaccine responses in individuals with haematological and rheumatological disease with previously exposure to B cell depleting agents. Vaccination within the first 6 months of B cell depletion is associated with significant impairment of vaccine responsiveness; however, rheumatology and haemato-oncological patients display different kinetics of B cell reconstitution corresponding to differential vaccine responsiveness over time., Graphical Abstract Graphical Abstract

Alternatively activated macrophages (M2 polarization) play an important role in asthma. Short-chain fatty acids (SCFAs) possessed immune-regulatory functions, but their effects on M2 polarization of alveolar macrophages and its underlying mechanisms are still unclear. In our study, murine alveolar macrophage MH-S cell line and human monocyte-derived macrophages were used to polarize to M2 subset with interleukin-4 (IL-4) treatment. The underlying mechanisms involved were investigated using molecule inhibitors/agonists. In vivo, female C57BL/6 mice were divided into five groups: CON group, ovalbumin (OVA) asthma group, OVA+Acetate group, OVA+Butyrate group, and OVA+Propionate group. Mice were fed with or without SCFAs (Acetate, Butyrate, Propionate) in drinking water for 20 days before developing OVA-induced asthma model. In MH-S, SCFAs inhibited IL-4-incuced protein or mRNA expressions of M2-associated genes in a dose-dependent manner. G-protein-coupled receptor 43 (GPR43) agonist 4-CMTB and histone deacetylase (HDAC) inhibitor (trichostatin A, TSA), but not GPR41 agonist AR420626 could inhibit the protein or mRNA expressions M2-associated genes. 4-CMTB, but not TSA, had no synergistic role in the inhibitory effect of SCFAs on M2 polarization. In vivo study indicated Butyrate and Propionate, but not Acetate, attenuated OVA-induced M2 polarization in the lung and airway inflammation. We also found the inhibitory effect of SCFAs on M2 polarization in human-derived macrophages. Therefore, SCFAs inhibited M2 polarization in MH-S likely through GPR43 activation and/or HDAC inhibition. Butyrate and Propionate but not Acetate could inhibit M2 polarization and airway inflammation in asthma model. SCFAs also abrogated M2 polarization in human-derived macrophages., SCFAs inhibited M2 polarization in MH-S likely through GPR43 activation and HDAC inhibition. Butyrate and Propionate but not Acetate could inhibit M2 polarization and airway inflammation in asthma model. SCFAs also abrogated M2 polarization in human-derived macrophages., Graphical Abstract Graphical Abstract

Summary NLRP3 inflammasome hyperactivation contributes to neuroinflammation in autoimmune disorders, but the underlying regulatory mechanism remains to be elucidated. We demonstrate that compared with wild-type (WT) mice, mice lacking thymic stromal lymphopoietin (TSLP) receptor (TSLPR) (Tslpr−/− mice) exhibit a significantly decreased experimental autoimmune encephalomyelitis (EAE) score, reduced CD4+ T cell infiltration, and restored myelin basic protein (MBP) expression in the brain after EAE induction by myelin oligodendrocyte glycoprotein35–55 (MOG35–55). TSLPR signals through Janus kinase (JAK)2, but not JAK1 or JAK3, to induce NLRP3 expression, and Tslpr−/− mice with EAE show decreased JAK2 phosphorylation and NLRP3 expression in the brain. JAK2 inhibition by ruxolitinib mimicked loss of TSLPR function in vivo and further decreased TSLP expression in the EAE mouse brain. The NLRP3 inhibitor MCC950 decreased CD4+ T cell infiltration, restored MBP expression, and decreased IL-1β and TSLP levels, verifying the pro-inflammatory role of NLRP3. In vitro experiments using BV-2 murine microglia revealed that TSLP directly induced NLRP3 expression, phosphorylation of JAK2 but not JAK1orJAK3, and IL-1β release, which were markedly inhibited by ruxolitinib. Furthermore, EAE induction led to an increase in the Th17 cell number, a decrease in the regulatory T (Treg) cell number in the blood, and an increase in the expression of the cytokine IL-17A in the WT mouse brain, which was drastically reversed in Tslpr−/− mice. In addition, ruxolitinib suppressed the increase in IL-17A expression in the EAE mouse brain. These findings identify TSLP as a prospective target for treating JAK2-NLRP3 axis-associated autoimmune inflammatory disorders., Thymic stromal lymphopoietin (TSLP)-mediated activation of inflammasome might be involved in experimental animal encephalitis. Janus kinase (JAK)2-directed NLRP3 inflammasome hyperactivation might play a critical role in the neuroinflammation. Ruxolitinib might be effective to alleviate NLRP3 inflammasome-mediated autoimmune inflammation in autoimmune encephalitis by inhibition of JAK2 signalling., Graphical Abstract Graphical Abstract

LITMUS was a single-centre, Phase 2a study designed to investigate whether the gene biomarker FGL2/IFNG previously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. Multiplex RT-PCR was used to amplify eight immunoregulatory genes in peripheral blood mononuclear cells (PBMC) from 69 adult liver transplant recipients. Patients with PBMC FGL2/IFNG ≥ 1 and a normal liver biopsy underwent immunosuppression (IS) withdrawal. The primary end point was the development of operational tolerance. Secondary end points included correlation of tolerance with allograft gene expression and immune cell markers. Twenty-eight of 69 patients (38%) were positive for the PBMC tolerance biomarker and 23 proceeded to IS withdrawal. Nine of the 23 patients had abnormal baseline liver biopsies and were excluded. Of the 14 patients with normal biopsies, eight (57%) have achieved operational tolerance and are off IS (range 12–57 months). Additional studies revealed that all of the tolerant patients and only one non-tolerant patient had a liver gene ratio of FOXP3/IFNG ≥ 1 prior to IS withdrawal. Increased CD4+ T regulatory T cells were detected both in PBMC and livers of tolerant patients following IS withdrawal. Higher expression of SELE (gene for E-selectin) and lower expression of genes associated with inflammatory responses (GZMB, CIITA, UBD, LSP1, and CXCL9) were observed in the pre-withdrawal liver biopsies of tolerant patients by RNA sequencing. These results suggest that measurement of PBMC FGL2/IFNG may enrich for the identification of operationally tolerant liver transplant patients, especially when combined with intragraft measurement of FOXP3/IFNG. Clinical Trial Registration: ClinicalTrials.gov (LITMUS: NCT02541916)., LITMUS was a single-centre, Phase 2 study designed to investigate whether the gene biomarker FGL2/IFNGpreviously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. The results suggest that measurement of PBMC FGL2/IFNGmay enrich for the identification of operationally tolerant liver transplant patients, especially when combined with intragraft measurement of FOXP3/IFNG., Graphical Abstract Graphical Abstract

Memory T cells are crucial players in vertebrate adaptive immunity but their development is incompletely understood. Here, we describe a method to produce human memory-like T cells from naive human T cells in culture. Using commercially available human T-cell differentiation kits, both purified naive CD8+ T cells and purified naive CD4+ T cells were activated via T-cell receptor signaling and appropriate cytokines for several days in culture. All the T-cell activators were then removed from the medium and the cultures were continued in hypoxic condition (1% O2 atmosphere) for several more days; during this period, most of the cells died, but some survived in a quiescent state for a month. The survivors had small round cell bodies, expressed differentiation markers characteristic of memory T cells and restarted proliferation when the T-cell activators were added back. We could also induce memory-like T cells from naive human T cells without hypoxia, if we froze the activated T cells or prepared the naive T cells from chilled filter buffy coats., Pre-activated human naïve CD4+ or CD8+ T cells were cultured in activator-free medium to induce cell death for 5 to 10 days. Although no cell survived in normal oxygen condition (20% O2), 2 to 30% of the activated T cells could survive in hypoxia (1% O2) and became memory-like T cells. We named this simple procedure as ‘the Death Assay’., Graphical Abstract Graphical Abstract

