Lifetime risk and genetic predisposition to post-traumatic OA of the knee in the UK Biobank.

OBJECTIVE: Acute knee injury is associated with post-traumatic OA (PTOA). Very little is known about the genome-wide associations of PTOA when compared with idiopathic OA (iOA). Our objective was to describe the development of knee OA after a knee injury and its genetic associations in UK Biobank (UKB). DESIGN: Clinically significant structural knee injuries in those ≤50 years were identified from electronic health records and self-reported data in 502,409 UKB participants. Time-to-first knee osteoarthritis (OA) code was compared in injured cases and age-/sex-matched non-injured controls using Cox Proportional Hazards models. A time-to-OA genome-wide association study (GWAS) sought evidence for PTOA risk variants 6 months to 20 years following injury. Evidence for associations of two iOA polygenic risk scores (PRS) was sought. RESULTS: Of 4233 knee injury cases, 1896 (44.8%) were female (mean age at injury 34.1 years [SD 10.4]). Over a median of 30.2 (IQR 19.5-45.4) years, 1096 (25.9%) of injured cases developed knee OA. The overall hazards ratio (HR) for knee OA after injury was 1.81 (1.70,1.93), P = 8.9 × 10-74. Female sex and increasing age at injury were associated with knee OA following injury (HR 1.15 [1.02,1.30];1.07 [1,07,1.07] respectively). OA risk was highest in the first 5 years after injury (HR 3.26 [2.67,3.98]), persisting for 40 years. In 3074 knee injury cases included in the time-to-OA GWAS, no variants reached genome-wide significance. iOA PRS was not associated with time-to-OA (HR 0.43 [0.02,8.41]). CONCLUSIONS: Increasing age at injury and female sex appear to be associated with future development of PTOA in UKB, the risk of which was greatest in the 5 years after injury. Further international efforts towards a better-powered meta-analysis will definitively elucidate genetic similarities and differences of PTOA and iOA.

Pregnancy-Associated Plasma Protein-aa Regulates Photoreceptor Synaptic Development to Mediate Visually Guided Behavior.

To guide behavior, sensory systems detect the onset and offset of stimuli and process these distinct inputs via parallel pathways. In the retina, this strategy is implemented by splitting neural signals for light onset and offset via synapses connecting photoreceptors to ON and OFF bipolar cells, respectively. It remains poorly understood which molecular cues establish the architecture of this synaptic configuration to split light-onset and light-offset signals. A mutant with reduced synapses between photoreceptors and one bipolar cell type, but not the other, could reveal a critical cue. From this approach, we report a novel synaptic role for pregnancy-associated plasma protein aa (pappaa) in promoting the structure and function of cone synapses that transmit light-offset information. Electrophysiological and behavioral analyses indicated pappaa mutant zebrafish have dysfunctional cone-to-OFF bipolar cell synapses and impaired responses to light offset, but intact cone-to-ON bipolar cell synapses and light-onset responses. Ultrastructural analyses of pappaa mutant cones showed a lack of presynaptic domains at synapses with OFF bipolar cells. pappaa is expressed postsynaptically to the cones during retinal synaptogenesis and encodes a secreted metalloprotease known to stimulate insulin-like growth factor 1 (IGF1) signaling. Induction of dominant-negative IGF1 receptor expression during synaptogenesis reduced light-offset responses. Conversely, stimulating IGF1 signaling at this time improved pappaa mutants' light-offset responses and cone presynaptic structures. Together, our results indicate Pappaa-regulated IGF1 signaling as a novel pathway that establishes how cone synapses convey light-offset signals to guide behavior.SIGNIFICANCE STATEMENT Distinct sensory inputs, like stimulus onset and offset, are often split at distinct synapses into parallel circuits for processing. In the retina, photoreceptors and ON and OFF bipolar cells form discrete synapses to split neural signals coding light onset and offset, respectively. The molecular cues that establish this synaptic configuration to specifically convey light onset or offset remain unclear. Our work reveals a novel cue: pregnancy-associated plasma protein aa (pappaa), which regulates photoreceptor synaptic structure and function to specifically transmit light-offset information. Pappaa is a metalloprotease that stimulates local insulin-like growth factor 1 (IGF1) signaling. IGF1 promotes various aspects of synaptic development and function and is broadly expressed, thus requiring local regulators, like Pappaa, to govern its specificity.

Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI.

STUDY QUESTION: How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER: We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men. WHAT IS KNOWN ALREADY: Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known. STUDY DESIGN, SIZE, DURATION: The study included a population-based mixed cross-sectional and longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2). MAIN RESULTS AND THE ROLE OF CHANCE: Voice break occurred at mean age 13.6 (95% CI: 13.5-13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0-11.7) nmol/L, 2.4 (2.2-2.5) IU/L and 24 (23-25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43-0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (-0.35 years/approximate SD, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations. WIDER IMPLICATIONS OF THE FINDINGS: We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. TRIAL REGISTRATION NUMBER: NCT01411527.

Evolution of reduced post-copulatory molecular interactions in Drosophila populations lacking sperm competition.

In many species with internal fertilization, molecules transferred in the male ejaculate trigger and interact with physiological changes in females. It is controversial to what extent these interactions between the sexes act synergistically to mediate the female switch to a reproductive state or instead reflect sexual antagonism evolved as a by product of sexual selection on males. To address this question, we eliminated sexual selection by enforcing monogamy in populations of Drosophila melanogaster for 65 generations and then measured the expression of male seminal fluid protein genes and genes involved in the female response to mating. In the absence of sperm competition, male and female reproductive interests are perfectly aligned and any antagonism should be reduced by natural selection. Consistent with this idea, males from monogamous populations showed reduced expression of seminal fluid protein genes, 16% less on average than in polygamous males. Further, we identified 428 genes that responded to mating in females. After mating, females with an evolutionary history of monogamy exhibited lower relative expression of genes that were up regulated in response to mating and higher expression of genes that were down-regulated--in other words, their post-mating transcriptome appeared more virgin-like. Surprisingly, these genes showed a similar pattern even before mating, suggesting that monogamous females evolved to be less poised for mating and the accompanying receipt of male seminal fluid proteins. This reduced investment by both monogamous males and females in molecules involved in post-copulatory interactions points to a pervasive role of sexual conflict in shaping these interactions.

Populations with elevated mutation load do not benefit from the operation of sexual selection.

Theory predicts that if most mutations are deleterious to both overall fitness and condition-dependent traits affecting mating success, sexual selection will purge mutation load and increase nonsexual fitness. We explored this possibility with populations of mutagenized Drosophila melanogaster exhibiting elevated levels of deleterious variation and evolving in the presence or absence of male-male competition and female choice. After 60 generations of experimental evolution, monogamous populations exhibited higher total reproductive output than polygamous populations. Parental environment also affected fitness measures - flies that evolved in the presence of sexual conflict showed reduced nonsexual fitness when their parents experienced a polygamous environment, indicating trans-generational effects of male harassment and highlighting the importance of a common garden design. This cost of parental promiscuity was nearly absent in monogamous lines, providing evidence for the evolution of reduced sexual antagonism. There was no overall difference in egg-to-adult viability between selection regimes. If mutation load was reduced by the action of sexual selection in this experiment, the resultant gain in fitness was not sufficient to overcome the costs of sexual antagonism.

Serum hsCRP and visfatin are elevated and correlate to carotid arterial stiffness in spinal cord-injured subjects.

