Improved dietary guidelines for vitamin D: application of individual participant data (IPD)-level meta-regression analyses

Dietary Reference Values (DRVs) for vitamin D have a key role in the prevention of vitamin D deficiency. However, despite adopting similar risk assessment protocols, estimates from authoritative agencies over the last 6 years have been diverse. This may have arisen from diverse approaches to data analysis. Modelling strategies for pooling of individual subject data from cognate vitamin D randomized controlled trials (RCTs) are likely to provide the most appropriate DRV estimates. Thus, the objective of the present work was to undertake the first-ever individual participant data (IPD)-level meta-regression, which is increasingly recognized as best practice, from seven winter-based RCTs (with 882 participants ranging in age from 4 to 90 years) of the vitamin D intake–serum 25-hydroxyvitamin D (25(OH)D) dose-response. Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of 25(OH)D concentrations >25, 30, and 50 nmol/L across the population are 10, 13, and 26 µg/day, respectively. In contrast, standard meta-regression analyses with aggregate data (as used by several agencies in recent years) from the same RCTs estimated that a vitamin D intake requirement of 14 µg/day would maintain 97.5% of 25(OH)D >50 nmol/L. These first IPD-derived estimates offer improved dietary recommendations for vitamin D because the underpinning modeling captures the between-person variability in response of serum 25(OH)D to vitamin D intake

Disease activity flares and pain flares in an early rheumatoid arthritis inception cohort; characteristics, antecedents and sequelae

© 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: RA flares are common and disabling. They are described in terms of worsening inflammation but pain and inflammation are often discordant. To inform treatment decisions, we investigated whether inflammatory and pain flares are discrete entities. Methods: People from the Early RA Network (ERAN) cohort were assessed annually up to 11 years after presentation (n = 719, 3703 person-years of follow up). Flare events were defined in 2 different ways that were analysed in parallel; DAS28 or Pain Flares. DAS28 Flares satisfied OMERACT flare criteria of increases in DAS28 since the previous assessment (≥1.2 points if active RA or ≥ 0.6 points if inactive RA). A ≥ 4.8-point worsening of SF36-Bodily Pain score defined Pain Flares. The first documented episode of each of DAS28 and Pain Flare in each person was analysed. Subgroups within DAS28 and Pain Flares were determined using Latent Class Analysis. Clinical course was compared between flare subgroups. Results: DAS28 (45%) and Pain Flares (52%) were each common but usually discordant, with 60% of participants in DAS28 Flare not concurrently in Pain Flare, and 64% of those in Pain Flare not concurrently in DAS28 Flare. Three discrete DAS28 Flare subgroups were identified. One was characterised by increases in tender/swollen joint counts (14.4%), a second by increases in symptoms (13.1%), and a third displayed lower flare severity (72.5%). Two discrete Pain Flare subgroups were identified. One occurred following low disease activity and symptoms (88.6%), and the other occurred on the background of ongoing active disease and pain (11.4%). Despite the observed differences between DAS28 and Pain Flares, each was associated with increased disability which persisted beyond the flare episode. Conclusion: Flares are both common and heterogeneous in people with RA. Furthermore our findings indicate that for some patients there is a discordance between inflammation and pain in flare events. This discrete flare subgroups might reflect different underlying inflammation and pain mechanisms. Treatments addressing different mechanisms might be required to reduce persistent disability after DAS28 and Pain Flares.Peer reviewedFinal Published versio

A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations

The present study used a systematic review approach to identify relevant randomised control trials (RCT) with vitamin D and then apply meta-regression to explore the most appropriate model of the vitamin D intake–serum 25-hydroxyvitamin D (25(OH)D) relationship to underpin setting reference intake values. Methods included an updated structured search on Ovid MEDLINE; rigorous inclusion/exclusion criteria; data extraction; and meta-regression (using different model constructs). In particular, priority was given to data from winter-based RCT performed at latitudes >49•58°N (n 12). A combined weighted linear model meta-regression analyses of natural log (Ln) total vitamin D intake (i.e. diet and supplemental vitamin D) versus achieved serum 25(OH)D in winter (that used by the North American Dietary Reference Intake Committee) produced a curvilinear relationship (mean (95% lower CI) serum 25(OH)D (nmol/l) = 9•2 (8•5) Ln (total vitamin D)). Use of non-transformed total vitamin D intake data (maximum 1400 IU/d; 35µg/d) provided for a more linear relationship (mean serum 25(OH)D (nmol/l) = 0•044 × (total vitamin D) + 33•035). Although inputting an intake of 600 IU/d (i.e. the RDA) into the 95% lower CI curvilinear and linear models predicted a serum 25(OH)D of 54•4 and 55•2 nmol/l, respectively, the total vitamin D intake that would achieve 50 (and 40) nmol/l serum 25(OH)D was 359 (111) and 480 (260) IU/d, respectively. Inclusion of 95% range in the model to account for inter-individual variability increased the predicted intake of vitamin D needed to maintain serum 25(OH)D ≥50 nmol/l to 930 IU/d. The model used to describe the vitamin D intake–status relationship needs to be considered carefully when setting new reference intake values in Europe

