Priority Outcomes in Sickle Cell Disease Treatment: Co-Creation and Implementation of a Preference Exercise With Patients and Caregivers to Inform Drug Development.

Involving patients as co-leaders and co-creators in research is key to reflecting the patient's voice in decision-making. However, co-creation of patient-centered data to inform decisions is rare, especially in early drug development where patient input is critical to prioritizing patient-relevant outcomes and endpoints for use in clinical trials. Despite the industry's growing commitment to patient centricity, most patients are excluded from sharing their expertise in research; more inclusive methods of engaging patients as research partners are needed. We describe a collaboration between a pharmaceutical company and a patient organization in co-leading and co-creating a program to understand priorities of patients and caregivers for treatment features and outcomes in sickle cell disease to inform endpoint selection in clinical development. The results of this program will be used as a basis for continued interaction between patients and the sponsor and to inform ongoing clinical development and evidence-generation activities. This case study demonstrates an approach to meaningful collaborations between patient organizations and pharmaceutical companies aimed at including the patient's voice early in the medical product lifecycle.

Findings in 3 clinical trials challenge the accuracy of the Institute of Medicine's estimated average requirements for vitamin A in children and women.

BACKGROUND: Vitamin A (VA) estimated average requirements (EARs) for women and children are extrapolated from rats and adult males. The retinol isotope dilution (RID) test can sensitively characterize VA status and intake requirements. OBJECTIVES: These studies evaluated current EARs for children 4-8 y and women 19-30 y old. METHODS: Zambian children (n = 133, ages 5-7 y), US women (n = 51, ages 19-27 y), and Indonesian women (n = 29, ages 19-30 y) were provided diets or supplements containing 30%-155% of VA EARs for 42-90 d. RID was performed before and after the intervention to quantify changes in total body VA stores (TBSs) and total liver VA reserves (TLRs). Linear regression was performed between VA intake and change in TBSs or TLRs. RESULTS: Baseline mean ± SD TLRs were hypervitaminotic in Zambian children (1.13 ± 0.41 µmol VA/g liver), optimal in US women (0.46 ± 0.32 µmol/g VA/g liver), and deficient to marginal in Indonesian women (0.10 ± 0.08 µmol VA/g liver). VA intakes, resulting in no change in TBSs or TLRs, were 185 (95% CI: 18, 288) or 257 (95% CI: 124, 411) and 285 or 330 (CIs undefined) µg retinol activity equivalents (RAE)/d in the Zambian and US trials, respectively, but inconclusive in Indonesian women. The regression was not significant in either group of women. CONCLUSIONS: Point estimates of VA intakes to maintain stores were below the current EARs of 275 (children) and 500 (women) µg RAE/d despite the TLRs being higher than the EARs were formulated to maintain (i.e., 0.07 µmol VA/g liver). Interventions based on these EARs may need to be scaled back. Lack of change in VA stores in women taking lower doses may result from physiological adaptation resulting in lower VA utilization. Longer, larger, and controlled studies are needed to accurately define EARs for VA.These trials were registered at Clinicaltrials.gov as NCT04123210 and NCT01814891.

Photogrammetric Outcomes of Primary Nasal Correction in Unilateral Cleft Lip Patients: Early Childhood Results From a Single Surgeon's Experience.

BACKGROUND: Concerns of nonlasting results and potential nasal growth damage precluded cleft nasal correction at the time of initial cleft lip repair. Our goal was to evaluate the outcome of primary cleft nasal correction in our patients with unilateral cleft lip. METHODS: A retrospective review of patients with complete and incomplete unilateral cleft lip who underwent primary cleft nasal correction from 2010 to 2017 by the same surgeon was performed. The cleft-to-noncleft nostril height, width, one-fourth medial part of nostril height, nasal sill height, and nostril area ratios, as well as inner nostril height-to-width ratios were determined from standard basilar view photographs taken in different time points (T1, <3 months; T2, 3-12 months; T3, 12-36 months; and T4, >36 months after surgery). A 5-point visual analog scale (1 = worst, 5 = best) was used to assess each patient's nose appearance. RESULTS: Seventy-two patients were identified (66.7% male, 51.3% with a complete cleft lip). Average visual analog scale scores T1-T4 were 3.88 ± 0.85, 3.72 ± 0.93, 3.54 ± 0.99, and 3.40 ± 0.71, respectively. Intraclass correlation ranged from 0.61 to 0.94. A significant decrease [mean difference (SD)] was found for cleft-to-noncleft nostril width ratio [0.15 (0.18)] from T1 to T2, and an increase for one-fourth medial height ratio [-0.09 (0.07)] and for inner nostril height-to-width ratio in the noncleft side [-0.23 (0.25)] from T1 to T3. Thirteen patients required secondary surgical revision. CONCLUSION: Based on photogrammetry, primary cleft nasal correction in our patients with unilateral cleft lip achieved acceptable and stable outcomes during early childhood.