STUDY DESIGN: Cross-sectional comparison, control group. OBJECTIVES: To investigate the relationship between carotid arterial stiffness and circulating markers for cardiovascular disease (CVD) in spinal cord-injured (SCI) subjects compared with able-bodied (AB) individuals. SETTING: University Research Laboratory, University of Louisville. METHODS: SCI (n=14) and AB (n=13) subjects between 20-52 years of age were recruited to participate in the study. B-mode Doppler ultrasound was used to obtain carotid artery diameter measurements. Arterial stiffness was assessed via the stiffness index and distensibility coefficient. Markers of CVD risk were obtained by fasting blood draw. RESULTS: Carotid arterial stiffness index (P=0.061) and distensibility coefficient (P=0.370) were not different between the SCI and AB groups. The SCI group had higher high-sensitivity C-reactive protein (hsCRP) (P=0.046), triglycerides (P=0.017), leptin (P=0.040) and visfatin (P<0.001) compared with the control group. Visfatin (r=0.559, P=0.047), hsCRP (r=0.633, P=0.037), insulin (r=0.637, P=0.019) and HOMA (r=0.614, P=0.026) significantly correlated with carotid arterial stiffness index in the SCI group. CONCLUSION: This study demonstrated that SCI subjects are at a high cardiovascular risk as indicated by elevated hsCRP levels. Elevations in hsCRP and visfatin may contribute to accelerated atherogenic processes in the SCI population.

Vitamin D deficiency in the spontaneously hypertensive heart failure [SHHF] prone rat.

BACKGROUND AND AIMS: Vitamin D deficiency has been associated with the etiology and pathogenesis of heart disease including congestive heart failure. We previously observed cardiac hypertrophy in vitamin D deficient rats and vitamin D receptor knockout mice. These studies indicate that the absence of vitamin D-mediated signal transduction and genomic activation results in increased sensitivity of the heart to ionotropic stimuli and cardiomyocyte hypertrophy. This study's aim is to investigate the relationship between vitamin D status and the heart failure phenotype in the rat. METHODS AND RESULTS: Vitamin D status was assessed by measuring 25-hydroxyvitamin D levels and related to heart weight in young, middle-aged and aging spontaneously hypertensive, heart failure (SHHF) prone rats. We also measured the effects of the vitamin D hormone,1,25(OH)(2)D(3), on cardiac function in SHHF rats. Cardiac hypertrophy in this model of the failing heart increased with age and related to decreasing vitamin D status. Vitamin D deficiency presented after cardiac hypertrophy was first observed. Additionally, we found that 1,25(OH)(2)D(3) treatment between 4.0 and 7.0 months of age prevented cardiac hypertrophy and permits decreased workload for the heart while allowing adequate blood perfusion and pressure, resulting in reduced cardiac index. CONCLUSIONS: Our findings suggest that low vitamin D status is associated with the progression and final terminal phase of the heart failure phenotype and not with initial heart hypertrophy. Also, we report that in the vitamin D sufficient SHHF rat, 1,25(OH)(2)D(3) treatment provided protection against the progression of the heart failure phenotype.

Prospective study of predictors of vitamin D status and survival in patients with colorectal cancer.

BACKGROUND: In an earlier study, a 25-hydroxyvitamin D(3) (25(OH)D) score calculated from known predictors of vitamin D status significantly predicted plasma levels of 25(OH)D and the risk of colorectal cancer, but the influence of the 25(OH)D score on survival after diagnosis is unknown. MATERIALS AND METHODS: We prospectively examined the influence of post-diagnosis predicted 25(OH)D levels on mortality among 1017 participants in the Nurses' Health Study and Health Professionals Follow-Up Study who were diagnosed with colorectal cancer from 1986 to 2004. Colorectal cancer-specific and overall mortality according to quintiles of predicted 25(OH)D levels were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) adjusted for other risk factors of survival. RESULTS: Higher predicted 25(OH)D levels were associated with a significant reduction in colorectal cancer-specific (P trend=0.02) and overall mortality (P trend=0.002). Compared with levels in the lowest quintile, participants with predicted 25(OH)D levels in the highest quintile had an adjusted HR of 0.50 (95% CI, 0.26-0.95) for cancer-specific mortality and 0.62 (95% CI, 0.42-0.93) for overall mortality. CONCLUSION: Higher predicted 25(OH)D levels after a diagnosis of colorectal cancer may be associated with improved survival. Further study of the vitamin D pathway in colorectal cancer is warranted.

Patient experience with family history tool: analysis of patients' experience sharing their family health history through patient-computer dialogue in a patient portal.