Background: Observed associations of high-protein diets with changes in insulin resistance are inconclusive.Objectives: We aimed to assess associations of changes in both reported and estimated protein (PRep; PEst) and energy intake (EIRep; EIEst) with changes in HOMA-IR, glycated hemoglobin (HbA1c), and BMI (in kg/m2), in 1822 decreasing to 833 adults (week 156) with overweight and prediabetes, during the 3-y PREVIEW (PREVention of diabetes through lifestyle intervention and population studies In Europe and around the World) study on weight-loss maintenance. Eating behavior and measurement errors (MEs) of dietary intake were assessed. Thus, observational post hoc analyses were applied.Methods: Associations of changes in EIEst, EIRep, PEst, and PRep with changes in HOMA-IR, HbA1c, and BMI were determined by linear mixed-model analysis in 2 arms [high-protein-low-glycemic-index (GI) diet and moderate-protein-moderate-GI diet] of the PREVIEW study. EIEst was derived from energy requirement: total energy expenditure = basal metabolic rate × physical activity level; PEst from urinary nitrogen, and urea. MEs were calculated as [(EIEst - EIRep)/EIEst] × 100% and [(PRep - PEst)/PEst] × 100%. Eating behavior was determined using the Three Factor Eating Questionnaire, examining cognitive dietary restraint, disinhibition, and hunger.Results: Increases in PEst and PRep and decreases in EIEst and EIRep were associated with decreases in BMI, but not independently with decreases in HOMA-IR. Increases in PEst and PRep were associated with decreases in HbA1c. PRep and EIRep showed larger changes and stronger associations than PEst and EIEst. Mean ± SD MEs of EIRep and PRep were 38% ± 9% and 14% ± 4%, respectively; ME changes in EIRep and En% PRep were positively associated with changes in BMI and cognitive dietary restraint and inversely with disinhibition and hunger.Conclusions: During weight-loss maintenance in adults with prediabetes, increase in protein intake and decrease in energy intake were not associated with decrease in HOMA-IR beyond associations with decrease in BMI. Increases in PEst and PRep were associated with decrease in HbA1c.This trial was registered at clinicaltrials.gov as NCT01777893.

Female genital tract chronic inflammation is common in clinics; the pathogenesis is not fully understood yet. House dust mite (HDM) involves the pathogenesis of many chronic diseases in human. This study aims to identify HDM-specific allergic response in the cervix of patients with cervical inflammation. Patients (n = 80) with chronic cervicitis (CC) and non-CC control (NC) subjects (n = 80) were recruited into this study. Vaginal lavage fluids (VLF) were collected from CC patients and NC subjects. Cellular components and fluid part of VLF were separated by centrifugation, and analyzed by flow cytometry and enzyme-linked immunosorbent assay. We found that a portion (52 out of 80) of CC patients responded to HDM, manifesting positive skin prick test, and HDM-specific IgE and IgG was detected in the VLF (designated CCp patients). VLF of CCp patients showed a Th2-dominant profile. HDM-specific Th2 cells were detected in VLF in CCp patients. Exposure to HDM in the culture induced proinflammatory cytokine release from CCp VLF CD4+ T cells. Exposure to CCp VLF CD4+ T cell-conditioned medium induced de novo Th2 response. Direct exposure to HDM induced allergic response in the cervix of CCp patients. In summary, a portion of CC patients respond to HDM challenge in the cervix. Exposure to HDM induces an allergy-like response in the cervix of CCp patients., We found that 52 out of 80 patients with chronic cervicitis showed allergic response to house dust mite. House dust mite-specific Th2 cells were detected in vagina lavage fluid. Direct exposure to house dust mite antigens induced allergic response in the cervix of patients with chronic cervicitis., Graphical Abstract Graphical Abstract

The coronavirus disease (COVID-19) is known to cause hyperferritinemia and hemophagocytic lymphohistiocytosis (HLH). Including this laboratory parameter, clinical symptoms similar to COVID-19 have been observed in adult-onset Still’s disease (AOSD), catastrophic antiphospholipid syndrome (CAPS), macrophage activation syndrome (MAS), and septic shock, which has led to the proposal of a concept called ‘hyperferritinemic syndromes.’ Additionally, high levels of some clinical markers in both COVID-19 and AOSD make them difficult to differentiate. While the efficacy of ciclesonide had been expected for mild pneumonia with COVID-19, the efficacy of tocilizumab, which is a known treatment for AOSD, was not established. Here, we report the first known occurrence of COVID-19, diagnosed in March 2020, preceded by the diagnosis of AOSD, in April 2019, in a 65-year-old, otherwise healthy man. Following the diagnosis of the latter, the patient was first given prednisolone and then tocilizumab, which led to remission. With the recurrence of joint pain and rash in March 2020, accompanied by low oxygen saturation levels (90%), and ground-glass appearance on chest CT, PCR test revealed COVID-19 infection. Ciclesonide was started on day 7 of the disease onset, which led to improved inflammatory markers by day 21. Thus, we infer that while tocilizumab is theoretically useful for COVID-19 due to its inhibition of interleukin 6 (IL-6), additional ciclesonide therapy might be required to prevent worsening of the condition. AOSD and COVID-19 must, therefore, be differentiated by levels of ferritin which differ between the two, and appropriate treatment must be allocated.

Background Atrophic gastritis (AG) and use of proton pump inhibitors (PPIs) result in gastric acid suppression that can impair the absorption of vitamin B-12 from foods. The crystalline vitamin B-12 form, found in fortified foods, does not require gastric acid for its absorption and could thus be beneficial for older adults with hypochlorhydria, but evidence is lacking. Objectives To investigate associations of AG and PPI use with vitamin B-12 status, and the potential protective role of fortified foods, in older adults. Methods Eligible participants (n = 3299) not using vitamin B-12 supplements were drawn from the Trinity-Ulster and Department of Agriculture cohort, a study of noninstitutionalized adults aged ≥60 y and recruited in 2008–2012. Vitamin B-12 status was measured using 4 biomarkers, and vitamin B-12 deficiency was defined as a combined indicator value

Background Limited evidence supports the common public health guideline that children >2 y of age should consume dairy with reduced fat content. Objectives We aimed to investigate the effects of whole-fat compared with reduced-fat dairy intake on measures of adiposity and biomarkers of cardiometabolic risk in healthy 4- to 6-y-old children. Methods The Milky Way Study enrolled 49 children (mean ± SD age: 5.2 ± 0.9 y; 47% girls) who were habitual consumers of whole-fat dairy, then randomly assigned them in a double-blind fashion to remain on whole-fat dairy or switch their dairy consumption to reduced-fat products for 3 mo. Primary endpoints included measures of adiposity, body composition, blood pressure, fasting serum lipids, blood glucose, glycated hemoglobin (HbA1c), and C-reactive protein (CRP) and were assessed at baseline and study end. Pre- and postintervention results were compared using linear mixed models, adjusted for growth, age, and sex. Results Dairy fat intake was reduced by an adjusted (mean ± SEM) 12.9 ± 4.1 g/d in the reduced-fat compared with the whole-fat dairy group (95% CI: –21.2, –4.6 g/d; P = 0.003), whereas dietary energy intakes remained similar (P = 0.936). We found no significant differential changes between dairy groups in any measure of adiposity, body composition, blood pressure, or fasting serum lipids, glucose, HbA1c, and CRP. Conclusions Our results suggest that although changing from whole-fat to reduced-fat dairy products does reduce dairy fat intake, it does not result in changes to markers of adiposity or cardiometabolic disease risk in healthy children. This trial was registered at www.anzctr.org.au as ACTRN12616001642471.

