Development of an International, Multicenter, Hyperbaric Oxygen Treatment Registry and Research Consortium: Protocol for Outcome Data Collection and Analysis.

BACKGROUND: Hyperbaric oxygen (HBO2)-oxygen at pressures higher than atmospheric-is approved for 14 indications by the Undersea and Hyperbaric Medical Society. HBO2's main effect is to increase oxygen content in plasma and body tissues, which can counteract hypoxia or ischemia. Laboratory studies show that HBO2 has effects beyond relieving hypoxia (eg, promoting angiogenesis in irradiated tissue, anti-inflammatory effects, radiosensitization of tumors, hypoxia preconditioning, and fungal growth inhibition) and has potential to treat conditions such as inflammatory bowel disease and pyoderma gangrenosum. Lack of consistently collected outcome data on a large cohort of individuals receiving HBO2 therapy limits its use for both established and new indications. A course of therapy often involves 30-40 visits to a hyperbaric chamber, so the number of patients seen at any given center is constrained by chamber capacity. As a result, published HBO2 outcome data tend to be from small case series because few patients with a particular condition are treated at a given center. To solve this problem, a registry that collects and pools data systematically from multiple institutions has been established. OBJECTIVE: The aim of this study is to collect consistent outcome data across multiple hyperbaric centers to assess treatment effectiveness and establish a research consortium. METHODS: A consortium of hyperbaric centers who have agreed to collect consistent outcome data on all patients seen has been assembled. Data are collected at each participating center using Research Electronic Data Capture (REDCap), a web-based, data collection system used frequently for research. Standard outcome measures have been defined for each condition, which are programmed into the REDCap data collection templates. Governance is through a consortium agreement that defines data security, data sharing, publications, liability, and other issues. Centers obtain Institutional Review Board (IRB) and ethics approval to participate, either from their own institutions or by relying on the IRB at the coordinating center at Dartmouth College. Dissemination will occur through a yearly report and by publications based on the data in the registry. RESULTS: Early results from some common indications show significant pretreatment to posttreatment changes. Additional indications and outcome measures are being added using the procedures outlined in the consortium agreement. CONCLUSIONS: The registry collects consistent outcome information for a therapy that needs further study and a stronger evidence base. It also overcomes the challenge of collecting data from an adequate number of patients for both established and emerging indications by combining data collection from multiple centers. The data entry requirements should be within the capabilities of existing staff at any given hyperbaric center. By using REDCap, the registry can be expanded to include detailed information on particular indications and long-term follow-up on selected patients without significantly increasing the basic data entry requirements. Through the registry, a network of enrolled hyperbaric centers has been established that provides the basis for a clinical trial network. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18857.

Unmetabolized Folic Acid, Tetrahydrofolate, and Colorectal Adenoma Risk.

In a randomized trial of folic acid supplementation for the prevention of colorectal adenomas, we previously found indications of increased risk during later treatment and follow-up. This could have been due to the unmetabolized folic acid (UFA) or natural reduced and methylated folates (mF) to which it is metabolized. In post hoc analyses, we measured mF (the sum of 5-methyl-tetrahydrofolate and 4-alfa-hydroxy-5-methyl-THF) and UFA concentrations in the serum of 924 participants. Using binomial regression models with a log link, we assessed the associations between plasma mF or UFA and adenoma occurrence. We found no association between plasma mF or UFA and overall adenoma risk. However, during later follow-up, the prespecified, composite endpoint of high-risk findings (advanced or multiple adenomas) was positively associated with plasma mF (Plinear trend = 0.009), with a 58% increased risk for participants in the upper versus lowest quartile. An irregular association was seen with plasma UFA, with suggestions of an inverse trend (Plinear trend=0.049). A modest, significant inverse association was also seen between mF and risk of serrated lesions, with a 39% lower risk for upper versus lower quartile participants (Plinear trend = 0.03). In conclusion, during the later follow-up period in which folic acid supplementation was previously seen to increase the risk of advanced and multiple adenomas, higher serum mF was associated with a higher risk of multiple and/or advanced adenomas, but no clear indication that UFA played a direct role. There were indications that higher mF was associated with reduced risk of serrated polyps. Cancer Prev Res; 10(8); 451-8. ©2017 AACR.

Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial.

