Zinc supplementation initiated prior to or during pregnancy modestly impacted maternal status and high prevalence of hypozincemia in pregnancy and lactation: the Women First Preconception Maternal Nutrition Trial.

BACKGROUND: Data regarding effects of small quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited. OBJECTIVES: Evaluate the effect of preconception vs prenatal zinc supplementation (vs control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low resource settings, and to assess associations with birth anthropometry. METHODS: From ∼100 women/arm at each of 3 sites (Guatemala, India, Pakistan) of the Women First Preconception Nutrition trial, we compared SZC at 12- and 34-weeks gestation (n=651 and 838, respectively) and 3-months postpartum (n=742) in women randomized to daily SQ-LNS containing 15 mg zinc from ≥3 months prior to conception (preconception, Arm 1), from ∼12 weeks gestation through delivery (early pregnancy, Arm 2) or not at all (control, Arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point. RESULTS: At 12-weeks gestation and 3-months postpartum, no statistical differences in mean SZC were observed among arms. At 34-weeks, mean SZC for Arms 1 and 2 were significantly higher than Arm 3 (50.3, 50.8, 47.8 µg/dL respectively; P=0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-weeks (<56 µg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 weeks (<50 µg/dL) 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-months postpartum (<66 µg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-weeks was associated with lower birth length-for-age Z-scores (all sites P=0.013, Pakistan P=0.008) and weight-for-age Z-scores (all sites P=0.017, Pakistan P=0.022). CONCLUSIONS: Despite daily zinc supplementation for ≥7 months, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. CLINICAL TRIAL REGISTRATION: The study protocol is registered at ClinicalTrials.gov #NCT01883193 at https://clinicaltrials.gov/ct2/show/NCT01883193?term=01883193&rank=1 and the protocol is available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000057/.

Predictive validity of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition indicators to diagnose malnutrition tool in hospitalized adults: a cohort study.

BACKGROUND: The lack of a widely accepted, broadly validated tool for diagnosing malnutrition in hospitalized patients limits the ability to assess the integral role of nutrition as an input and outcome of health, disease, and treatment. OBJECTIVES: This study aimed to evaluate the predictive validity of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition (ASPEN) indicators to diagnose malnutrition (AAIM) tool and determine if it can be simplified. METHODS: A prospective cohort study was conducted from August 2019 to September 2022 with 32 hospitals in United States. At baseline, 290 adult patients were evaluated for a diagnosis of malnutrition using the AAIM tool, which assesses weight loss, inadequate energy intake, subcutaneous fat and muscle loss, edema, and hand grip strength. Healthcare outcomes were extracted from the medical record: composite incidence of emergency department (ED) visits and hospital readmissions within 90 d postdischarge; length of hospital stay (LOS); and Medicare Severity Disease Related Group (MS-DRG) relative weight (i.e., healthcare resource utilization). We used multilevel, multivariable negative binomial or generalized linear regression models to evaluate relationships between malnutrition diagnosis and healthcare outcomes. RESULTS: After adjusting for disease severity and acuity and sociodemographic characteristics, individuals diagnosed with severe malnutrition had a higher incidence rate of ED visits and hospital readmissions (incidence rate ratio: 1.89; 95% CI: 1.14, 3.13; P = 0.01), and individuals diagnosed with moderate malnutrition had a 25.2% longer LOS (95% CI: 2.0%, 53.7%; P = 0.03) and 15.1% greater healthcare resource utilization (95% CI: 1.6%, 31.9%; P = 0.03) compared with individuals with no malnutrition diagnosis. Observed relationships remained consistent when only considering malnutrition diagnoses supported by at least 2 of these indicators: weight loss, subcutaneous fat loss, muscle wasting, and inadequate energy intake. CONCLUSIONS: Findings from this multihospital study confirm the predictive validity of the original or simplified AAIM tool and support its routine use for hospitalized adult patients. This trial was registered at clinicaltrials.gov as NCT03928548 (https://classic. CLINICALTRIALS: gov/ct2/show/NCT03928548).

Completion of a Nutrition-Focused Physical Exam with hospitalized adults and pediatric patients: Secondary analysis of a prospective cohort study.