Objectives The aim of this study is to investigate the outcomes of coronavirus disease 2019 (COVID-19) in our cohort of Behçet’s disease (BD) patients and to reveal the rate of BD exacerbations due to COVID-19. Methods Patients who have been followed with a diagnosis of BD were retrospectively investigated for a positive severe acute respiratory syndrome–coronavirus 2 polymerized chain reaction (PCR) test. Data regarding demographics, clinical features and COVID-19 outcomes were collected from medical records for patients with a positive PCR. PCR-positive patients were reached via phone numbers, and ‘Behçet’s Disease Current Activity Form’ (BDCAF) scores for pre- and post-COVID-19 BD symptoms were calculated. Results Out of a total 648 BD patients, 59 were detected to have a positive PCR test. Three of the 59 patients (5.0%) were found to be hospitalized, none of them was admitted to the ICU or died. An increasing trend in the frequency of comorbid diseases and older age was observed in hospitalized patients. 32.2% of BD patients suffered from exacerbation of at least one symptom related to BD. Conclusions We observed no ICU admission or mortality with COVID-19 in our BD patient cohort. A substantial number of patients suffered from exacerbation of BD symptoms.

Background The achievement of target 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy may be altered by maternal obesity. Objective The authors examined the effects of maternal supplementation of 10 μg compared with 20 μg vitamin D3/d on maternal and umbilical cord 25(OH)D. The secondary aim was to investigate the influence of maternal BMI (in kg/m2) on the response of the primary outcomes. Methods The authors performed a 2-arm parallel double-blind randomized trial with 240 pregnant women recruited throughout the year in Northern Ireland. Women were stratified by BMI to receive 10 or 20 µg vitamin D3/d from 12 gestational wk (GW) until delivery. Maternal blood samples collected at 12, 28, and 36 GW and from the umbilical cord were analyzed for total serum 25(OH)D. A total of 166 women completed the study. Results Mean ± SD 25(OH)D at 36 GW was 80.8 ± 28.2 compared with 94.4 ± 33.2 nmol/L (P < 0.001) (10 compared with 20 µg vitamin D3/d, respectively). In those classified with 25(OH)D

Background Moderate acute malnutrition (MAM) affects 33 million children annually. Investments in formulations of corn-soy blended flours and lipid-based nutrient supplements have effectively improved MAM recovery rates. Information costs and cost-effectiveness differences are still needed. Objectives We assessed recovery and sustained recovery rates of MAM children receiving a supplementary food: ready-to-use supplementary food (RUSF), corn soy whey blend with fortified vegetable oil (CSWB w/oil), or Super Cereal Plus with amylase (SC + A) compared to Corn Soy Blend Plus with fortified vegetable oil (CSB+ w/oil). We also estimated differences in costs and cost effectiveness of each supplement. Methods In Sierra Leone, we randomly assigned 29 health centers to provide a supplement containing 550 kcal/d for ∼12 wk to 2691 children with MAM aged 6–59 mo. We calculated cost per enrollee, cost per child who recovered, and cost per child who sustained recovery each from 2 perspectives: program perspective and caregiver perspective, combined. Results Of 2653 MAM children (98.6%) with complete data, 1676 children (63%) recovered. There were no significant differences in the odds of recovery compared to CSB+ w/oil [0.83 (95% CI: 0.64–1.08) for CSWB w/oil, 1.01 (95% CI: 0.78–1.3) for SC + A, 1.05 (95% CI: 0.82–1.34) for RUSF]. The odds of sustaining recovery were significantly lower for RUSF (0.7; 95% CI 0.49–0.99) but not CSWB w/oil or SC + A [1.08 (95% CI: 0.73–1.6) and 0.96 (95% CI: 0.67–1.4), respectively] when compared to CSB+ w/oil. Costs per enrollee [US dollars (USD)/child] ranged from $105/child in RUSF to $112/child in SC + A and costs per recovered child (USD/child) ranged from $163/child in RUSF to $179/child in CSWB w/oil, with overlapping uncertainty ranges. Costs were highest per sustained recovery (USD/child), ranging from $214/child with the CSB+ w/oil to $226/child with the SC + A, with overlapping uncertainty ranges. Conclusions The 4 supplements performed similarly across recovery (but not sustained recovery) and costed measures. Analyses of posttreatment outcomes are necessary to estimate the full cost of MAM treatment. This trial was registered at clinicaltrials.gov as NCT03146897.

Background Climate change presents an increasing challenge for food-nutrition security. Nutrition metrics calculated from quantitative food system projections can help focus policy actions. Objectives To estimate future chronic and hidden hunger disability-adjusted life years (DALYs)—due to protein-energy undernutrition and micronutrient deficiencies, respectively—using food systems projections to evaluate the potential impact of climate change and agricultural sector investment for adaptation. Methods We use a novel combination of a chronic and hidden hunger DALY estimation procedure and food system projections from quantitative foresight modeling to assess DALYs under alternative agricultural sector scenarios to midcentury. Results Total chronic and hidden hunger DALYs are projected to increase globally out to 2050—by over 30 million compared with 2010—even without climate change. Climate change increases total DALY change between 2010 and 2050 by nearly 10% compared with no climate change. Agricultural sector investments show promise for offsetting these impacts. With investments, DALY incidence due to chronic and hidden hunger is projected to decrease globally in 2050 by 0.24 and 0.56 per 1000 capita, respectively. Total global DALYs will still rise because projected population growth will outpace the rate reduction, especially in Africa south of the Sahara. However, projections also show important regional reductions in total DALYs due to chronic (13.9 million in South Asia, 4.3 million in East Asia and the Pacific) and hidden hunger (7.5 million in East Asia and the Pacific) with investments. Conclusions Food system projections to 2050 show a decreasing DALY incidence from both chronic and hidden hunger. Population growth is projected to outpace these improvements and lead to increasing total chronic and hidden hunger DALYs globally, concentrated in Africa south of the Sahara. Climate change increases per-capita chronic and hidden hunger DALY incidence compared with no climate change. Agricultural sector investments show the potential to offset the climate impact on DALYs.

Background Dietary factors, such as consumption of preserved foods, fresh vegetables, and fruits, have been linked to the risk of nasopharyngeal carcinoma (NPC). However, little is known about associations between dietary patterns and the risk of NPC in NPC-endemic areas. Objectives We aimed to evaluate whether dietary patterns are associated with NPC risk. Methods We studied 2554 newly diagnosed NPC patients aged 20–74 y living in 3 endemic regions of southern China, and 2648 population-based controls frequency-matched to case patients by age, sex, and region, between 2010 and 2014. Dietary components were derived from food frequency data in adulthood and adolescence using principal component analysis. Four dietary components were identified and highly similar in adulthood and adolescence. We used multivariable unconditional logistic regression to calculate ORs with 95% CIs for the association between dietary patterns and NPC risk. Results Compared with the lowest quartile, individuals in the highest quartile of the “plant-based factor” in adulthood had a 52% (OR: 0.48; 95% CI: 0.38, 0.59) decreased risk of NPC, and those in the highest quartile of the “animal-based factor” had a >2-fold (OR: 2.26; 95% CI: 1.85, 2.77) increased risk, with a monotonic dose-response trend (P-trend

Background Adequate gestational weight gain (GWG) is essential for healthy fetal growth. However, in low- and middle-income countries, where malnutrition is prevalent, little information is available about GWG and how it might be modified by nutritional status and interventions. Objective We describe GWG and its associations with fetal growth and birth outcomes. We also examined the extent to which prepregnancy BMI, and preconception and early weight gain modify GWG, and its effects on fetal growth. Methods This was a secondary analysis of the Women First Trial, including 2331 women within the Democratic Republic of Congo (DRC), Guatemala, India, and Pakistan, evaluating weight gain from enrollment to ∼12 weeks of gestation and GWG velocity (kg/wk) between ∼12 and 32 weeks of gestation. Adequacy of GWG velocity was compared with 2009 Institute of Medicine recommendations, according to maternal BMI. Early weight gain (EWG), GWG velocity, and adequacy of GWG were related to birth outcomes using linear and Poisson models. Results GWG velocity (mean ± SD) varied by site: 0.22 ± 0.15 kg/wk in DRC, 0.30 ± 0.23 in Pakistan, 0.31 ± 0.14 in Guatemala, and 0.39 ± 0.13 in India, (P