Duration of Retinol Isotope Dilution Studies with Compartmental Modeling Affects Model Complexity, Kinetic Parameters, and Calculated Vitamin A Stores in US Women.

Background: Retinol isotope dilution (RID) indirectly estimates vitamin A (VA) status. Multicompartment modeling of RID data is used to refine study designs and equations to calculate VA stores. Previous studies suggest that VA in slowly turning over pools is not traced if follow-up is not long enough; however, shorter RID studies are being investigated. Few long-term models have been published. Objective: We determined the effect of time on mathematical models of VA kinetics, model parameters, and outcomes. Methods: In this longitudinal study, women (mean ± SD age: 22 ± 3 y; n = 7) were given 2.0 µmol [14,15]-13C2-retinyl acetate. Blood samples were staggered from 4 h to 152 d; the fraction of dose in serum was modeled with compartmental models. Four model-time categories were created: full models that used all data (median: 137 d; range 97-152 d) and truncated shorter studies of 14, 27, and 52 d (range: 42-62 d). Outcomes included number of compartments to adequately model serum data, kinetic parameters, total traced VA mass, and time-to-dose equilibration. To gain insight into longer follow-up, an additional participant was given 17.5 µmol 13C4-VA, and data were modeled as long as enrichment was above baseline (5 y). Results: Longer follow-up times affected kinetic parameters and outcomes. Compared with the 14-d models, long-term full models required an additional compartment for adequate fit (14.3% compared with 100%; P = 0.0056) and had longer [median (quartile 1, quartile 3)] whole-body half-life [15.0 d (10.5, 72.6 d) compared with 135 d (115, 199 d); P = 0.0006], time-to-dose equilibration [3.40 d (3.14, 6.75 d) compared with 18.9 d (11.2, 25.7 d); P < 0.0001], and total traced mass [166 µmol VA (162, 252 µmol VA) compared with 476 µmol VA (290, 752 µmol VA); P = 0.0031]. Conclusions: Extended RID sampling alters numerous mathematically modeled, time-dependent outcomes in women. Length of study should be considered when using mathematical models for calculating total-body VA stores or kinetic parameters related to VA turnover. This study is registered at www.clinicaltrials.gov as NCT03248700.

Serum carotenoid interactions in premenopausal women reveal α-carotene is negatively impacted by body fat.