BACKGROUND: Nutrition-Focused Physical Exam (NFPE) feasibility is not well-studied. We describe registered dietitian nutritionist (RDN)-reported NFPE completion for hospitalized adult and pediatric patients overall and by assessment parameters. METHODS: Trained RDNs systematically conducted NFPEs for hospitalized adult and pediatric patients during the Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition Indicators to diagnose Malnutrition multisite cohort study (ClinicalTrials.gov: NCT03928548). RDNs reported their ability to evaluate assessment sites for subcutaneous fat and muscle loss, fluid accumulation, and micronutrient status and to complete handgrip strength (adults and children ≥6 years) and mid-upper arm circumference measurements (children). RDNs noted if they could complete the full NFPE; if not, they noted challenges. We descriptively summarized results and used multilevel logistic regression models to examine relationships between patient characteristics and NFPE completion. RESULTS: RDNs from 39 adult and 29 pediatric US hospitals conducted NFPEs for 327 adults and 214 children aged 1 month to 17.9 years. RDNs reported completing the examination for 44% (n = 145) of adults and 15% (n = 33) of children. They successfully evaluated 25 of 27 and 19 of 26 unique NFPE components in >80% of adults and children, respectively. Common reasons the full NFPE was not completed were limited mobility in adults and patient refusal in children. RDNs had lower odds of completing NFPEs in adults with lower vs higher education levels or higher vs lower nutrition complexity and in younger vs older children. CONCLUSION: RDNs evaluated NFPE components for a high proportion (>80%) of hospitalized patients.

mini-MED: study protocol for a randomized, multi-intervention, semi-controlled feeding trial of a Mediterranean-amplified vs. habitual Western dietary pattern for the evaluation of food-specific compounds and cardiometabolic health.

BACKGROUND: Diet is among the most influential lifestyle factors impacting chronic disease risk. Nutrimetabolomics, the application of metabolomics to nutrition research, allows for the detection of food-specific compounds (FSCs) that can be used to connect dietary patterns, such as a Mediterranean-style (MED) diet, to health. This validation study is based upon analyses from a controlled feeding MED intervention, where our team identified FSCs from eight foods that can be detected in biospecimens after consumption and may therefore serve as food intake biomarkers. METHODS: Individuals with overweight/obesity who do not habitually consume a MED dietary pattern will complete a 16-week randomized, multi-intervention, semi-controlled feeding study of isocaloric dietary interventions: (1) MED-amplified dietary pattern, containing 500 kcal/day from eight MED target foods: avocado, basil, cherry, chickpea, oat, red bell pepper, walnut, and a protein source (alternating between salmon or unprocessed, lean beef), and (2) habitual/Western dietary pattern, containing 500 kcal/day from six non-MED target foods: cheesecake, chocolate frozen yogurt, refined grain bread, sour cream, white potato, and unprocessed, lean beef. After a 2-week washout, participants complete four, 4-week intervention periods, with biospecimen sampling and outcome assessments at baseline and at intervention weeks 4, 8, 12, and 16. The primary outcome is change in the relative abundance of FSCs from the eight MED target foods in participant biospecimens from baseline to the end of each intervention period. Secondary outcomes include mean change in cardiometabolic health indicators, inflammatory markers, and adipokines. Exploratory outcomes include change in diversity and community composition of the gut microbiota. DISCUSSION: Our stepwise strategy, beginning with identification of FSCs in whole diets and biospecimens, followed by relating these to health indicators will lead to improved methodology for assessment of dietary patterns and a better understanding of the relationship between food and health. This study will serve as a first step toward validating candidate food intake biomarkers and allow for assessment of relationships with cardiometabolic health. The identification of food intake biomarkers is critical to future research and has implications spanning health promotion and disease prevention for many chronic conditions. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT05500976 ; Date of registration: August 15, 2022.

Infant and young child feeding indicators are positively associated with length and family care indicators in the children of the Women First trial participants.