Author(s): Koponen, Kari K; Salosensaari, Aaro; Ruuskanen, Matti O; Havulinna, Aki S; Mannisto, Satu; Jousilahti, Pekka; Palmu, Joonatan; Salido, Rodolfo; Sanders, Karenina; Brennan, Caitriona; Humphrey, Gregory C; Sanders, Jon G; Meric, Guillaume; Cheng, Susan; Inouye, Michael; Jain, Mohit; Niiranen, Teemu J; Valsta, Liisa M; Knight, Rob; Salomaa, Veikko V | Abstract: BackgroundDiet has a major influence on the human gut microbiota, which has been linked to health and disease. However, epidemiological studies on associations of a healthy diet with the microbiota utilizing a whole-diet approach are still scant.ObjectivesTo assess associations between healthy food choices and human gut microbiota composition, and to determine the strength of association with functional potential.MethodsThis population-based study sample consisted of 4930 participants (ages 25-74; 53% women) in the FINRISK 2002 study. Intakes of recommended foods were assessed using a food propensity questionnaire, and responses were transformed into healthy food choices (HFC) scores. Microbial diversity (alpha diversity) and compositional differences (beta diversity) and their associations with the HFC score and its components were assessed using linear regression. Multiple permutational multivariate ANOVAs were run from whole-metagenome shallow shotgun-sequenced samples. Associations between specific taxa and HFC were analyzed using linear regression. Functional associations were derived from Kyoto Encyclopedia of Genes and Genomes orthologies with linear regression models.ResultsBoth microbial alpha diversity (β/SD, 0.044; SE, 6.18n×n10-5; Pn=n2.21n×n10-3) and beta diversity (R2, 0.12; Pn≤n1.00n×n10-3) were associated with the HFC score. For alpha diversity, the strongest associations were observed for fiber-rich breads, poultry, fruits, and low-fat cheeses (all positive). For beta diversity, the most prominent associations were observed for vegetables, followed by berries and fruits. Genera with fiber-degrading and SCFA-producing capacities were positively associated with the HFC score. The HFC score was associated positively with functions such as SCFA metabolism and synthesis, and inversely with functions such as fatty acid biosynthesis and the sulfur relay system.ConclusionsOur results from a large, population-based survey confirm and extend findings of other, smaller-scale studies that plant- and fiber-rich dietary choices are associated with a more diverse and compositionally distinct microbiota, and with a greater potential to produce SCFAs.

Background Recent work has challenged the long-held assumption that appetite functions to maintain stable body mass and fat mass (FM), suggesting instead that appetite matches food intake to energy expenditure and its correlate, fat-free mass (FFM). Whether this scenario applies to young infants, in chronic positive energy balance, remains unknown. Objectives To test associations of components of energy expenditure and body composition with milk intake (MI) and energy intake (EI) in 12-week infants, by reanalyzing published cross-sectional data. Methods Data were available for 48 infants. In addition to anthropometric measurements, we assessed MI and EI by test-weighing, sleeping metabolic rate (SMR) by indirect calorimetry, and FFM, FM, and total energy expenditure (TEE) by doubly labeled water. Mean parental height was calculated as a marker of infant growth drive. Correlation and multiple regression analyses were applied. Results MI and EI correlated with FFM (r = 0.47 and 0.57, respectively; P 0.6). MI and EI correlated with SMR (r = 0.42 and 0.53, respectively; P 0.2). In a multiple regression analysis, MI was independently associated with TEE (partial r = 0.39) and FFM (partial r = 0.35). EI showed similar associations. Mean parental height was correlated with weight gain, MI, and EI. Conclusions As in adults, MI and EI in young infants were strongly associated with FFM and with total and sleeping components of energy expenditure, but not with fatness. The infant's growth drive contributed to these associations. This suggests that appetite is regulated by the rate of energy expenditure, the size of energy-using tissues, and tissue deposition rate, and that the high levels of body fat characteristic of infants may not constrain weight gain.

Background Infants born at very low birth weight (VLBW) are vulnerable to deficits in fatty acids (FAs) but little is known of factors that influence the intakes or composition of their human milk feeds. Objectives We aimed to identify sources of variability in the fat composition of human milk fed to VLBW infants and examine the impact of milk source (mother's own or donor) on fat and FA intakes. Methods Serial samples of mother's milk (n = 476) and donor milk (n = 53) fed to infants born weighing

Background Prenatal nutrition interventions can lead to improved birth outcomes, which in turn are associated with better education and human capital outcomes later in life. Objective We estimated the impact of scaling up iron-folic acid (IFA), calcium, multiple micronutrient (MMS), and balanced energy protein (BEP) supplementation for pregnant women, on human capital outcomes in low- and middle-income countries (LMIC). Methods We used mathematical modeling with proportional reductions in adverse birth outcomes to estimate the potential gains in school years and lifetime income due to scaling up each prenatal nutrition intervention. Estimates of intervention effects on birth outcomes were derived from meta-analyses of randomized trials. Estimates of the associations between birth outcomes and schooling and lifetime income were derived from de novo meta-analyses of observational studies. Results Across 132 LMIC, scaling up prenatal nutrition interventions to 90% coverage was estimated to increase school years and lifetime income per birth cohort by: 2.28 million y (95% uncertainty intervals (UI): -0.44, 6.26) and $8.26 billion (95% UI: -1.60, 22.4) for IFA; 4.08 million y (95% UI: 0.12, 9.68) and $18.9 billion (95% UI: 0.59, 44.6) for calcium; 5.02 million y (95% UI: 1.07, 11.0) and $18.1 billion (95% UI: 3.88, 39.1) for MMS; and 0.53 million y (95% UI: -0.49, 1.70) and $1.34 billion (95% UI: -1.10, 3.10 billion) for BEP supplementation. South Asia and Sub-Saharan Africa tended to have the largest estimated regional gains in school years for scaling up each intervention due to the large population size and high burden of poor birth outcomes. Absolute income benefits for each intervention were estimated to be the largest in Latin America, where returns to education and incomes are higher relative to other regions. Conclusion Increasing coverage of prenatal nutrition interventions in LMIC may lead to substantial gains in schooling and lifetime income. Decision makers should consider the potential long-term human capital returns of investments in maternal nutrition.

Background Population-based studies generally show neutral associations between dairy consumption and ischemic heart disease (IHD) mortality, whereas weak inverse associations were found for cardiovascular disease (CVD) and stroke mortality. Whether dairy consumption affects long-term survival after myocardial infarction (MI) is unknown. Objectives We studied types of dairy and long-term mortality risk in drug-treated post-MI patients. Methods We included 4365 Dutch patients from the Alpha Omega Cohort aged 60–80 y (21% women) with an MI ≤10 y before enrollment. Dietary data were collected at baseline (2002–2006) using a 203-item FFQ and patients were followed for cause-specific mortality through December 2018. HRs of CVD, IHD, stroke, and all-cause mortality for types of dairy were obtained from Cox models, adjusting for age, sex, energy intake, physical activity, smoking, alcohol intake, diabetes, obesity, and dietary factors. Results Most patients were Dutch, 24% were obese, 20% had diabetes, and 97% used cardiovascular medication. Median intakes were 39 g/d for plain yogurt, 88 g/d for total nonfermented milk, and 17 g/d for hard cheeses. Of the cohort, 10% consumed high-fat milk. During ∼12 y of follow-up (48,473 person-years) 2035 deaths occurred, including 903 from CVD, 558 from IHD, and 170 from stroke. Yogurt was linearly inversely associated with CVD mortality (HR: 0.96; 95% CI: 0.93, 0.99; per 25 g/d) and nonlinearly inversely associated with all-cause mortality. Milk was not associated with any of the outcomes (HRs: ∼1.0 per 100 g/d), except for a higher mortality risk in high-fat milk consumers (HR: 1.30; 95% CI: 1.13, 1.49). Other dairy groups were not associated with mortality risk. Conclusions In Dutch post-MI patients, yogurt consumption was inversely associated with CVD mortality and all-cause mortality. Associations for milk and other dairy products were neutral or inconsistent. This trial was registered at clinicaltrials.gov as NCT03192410.