IMPORTANCE: Despite epidemiological and preclinical evidence suggesting that vitamin D and calcium inhibit colorectal carcinogenesis, daily supplementation with these nutrients for 3 to 5 years was not found to significantly reduce the risk of recurrent colorectal adenomas in a recent randomized clinical trial. OBJECTIVE: To investigate whether common variants in 7 vitamin D and calcium pathway genes (VDR, GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, and CASR) modify the effects of vitamin D3 or calcium supplementation on colorectal adenoma recurrence. DESIGN, SETTING, AND PARTICIPANTS: We examined 41 candidate single-nucleotide polymorphisms (SNPs) in 2259 participants in a randomized, double-blind, placebo-controlled trial conducted at 11 clinical centers in the United States. Eligibility criteria included a recently diagnosed adenoma and no remaining colorectal polyps after complete colonoscopy. The study's treatment phase ended on August 31, 2013, and the analysis for the present study took place from July 28, 2014, to October 19, 2016. INTERVENTIONS: Daily oral supplementation with vitamin D3 (1000 IU) or calcium carbonate (1200 mg elemental calcium) or both or neither. MAIN OUTCOMES AND MEASURES: The outcomes assessed were the occurrence of 1 or more adenomas or advanced adenomas (estimated diameter, ≥1 cm; or with villous histologic findings, high-grade dysplasia, or cancer) during follow-up. Treatment effects and genotype associations and interactions were estimated as adjusted risk ratios (RRs) and 95% confidence intervals (CIs). The effective number of independent SNPs was calculated to correct for multiple testing. RESULTS: Among the 2259 participants randomized, 1702 were non-Hispanic whites who completed the trial and had genotype data for analysis (1101 men; mean [SD] age 58.1 [6.8] years). The effect of vitamin D3 supplementation on advanced adenomas, but not on adenoma risk overall, significantly varied according to genotype at 2 VDR SNPs (rs7968585 and rs731236) in linkage disequilibrium (D' = 0.98; r2 = 0.6). For rs7968585, among individuals with the AA genotype (26%), vitamin D3 supplementation reduced risk by 64% (RR, 0.36; 95% CI, 0.19-0.69; P = .002; absolute risk decreased from 14.4% to 5.1%). Among individuals with 1 or 2 G alleles (74%), vitamin D3 supplementation increased risk by 41% (RR, 1.41; 95% CI, 0.99-2.00; P = .05; absolute risk increased from 7.7% to 11.1%; P < .001 for interaction). There were no significant interactions of genotypes with calcium supplementation. CONCLUSIONS AND RELEVANCE: Our findings suggest that benefits from vitamin D3 supplementation for the prevention of advanced colorectal adenomas may vary according to vitamin D receptor genotype. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00153816.

Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms.

BACKGROUND: Repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy. OBJECTIVE: We sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis. METHODS: We randomly assigned 93 adults with grass pollen-induced allergic rhinitis to receive 7 preseasonal intradermal allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season (area under the curve). Analysis was by intention to treat. Skin biopsy specimens were collected after intradermal allergen challenges, and late-phase responses were measured 4 and 7, 10, or 13 months after treatment. RESULTS: There was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, -172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, -11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense-specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the TH2 surface marker CRTH2 (P = .04) and lower expression of the TH1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03). CONCLUSION: Intradermal allergen immunotherapy suppressed skin late-phase responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms.

Lifestyle and Other Factors Explain One-Half of the Variability in the Serum 25-Hydroxyvitamin D Response to Cholecalciferol Supplementation in Healthy Adults.

BACKGROUND: Many factors have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentrations in observational studies, with variable consistency. However, less information is available on factors affecting the magnitude of changes in serum 25(OH)D resulting from vitamin D supplementation. OBJECTIVE: This study aimed to identify factors associated with the serum 25(OH)D response to supplementation with 1000 IU cholecalciferol/d during the first year of a large, multicenter, randomized, placebo-controlled colorectal adenoma chemoprevention trial. METHODS: Eligible older adults who were not vitamin D-deficient [serum 25(OH)D ≥12 ng/mL] were randomly assigned in a modified 2 × 2 factorial design to 1 of 4 groups: daily 1000 IU cholecalciferol, 1200 mg Ca as carbonate, both, or placebo. Women could elect 2-group (calcium ± cholecalciferol) random assignment. In secondary analyses, we used multivariable models to assess factors associated with serum 25(OH)D concentrations in all enrollees (n = 2753) and with relative changes in serum 25(OH)D after 1 y cholecalciferol supplementation among those randomly assigned (n = 2187). RESULTS: In multivariable models, 8 factors accounted for 50% of the variability of proportional change in serum 25(OH)D after cholecalciferol supplementation. Larger increases were associated with being female (34.5% compared with 20.5%; P < 0.001) and with lower baseline serum 25(OH)D (P < 0.0001), optimal adherence to study pill intake (P = 0.0002), wearing long pants and sleeves during sun exposure (P = 0.0002), moderate activity level (P = 0.01), use of extra vitamin D-containing supplements during the trial (P = 0.03), and seasons of blood draw (P ≤ 0.002). Several genetic polymorphisms were associated with baseline serum 25(OH)D and/or serum response, but these did not substantially increase the models' R2 values. Other factors, including body mass index, were associated with serum 25(OH)D at baseline but not with its response to supplemental cholecalciferol. CONCLUSIONS: The factors that most affected changes in serum 25(OH)D concentrations in response to cholecalciferol supplementation included sex, baseline serum 25(OH)D, supplement intake adherence, skin-covering clothes, physical activity, and season. Genetic factors did not play a major role. This trial was registered at www.clinicaltrials.gov as NCT00153816.

Randomized controlled trials: who fails run-in?

BACKGROUND: Early identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability. METHODS: We conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666). RESULTS: Overall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03). Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF. CONCLUSIONS: There were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00153816 . Registered September 2005.

The geko™ electro-stimulation device for venous thromboembolism prophylaxis: a NICE medical technology guidance.

The geko™ device is a single-use, battery-powered, neuromuscular electrostimulation device that aims to reduce the risk of venous thromboembolism (VTE). The National Institute for Health and Care Excellence (NICE) selected the geko™ device for evaluation, and invited the manufacturer, Firstkind Ltd, to submit clinical and economic evidence. King's Technology Evaluation Centre, an External Assessment Centre (EAC) commissioned by the NICE, independently assessed the evidence submitted. The sponsor submitted evidence related to the geko™ device and, in addition, included studies of other related devices as further clinical evidence to support a link between increased blood flow and VTE prophylaxis. The EAC assessed this evidence, conducted its own systematic review and concluded that there is currently limited direct evidence that geko™ prevents VTE. The sponsor's cost model is based on the assumption that patients with an underlying VTE risk and subsequently treated with geko™ will experience a reduction in their baseline risk. The EAC assessed this cost model but questioned the validity of some model assumptions. Using the EACs revised cost model, the cost savings for geko™ prophylaxis against a 'no prophylaxis' strategy were estimated as £197 per patient. Following a second public consultation, taking into account a change in the original draft recommendations, the NICE medical technologies guidance MTG19 was issued in June 2014. This recommended the adoption of the geko™ for use in people with a high risk of VTE and when other mechanical/pharmacological methods of prophylaxis are impractical or contraindicated in selected patients within the National Health Service in England.

Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial.

CONTEXT: Adequate serum 25-hydroxyvitamin D concentrations, [25(OH)D], are required for optimal bone health, and low levels are associated with chronic diseases. OBJECTIVE: We investigated whether 41 candidate single nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes (GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR, and CASR) are associated with [25(OH)D] or modify the increase in [25(OH)D] from vitamin D3 supplementation. DESIGN AND SETTING: Baseline and year 1 [25(OH)D] measurements from a randomized controlled trial conducted at 11 clinical centers in the United States. PARTICIPANTS: A total of 1787 healthy non-Hispanic white participants aged 45-75 years. INTERVENTIONS: Vitamin D3 (1000 IU/d), calcium carbonate (1200 mg/d elemental), both, or placebo. MAIN OUTCOME MEASURES: Genotype main effects and interactions with vitamin D3 treatment estimated using multiple linear regression. RESULTS: The baseline serum [25(OH)D] was 25.4 ± 8.7 ng/mL (mean ± SD). Associations with baseline levels were discovered for SNPs in CYP24A1 (rs2209314, rs2762939) and confirmed for SNPs in GC and CYP2R1. After 1 year, [25(OH)D] increased on average by 6.1 ± 8.9 ng/mL on vitamin D3 treatment and decreased by 1.1 ± 8.4 ng/mL on placebo. The increase in [25(OH)D] due to vitamin D3 supplementation was modified by genotypes at rs10766197 near CYP2R1, rs6013897 near CYP24A1, and rs7968585 near VDR. CONCLUSIONS: The increase in [25(OH)D] attributable to vitamin D3 supplementation may vary according to common genetic differences in vitamin D 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and the vitamin D receptor (VDR) genes. These findings have implications for achieving optimal vitamin D status and potentially for vitamin D-related health outcomes.