OBJECTIVE: The collection and use of a family health history are important for assessing the patient's risk of disease, but history taking is often impeded by practical barriers in the office. Provision for patient-computer dialogue, linked with the electronic health record, may enable patients to contribute their history while bypassing these barriers. We sought to assess the patient experience using such a tool. MATERIALS AND METHODS: We linked the family history module of a computer-based medical history to the patient portal of a large academic health system. The interview consisted of 39 primary questions with a predetermined high test-retest reliability. Patients' results were structured and summarized, and available within their electronic health record. Patients optionally completed a survey about their experience. We inductively analyzed free-text responses collected between 2014 and 2016. RESULTS: Among 97 781 patient portal users, 9562 patients accessed and 4223 patients completed the family medical history interview. Of these patients, 1451 completed our survey. Main themes that were identified included (1) patient empowerment, (2) anticipated value, (3) validity concerns, (4) privacy concerns, and (5) reflections on patient-computer dialogue. Patients also provided suggestions for the improvement of future family history tools. DISCUSSION: Patients providing their family health information is an example of collaborative electronic work with clinicians and was seen as valuable by those who participated. Concerns related to contextual information and uncertainty need to be addressed. CONCLUSIONS: Patient-computer dialogue to collect family medical history empowered patients and added perceived value and efficiency to the patient experience of care.

Adult zebrafish primarily use vision to guide piscivorous foraging behavior.

The sensory modalities used by predatory fish to detect and capture prey are a key dimension of their foraging strategy. Determining the sensory cues that guide predation can also further conservation efforts under environmental change, and address the welfare of research animals. Here, we experimentally manipulated the sensory modalities used by adult zebrafish (Danio rerio) when foraging for larval conspecifics in captivity. We used minimally invasive techniques to test the consequences of eliminating visual, olfactory, and mechanosensory cues for predator behavior and success. Our results indicate that zebrafish require visual cues, but not olfactory or mechanosensory input. Reducing the visual contrast between prey and their surroundings decreased capture rates, suggesting that contrast underlies visual foraging. Video recordings of zebrafish during foraging indicate that they actively hunt larval fish, rather than employing a sit-and-wait approach. Together, our findings indicate adult zebrafish rely on visual cues to guide an active predation strategy.

Low vitamin D status despite abundant sun exposure.

CONTEXT: Lack of sun exposure is widely accepted as the primary cause of epidemic low vitamin D status worldwide. However, some individuals with seemingly adequate UV exposure have been reported to have low serum 25-hydroxyvitamin D [25(OH)D] concentration, results that might have been confounded by imprecision of the assays used. OBJECTIVE: The aim was to document the 25(OH)D status of healthy individuals with habitually high sun exposure. SETTING: This study was conducted in a convenience sample of adults in Honolulu, Hawaii (latitude 21 degrees ). PARTICIPANTS: The study population consisted of 93 adults (30 women and 63 men) with a mean (sem) age and body mass index of 24.0 yr (0.7) and 23.6 kg/m(2) (0.4), respectively. Their self-reported sun exposure was 28.9 (1.5) h/wk, yielding a calculated sun exposure index of 11.1 (0.7). MAIN OUTCOME MEASURES: Serum 25(OH)D concentration was measured using a precise HPLC assay. Low vitamin D status was defined as a circulating 25(OH)D concentration less than 30 ng/ml. RESULTS: Mean serum 25(OH)D concentration was 31.6 ng/ml. Using a cutpoint of 30 ng/ml, 51% of this population had low vitamin D status. The highest 25(OH)D concentration was 62 ng/ml. CONCLUSIONS: These data suggest that variable responsiveness to UVB radiation is evident among individuals, causing some to have low vitamin D status despite abundant sun exposure. In addition, because the maximal 25(OH)D concentration produced by natural UV exposure appears to be approximately 60 ng/ml, it seems prudent to use this value as an upper limit when prescribing vitamin D supplementation.

Demonstration of a lack of change in serum 1 alpha,25-dihydroxyvitamin D in response to parathyroid extract in pseudohypoparathyroidism.