Background Sodium intake in the USA exceeds recommendations. The replacement of added sodium chloride (NaCl) with potassium chloride (KCl) provides a potential strategy to reduce sodium intake. Objective The purpose of this study was to quantitatively estimate changes in intakes of sodium and potassium by the US population assuming use of potassium-based NaCl replacers in top dietary sodium sources. Methods Data collected in the What We Eat in America (WWEIA) component of the 2015–2016 and 2009–2010 NHANES were used to identify top-ranking sources of dietary sodium among the population aged 2 y and older based on contributions from food categories aligning with the FDA draft guidance for voluntary sodium reduction. Predicted nutrient intakes were estimated in models assuming total and feasible and practical (F&P) replacement of added NaCl with KCl in foods and ingredients within the top food sources of sodium. An expert elicitation was conducted to collect information on the F&P KCl replacement of added NaCl. Results Using 2015–2016 consumption data, the total replacement of added NaCl with KCl in the 18 top-ranking sources of dietary sodium results in a predicted sodium intake of 2004 mg/d from the replacement of 1406 mg/d sodium with 1870 mg/d potassium as KCl. Modeled F&P replacement predicted sodium intakes of 3117 mg/d (range of 2953 to 3255 mg/d) from the replacement of 294 mg/d sodium (155 to 457 mg/d) with 390 mg/d potassium (206 to 608 mg/d). Similar results are seen with 2009–2010 data. Conclusions The F&P replacement of NaCl with KCl in top-ranking sources of dietary sodium modeled in this study can result in decreased sodium to a level consistent with the short-term intake goal targeted by the FDA of 3000 mg/d, with the mean potassium intake remaining in the range recommended for the apparently healthy population.

Background RBC long-chain omega-3 (n–3) fatty acid (FA) percentages (of total fatty acids) are associated with lower risk for total mortality, but it is unknown if a suite of FAs could improve risk prediction. Objectives The objective of this study was to compare a combination of RBC FA levels with standard risk factors for cardiovascular disease (CVD) in predicting risk of all-cause mortality. Methods Framingham Offspring Cohort participants without prevalent CVD having RBC FA measurements and relevant baseline clinical covariates (n = 2240) were evaluated during 11 y of follow-up. A forward, stepwise approach was used to systematically evaluate the association of 8 standard risk factors (age, sex, total cholesterol, HDL cholesterol, hypertension treatment, systolic blood pressure, smoking status, and prevalent diabetes) and 28 FA metrics with all-cause mortality. A 10-fold cross-validation process was used to build and validate models adjusted for age and sex. Results Four of 28 FA metrics [14:0, 16:1n–7, 22:0, and omega-3 index (O3I; 20:5n–3 + 22:6n–3)] appeared in ≥5 of the discovery models as significant predictors of all-cause mortality. In age- and sex-adjusted models, a model with 4 FA metrics was at least as good at predicting all-cause mortality as a model including the remaining 6 standard risk factors (C-statistic: 0.778; 95% CI: 0.759, 0.797; compared with C-statistic: 0.777; 95% CI: 0.753, 0.802). A model with 4 FA metrics plus smoking and diabetes (FA + Sm + D) had a higher C-statistic (0.790; 95% CI: 0.770, 0.811) compared with the FA (P

Adequate iron intake is essential for optimal child development, but iron deficiency and anemia among infants and young children are widespread in low- and middle-income countries. Large-scale food fortification strategies hold great promise for reducing micronutrient deficiencies; however, for children

Background The dietary polyphenol resveratrol prevents various malignancies in preclinical models, including prostate cancer. Despite attempts to translate findings to humans, gaps remain in understanding pharmacokinetic-pharmacodynamic relations and how tissue concentrations affect efficacy. Such information is necessary for dose selection and is particularly important given the low bioavailability of resveratrol. Objectives This study aimed to determine concentrations of resveratrol in prostate tissue of men after a dietary-achievable (5 mg) or pharmacological (1 g) dose. We then examined whether clinically relevant concentrations of resveratrol/its metabolites had direct anticancer activity in prostate cell lines. Methods A window trial was performed in which patients were allocated to 5 mg or 1 g resveratrol daily, or no intervention, before prostate biopsy. Patients (10/group) ingested resveratrol capsules for 7–14 d before biopsy, with the last dose [14C]-labeled, allowing detection of resveratrol species in prostate tissue using accelerator MS. Cellular uptake and antiproliferative properties of resveratrol/metabolites were assessed in cancer and nonmalignant cell cultures using HPLC with UV detection and cell counting, respectively. Results [14C]-Resveratrol species were detectable in prostate tissue of all patients analyzed, with mean ± SD concentrations of 0.08 ± 0.04 compared with 22.1 ± 8.2 pmol/mg tissue for the 5 mg and the 1 g dose, respectively. However, total [14C]-resveratrol equivalents in prostate were lower than we previously reported in plasma and colorectum after identical doses. Furthermore, resveratrol was undetectable in prostate tissue; instead, sulfate and glucuronide metabolites dominated. Although resveratrol reduced prostate cell numbers in vitro over 7 d, the concentrations required (≥10 µM) exceeded the plasma maximum concentration. Resveratrol mono-sulfates and glucuronides failed to consistently inhibit cell growth, partly due to poor cellular uptake. Conclusions Low tissue concentrations of resveratrol species, coupled with weak antiproliferative activity of its conjugates, suggest daily doses of ≤1 g may not have direct effects on human prostate. This trial was registered at clinicaltrialsregister.eu as EudraCT 2007-002131-91.

Background It remains unclear whether red meat consumption is causatively associated with cardiovascular disease (CVD) risk, and few randomized controlled studies have examined the effect of incorporating lean beef into a healthy dietary pattern. Objectives To evaluate the effects of a Mediterranean (MED) diet (carbohydrate 42%, protein 17%, fat 41%, SFAs 8%, MUFAs 26%, PUFAs 8%) with 14 (MED0.5; 0.5 oz), 71 (MED2.5; 2.5 oz), and 156 (MED5.5; 5.5 oz) g/d/2000 kcal lean beef compared with an average American diet (AAD; carbohydrate 52%, protein 15%, fat 33%, SFAs 12%, MUFAs 13%, PUFAs 8%) on lipid and lipoprotein concentrations, particle number, and size. Methods This was a multicenter, 4-period controlled feeding, randomized crossover study. Fifty-nine generally healthy males and females (BMI 20–38 kg/m2; age 30–65 y) consumed each diet for 4 wk with a ≥1-wk washout between the diets. Fasting blood samples were collected at baseline and at the end of each 4-wk period. Lipid subfractions were measured by NMR. Results Compared with the AAD, all 3 MED diets decreased LDL cholesterol (MED0.5: −10.3 mg/dL; 95% CI: −5.4, −15.7 mg/dL; MED2.5: −9.1 mg/dL; 95% CI: −3.9, −14.3 mg/dL; MED5.5: −6.9 mg/dL; 95% CI: −1.7, −12.1 mg/dL; P