Increasing body mass indices (BMIs) across the globe reflect pandemic shifts towards habitual positive energy imbalances. Excess body fat in individuals is often associated with high-energy and high-fat diets scanty in fresh produce. Carotenoids are fat-soluble pigments plentiful in many fruits and vegetables. They are well-known for provitamin A and antioxidant functions, but little research has been done related to carotenoid-body mass interactions. Serum carotenoids were analyzed relative to body fat to determine correlations between major serum carotenoids, retinol, BMI, fat mass, and lean mass. Healthy women ( n = 76), 19-50 years old, were categorized into two comparison groups determined by percent body fat measured by air displacement plethysomography (BOD POD®), i.e. <31% and ≥31% fat mass. Anthropometric and three-day diet records were completed for BMI and nutrient intake calculations, respectively. Serum α-carotene concentrations were strongly inversely associated with all measures of body composition ( P < 0.001 α-carotene) controlling for dietary intake and age, while ß-carotene, lutein, and lycopene were not ( P > 0.05). Dietary intake between groups did not differ, including carrot consumption (a high dietary source of α-carotene). These results confirm previous carotenoid-health research and propose the need for further investigation of potential protective roles that α-carotene may perform for optimal health. Serum α-carotene may provide a deeper and clinically relevant purpose, beyond previous suggestions for its use as a biomarker for fruit and vegetable consumption, in that α-carotene may be a biomarker for chronic disease risk frequently linked with obesity. Impact statement Carotenoids are important pigments in fruit and vegetables and found in human serum. This study isolated a negative relationship between serum α-carotene and body fatness. As humans begin to live over a century, determining biomarkers of ultimate health is important. α-Carotene does not have the same distribution in the food supply as ß-carotene and therefore is often overlooked in surveys. In part, this is due to the fact that ß-carotene provides two molecules of vitamin A, while α-carotene provides one upon central cleavage. This study shows a very clear association between α-carotene and body fatness, which appears to go beyond its fat-soluble nature. Dietary intake data were not able to explain the association. Further work is needed to determine what dietary components infer health benefits.

Vitamin A isotope dilution predicts liver stores in line with long-term vitamin A intake above the current Recommended Dietary Allowance for young adult women.

BACKGROUND: The Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for vitamin A are 1.7 and 2.4 µmol/d (500 and 700 µg retinol activity equivalents/d), respectively, for nonpregnant, nonlactating women aged >19 y. This intake is presumed to maintain a minimally acceptable liver concentration of 0.07 µmol (20 µg) retinol/g; however, liver reserves have not been evaluated with respect to vitamin A intake in women of any age group defined in the Dietary Reference Intakes. OBJECTIVE: This cross-sectional study examined vitamin A intake and liver reserves estimated by stable-isotope dilution testing. DESIGN: Forty nonpregnant, nonlactating women (mean ± SD age: 22.4 ± 2.3 y) completed a Harvard food-frequency questionnaire (FFQ) and 3-d diet record (3DDR) before undergoing vitamin A status assessment by using a [(13)C2]retinol stable-isotope dilution test. RESULTS: Vitamin A intake was 70% higher than the RDA by both dietary-assessment methods (P < 0.001). The mean (±SD) liver concentration of vitamin A was 0.45 ± 0.31 µmol/g (129 ± 89 µg/g) and ranged from 0.09 (26 µg/g) to 1.79 µmol/g (513 µg/g). Liver and total-body vitamin A were highly correlated with intake measured by FFQ (P ≤ 0.009), but 3DDR was not (P ≥ 0.22). Prediction equations were developed for 3- and 7-d data. CONCLUSIONS: In this well-nourished population, vitamin A consumption was considerably higher than recommended, and liver reserves were consistent with intake. Because of their sensitivity, stable-isotope techniques can help to describe the vitamin A status and better characterize the intake needs of all groups defined in the Dietary Reference Intakes. Registration was not required for this trial.

3, 4-Didehydroretinol kinetics differ during lactation in sows on a retinol depletion regimen and the serum:milk 3, 4-didehydroretinol:retinol ratios are correlated.

3, 4-Didehydroretinol (DR) metabolism was previously followed in vitamin A (VA)-replete lactating sows. This study followed DR appearance and clearance after dosage in serum and milk during 2 lactation cycles in sows (n = 8) fed VA-free feed for 3 gestation-lactation cycles. During lactations 2 and 3, 35 µmol 3, 4-didehydroretinyl acetate was given orally after overnight food deprivation. Blood and milk were collected at 0, 1.5, 3, 5, 7, 9, 16, 24, 36, 48, 60, and 72 h; livers were obtained at kill. Samples were analyzed for DR, retinol (R), and 3, 4-didehydroretinyl esters. During lactations 2 and 3, the 5-h serum DR:R ratios were 0.028 ± 0.017 and 0.069 ± 0.042, respectively, and serum R concentrations were 0.75 ± 0.23 and 0.86 ± 0.37 µmol/L, respectively. The DR:R ratio and serum R were 0.018 ± 0.013 and 0.94 ± 0.12 µmol/L, respectively, in VA-replete sows from the same herd. After lactation 3, liver VA was 0.23 ± 0.05 µmol/g, indicating low-normal VA status. Serum DR area-under-the curve from 0 to 48 h increased as liver stores decreased. Thirteen to 23% of DR dose was secreted into milk, consistent with VA-replete sows. Milk DR concentrations were greater during lactation 3 than 2. Peak concentration occurred earlier and the half-life was shorter for milk DR in the more VA-depleted sows. The milk and serum DR:R were correlated from 3 to 9 h (r = 0.70; P < 0.0001) and increased as VA stores decreased regardless of serum R concentration. Milk DR:R may replace serum measurements during lactation.

Strategies to increase vegetable or reduce energy and fat intake induce weight loss in adults.

For obese individuals seeking to optimize health and well-being, healthy dietary strategies are important. Vegetables and fruits contribute to a healthy diet, and increased consumption may cause weight reduction by displacing foods high in energy and fat. The objective of this study was to determine if advising high vegetable (8 servings) and moderate fruit (2-3 servings) consumption would result in weight reduction in obese individuals. We compared this to advising a more traditional strategy of reducing daily energy intake by 500 kcal (2.1 MJ)/d and limiting energy from fat to

13C natural abundance in serum retinol acts as a biomarker for increases in dietary provitamin A.

The natural isotopic composition of 13C and 12C in tissues is largely determined by the diet. Sources of provitamin A carotenoids (e.g., vegetables) typically have a lower 13C to 12C ratio (13C:12C) than preformed vitamin A sources (i.e., dairy and meat) from corn-fed animals, which are prevalent in the US. The 13C:12C of serum retinol (13C:12C-retinol) was evaluated as a biomarker for vegetable intake in a 3-mo dietary intervention designed to promote weight-loss by increased vegetable consumption or reduced calorie and fat intake. Subjects were 21-50 y of age with a BMI between 30-40 kg/m2 and were enrolled from one geographic area in the US. The high vegetable group (n=20) was encouraged to increase daily vegetable and fruit consumption to 0.95 liter vegetables and 0.24-0.35 liter fruits. The caloric reduction group (n=17) was encouraged to lower caloric intake by 500 kcal and consume

One-time graded doses of vitamin A to weanling piglets enhance hepatic retinol but do not always prevent vitamin A deficiency.

BACKGROUND: Vitamin A supplements are administered to infants in developing countries at immunization contacts; doses of 50000 IU vitamin A are recommended. Doses of 100000 IU are given to children aged 0.5-1 y. The efficacy of these doses has not been adequately determined. OBJECTIVE: We aimed to quantify liver vitamin A after the administration of vitamin A doses to piglets. Piglets are a good model for infants because of their similar size, gastrointestinal anatomy, and vitamin A requirements. DESIGN: Castrated male piglets born to sows fed a vitamin A-depleted diet throughout 1 (parity A) or 3 (parity B) pregnancy and lactation cycles were randomly assigned to receive 1 of 4 oral vitamin A doses (ie, 0, 25000, 50000, or 100000 IU) at weaning (days 9-14). A vitamin A-depleted diet was fed until the piglets were killed on day 10. Serum retinol was measured on days 1, 2, 4, 7, and 10. The modified relative dose response was measured before supplementation and at the time of killing, and liver vitamin A concentration was measured. RESULTS: In both parities, 25000 IU did not result in a mean liver retinol reserve > 0.07 micromol/g liver (the deficiency cutoff). The 50000-IU dose increased mean reserves above 0.07 micromol/g only in parity A. Liver vitamin A reserves with the 100000-IU treatment were only 5% above those with the 50000-IU treatment. The modified relative dose-response test reflected differences in liver vitamin A stores in parity B, and the 0-IU group differed significantly from the 100000-IU group (P = 0.011). CONCLUSION: This piglet model suggests that, for supplementation to infants <6 mo old, a 50000-IU dose is likely to be more efficacious in mitigating deficiency than is a 25000-IU dose.

One-time vitamin A supplementation of lactating sows enhances hepatic retinol in their offspring independent of dose size.

BACKGROUND: Single megadoses of vitamin A between 200,000 and 400,000 IU have been administered to lactating mothers to improve the vitamin A status of both mothers and breastfeeding infants. However, the most beneficial dosing regimen is not known. OBJECTIVE: The effect of megadoses of vitamin A supplements given to lactating sows on hepatic vitamin A concentrations in their nursing offspring was examined. DESIGN: Lactating sows were given a high (2.1 mmol), low (1.05 mmol), or control (0 mmol) dose of retinyl acetate in oil (n=3 sows per treatment). Piglets nursed for 3 or 14 d, consumed a vitamin A-free diet for the next 4 d, and were then killed. Liver and serum samples were analyzed for vitamin A. RESULTS: After 3 d, piglets of the control, low-dose, and high-dose sows had different (P=0.034) hepatic vitamin A concentrations, ie, 0.078+/-0.004, 0.14+/-0.053, and 0.13+/-0.026 micromol/g, respectively. Liver vitamin A concentrations on day 18 were 0.069+/-0.004, 0.14+/-0.044, and 0.11+/-0.026 micromol/g in the control, low-dose, and high-dose piglets, respectively (P=0.017). Liver vitamin A concentrations in piglets of the low- and high-dose sows were not significantly different (day 3: P=0.97; day 18: P=0.59). Serum retinol concentrations were higher (P=0.02) at early kill (0.95+/-0.22 micromol/L) than at late kill (0.76+/-0.24 micromol/L) but were not significantly different between groups. CONCLUSIONS: Maternal vitamin A supplementation enhances liver vitamin A concentrations in offspring. Larger one-time doses are not more effective than are smaller doses. Additional research is needed to determine the most effective maternal dosing regimens for improving infant vitamin A status.

Adjustments to the modified relative dose response (MRDR) test for assessment of vitamin A status minimize the blood volume used in piglets.

The modified relative dose response (MRDR) test is widely used in public health research to assess vitamin A (VA) status of populations and individuals. However, method adjustments intended to make the test more useful in large field studies and/or less invasive have not been systematically verified. To compare the similarity between modified tests and the standard MRDR test, and validate both modified and standard tests against liver reserves of VA, we used a piglet model. Following the typical MRDR procedure, piglets (n = 10) were dosed with 5.3 micromol 3,4-didehydroretinyl acetate. Method adjustments were made to the postdose blood sample collection time to decrease both the amount of serum analyzed and sample throughput time. We collected 3 blood samples/piglet at 3, 5, and 7 h or 4, 6, and 8 h postdose. Postdose blood samples obtained between 4 and 7 h gave MRDR values that did not differ. Serum volumes as small as 200 microL, half the volume of the standard method, yielded accurate MRDR values. Method adjustments to reduce sample throughput time require further investigation. In conclusion, because 200 microL of serum can be used in the test, only 0.5 mL, as opposed to 1 mL of blood has to be collected from an individual. This adjustment allows for easier application of the test to individuals, especially infants, from whom it is difficult to obtain a large venous blood sample, thus increasing the utility of the test for researchers.

A theoretical increase in infants' hepatic vitamin a is realized using a supplemented lactating sow model.

Vitamin A deficiency (VAD) is a public health problem affecting millions in developing nations. Supplementation for lactating women, whose needs are high, involves large oral doses of the preformed vitamin. The safety and efficacy of these doses has been inadequately studied. Lactating women typically receive 210 micro mol of retinyl ester during early lactation, but 420 micro mol has also been administered. If larger doses of vitamin A are not significantly more effective in preventing VAD in mothers and infants, then smaller doses would be recommended. We therefore examined the vitamin A concentration of milk from lactating sows (n = 15) that were provided two different doses of vitamin A (i.e., 1050 or 2100 micro mol, n = 6/group) or corn oil (n = 3), corresponding to doses given women on the basis of body weight. Compared with controls, an overall significant treatment effect was found (P = 0.0019), but there was no difference in milk concentration between treatment groups. Theoretically, applying the mean milk vitamin A concentrations of the groups through 12 h and values to 48 h from 4 sows, we estimate that an infant of a supplemented mother could realize an increase of +0.08 or 0.16 micro mol/g liver from the low or high dose, respectively.