This research describes the proportion of children in four low- and middle-income countries with adequate dietary practices at 6, 12, 18 and 24 months of age and how these practices changed over time using the World Health Organisation and UNICEF's infant young child feeding (IYCF) indicators. The associations between the IYCF indicators and anthropometric z-scores from 6 to 24 months, and between the IYCF indicators and the family care indicators (FCIs) at 24 months are described. This was a longitudinal study of offspring from participants in the Women First Preconception Maternal Nutrition Trial conducted in Sud-Ubangi, Democratic Republic of Congo; Chimaltenango, Guatemala; Belagavi, North Karnataka, India; and Thatta, Sindh Province, Pakistan. The frequency of the minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum adequate diet (MAD) increased between 6 and 24 months, but even at 24 months MAD remained below 50% at all sites. MDD (ß = 0.12; 95% CI = 0.04-0.22) and MMF (ß = 0.10; 95% CI = 0.03-0.17) were positively associated with length-for-age z-score at 24 months. All IYCF indicators were positively associated with mean total FCI score: MDD (proportion ratio [PR] = 1.04; 95% CI = 1.02-1.07), MMF (PR = 1.02; 95% CI = 1.01-1.04), MAD (PR = 1.05; 95% CI = 1.02-1.08). Although there are multiple barriers to young children having an adequate diet, our results support a positive association between familial interactions and improved IYCF feeding practices.

Women in Selected Communities of Punjab, India Have a High Prevalence of Iron, Zinc, Vitamin B12, and Folate Deficiencies: Implications for a Multiply-Fortified Salt Intervention.

Dietary intake and biomarkers of micronutrient status of 100 non-pregnant women of reproductive age (NPWRA) were assessed to determine optimal levels of iron, zinc, vitamin B12, and folic acid to include in multiply-fortified salt (MFS) that will be evaluated in an upcoming trial. Weighed food records were obtained from participants to measure intake of micronutrients and discretionary salt, and to assess adequacy using Indian Nutrient Reference Values (NRVs). Statistical modeling was used to determine optimal fortification levels to reduce inadequate micronutrient intake while limiting intake above the upper limit. Fasting blood samples were obtained to assess iron, zinc, vitamin B12, and folate status. In usual diets, inadequate intake of iron (46%), zinc (95%), vitamin B12 (83%), and folate (36%) was high. Mean intake of discretionary salt was 4.7 g/day. Prevalence estimates of anemia (37%), iron deficiency (67%), zinc deficiency (34%), vitamin B12 insufficiency (37%), and folate insufficiency (70%) were also high. Simulating the addition of optimized MFS to usual diets resulted in percentage point (pp) reductions in inadequate intake by 29 pp for iron, 76 pp for zinc, 81 pp for vitamin B12, and 36 pp for folate. MFS holds potential to reduce the burden of micronutrient deficiencies in this setting.

Factors Associated with IRB Review Time in a Non-Federally Funded Study Using an sIRB of Record.

From 2018 to 2020, U.S. federal mandates began requiring the use of a single institutional review board (sIRB) of record for federally funded, multisite studies. With an interest in the efficiency of site activation, we compared the frequency with which local review and approval and three different reliance options (ways to establish a reliance agreement between the sIRB and the relying institution) were used during this period in a multisite, non-federally funded study (ClinicalTrials.gov identifier: NCT03928548). Using general linear models, we analyzed the relationships between local reliance or approval and sIRB of record approval times and (a) the regulatory option selected and (b) relying-site and process characteristics. Eighty-five sites received sIRB approval through 72 submissions (40% using local review, 46% using the SMART IRB agreement, 10% using an IRB authorization agreement, and 4% using a letter of support). Median time to establish a local reliance or study approval and sIRB approval were longest for sites using a SMART IRB agreement. Study-site region and the time of submission were significantly associated with local reliance or approval time, which averaged 129 and 107 days faster for Midwestern (p = 0.03) or Western (p = 0.02) sites, respectively, and 70 days slower for Northeastern sites (p = 0.42) compared with sites in the South, and 91 days slower when regulatory communication was initiated during or after February 2019 compared with before (p = 0.02). Similar relationships between sIRB approval time and region and time frame were observed; in addition, approval time was 103 days slower for sites affiliated with a research 1 (R1) university versus not (p = 0.02). Region of the country, time frame, and R1 university affiliation were associated with variations in study-site activation in a non-federally funded, multisite study.

Effects of Different Doses, Forms, and Frequencies of Zinc Supplementation on Biomarkers of Iron and Zinc Status among Young Children in Dhaka, Bangladesh.