Studies were carried out to compare the effects of parathyroid extract (PTE) on serum and urinary calcium (Ca) and phosphorus (P), serum 25-hydroxyvitamin D (25-OHD), serum 24,25-dihydroxyvitamin D (24,25(OH)2D), serum 1 alpha,25-dihydroxyvitamin D (1 alpha,25(OH)2D), and urinary cyclic AMP in two normal subjects, two patients with hypoparathyroidism (HP) and six patients with pseudohypoparathyroidism (PHP), some of whom were on suboptimal treatment with vitamin D. Two of the patients with PHP were studied while on long-term treatment with 1 alpha,25-(OH)2D3. Before PTE, serum 1 alpha, 25(OH)2D was at the lower limit of normal in one patient and was abnormally low in the other five patients. None of these individuals was on treatment with 1 alpha,25(OH)2D3. Serum 25-OHD and 24,25(OH)2D were either increased or at the upper limit of normal in the patients given vitamin D and were normal in the other patients. PTE lowered the serum P and increased the serum 1 alpha,25(OH)2D, serum and urinary Ca, urinary P, and urinary cyclic AMP in the normal subjects and patients with HP. In individual studies, changes in serum 1 alpha,25(OH)2D and serum Ca occurred in parallel before, during, and after PTE. In contrast, PTE had very little effect in the patients with PHP. Whereas there were highly significant positive correlations between serum 1 alpha,25(OH)2D in each of the normal subjects and patients with HP, there were significant correlations in only one of the patients with PHP. An increase in serum Ca in response to PTE was observed in one of the two patients with PHP who were on long-term treatment with 1 alpha,25(OH)2D3. In these individuals, PTE produced only slight increases in serum 1 alpha,25(OH)2D. Serum 25-OHD and 24,25(OH)2D were not changed by PTE in any of the subjects or patients. The results provide evidence that hypocalcemia in HP and PHP arises in part from low circulating 1 alpha,25-(OH)2D, and indicate that the lack of change in serum 1 alpha,25(OH)2D with PTE in patients with PHP is related to impaired renal adenylate cyclase and phosphaturic responses. These and previous results support the idea that diminished renal production of 1 alpha,25(OH)2D, because of a defect in the parathyroid hormone-responsive adenylate cyclase system, may be a contributing factor in the pathogenesis of the abnormal calcium metabolism in PHP.

Human plasma transport of vitamin D after its endogenous synthesis.

Transport of vitamin D3 from its sites of cutaneous synthesis into the circulation has been assumed to be via the plasma vitamin D binding protein (DBP). We studied vitamin D transport from the skin in seven healthy volunteers who received whole body irradiation with 27 mJ/cm2 dosage of ultraviolet B light (290-320 nm). Samples of venous blood were collected serially in EDTA and immediately chilled. In KBr, plasma samples were ultracentrifuged to provide a rapid separation of proteins of density < and > 1.3 g/ml. Upper and lower phases and serial fractions were analyzed for vitamin D3 (extraction, HPLC), cholesterol (enzyme assay), and human DBP (hDBP) (radial immunodiffusion). Total plasma vitamin D (basal level < 1 ng/ml) increased by 10 h and peaked at 24 h (9 +/- 1 ng/ml). 98% of the D3 remained at the density > 1.3 layers for up to 7 d, whereas cholesterol (> 85%) was detected at density < 1.3 and all of the hDBP was at density > 1.3. In three volunteers who each ingested 1.25 mg of vitamin D2, the total plasma D2 increased to 90 +/- 32 ng/ml by 4 h, and the D2 was evenly distributed between the upper and lower layers at 4, 8, and 24 h after the dose, indicating a continuing association of the vitamin with chylomicrons and lipoproteins, as well as with hDBP. Actin affinity chromatography removed D3 from plasma of irradiated subjects, indicating the association of the D3 with DBP. These findings indicate that endogenously synthesized vitamin D3 travels in plasma almost exclusively on DBP, providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol observed after depot, parenteral administration of vitamin D. In contrast, the association of orally administered vitamin D with chylomicrons and lipoproteins allows for receptor-mediated, rapid hepatic delivery of vitamin D, and the reported rapid but less-sustained increases in plasma 25-hydroxycholecalciferol.

Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein.

A line of mice deficient in vitamin D binding protein (DBP) was generated by targeted mutagenesis to establish a model for analysis of DBP's biological functions in vitamin D metabolism and action. On vitamin D-replete diets, DBP-/- mice had low levels of total serum vitamin D metabolites but were otherwise normal. When maintained on vitamin D-deficient diets for a brief period, the DBP-/-, but not DBP+/+, mice developed secondary hyperparathyroidism and the accompanying bone changes associated with vitamin D deficiency. DBP markedly prolonged the serum half-life of 25(OH)D and less dramatically prolonged the half-life of vitamin D by slowing its hepatic uptake and increasing the efficiency of its conversion to 25(OH)D in the liver. After an overload of vitamin D, DBP-/- mice were unexpectedly less susceptible to hypercalcemia and its toxic effects. Peak steady-state mRNA levels of the vitamin D-dependent calbindin-D9K gene were induced by 1,25(OH)2D more rapidly in the DBP-/- mice. Thus, the role of DBP is to maintain stable serum stores of vitamin D metabolites and modulate the rates of its bioavailability, activation, and end-organ responsiveness. These properties may have evolved to stabilize and maintain serum levels of vitamin D in environments with variable vitamin D availability.

Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency.

OBJECTIVE: With vitamin D deficiency as a serious public health problem, vitamin D status at birth was measured in neonates at latitude 32 degrees 72' (southeastern United States). STUDY DESIGN: In umbilical cord blood, vitamin D status, demonstrated by circulating 25-hydroxyvitamin D, was measured and related to race and season of birth. RESULT: The mean+/-standard deviation of 25-hydroxyvitamin D in 100 cord blood samples was 13.5+/-8.3 ng/ml for the cohort. African-American infants, with a mean+/-standard deviation of 10.5+/-6.0 ng/ml, demonstrated significantly lower vitamin D status than Caucasian infants, with a mean+/-standard deviation of 19.5+/-9.6 ng/ml (P<0.0001). By season, the mean 25-hydroxyvitamin D level at birth in November-March compared to April-October was 11.3 ng/ml lower in Caucasian infants (from 29.0 to 17.7 ng/ml) and 3 ng/ml lower in African-American infants (from 13.1 to 10.1 ng/ml). CONCLUSION: The prevalence of vitamin D insufficiency is high in this cohort. African-American infants demonstrate significantly lower vitamin D status at birth than Caucasian infants. Seasonality, while significant in both groups, had a greater impact on the vitamin D status of Caucasian newborns.

Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancy cohorts compared with South Carolina March of Dimes 2009-2011 rates.

BACKGROUND: Two vitamin D pregnancy supplementation trials were recently undertaken in South Carolina: The NICHD (n=346) and Thrasher Research Fund (TRF, n=163) studies. The findings suggest increased dosages of supplemental vitamin D were associated with improved health outcomes of both mother and newborn, including risk of preterm birth (<37 weeks gestation). How that risk was associated with 25(OH)D serum concentration, a better indicator of vitamin D status than dosage, by race/ethnic group and the potential impact in the community was not previously explored. While a recent IOM report suggested a concentration of 20 ng/mL should be targeted, more recent work suggests optimal conversion of 25(OH)D-1,25(OH)2D takes place at 40 ng/mL in pregnant women. OBJECTIVE: Post-hoc analysis of the relationship between 25(OH)D concentration and preterm birth rates in the NICHD and TRF studies with comparison to Charleston County, South Carolina March of Dimes (CC-MOD) published rates of preterm birth to assess potential risk reduction in the community. METHODS: Using the combined cohort datasets (n=509), preterm birth rates both for the overall population and for the subpopulations achieving 25(OH)D concentrations of ≤20 ng/mL, >20 to <40 ng/mL, and ≥40 ng/mL were calculated; subpopulations broken down by race/ethnicity were also examined. Log-binomial regression was used to test if an association between 25(OH)D serum concentration and preterm birth was present when adjusted for covariates; locally weighted regression (LOESS) was used to explore the relationship between 25(OH)D concentration and gestational age (weeks) at delivery in more detail. These rates were compared with 2009-2011 CC-MOD data to assess potential risk reductions in preterm birth. RESULTS: Women with serum 25(OH)D concentrations ≥40 ng/mL (n=233) had a 57% lower risk of preterm birth compared to those with concentrations ≤20 ng/mL [n=82; RR=0.43, 95% confidence interval (CI)=0.22,0.83]; this lower risk was essentially unchanged after adjusting for covariates (RR=0.41, 95% CI=0.20,0.86). The fitted LOESS curve shows gestation week at birth initially rising steadily with increasing 25(OH)D and then plateauing at ∼40 ng/mL. Broken down by race/ethnicity, there was a 79% lower risk of preterm birth among Hispanic women with 25(OH)D concentrations ≥40 ng/mL (n=92) compared to those with 25(OH)D concentrations ≤20 ng/mL (n=29; RR=0.21, 95% CI=0.06,0.69) and a 45% lower risk among Black women (n=52 and n=50; RR=0.55, 95% CI=0.17,1.76). There were too few white women with low 25(OH)D concentrations for assessment (n=3). Differences by race/ethnicity were not statistically significant with 25(OH)D included as a covariate. Compared to the CC-MOD reference group, women with serum concentrations ≥40 ng/mL in the combined cohort had a 46% lower rate of preterm birth overall (n=233, p=0.004) with a 66% lower rate among Hispanic women (n=92, p=0.01) and a 58% lower rate among black women (n=52, p=0.04). CONCLUSIONS: In this post-hoc analysis, achieving a 25(OH)D serum concentration ≥40 ng/mL significantly decreased the risk of preterm birth compared to ≤20 ng/mL. These findings suggest the importance of raising 25(OH)D levels substantially above 20 ng/mL; reaching 40 ng/mL during pregnancy would reduce the risk of preterm birth and achieve the maximal production of the active hormone.

Hypovitaminosis D in pregnancy in the Mediterranean region: a systematic review.

Despite high levels of sunshine, maternal hypovitaminosis D during pregnancy is prevalent in the Mediterranean region. The aim of this study is to systematically review trials that investigated vitamin D concentrations during pregnancy in this region, in order to determine predictors of hypovitaminosis D and explain this phenomenon. After applying inclusion/exclusion criteria, 15 studies were entered into the systematic review involving 2649 pregnant women and 820 neonates. The main outcome was maternal vitamin D status, assessed by serum 25-hydroxy-vitamin D (25(OH)D) concentrations. Possible predictors of the outcome included maternal age, body mass index (BMI), race, socioeconomic status, skin type, gestational age, sun exposure, calcium and vitamin D intake and supplementation, smoking status, parity and season of delivery. Studies differed widely in vitamin D deficiency criteria, method of measurement and outcomes. The prevalence of vitamin D insufficiency ranges from 9.3 to 41.4%, whereas that of vitamin D deficiency from 22.7 to 90.3%. A positive association with 25(OH)D concentrations exists for light skin color, white race, uncovered dressing pattern, maternal vitamin D supplementation and season of gestation (spring/summer). An inverse association exists for BMI and gestational age, whereas data for smoking and socioeconomic status are controversial. We concluded that vitamin D deficiency in pregnancy seems to be quite common, even in the Mediterranean region. Racial, social and cultural habits, as well as the absence of preventive supplementation/dietary strategies, seem to negate the benefits of sun exposure.

Improving health care proxy documentation using a web-based interview through a patient portal.