Vitamin D3 supplementation and upper respiratory tract infections in a randomized, controlled trial.

BACKGROUND: Randomized controlled trials testing the association between vitamin D status and upper respiratory tract infection (URTI) have given mixed results. During a multicenter, randomized controlled trial of colorectal adenoma chemoprevention, we tested whether 1000 IU/day vitamin D(3) supplementation reduced winter episodes and duration of URTI and its composite syndromes, influenza-like illness (ILI; fever and ≥2 of sore throat, cough, muscle ache, or headache) and colds (no fever, and ≥2 of runny nose, nasal congestion, sneezing, sore throat, cough, swollen or tender neck glands). METHODS: The 2259 trial participants were aged 45-75, in good health, had a history of colorectal adenoma, and had a serum 25-hydroxyvitamin D level ≥12 ng/mL. They were randomized to vitamin D(3) (1000 IU/day), calcium (1200 mg/day), both, or placebo. Of these, 759 participants completed daily symptom diaries. Secondary data included semiannual surveys of all participants. RESULTS: Among those who completed symptom diaries, supplementation did not significantly reduce winter episodes of URTI (rate ratio [RR], 0.93; 95% confidence interval [CI], .79-1.09) including colds (RR, 0.93; 95% CI, .78-1.10) or ILI (RR, 0.95; 95% CI, .62-1.46), nor did it reduce winter days of illness (RR, 1.13; 95% CI, .90-1.43). There was no significant benefit according to adherence, influenza vaccination, body mass index, or baseline vitamin D status. Semiannual surveys of all participants (N = 2228) identified no benefit of supplementation on ILI (odds ratio [OR], 1.14; 95% CI, .84-1.54) or colds (OR, 1.03; 95% CI, .87-1.23). CONCLUSIONS: Supplementation with 1000 IU/day vitamin D(3) did not significantly reduce the incidence or duration of URTI in adults with a baseline serum 25-hydroxyvitamin D level ≥12 ng/mL.

Benefits of endocardial and multisite pacing are dependent on the type of left ventricular electric activation pattern and presence of ischemic heart disease: insights from electroanatomic mapping.

BACKGROUND: There is considerable heterogeneity in the myocardial substrate of patients undergoing cardiac resynchronization therapy (CRT), in particular in the etiology of heart failure and in the location of conduction block within the heart. This may account for variability in response to CRT. New approaches, including endocardial and multisite left ventricular (LV) stimulation, may improve CRT response. We sought to evaluate these approaches using noncontact mapping to understand the underlying mechanisms. METHODS AND RESULTS: Ten patients (8 men and 2 women; mean [SD] age 63 [12] years; LV ejection fraction 246%; QRS duration 161 [24] ms) fulfilling conventional CRT criteria underwent an electrophysiological study, with assessment of acute hemodynamic response to conventional CRT as well as LV endocardial and multisite pacing. LV activation pattern was assessed using noncontact mapping. LV endocardial pacing gave a superior acute hemodynamic response compared with conventional CRT (26% versus 37% increase in LV dP/dt(max), respectively; P<0.0005). There was a trend toward further incremental benefit from multisite LV stimulation, although this did not reach statistical significance (P=0.08). The majority (71%) of patients with nonischemic heart failure etiology or functional block responded to conventional CRT, whereas those with myocardial scar or absence of functional block often required endocardial or multisite pacing to achieve CRT response. CONCLUSIONS: Endocardial or multisite pacing may be required in certain subsets of patients undergoing CRT. Patients with ischemic cardiomyopathy and those with narrower QRS, in particular, may stand to benefit.

Non-randomized open trial of eicosapentaenoic acid (EPA), an omega-3 fatty acid, in ten people with chronic epilepsy.

This is a non-randomized open assessment of eicosapentaenoic acid (EPA) supplementation in ten people (five males) with refractory focal seizures. Each received 1000 mg of EPA daily for 3 months. Six people had fewer seizures during the supplementation period compared with baseline (range 12 to 59% reduction) and one other person had markedly reduced seizure severity. The mean reduction in seizure frequency was 16% (95% CI - 10% to 35%, p=0.26). With the small number of participants and open nature of the study, interpretation of the results is difficult, but a possible weak effect of EPA on seizures cannot be discounted. Further examination of EPA supplementation should be undertaken with larger numbers of people in controlled trials. Higher doses and longer duration of treatment should be considered.