The dynamic relationships between the active and catabolic vitamin D metabolites, their ratios, and associations with PTH

Vitamin D status, assessed by serum concentration of 25(OH)D, is the prime candidate marker for many disease-association studies, but the interplay between the subsequent 1,25-dihydroxyvitamin D (1,25(OH)2D) and 24,25-dihydroxyvitamin D (24,25(OH)2D) metabolites is unclear. In this study, we conducted an analysis from a large cohort of healthy, physically fit, young army recruits (n = 940). We found a significant, inverse relationship between serum 25(OH)D and 1,25(OH)2D:24,25(OH)2D vitamin D metabolite ratio (VMR) (r(2)Exp = 0.582, p /=35 to be the threshold value for vitamin D insufficiency, and >/=51 to be predictive of vitamin D deficiency. Our three-dimensional model provides mechanistic insight into the vitamin D-PTH endocrine system, and further substantiates the role of 24,25(OH)2D in human physiology. The model sets a new paradigm for vitamin D treatment strategy, and may help the establishment of vitamin D-adjusted PTH reference intervals. The study was approved by the UK Ministry of Defence research ethics committee (MODREC 165/Gen/10 and 692/MoDREC/15). ClinicalTrials.gov Identifier NCT02416895

Pulmonary rehabilitation in idiopathic pulmonary fibrosis and COPD: a propensity matched real-world study

BACKGROUND: The adherence to and clinical efficacy of pulmonary rehabilitation in idiopathic pulmonary fibrosis (IPF), particularly in comparison to people with chronic obstructive pulmonary disease (COPD), remains uncertain. The objectives of this real-world study were to compare the responses of patients with IPF with a matched group of patients with COPD undergoing the same supervised, outpatient pulmonary rehabilitation program, and to determine whether pulmonary rehabilitation is associated with survival in IPF. RESEARCH QUESTION: Do people with IPF improve to the same extent with pulmonary rehabilitation as a matched group of individuals with COPD, and are non-completion of and/or non-response to pulmonary rehabilitation associated with one-year all-cause mortality in IPF? STUDY DESIGN AND METHODS: Using propensity score matching, 163 patients with IPF were matched 1:1 with a control group of 163 patients with COPD referred to pulmonary rehabilitation. We compared between-group pulmonary rehabilitation completion rates and response. Survival status in the IPF cohort was recorded over one-year following pulmonary rehabilitation discharge. Cox proportional-hazards regression explored the association between pulmonary rehabilitation status and all-cause mortality. RESULTS: Similar pulmonary rehabilitation completion rates (IPF: 69%; COPD: 63%; p=0.24) and improvements in exercise response were observed in both groups with no significant mean (95% confidence interval (CI)) between-group differences in incremental shuttle walk (ISW) change (2 (-18 to 22) meters). Pulmonary rehabilitation non-completion (hazard ratio (HR) (95%CI) 5.62 (2.24 to 14.08)) and non-response (HR (95%CI) 3.91 (1.54 to 9.93)) were independently associated with increased one-year all-cause mortality in IPF. INTERPRETATION: Compared with a matched group of patients with COPD, this real-word study demonstrates that patients with IPF have similar completion rates and magnitude of response to pulmonary rehabilitation. In IPF, non-completion of and non-response to pulmonary rehabilitation were associated with increased all-cause mortality. These data reinforce the benefits of pulmonary rehabilitation in patients with IPF

The minimum clinically important difference of the incremental shuttle walk test in bronchiectasis: a prospective cohort study.

The incremental shuttle walk test (ISW) is an externally-paced field walking test that measures maximal exercise capacity1 and is widely used in patients with chronic obstructive pulmonary disease (COPD) undergoing pulmonary rehabilitation (PR). Its psychometric properties, including reliability, construct validity2 and responsiveness to intervention,2-5 have been demonstrated in patients with bronchiectasis, but little data exist on the minimum clinically important difference (MCID). Although two studies have investigated the MCID of ISW in patients with bronchiectasis, the generalisability of these data is limited because of the study sample characteristics,6 or did not involve an exercise-based intervention.2 The MCID enables clinicians and researchers to understand the clinical significance of change data and forms an important part of the evidence required by regulatory agencies for approval for use in clinical trials. Accordingly, the aim of this study was to provide MCID estimates of the ISW in response to intervention, namely PR, in patients with bronchiectasis

Change in gait speed and adverse outcomes in patients with idiopathic pulmonary fibrosis: a prospective cohort study.