OBJECTIVE: Health care proxy (HCP) documentation is suboptimal. To improve rates of proxy selection and documentation, we sought to develop and evaluate a web-based interview to guide patients in their selection, and to capture their choices in their electronic health record (EHR). METHODS: We developed and implemented a HCP interview within the patient portal of a large academic health system. We analyzed the experience, together with demographic and clinical factors, of the first 200 patients who used the portal to complete the interview. We invited users to comment about their experience and analyzed their comments using established qualitative methods. RESULTS: From January 20, 2015 to March 13, 2015, 139 of the 200 patients who completed the interview submitted their HCP information for their clinician to review in the EHR. These patients had a median age of 57 years (Inter Quartile Range (IQR) 45-67) and most were healthy. The 99 patients who did not previously have HCP information in their EHR were more likely to complete and then submit their information than the 101 patients who previously had a proxy in their health record (odds ratio 2.4, P = .005). Qualitative analysis identified several ways in which the portal-based interview reminded, encouraged, and facilitated patients to complete their HCP. CONCLUSIONS: Patients found our online interview convenient and helpful in facilitating selection and documentation of an HCP. Our study demonstrates that a web-based interview to collect and share a patient's HCP information is both feasible and useful.

Mapping the domains of the interaction of the vitamin D receptor and steroid receptor coactivator-1.

The vitamin D receptor (VDR) binds to the vitamin D response element (VDRE) and mediates the effects of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], on gene expression. The VDR binds to the VDRE as a heterodimeric complex with retinoid X receptor. In the present study, we have used a yeast two-hybrid system to clone complementary DNA that codes for VDR-interacting protein(s). We found that the human steroid receptor coactivator-1 (SRC-1) interacts with the VDR in a ligand-dependent manner, as demonstrated by beta-galactosidase production. The interaction of the VDR and the SRC-1 takes place at physiological concentrations of 1,25(OH)2D3. A 48.2-fold stimulation of beta-galactosidase activity was observed in the presence of 10(-10) M 1,25-(OH)2D3. In addition, a direct interaction between the ligand-activated glutathione-S-transferase-VDR and 35S-labeled SRC-1 was observed in vitro. Deletion-mutation analysis of the VDR established that the ligand-dependent activation domain (AF-2) of the VDR is required for the interaction with SRC-1. One deletion mutant, pGVDR-(1-418), bound the ligand but failed to interact with the SRC-1, whereas another deletion mutant, pGVDR-(1-423), bound the ligand and interacted with the SRC-1. We demonstrated that all the deletion mutants were expressed as analyzed by a Gal4 DNA-binding domain antibody. Deletion mutation analysis of the SRC-1 demonstrated that 27 amino acids (DPCNTNPTPMTKATPEEIKLEAQSQFT) of the SRC-1 are essential for interaction with the AF-2 motif of the VDR.

Bioavailability of vitamin D from fortified process cheese and effects on vitamin D status in the elderly.

We conducted 2 studies to determine the effect of vitamin D-fortified cheese on vitamin D status and the bioavailability of vitamin D in cheese. The first study was designed to determine the effect of 2 mo of daily consumption of vitamin D3-fortified (600 IU/d) process cheese on serum 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), and osteocalcin (OC) concentrations among 100 older (> or =60 yr) men and women. Participants were randomized to receive vitamin D-fortified cheese, nonfortified cheese, or no cheese. Serum levels of 25-OHD, PTH, and OC were measured at the beginning and end of the study. There were no differences in 25-OHD, PTH, or OC after 2 mo of fortified cheese intake. The vitamin D-fortified cheese group had a greater decrease in 25-OHD than other groups, due to higher baseline 25-OHD. A second study was conducted to determine whether the bioavailability of vitamin D2 in cheese (delivering 5880 IU of vitamin D2/56.7-g serving) and water (delivering 32,750 IU/250 mL) is similar and whether absorption differs between younger and older adults. The second study was a crossover trial involving 2 groups of 4 participants each (younger and older group) that received single acute feedings of either vitamin D2-fortified cheese or water. Serial blood measurements were taken over 24 h following the acute feeding. Peak serum vitamin D and area under the curve were similar between younger (23 to 50 yr) and older (72 to 84 yr) adults, and vitamin D2 was absorbed more efficiently from cheese than from water. These studies demonstrated that vitamin D in fortified process cheese is bioavailable, and that young and older adults have similar absorption. Among older individuals, consuming 600 IU of vitamin D3 daily from cheese for 2 mo was insufficient to increase serum 25-OHD during limited sunlight exposure.