Background Monitoring gestational weight gain (GWG) is fundamental to ensure a successful pregnancy for the mother and the offspring. There are several international GWG charts, but just a few for low- and middle-income countries. Objectives To construct GWG charts according to pre-pregnancy BMI for Brazilian women. Methods This is an individual patient data analysis using the Brazilian Maternal and Child Nutrition Consortium data, comprising 21 cohort studies. External validation was performed using “Birth in Brazil,” a nationwide study. We selected adult women with singleton pregnancies who were free of infectious and chronic diseases, gestational diabetes, and hypertensive disorders; who delivered a live birth at term; and whose children were adequate for gestational age, and with a birth weight between 2500–4000 g. Maternal self-reported pre-pregnancy weight and weight measured between 10–40 weeks of gestation were used to calculate GWG. Generalized Additive Models for Location, Scale and Shape were fitted to create GWG charts according to gestational age, stratified by pre-pregnancy BMI. Results The cohort included 7086 women with 29,323 weight gain measurements to construct the charts and 4711 women with 31,052 measurements in the external validation. The predicted medians for GWG at 40 weeks, according to pre-pregnancy BMI, were: underweight, 14.1 kg (IQR, 10.8–17.5 kg); normal weight, 13.8 kg (IQR, 10.7–17.2 kg); overweight, 12.1 kg (IQR, 8.5–15.7 kg); obesity, 8.9 kg (IQR, 4.8–13.2 kg). The 10th, 25th, 50th, 75th, and 90th percentiles were estimated. Results for internal and external validation showed that the percentages below the selected percentiles were close to those expected. Conclusions The charts proposed provide a description of GWG patterns according to gestational age and pre-pregnancy BMI among healthy Brazilian women with good neonatal outcomes. The external validation indicates that this new tool can be used to monitor GWG in the primary health-care setting and to test potential recommended values.

BACKGROUND: Diet, in particular the Mediterranean diet, has been associated with better cognitive function and less cognitive decline in older populations.OBJECTIVES: To quantify associations of a healthy diet, defined by adherence to either the Mediterranean diet, the WHO guidelines, or Dutch Health Council dietary guidelines, with cognitive function and cognitive decline from middle age into old age.METHODS: From the Doetinchem Cohort Study, a large population-based longitudinal study, 3644 participants (51% females) aged 45-75 y at baseline, were included. Global cognitive function, memory, processing speed, and cognitive flexibility were assessed at 5-y time intervals up to 20-y follow-up. Adherence to the Mediterranean diet was measured with the modified Mediterranean Diet Score (mMDS), adherence to the WHO dietary guidelines with the Healthy Diet Indicator (HDI), and adherence to the Dutch Health Council dietary guidelines 2015 with the modified Dutch Healthy Diet 2015 index (mDHD15-index). The scores on the dietary indices were classified in tertiles (low, medium, high adherence). Linear mixed models were used to model level and change in cognitive function by adherence to healthy diets.RESULTS: The highest tertiles of the mMDS, HDI, and mDHD15-index were associated with better cognitive function compared with the lowest tertiles (P values CONCLUSIONS: Healthier dietary habits, determined by higher adherence to dietary guidelines, are associated with better cognitive function and slower cognitive decline with aging from middle age onwards.

Intestinal catheters have been used for decades in human nutrition, physiology, pharmacokinetics, and gut microbiome research, facilitating the delivery of compounds directly into the intestinal lumen or the aspiration of intestinal fluids in human subjects. Such research provides insights about (local) dynamic metabolic and other intestinal luminal processes, but working with catheters might pose challenges to biomedical researchers and clinicians. Here, we provide an overview of practical and technical aspects of applying naso- and oro-intestinal catheters for delivery of compounds and sampling luminal fluids from the jejunum, ileum, and colon in vivo. The recent literature was extensively reviewed, and combined with experiences and insights we gained through our own clinical trials. We included 60 studies that involved a total of 720 healthy subjects and 42 patients. Most of the studies investigated multiple intestinal regions (24 studies), followed by studies investigating only the jejunum (21 studies), ileum (13 studies), or colon (2 studies). The ileum and colon used to be relatively inaccessible regions in vivo. Custom-made state-of-the-art catheters are available with numerous options for the design, such as multiple lumina, side holes, and inflatable balloons for catheter progression or isolation of intestinal segments. These allow for multiple controlled sampling and compound delivery options in different intestinal regions. Intestinal catheters were often used for delivery (23 studies), sampling (10 studies), or both (27 studies). Sampling speed decreased with increasing distance from the sampling syringe to the specific intestinal segment (i.e., speed highest in duodenum, lowest in ileum/colon). No serious adverse events were reported in the literature, and a dropout rate of around 10% was found for these types of studies. This review is highly relevant for researchers who are active in various research areas and want to expand their research with the use of intestinal catheters in humans in vivo.

Critical advancement is needed in the study of human milk as a biological system that intersects and interacts with myriad internal (maternal biology) and external (diet, environment, infections) factors and its plethora of influences on the developing infant. Human-milk composition and its resulting biological function is more than the sum of its parts. Our failure to fully understand this biology in a large part contributes to why the duration of exclusive breastfeeding remains an unsettled science (if not policy). Our current understanding of human-milk composition and its individual components and their functions fails to fully recognize the importance of the chronobiology and systems biology of human milk in the context of milk synthesis, optimal timing and duration of feeding, and period of lactation. The overly simplistic, but common, approach to analyzing single, mostly nutritive components of human milk is insufficient to understand the contribution of either individual components or the matrix within which they exist to both maternal and child health. There is a need for a shift in the conceptual approach to studying human milk to improve strategies and interventions to support better lactation, breastfeeding, and the full range of infant feeding practices, particularly for women and infants living in undernourished and infectious environments. Recent technological advances have led to a rising movement towards advancing the science of human-milk biology. Herein, we describe the rationale and critical need for unveiling the multifunctionality of the various nutritional, nonnutritional, immune, and biological signaling pathways of the components in human milk that drive system development and maturation, growth, and development in the very early postnatal period of life. We provide a vision and conceptual framework for a research strategy and agenda to change the field of human-milk biology with implications for global policy, innovation, and interventions.

Background Four models are commonly used to adjust for energy intake when estimating the causal effect of a dietary component on an outcome: 1) the “standard model” adjusts for total energy intake, 2) the “energy partition model” adjusts for remaining energy intake, 3) the “nutrient density model” rescales the exposure as a proportion of total energy, and 4) the “residual model” indirectly adjusts for total energy by using a residual. It remains underappreciated that each approach evaluates a different estimand and only partially accounts for confounding by common dietary causes. Objectives We aimed to clarify the implied causal estimand and interpretation of each model and evaluate their performance in reducing dietary confounding. Methods Semiparametric directed acyclic graphs and Monte Carlo simulations were used to identify the estimands and interpretations implied by each model and explore their performance in the absence or presence of dietary confounding. Results The “standard model” and the mathematically identical “residual model” estimate the average relative causal effect (i.e., a “substitution” effect) but provide biased estimates even in the absence of confounding. The “energy partition model” estimates the total causal effect but only provides unbiased estimates in the absence of confounding or when all other nutrients have equal effects on the outcome. The “nutrient density model” has an obscure interpretation but attempts to estimate the average relative causal effect rescaled as a proportion of total energy. Accurate estimates of both the total and average relative causal effects may instead be derived by simultaneously adjusting for all dietary components, an approach we term the “all-components model.” Conclusions Lack of awareness of the estimand differences and accuracy of the 4 modeling approaches may explain some of the apparent heterogeneity among existing nutritional studies. This raises serious questions regarding the validity of meta-analyses where different estimands have been inappropriately pooled.

Background Naturally occurring aflatoxins may contribute to poor growth and nutritional statuses in children. Objectives We analyzed the relationship between contemporary and lagged aflatoxin exposure and 1) length-for-age z-score (LAZ); and 2) length, knee-heel length, stunting, weight-for-age z-score (WAZ), and weight-for-length z-score (WLZ). Methods We conducted a longitudinal birth cohort study involving 1675 mother-infant dyads in rural Nepal. Participants were repeatedly visited from pregnancy to 2 years of age (2015–2019). One blood sample was collected during pregnancy and 4 samples were collected from the children at 3, 6, 12, and 18–22 months of age to measure concentrations of aflatoxin B1 (AFB1)-lysine adduct. Multivariate linear fixed-effects and logistic models with generalized estimating equations were used to identify associations between child growth and aflatoxin exposure. Results AFB1-lysine adducts were detected in the majority of children (at 3 months, 80.5%; at 6 months, 75.3%; at 12 months, 81.1%; and at 18–22 months, 85.1%) and in 94.3% of pregnant women. Changes in contemporary ln child AFB1‐lysine adduct concentrations were significantly associated with changes in LAZ (β, −0.05; 95% CI, −0.09 to −0.02; P = 0.003), length (β, −0.19; 95% CI, −0.29 to −0.10; P

Background Diets combining adequate nutritional quality and low climate impact are highly needed for human and planet health. Objectives We aimed to 1) evaluate nutrient density indexes' ability to predict mortality, and 2) assess the effects of diets varying in nutrient density and climate impact on total mortality. Methods Dietary data from 49,124 women and 47,651 men aged 35-65 y in the population-based prospective study Vasterbotten Intervention Programme (Sweden) were used. Greenhouse gas emissions (GHGEs) were estimated using data from life cycle assessments. Fifteen variants of nutrient density indexes were evaluated and the index that best predicted mortality was used to estimate participants' nutrient density. GHGEs and nutrient density were adjusted for energy intakes. Total mortality risk was estimated by Cox proportional hazards models for 4 groups of women and men, respectively, i.e., higher nutrient density, lower climate impact (HNutr/LClim); higher nutrient density, higher climate impact (HNutr/HClim); lower nutrient density, lower climate impact (LNutr/LClim); and lower nutrient density, higher climate impact (LNutr/HClim-reference group). Results NRF11.3, a Sweden-adapted variant of the Nutrient Rich Foods index, was identified to have the best ability to predict mortality in the study population. Median follow-up times for women and men were 16.0 and 14.7 y, respectively. For women a significantly lower mortality risk was found for HNutr/LClim (HR: 0.87; 95% CI: 0.79, 0.96; P = 0.008) and HNutr/HClim (HR: 0.87; 95% CI: 0.78, 0.97; P = 0.011) than for LNutr/HClim. Among men LNutr/LClim had a significantly higher mortality risk (HR: 1.10; 95% CI: 1.01, 1.21; P = 0.033) than LNutr/HClim. Conclusions Diets beneficial for both health and climate are feasible and associated with lower mortality risk in women. Further studies are needed to understand how men may transition into diets that are more sustainable from a combined health and climate perspective.

Background In lower-middle-income settings, growth faltering in the first 6 mo of life occurs despite exclusive breastfeeding. Objective The aim was to test the efficacy of an approach to improve the dietary adequacy of mothers during lactation and thus improve the growth of their infants. Methods Eligible mother–infant dyads (infants ≤7 d of age) were randomly assigned to either intervention or control groups. Mothers in the intervention group received snacks that were to be consumed daily, which provided 600 kcal of energy—with 25–30% of energy derived from fats (150–180 kcal) and 13% of energy from protein (80 kcal). Micronutrients were supplemented as daily tablets. We provided counseling on breastfeeding and infant-care practices to mothers in both groups. The primary outcome was attained infant length-for-age z scores (LAZ) at 6 mo of age. Secondary outcomes included exclusive breastfeeding proportion reported by the mother, maternal BMI and midupper arm circumference (MUAC), hemoglobin concentrations in mothers and infants, and the proportion of anemic infants at 6 mo of age. Results We enrolled 816 mother–infant dyads. The intervention did not achieve a significant effect on LAZ at 6 mo (adjusted mean difference: 0.09; 95% CI: −0.03, 0.20). Exclusive breastfeeding at 5 mo was higher (45.1% vs. 34.5%; RR: 1.31; 95% CI: 1.04, 1.64) in the intervention group compared with the controls. There were no significant effects on mean hemoglobin concentration or the proportion of anemic infants at 6 mo of age compared with the control group. We noted significant effects on maternal nutritional status (BMI, MUAC, hemoglobin concentration, and proportion anemic). Conclusions Postnatal supplementation of 600 kcal energy, 20 g protein, and multiple micronutrients daily to lactating mothers did not affect infant LAZ at age 6 mo. Such supplementation may improve maternal nutritional status. This trial was registered at Clinical Trials Registry–India as CTRI/2018/04/013095.

Background Women of childbearing age (WCBA) and women of menopausal age (WMENO) have distinct nutritional needs. Understanding nutrient intake and status in these life stages is critical for tailoring dietary recommendations. Objectives The objectives of this study were to evaluate total estimated usual nutrient intakes from food and food plus supplements and to compare these to established recommendations for WCBA and WMENO life stages and examine associations between self-reported estimated usual intakes and nutrient status biomarkers. Methods Twenty-four-hour dietary recall data from 2011–2016 NHANES were used to estimate usual intake of nutrients from food and food plus supplements for WCBA (aged 15–44 y, n = 4,134) and WMENO (aged 40–65 y, n = 3,438). Estimates of mean usual intake were derived and compared across clinically defined nutrient biomarker categories. Results Both young (aged 15–30 y) and older (aged 31–44 y) WCBA had intakes from food below the Estimated Average Requirement (EAR) for calcium (49% and 44%, respectively), magnesium (62%, 44%), and vitamins A (50%, 44%), C (47%, 46%), D (>97%, >97%), and E (92%, 88%). Similarly, perimenopausal (aged 40–50 y) and menopausal (aged 51–65 y) women had intakes from food below the EAR for calcium (48% and 74%, respectively), magnesium (50%, 49%), and vitamins A (44%, 37%), C (44%, 41%), D (>97%, >97%), and E (88%, 86%). Nutrient gaps decreased with supplement usage. For folate, vitamins D and B-12, and DHA, women in the lowest biomarker category (indicating increased risk of deficiency) had significantly lower intake from food (315.2 ± 25.9 compared with 463.8 ± 5.2 µg dietary folate equivalents, 3.5 ± 0.1 compared with 4.2 ± 0.1 µg, 3.6 ± 0.2 compared with 4.3 ± 0.1 µg, and 0.037 ± 0.005 compared with 0.070 ± 0.006 g, respectively; P

BACKGROUND: Dietary protein has been related to muscle function in aging. Beyond total intake, parameters such as protein distribution across meals might also be important. OBJECTIVES: We aimed to examine prospective associations of different protein intake parameters with muscle strength and physical performance in community-dwelling older men and women. METHODS: In total, 524 men and 574 women aged 67-84 y at baseline (T1) were followed annually for 3 y (T2, T3, T4). Outcomes included handgrip strength (kPa), knee extensor strength (kg), and physical performance (Timed Up and Go, s) at T4, and their 3-y changes (T4 minus T1). Protein intake parameters were assessed using nine 24-h recalls collected over 3 y (T1, T2, T3) and included daily total intake (g/d), number of protein-providing meals and snacks, and protein distribution across meals (expressed as CV). Associations were examined by multivariable linear regression models including all protein intake parameters simultaneously. Also, the optimal protein dose (g) per meal for the maximum effect size of total daily intake was determined. RESULTS: Higher daily protein intake was associated with better knee extensor strength and physical performance at T4 in both sexes and less physical performance decline in women. Optimal protein doses per meal were 30-35 g in men and 35-50 g in women for these outcomes. In men, more uneven protein distribution was associated with better physical performance at T4 and less handgrip strength decline. In women, a higher number of protein-providing snacks was associated with better handgrip strength and knee extensor strength at T4 and less handgrip strength decline. In neither sex was number of protein-providing meals associated with outcomes. CONCLUSIONS: Higher daily protein intake, up to 30-50 g protein/meal, may contribute to better knee extensor strength and physical performance in generally well-functioning older men and women. More aspects of protein intake may contribute to muscle strength and physical performance than solely the daily quantity, notably the protein dose per meal.

BACKGROUND: Nudging and salient pricing are promising strategies to promote healthy food purchases, but it is possible their effects differ across food groups.OBJECTIVE: To investigate in which food groups nudging and/or pricing strategies most effectively changed product purchases and resulted in within-food groups substitutions or spillover effects.METHODS: In total, 318 participants successfully completed a web-based virtual supermarket experiment in the Netherlands. We conducted a secondary analysis of a mixed randomized experiment consisting of 5 conditions (within subject) and 3 arms (between subject) to investigate the single and combined effects of nudging (e.g., making healthy products salient), taxes (25% price increase), and/or subsidies (25% price decrease) across food groups (fruit and vegetables, grains, dairy, protein products, fats, beverages, snacks, and other foods). Generalized linear mixed models were used to estimate the incidence rate ratios and 95% CIs for changes in the number of products purchased.RESULTS: Compared with the control condition, the combination of subsidies on healthy products and taxes on unhealthy products in the nudging and price salience condition was overall the most effective, as the number of healthy purchases from fruit and vegetables increased by 9% [incidence rate ratio (IRR) = 1.09; 95% CI: 1.02, 1.18], grains by 16% (IRR = 1.16; 95% CI: 1.05, 1.28), and dairy by 58% (IRR = 1.58; 95% CI: 1.31, 1.89), whereas the protein and beverage purchases did not significantly change. Regarding unhealthy purchases, grains decreased by 39% (IRR = 0.72; 95% CI: 0.63, 0.82) and dairy by 30% (IRR = 0.77; 95% CI: 0.68, 0.87), whereas beverage and snack purchases did not significantly change. The groups of grains and dairy showed within-food group substitution patterns toward healthier products. Beneficial spillover effects to minimally targeted food groups were seen for unhealthy proteins (IRR = 0.81; 95% CI: 0.73, 0.91).CONCLUSIONS: Nudging and salient pricing strategies have a differential effect on purchases of a variety of food groups. The largest effects were found for dairy and grains, which may therefore be the most promising food groups to target in order to achieve healthier purchases. The randomized trial on which the current secondary analyses were based is registered in the Dutch trial registry (NTR7293; www.trialregister.nl).

Background Many studies have shown that food variety—the presence of multiple foods and/or sensory characteristics within and across meals—increases intake. However, studies report mixed findings, and effect size remains unclear. Objectives A systematic review and meta-analysis were conducted to 1) synthesize data across experimental studies that examined effects of variety on total meal intake, relative to a control condition with comparatively less variety; 2) quantify support for this effect; and 3) assist in the identification of important moderating factors (registration: CRD42019153585). Methods In November 2019, we searched the following databases for relevant experimental studies, published in English from 1980, with human participants: PubMed, Cochrane Library, Web of Science, ClinicalTrials.gov, PsycINFO, and OpenGrey. This search was updated in September 2020. Means, standard deviations, and sample sizes were extracted from included articles, and Hedges' g was used to calculate effect sizes. Risk of bias was assessed using the Cochrane Collaboration's tool. Results Of 7259 references identified in an initial search, 34 articles consisting of 37 studies contained sufficient information for review, and data from 30 studies (39 comparisons) were included in the meta-analysis. Results from a random-effects model showed a significant small to medium effect of variety on intake (in weight and energy), with greater variety being associated with increased consumption (Hedges' g = 0.405; 95% CI: 0.259, 0.552). However, heterogeneity was considerable across studies (I2 = 84%), and this was unexplained by subgroup analyses based on form of variety, test foods, sensory characteristics, age, sex, and body weight. Conclusions Our findings support the conclusion that variety is a robust driver of food intake. However, risk of bias was high across studies, and this review highlights methodologic limitations of studies. It is recommended that further attention is given to the development of preregistered, well-powered randomized controlled studies in eating behavior research.

Background Although there is growing evidence on the role of preconception nutrition for birth outcomes, very few studies have evaluated the long-term effects of nutrition interventions during the preconception period on offspring cognitive outcomes. Objective We evaluate the impact of preconception weekly multiple micronutrients (MMs) or iron and folic acid (IFA) supplementation compared with folic acid (FA) alone on offspring intellectual functioning at age 6-7 y. Methods We followed 1599 offspring born to women who participated in a double-blinded randomized controlled trial of preconception supplementation in Vietnam. Women received weekly supplements containing either 2800 μg FA only, 60 mg iron and 2800 μg FA, or MMs (15 micronutrients including IFA) from baseline until conception, followed by daily prenatal IFA supplements until delivery. We used the Wechsler Intelligence Scale for Children to measure full-scale IQ (FSIQ) and 4 related domains of intellectual functioning [Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores] at 6-7 y. Group comparisons were done using ANOVA tests for all children and the subgroup born to women who consumed the supplements ≥26 wk before conception (per-protocol analyses). Results The final sample with data at 6-7 y (n = 1321) was similar for baseline maternal and offspring birth characteristics and age at follow-up by treatment group. Compared with the offspring in the FA group, those in the MM group had higher FSIQ (β = 1.7; 95% CI: 0.1, 3.3), WMI (β = 1.7; 95% CI: 0.2, 3.2), and PSI (β = 2.5; 95% CI: 0.9, 4.1). Similar findings were observed in the per-protocol analyses. There were no significant differences by treatment group for VCI and PRI. Conclusions Preconception supplementation with MMs improved certain domains of intellectual functioning at age 6-7 y compared with FA. These findings suggest the potential for preconception micronutrient interventions to have long-term benefits for offspring cognition.

Background Worldwide, the prevalence of dementia is increasing and diet as a modifiable factor could play a role. Meat consumption has been cross-sectionally associated with dementia risk, but specific amounts and types related to risk of incident dementia remain poorly understood. Objective We aimed to investigate associations between meat consumption and risk of incident dementia in the UK Biobank cohort. Methods Meat consumption was estimated using a short dietary questionnaire at recruitment and repeated 24-h dietary assessments. Incident all-cause dementia comprising Alzheimer disease (AD) and vascular dementia (VD) was identified by electronic linkages to hospital and mortality records. HRs for each meat type in relation to each dementia outcome were estimated in Cox proportional hazard models. Interactions between meat consumption and the apolipoprotein E (APOE) e4 allele were additionally explored. Results Among 493,888 participants included, 2896 incident cases of all-cause dementia, 1006 cases of AD, and 490 cases of VD were identified, with mean ± SD follow-up of 8 ± 1.1 y. Each additional 25 g/day intake of processed meat was associated with increased risks of incident all-cause dementia (HR: 1.44; 95% CI: 1.24, 1.67; P-trend < 0.001) and AD (HR: 1.52; 95% CI: 1.18, 1.96; P-trend = 0.001). In contrast, a 50-g/d increment in unprocessed red meat intake was associated with reduced risks of all-cause dementia (HR: 0.81; 95% CI: 0.69, 0.95; P-trend = 0.011) and AD (HR: 0.70; 95% CI: 0.53, 0.92; P-trend = 0.009). The linear trend was not significant for unprocessed poultry and total meat. Regarding incident VD, there were no statistically significant linear trends identified, although for processed meat, higher consumption categories were associated with increased risks. The APOE e4 allele increased dementia risk by 3 to 6 times but did not modify the associations with diet significantly. Conclusion These findings highlight processed-meat consumption as a potential risk factor for incident dementia, independent of the APOE e4 allele.