Vitamin D in pregnancy: Where we are and where we should go

Vitamin D deficiency has been widely reported among pregnant women and infants around the world. Women with low sun exposure, high BMI, low vitamin D intakes and socioeconomic disadvantage with poor quality diets are at greatest risk of vitamin D deficiency, leading to very low serum concentrations of 25-hydroxyvitamin D (25(OH)D) in their offspring and an increased risk of nutritional rickets. Many observational studies, supported by compelling in vitro and in vivo data, have generated evidence suggesting that low vitamin D status in pregnancy may also contribute to the risk of adverse perinatal outcomes including hypertensive disorders (e.g., preeclampsia), fetal growth restriction, and preterm birth. However, the few large randomized controlled trials (RCTs) conducted to date have generated conflicting evidence for a role of vitamin D supplementation in improving perinatal outcomes. Vitamin D supplementation policies during pregnancy and implementation of policies vary within and between jurisdictions. Regulatory authorities have cited insufficient evidence to establish pregnancy-specific targets for serum 25(OH)D concentrations or prenatal vitamin D intake that effectively reduce the risks of adverse perinatal and infant outcomes. This paper arises from a Debate on Vitamin D Requirements during Pregnancy, held at the 22nd Vitamin D Workshop, 2019. From varied perspectives, our objectives were to evaluate the evidence for: vitamin D metabolism in pregnancy and the prevalence of gestational vitamin D deficiency worldwide; the translation of laboratory research findings to clinical studies on the role of vitamin D in perinatal health; the challenges of designing and conducting clinical trials to establish prenatal vitamin D requirements; and results to date of major large RCTs of prenatal vitamin D supplementation. Lastly, we explored potential next steps towards generating robust clinical data in this field to address both public health protection and patient care

Loop colostomies are safe in anorectal malformations

Aim of the study: Divided colostomy (DC) has been recommended in anorectal malformations (ARMs) with previously reported advantages of decreasing overflow into the distal limb and urinary tract infections (UTIs). Skin bridge loop colostomy (LC) is a technically easier alternative without an increase in these complications. We report our institutional experience of LC in ARM. Methods: Retrospective study (Institution-approved Clinical Audit) reviewing the clinical records of all patients with ARM undergoing stoma formation in a single UK tertiary pediatric surgical center (2000–2015). Data collected included type of ARM, associated anomalies, type and level of colostomy, time to stoma closure, complications and UTIs. Results: One hundred and eighty-two (95 female) patients underwent colostomy formation for ARM. The vast majority (171/ 94%) underwent LC; 9 (5%) had a divided colostomy (DC) and 2 (1%) had no available data. The spectrum of defects in girls included rectovestibular (62/65%), rectovaginal (4/4%) and cloaca (29/31%). In boys, 71 (82%) had a fistula to the urinary tract and 16 (18%) presented with a perineal fistula. Urological abnormalities coexisted in 87 (47.8%) patients. Thirty five (21%) patients developed UTIs. Among the 19 girls who developed UTI, 8 had rectovestibular fistula and 11 had cloaca. Of the 16 boys who developed UTI, 14 had a fistula to the urinary tract and 11 had an independent urological abnormality. The mean time from stoma formation to stoma closure was 10 (3–52) months. Complications were reported in 22 (12%) LCs. Fifteen patients (9%) developed a stoma prolapse following LC with 10 (6%) requiring surgical revision. Conclusions: This is the largest reported series of outcomes following LC for ARM. LC is easier to perform and to close, requiring minimal surgical access, with comparable complications and outcomes to those published for DC. Type of study: Retrospective comparative study. Level of evidence: III

Dietary vitamin D2 - a potentially underestimated contributor to vitamin D nutritional status of adults?

It has been suggested that vitamin D2 is not very prevalent in the human food chain. However, data from a number of recent intervention studies suggest that the majority of subjects had measurable serum 25-hydroxyvitamin D2 (25(OH)D2) concentrations. Serum 25(OH)D2, unlike 25(OH)D3, is not directly influenced by exposure of skin to sun and thus has dietary origins; however, quantifying dietary vitamin D2 is difficult due to the limitations of food composition data. Therefore, the present study aimed to characterise serum 25(OH)D2 concentrations in the participants of the National Adult Nutrition Survey (NANS) in Ireland, and to use these serum concentrations to estimate the intake of vitamin D2 using a mathematical modelling approach. Serum 25(OH)D2 concentration was measured by a liquid chromatography–tandem MS method, and information on diet as well as subject characteristics was obtained from the NANS. Of these participants, 78·7 % (n 884) had serum 25(OH)D2 concentrations above the limit of quantification, and the mean, maximum, 10th, 50th (median) and 90th percentile values of serum 25(OH)D2 concentrations were 3·69, 27·6, 1·71, 2·96 and 6·36 nmol/l, respectively. To approximate the intake of vitamin D2 from these serum 25(OH)D2 concentrations, we used recently published data on the relationship between vitamin D intake and the responses of serum 25(OH)D concentrations. The projected 5th to 95th percentile intakes of vitamin D2 for adults were in the range of 0·9–1·2 and 5–6 μg/d, respectively, and the median intake ranged from 1·7 to 2·3 μg/d. In conclusion, the present data demonstrate that 25(OH)D2 concentrations are present in the sera of adults from this nationally representative sample. Vitamin D2 may have an impact on nutritional adequacy at a population level and thus warrants further investigation

General practitioners’ perspectives on campaigns to promote rapid help-seeking behaviour at the onset of rheumatoid arthritis

Objective. To explore general practitioners’ (GPs’ ) perspectives on public health campaigns to encourage people with the early symptoms of rheumatoid arthritis (RA) to seek medical help rapidly. Design. Nineteen GPs participated in four semistructured focus groups. Focus groups were audio-recorded, transcribed verbatim, and analysed using thematic analysis. Results. GPs recognised the need for the early treatment of RA and identified that facilitating appropriate access to care was important. However, not all held the view that a delay in help seeking was a clinically significant issue. Furthermore, many were concerned that the early symptoms of RA were often non-specific, and that current knowledge about the nature of symptoms at disease onset was inadequate to inform the content of a help-seeking campaign. They argued that a campaign might not be able to specifically target those who need to present urgently. Poorly designed campaigns were suggested to have a negative impact on GPs’ workloads, and would “clog up” the referral pathway for genuine cases of RA. Conclusions. GPs were supportive of strategies to improve access to Rheumatological care and increase public awareness of RA symptoms. However, they have identified important issues that need to be considered in developing a public health campaign that forms part of an overall strategy to reduce time to treatment for patients with new onset RA. This study highlights the value of gaining GPs’ perspectives before launching health promotion campaigns

Convective scaling of the average dissipation rate of temperature variance in the atmospheric surface layer

The flux of sensible heat from the land surface is related to the average rate of dissipation of temperature fluctuations in the atmospheric surface layer through the temperature variance budget equation. In many cases it is desirable to estimate the heat flux from measurement or inference of the dissipation rate. Here we study how the dissipation rate scales with atmospheric stability, using three inertial range methods to calculate the dissipation rate: power spectra, second order structure functions, and third order structure functions. Experimental data are analyzed from a pair of field experiments, during which turbulent fluctuations of velocity and temperature were measured over a broad range of neutral and unstable atmospheric flows. It is shown that the temperature dissipation rate scales with a single convective power law continuously from near-neutral to strongly unstable stratification. The dissipation scaling is found to nearly match production in the near-neutral region, but to be consistently lower than production in the more convective regimes. The convective scaling is shown to offer a simplified means of computing sensible heat flux from the dissipation rate of temperature variance

meCLICK-Seq, a Substrate-Hijacking and RNA Degradation Strategy for the Study of RNA Methylation.

The fates of RNA species in a cell are controlled by ribonucleases, which degrade them by exploiting the universal structural 2'-OH group. This phenomenon plays a key role in numerous transformative technologies, for example, RNA interference and CRISPR/Cas13-based RNA editing systems. These approaches, however, are genetic or oligomer-based and so have inherent limitations. This has led to interest in the development of small molecules capable of degrading nucleic acids in a targeted manner. Here we describe click-degraders, small molecules that can be covalently attached to RNA species through click-chemistry and can degrade them, that are akin to ribonucleases. By using these molecules, we have developed the meCLICK-Seq (methylation CLICK-degradation Sequencing) a method to identify RNA modification substrates with high resolution at intronic and intergenic regions. The method hijacks RNA methyltransferase activity to introduce an alkyne, instead of a methyl, moiety on RNA. Subsequent copper(I)-catalyzed azide-alkyne cycloaddition reaction with the click-degrader leads to RNA cleavage and degradation exploiting a mechanism used by endogenous ribonucleases. Focusing on N6-methyladenosine (m6A), meCLICK-Seq identifies methylated transcripts, determines RNA methylase specificity, and reliably maps modification sites in intronic and intergenic regions. Importantly, we show that METTL16 deposits m6A to intronic polyadenylation (IPA) sites, which suggests a potential role for METTL16 in IPA and, in turn, splicing. Unlike other methods, the readout of meCLICK-Seq is depletion, not enrichment, of modified RNA species, which allows a comprehensive and dynamic study of RNA modifications throughout the transcriptome, including regions of low abundance. The click-degraders are highly modular and so may be exploited to study any RNA modification and design new technologies that rely on RNA degradation.UKRI (BBSRC DTP scholarships to S.M. and H.K.C) and the Jardine Foundation and Cambridge Trust (PhD scholarship to M.E.H.)