Young children in resource-constrained settings are susceptible to zinc deficiency and its deleterious health effects. The objective of this secondary analysis was to evaluate the effects of the following six interventions on biomarkers of iron and zinc status among a subgroup of young children in Dhaka, Bangladesh, who participated in the Zinc in Powders Trial (ZiPT): (1) standard micronutrient powders (MNPs) containing 4.1 mg zinc and 10 mg iron, daily; (2) high-zinc (10 mg) and low-iron (6 mg) (HiZn LoFe) MNP, daily; (3) HiZn (10 mg) and LoFe (6 mg)/HiZn (10 mg) and no-iron MNPs on alternating days; (4) dispersible zinc tablet (10 mg), daily; (5) dispersible zinc tablet (10 mg), daily for 2 weeks at enrollment and at 12 weeks; (6) placebo powder, daily. At the end of the 24 week intervention period, children in the daily dispersible zinc tablet group exhibited a mean serum zinc concentration (SZC) of 92.5 µg/dL, which was significantly higher than all other groups except the HiZn LoFe MNP alternating group (81.3 µg/dL). MNPs containing 10 mg and 6 mg of iron had a similar impact on biomarkers of iron status, with no evidence of an adverse interaction with zinc.

Quintuply-fortified salt for the improvement of micronutrient status among women of reproductive age and preschool-aged children in Punjab, India: protocol for a randomized, controlled, community-based trial.

BACKGROUND: Multiple micronutrient (MN) deficiencies remain highly prevalent among women of reproductive age (WRA) and preschool-aged children (PSC) in many areas within India. Salt is an attractive vehicle for MN fortification in this context, as it is universally consumed in fairly consistent amounts and coverage of iodized salt (IS) is 94%. The overall objective of this trial is to evaluate the nutritional impact of quintuply-fortified salt with iron in the form of encapsulated ferrous fumarate, zinc, vitamin B12, folic acid, and iodine (eFF-Q5S) vs. quintuply-fortified salt with iron in the form of ferric pyrophosphate plus EDTA, zinc, vitamin B12, folic acid, and iodine (FePP-Q5S) vs. IS for the improvement of MN status among non-pregnant WRA and PSC. METHODS: The study is a community-based, randomized, controlled trial that will be conducted in Punjab, India. 780 non-pregnant WRA 18-49 years old and 468 PSC 12-59 months old will be enrolled and assigned to one of three intervention groups. Salt will be provided to participants monthly for 12 months. Primary outcomes include changes in mean concentration of biomarkers of iron, zinc, vitamin B12, folate and iodine. Secondary outcomes include changes in the composition of the gut microbiome, and discretionary salt intake of PSC. DISCUSSION: If proven efficacious, multiply-fortified salt (MFS) has the potential to drastically reduce the burden of MN deficiencies in India, and around the world. Although effectiveness research will be needed to examine the impact of MFS under programmatic conditions, salt fortification will piggy-back on existing platforms to produce IS and doubly-fortified salt (DFS), making it possible to scale-up the intervention quickly. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05166980; date of registration: December 22, 2021. Clinical Trials Registry-India: CTRI/2022/040332 and CTRI/2022/02/040333; date of registration: February 15, 2022.

Zinc Kinetics Correlate With Length-for-Age z Scores in Bangladeshi Infants.

OBJECTIVES: Stunting [length-for-age z score (LAZ) <-2] has multiple causes and is prevalent in areas with low dietary zinc (Zn) intake. Zinc kinetics from non-stunted infants were used in a published model for predicting linear growth; here, we directly measure zinc kinetics in stunted infants. METHODS: Zinc kinetics were determined in 9-month-old Bangladeshi infants (n = 10), who were non-wasted [weight-for-length z score (WLZ) > -2], ranging in LAZ from -2.9 to -0.43. Stable isotopes were administered 2 hours after a meal as oral ( 70 Zn) and intravenous ( 67 Zn) tracers. After isotope administration, blood was sampled within 5 hours and all urine and feces were collected for 24 hours. Urine was sampled twice-daily out to 9 days. Data were analyzed by compartmental modeling. Daily zinc intake was estimated by the model as the sum of zinc used for growth plus that lost via urine and feces. Zinc absorbed (the amount required to maintain steady state) was the sum of zinc used for growth plus urine and endogenous fecal excretions. RESULTS: The LAZ score correlated with serum zinc concentration ( R = 0.77, P = 0.001), urinary zinc excretion ( R = 0.66, P = 0.010), and fractional zinc absorption from calculated daily intake ( R = 0.58, P = 0.030). In stunted infants (n = 8), the amount of zinc absorbed did not increase with calculated zinc intake unlike published values for non-stunted infants. CONCLUSIONS: Zinc kinetics in Bangladeshi infants correlate with LAZ and show that malabsorption of supplemental sources of zinc may occur in stunted infants.