BACKGROUND AND OBJECTIVE: Gait speed is associated with survival in individuals with idiopathic pulmonary fibrosis (IPF). The extent to which four-metre gait speed (4MGS) decline predicts adverse outcome in IPF remains unclear. We aimed to examine longitudinal 4MGS change and identify a cut-point associated with adverse outcome. METHODS: In a prospective cohort study, we recruited 132 individuals newly diagnosed with IPF and measured 4MGS change over 6 months. Death/first hospitalization at 6 months were composite outcome events. Complete data (paired 4MGS plus index event) were available in 85 participants; missing 4MGS data were addressed using multiple imputation. Receiver-Operating Curve plots identified a 4MGS change cut-point. Cox proportional-hazard regression assessed the relationship between 4MGS change and time to event. RESULTS: 4MGS declined over 6 months (mean [95% CI] change: -0.05 [-0.09 to -0.01] m/s; p = 0.02). A decline of 0.07 m/s or more in 4MGS over 6 months had better discrimination for the index event than change in 6-minute walk distance, forced vital capacity, Composite Physiologic Index or Gender Age Physiology index. Kaplan-Meier curves demonstrated a significant difference in time to event between 4MGS groups (substantial decline: >-0.07 m/s versus minor decline/improvers: ≤-0.07 m/s; p = 0.007). Those with substantial decline had an increased risk of hospitalization/death (adjusted hazard ratio [95% CI] 4.61 [1.23-15.83]). Similar results were observed in multiple imputation analysis. CONCLUSION: In newly diagnosed IPF, a substantial 4MGS decline over 6 months is associated with shorter time to hospitalization/death at 6 months. 4MGS change has potential as a surrogate endpoint for interventions aimed at modifying hospitalization/death

Supplementary Energy Increases Bone Formation during Arduous Military Training

Purpose: This study aimed to investigate the effect of supplementary energy on bone formation and resorption during arduous military training in energy deficit. Methods: Thirty male soldiers completed an 8-wk military combat course (mean ± SD, age = 25 ± 3 yr, height = 1.78 ± 0.05 m, body mass = 80.9 ± 7.7 kg). Participants received either the habitual diet (control group, n = 15) or an additional 5.1 MJ·d−1 to eliminate the energy deficit (supplemented group, n = 15). Circulating markers of bone formation and resorption, and reproductive, thyroid, and metabolic status, were measured at baseline and weeks 6 and 8 of training. Results: Bone-specific alkaline phosphatase decreased in controls (−4.4 ± 1.9 μg·L−1) and increased in the supplemented group (16.0 ± 6.6 μg·L−1), between baseline and week 8 (P < 0.001). Procollagen type 1 N-terminal propeptide increased between baseline and week 6 for both groups (5.6 ± 8.1 μg·L−1, P = 0.005). Beta carboxy-terminal cross-linking telopeptide of type 1 collagen decreased between baseline and week 8 for both groups (−0.16 ± 0.20 μg·L−1, P < 0.001). Prolactin increased from baseline to week 8 for the supplemented group (148 ± 151 IU·L−1, P = 0.041). The increase in adiponectin from baseline to week 8 was higher in controls (4.3 ± 1.8 mg·L−1, P < 0.001) than that in the supplemented group (1.4 ± 1.0 mg·L−1, P < 0.001). Insulin-like growth factor binding protein-3 was lower at week 8 than baseline for controls (−461 ± 395 ng·mL−1, P < 0.001). Conclusion: The increase in bone-specific alkaline phosphatase, a marker of bone formation, with supplementation supports a role of energy in osteoblastic activity; the implications for skeletal adaptation and stress fracture risk are unclear. The mechanism is likely through protecting markers of metabolic, but not reproductive or thyroid, function

Minimal clinically important difference for daily pedometer step count in COPD

Original research letter to the editor.Jazz Pharmaceuticals; Mundipharma; Novartis; Pfizer; National Institute for Health Research; British Lung Foundation

Mood disorder in idiopathic pulmonary fibrosis: response to pulmonary rehabilitation

Supplementary materials are available online at https://openres.ersjournals.com/content/9/3/00585-2022.figures-only#fig-data-supplementary-materials .Copyright © The authors 2023. Background: Pulmonary rehabilitation improves mood disorder in COPD, but there are limited data in idiopathic pulmonary fibrosis (IPF). The aims of this cohort study were to investigate whether pulmonary rehabilitation reduces mood disorder in IPF, and estimate the minimal important difference (MID) of the Hospital Anxiety and Depression Scale (HADS). Methods: HADS and core pulmonary rehabilitation outcomes were measured in 166 participants before and after an 8-week, in-person, outpatient pulmonary rehabilitation programme. Anchor- and distribution-based methods were used to calculate the MID of HADS-Anxiety (A) and HADS-Depression (D). Results: Suggestive or probable anxiety and depression (HADS ≥8) were present in 35% and 37% of participants, respectively, at baseline, and this reduced significantly following pulmonary rehabilitation (post-pulmonary rehabilitation: HADS-A 23%, HADS-D 26%). Overall, there was a significant reduction in HADS-D (mean change −1.1, 95% CI −1.6– −0.5), but not HADS-A (−0.6, −1.3–0.15) with pulmonary rehabilitation. Subgroup analysis of those with HADS ≥8 revealed significant improvements in HADS domains (mean change: HADS-A −4.5, 95% CI −5.7– −3.4; median change: HADS-D −4.0, interquartile range −6.0– −1.0). The mean (range) MID estimates for HADS-A and HADS-D were −2 (−2.3– −1.7) and −1.2 (−1.9– −0.5), respectively. Conclusion: In people with IPF and suggestive or probable mood disorder, pulmonary rehabilitation reduces anxiety and depression.National Institute for Health Research Doctoral Research Fellowship (2014-07-089); Medical Research Council New Investigator Research Grant (98576)

ProCOC: The prostate cancer outcomes cohort study

BACKGROUND: Despite intensive research over the last several decades on prostate cancer, many questions particularly those concerning early diagnosis and the choice of optimal treatment for each individual patient, still remain unanswered. The goal of treating patients with localized prostate cancer is a curative one and includes minimizing adverse effects to preserve an adequate quality of life. Better understanding on how the quality of life is affected depending on the treatment modality would assist patients in deciding which treatment to choose; furthermore, the development of prognostic biomarkers that indicate the future course of the illness is a promising approach with potential and the focus of much attention. These questions can be addressed in the context of a cohort study. METHODS/DESIGN: This is a prospective, multi-center cohort study within the canton of Zurich, Switzerland. We will include patients with newly diagnosed localized prostate cancer independently of treatment finally chosen. We will acquire clinical data including quality of life and lifestyle, prostate tissue specimen as well as further biological samples (blood and urine) before, during and after treatment for setup of a bio-bank. Assessment of these data and samples in the follow up will be done during routine controls. Study duration will be at least ten years. Influence of treatment on morbidity and mortality, including changes in quality of life, will be identified and an evaluation of biomarkers will be performed. Further we intend to set up a bio-bank containing blood and urine samples providing research of various natures around prostate cancer in the future. DISCUSSION: We presume that this study will provide answers to pertinent questions concerning prognosis and outcomes of men with localised prostate cancer

Vitamin D metabolites are associated with musculoskeletal injury in young adults: a prospective cohort study

The relationship between vitamin D metabolites and lower body (pelvis and lower limb) overuse injury is unclear. In a prospective cohort study, we investigated the association between vitamin D metabolites and incidence of lower body overuse musculoskeletal and bone stress injury in young adults undergoing initial military training during all seasons. In 1637 men and 530 women (age, 22.6 ± 7.5 years; BMI, 24.0 ± 2.6 kg∙m-2 ; 94.3% white ethnicity), we measured serum 25-hydroxyvitamin D (25(OH)D) and 24,25- dihydroxyvitamin D (24,25(OH)2D) by high-performance liquid chromatography tandem mass spectrometry, and 1,25-dihydroxyvitamin D (1,25(OH)2D) by immunoassay during week 1 of training. We examined whether the relationship between 25(OH)D and 1,25(OH)2D:24,25(OH)2D ratio was associated with overuse injury. During 12 weeks training, 21.0% sustained ≥1 overuse musculoskeletal injury, and 5.6% sustained ≥1 bone stress injury. After controlling for sex, BMI, 2.4 km run time, smoking, bone injury history, and Army training course (Officer, standard, or Infantry), lower body overuse musculoskeletal injury incidence was higher for participants within the second lowest versus highest quartile of 24,25(OH)2D (OR: 1.62 [95%CI 1.13–2.32; P = 0.009]) and lowest versus highest cluster of 25(OH)D and 1,25(OH)2D:24,25(OH)2D (OR: 6.30 [95%CI 1.89–21.2; P = 0.003]). Lower body bone stress injury incidence was higher for participants within the lowest versus highest quartile of 24,25(OH)2D (OR: 4.02 [95%CI 1.82–8.87; P < 0.001]) and lowest versus highest cluster of 25(OH)D and 1,25(OH)2D:24,25(OH)2D (OR: 22.08 [95%CI 3.26–149.4; P = 0.001]), after controlling for the same covariates. Greater conversion of 25(OH)D to 24,25(OH)2D, relative to 1,25(OH)2D (i.e., low 1,25(OH)2D:24,25(OH)2D), and higher serum 24,25(OH)2D were associated with a lower incidence of lower body overuse musculoskeletal and bone stress injury. Serum 24,25(OH)2D may have a role in preventing overuse injury in young adults undertaking arduous physical training

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease