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Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first st
Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical an
BackgroundWomen are at a greater risk of a major adverse cardiovascular event (MACE) after percutaneous coronary intervention than men. A history of preterm delivery is a female-specific risk factor for coronary artery disease, but its relevance in the treatment of coronary artery disease is unknown.ObjectivesThe purpose of this study was to analyze the association between a history of preterm del
Objectives Evaluate the natural course of anterior cruciate ligament (ACL) healing on MRI within 5 years of acute ACL rupture and compare 2-year and 5-year outcomes based on healing status and treatment group. Methods Secondary analysis of 120 Knee Anterior Cruciate Ligament Nonsurgical vs Surgical Treatment (KANON) trial participants randomised to rehabilitation and optional delayed ACL reconstru
Indoor environments have a large impact on health and well-being, so it is important to understand what makes them healthy and sustainable. There is substantial knowledge on individual factors and their effects, though understanding how factors interact and what role occupants play in these interactions (both causative and receptive) is lacking. We aimed to: (i) explore interactions between factor
The derivation of astrocytes from human pluripotent stem cells is currently slow and inefficient. We demonstrate that overexpression of the transcription factors SOX9 and NFIB in human pluripotent stem cells rapidly and efficiently yields homogeneous populations of induced astrocytes. In our study these cells exhibited molecular and functional properties resembling those of adult human astrocytes
Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the t
Objective: To assess the proportion of participants reconsidering their willingness to undergo surgery after 3 and 12 months. Secondary aims were to analyze and compare the characteristics of individuals willing and unwilling to undergo joint surgery for osteoarthritis (OA) before a first-line intervention, and to study the association between pain intensity, walking difficulties, self-efficacy, a
Astrocytes are essential cells for normal brain functionality and have recently emerged as key players in many neurological diseases. However, the limited availability of human primary astrocytes for cell culture studies hinders our understanding of their physiology and precise role in disease development and progression. Here, we describe a detailed step-by-step protocol to rapidly and efficientl
Recent advances in genome editing have brought new hopes for personalized and precision medicine but have also dramatically facilitated disease modeling studies. Combined with reprogramming approaches, stem cells and differentiation toward neural lineages, genome engineering holds great potential for regenerative approaches and to model neurological disorders. The use of patient-specific induced p
B lymphocyte development is dependent on the interplay between the chromatin landscape and lineage-specific transcription factors. It has been suggested that B lineage commitment is associated with major changes in the nuclear chromatin environment, proposing a critical role for lineage-specific transcription factors in the formation of the epigenetic landscape. In this report, we have used chromo
Direct conversion of human somatic cells to induced neurons (iNs), using lineage-specific transcription factors has opened new opportunities for cell therapy in a number of neurological diseases, including epilepsy. In most severe cases of epilepsy, seizures often originate in the hippocampus, where populations of inhibitory interneurons degenerate. Thus, iNs could be of potential use to replace t
Background: Surgery for prostate cancer has a large impact on quality of life (QoL). Objective: To evaluate predictors for the level of self-assessed QoL at 3 mo, 12 mo, and 24 mo after robot-assisted laparoscopic (RALP) and open radical prostatectomy (ORP). Design, setting, and participants: The LAParoscopic Prostatectomy Robot Open study, a prospective, controlled, nonrandomised trial of more th
Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine-a nicotine metabolite and biomarker of recent tobacco exposure-provides additional information on lung cancer risk. Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnos
Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concent
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comp
Background: HIV type 2 (HIV-2) is considered more benign and has fewer pathogenic consequences than HIV type 1 (HIV-1) for most infected individuals. However, reliable estimates of time to AIDS and mortality among those with HIV-2 infection are absent. We therefore aimed to compare the time to AIDS and mortality, and the CD4 T-cell dynamics between those infected with HIV-1 and HIV-2. Methods: We
Background: A sizeable body of evidence suggests that statins can cease breast cancer progression and prevent breast cancer recurrence. The latest studies have, however, not been supportive of such clinically beneficial effects. These discrepancies may be explained by insufficient power. This considerably sized study investigates the association between both pre- and post-diagnostic statin use and
Background: The Bone Scan Index (BSI) is used to quantitatively assess the total tumour burden in bone scans of patients with metastatic prostate cancer. The clinical utility of BSI has recently been validated as a prognostic imaging biomarker. However, the clinical utility of the on-treatment change in BSI is dependent on the reproducibility of bone scans. The objective of this prospective study
The combination of a negative D-dimer and a Wells score can rule out, but not confirm, a diagnosis of deep venous thrombosis (DVT). We aimed to identify new diagnostic biomarkers for DVT and to investigate their relationship with hypercoagulability markers [D-dimer and activated protein C-protein C inhibitor (APC-PCI) complex]. We screened 92 cardiovascular-specific proteins in plasma samples from