Exchangeable Zinc Pool Size Reflects Form of Zinc Supplementation in Young Children and Is Not Associated with Markers of Inflammation.

A sensitive and reliable biomarker of zinc status has yet to be identified, but observational research suggests that the exchangeable zinc pool (EZP) size may be a possible biomarker. This randomized, placebo-controlled trial aimed to compare the change in EZP size from baseline to endline in 174 children who were preventatively supplemented with 10 mg of zinc as part of a multiple micronutrient power (MNP) or as a standalone dispersible tablet for 24 weeks versus a placebo powder. The effects of systemic inflammation on EZP size were also evaluated. Zinc stable isotopes were administered intravenously to children at baseline and endline, and the EZP was measured by the urine extrapolation method. A total of 156 children completed the study with the zinc dispersible tablet group having the greatest increase in EZP (14.1 mg) over 24 weeks when compared with the MNP group (6.8 mg) (p < 0.01) or placebo group (2.0 mg) (p < 0.001). Median EZP size was not different between children with normal or elevated serum inflammatory markers. EZP size was responsive to longitudinal zinc supplementation and reflected the expected difference in bioavailability for two forms of supplementation. The apparent absence of an effect of inflammation on EZP size may offer an advantage for use as a biomarker for group comparisons between different interventions.

Academy of Nutrition and Dietetics Nutrition Research Network: Rationale and Protocol for a Study to Validate the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition Consensus-Derived Diagnostic Indicators For Adult And Pediatric Malnutrition and to Determine Optimal Registered Dietitian Nutritionist Staffing in Acute Care Hospital Settings.

No systematic, universally accepted method of diagnosing malnutrition in hospitalized patients exists, which may contribute to underdiagnosis, undertreatment, and poorer patient outcomes. To address this issue, the Academy of Nutrition and Dietetics is conducting a cohort study to: assess the predictive validity of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition indicators for the diagnosis of adult and pediatric malnutrition in hospital settings; assess the interrater reliability of the indicators for the diagnosis of adult and pediatric malnutrition; and quantify the level of registered dietitian nutritionist care needed to improve patient outcomes. Up to 60 adult and 60 pediatric hospital sites will collect data to estimate level of registered dietitian nutritionist care, along with patient medical history and Malnutrition Screening Tool (adult) or STRONGkids (pediatric) results. A subset of 600 adult and 600 pediatric patients (∼1:1 screened as high- or low-risk for malnutrition) will be randomly selected for the indicators for the diagnosis of adult and pediatric malnutrition and Nutrition Focused Physical Exam data collection; 100 adult and 100 pediatric patients in this group will also undergo a bioelectrical impedance analysis measurement. Additional nutrition care and medical outcomes (eg, mortality and length of stay) will be collected for a 3-month period after the initial nutrition encounter. Multilevel linear, logistic, Poisson, or Cox regression models will be used to assess indicators for the diagnosis of adult and pediatric malnutrition validity and registered dietitian nutritionist staffing levels as appropriate for each medical outcome. Validation results will allow US clinicians to standardize the way they diagnose malnutrition in hospitalized patients, and the staffing data will support advocacy for available registered dietitian nutritionist-delivered malnutrition treatment to improve patient outcomes.

TGF-ß2 Reduces the Cell-Mediated Immunogenicity of Equine MHC-Mismatched Bone Marrow-Derived Mesenchymal Stem Cells Without Altering Immunomodulatory Properties.

Allogeneic mesenchymal stem cells (MSCs) are a promising cell therapy for treating numerous diseases, but major histocompatibility complex (MHC)-mismatched MSCs can be rejected by the recipient's immune system. Pre-treating MSCs with transforming growth factor-ß2 (TGF-ß2) to downregulate surface expression of MHC molecules may enhance the ability of allogeneic MSCs to evade immune responses. We used lymphocyte proliferation assays and ELISAs to analyze the immunomodulatory potential of TGF-ß2-treated equine bone marrow-derived MSCs. T cell activation and cytotoxicity assays were then used to measure the in vitro cell-mediated immunogenicity. Similar to untreated MSCs, TGF-ß2-treated MSCs inhibited T cell proliferation and did not stimulate MHC-mismatched T cells to proliferate. Additionally, similar quantities of prostaglandin E2 and TGF-ß1 were detected in assays with untreated and TGF-ß2-treated MSCs supporting that TGF-ß2-treated MSCs retain their strong immunomodulatory properties in vitro. Compared to untreated MSCs, TGF-ß2-treated MSCs induced less T cell activation and had reduced cell-mediated cytotoxicity in vitro. These results indicate that treating MSCs with TGF-ß2 is a promising strategy to reduce the cell-mediated immunogenicity of MHC-mismatched MSCs and facilitate allogeneic MSC therapy.

Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery.

Here we report an ultra-long-acting tunable, biodegradable, and removable polymer-based delivery system that offers sustained drug delivery for up to one year for HIV treatment or prophylaxis. This robust formulation offers the ability to integrate multiple drugs in a single injection, which is particularly important to address the potential for drug resistance with monotherapy. Six antiretroviral drugs were selected based on their solubility in N-methyl-2-pyrrolidone and relevance as a combination therapy for HIV treatment or prevention. All drugs released with concentrations above their protein-adjusted inhibitory concentration and retained their physical and chemical properties within the formulation and upon release. The versatility of this formulation to integrate multiple drugs and provide sustained plasma concentrations from several weeks to up to one year, combined with its ability to be removed to terminate the treatment if necessary, makes it attractive as a drug delivery platform technology for a wide range of applications.

Zinc Absorption and Endogenous Fecal Zinc Losses in Bangladeshi Toddlers at Risk for Environmental Enteric Dysfunction.

OBJECTIVES: Environmental enteric dysfunction (EED) impairs zinc absorption from food, and zinc deficiency may contribute to the poor growth associated with EED. We examined zinc absorption from a standardized aqueous zinc dose, and habitual daily endogenous fecal zinc excretion (EFZ) and compared these outcomes between children grouped by the lactulose to mannitol ratio (L:M). METHODS: Bangladeshi toddlers (18-24 months) with low (<0.09) and high (≥0.09) L:M were administered isotope-labeled 3 mg aqueous zinc in the fasted state. Fractional absorption of zinc (FAZ) and EFZ were measured by dual stable isotope tracer method and an isotope dilution method, respectively. Secondary aims included examining relationships of biomarkers of systemic and intestinal inflammation and gut function with FAZ and EFZ. RESULTS: Forty children completed the study; nearly all had evidence of EED. No differences in zinc homeostasis measurements (mean ±â€ŠSD) were observed between high and low L:M groups: FAZ was 0.38 ±â€Š0.19 and 0.31 ±â€Š0.19, respectively; both figures were within estimated reference range. Means of EFZ were 0.73 ±â€Š0.27 and 0.76 ±â€Š0.20 mg/day for high and low L:M, respectively, and were 10% to 15% above estimated reference range. Regression analyses indicated that biomarkers of systemic inflammation were directly associated with increasing FAZ, consistent with increased gut permeability. Biomarkers of intestinal inflammation were negatively associated with EFZ, consistent with low-zinc intake and chronic deficiency. CONCLUSIONS: In these children at risk of EED, endogenous zinc losses were not markedly increased. Results suggest that efforts to improve zinc status in EED should focus on substantially improving zinc intakes.

Zinc Absorption from Micronutrient Powders Is Low in Bangladeshi Toddlers at Risk of Environmental Enteric Dysfunction and May Increase Dietary Zinc Requirements.

Background: Environmental enteric dysfunction (EED), a chronic inflammatory disorder of the small bowel, is suspected to impair absorption of micronutrients, including zinc. Objective: The objective of this study was to compare zinc absorption from micronutrient powder (MNP) over a range of zinc doses in young children screened for EED with use of the lactulose:mannitol ratio (L:M). Methods: Bangladeshi children aged 18-24 mo, grouped according to high and low L:M (≥0.09 and <0.09, respectively), were randomly assigned to MNP with 0, 5, 10, or 15 mg Zn/sachet (10 subjects per dose per L:M group). Over a day, fractional absorption of zinc was measured from an MNP-fortified meal and from unfortified meals with stable isotope tracers; total daily absorbed zinc (TAZ, milligrams per day) was determined as the primary outcome. Secondary outcomes included investigation of relations of TAZ to intake, to physiologic requirement, and to other variables, including biomarkers of systemic and intestinal inflammation, using nonlinear models. TAZ was also compared with published data on child zinc absorption. Results: In 74 subjects who completed the study, zinc absorption did not differ by L:M grouping. Most biomarkers of intestinal inflammation were elevated in both L:M groups. For combined L:M groups, mean ± SD TAZ for each MNP dose (0, 5, 10, and 15 mg/sachet) was 0.57 ± 0.30, 0.68 ± 0.31, 0.90 ± 0.43, and 1.0 ± 0.39 mg/d, respectively (P = 0.002), and exceeded the estimated physiologic requirement only for the 10- and 15-mg MNP doses. Zinc absorption was notably lower at all intake levels compared with published data (P < 0.0001) and was inversely related to serum α-1 acid glycoprotein and to fecal Entamoeba histolytica (P = 0.02). Conclusion: Results indicate impaired absorption of zinc, which may predispose to zinc deficiency in young children with evidence of enteropathy. These findings suggest that current doses of zinc in MNP may be insufficient to yield zinc-related preventative benefits in similar settings. This study is registered at clinicaltrials.gov as NCT02758444.

Pooled Platelet-Rich Plasma Lysate Therapy Increases Synoviocyte Proliferation and Hyaluronic Acid Production While Protecting Chondrocytes From Synoviocyte-Derived Inflammatory Mediators.

Platelet-rich plasma (PRP) preparations are being used with moderate success to treat osteoarthritis (OA) in humans and in veterinary species. Such preparations are hindered, however, by being autologous in nature and subject to tremendous patient and processing variability. For this reason, there has been increasing interest in the use of platelet lysate preparations instead of traditional PRP. Platelet lysate preparations are acellular, thereby reducing concerns over immunogenicity, and contain high concentrations of growth factors and cytokines. In addition, platelet lysate preparations can be stored frozen for readily available use. The purpose of this study was to evaluate the effects of a pooled allogeneic platelet-rich plasma lysate (PRP-L) preparation on equine synoviocytes and chondrocytes challenged with inflammatory mediators in-vitro to mimic the OA joint environment. Our hypothesis was that PRP-L treatment of inflamed synoviocytes would protect chondrocytes challenged with synoviocyte conditioned media by reducing synoviocyte pro-inflammatory cytokine production while increasing synoviocyte anti-inflammatory cytokine production. Synoviocytes were stimulated with either interleukin-1ß (IL-1ß) or lipopolysaccharide (LPS) for 24 h followed by no treatment or treatment with platelet-poor plasma lysate (PPP-L) or PRP-L for 48 h. Synoviocyte growth was evaluated at the end of the treatment period and synoviocyte conditioned media was assessed for concentrations of hyaluronic acid (HA), IL-1ß, tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Chondrocytes were then challenged for 48 h with synoviocyte conditioned media from each stimulation and treatment group and examined for gene expression of collagen types I (COL1A1), II (COL2A1), and III (COL3A1), aggrecan (ACAN), lubricin (PRG4), and matrix metallopeptidase 3 (MMP-3) and 13 (MMP-13). Treatment of inflamed synoviocytes with PRP-L resulted in increased synoviocyte growth and increased synoviocyte HA and IL-6 production. Challenge of chondrocytes with conditioned media from PRP-L treated synoviocytes resulted in increased collagen type II and aggrecan gene expression as well as decreased MMP-13 gene expression. The results of this study support continued investigation into the use of pooled PRP-L for the treatment of osteoarthritis and warrant further in-vitro studies to discern the mechanisms of action of PRP-L.

ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions.

The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human CD4+ cells that are shed into cervicovaginal secretions (CVS). A high percentage of the CD4+ T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of CD4+ and CD8+ T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA+ cells in both the FRT and CVS.

Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission.

Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection.