Efficacy and safety of a contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive: a 1-year randomized trial

Abstract This open-label, randomized, Phase III study compared the efficacy and tolerability of and compliance with NuvaRing, a combined contraceptive vaginal ring releasing 15 Ag of ethinylestradiol (EE) and 120 Ag of etonogestrel daily, with those of and with a combined oral contraceptive (COC) containing 150 Ag of levonorgestrel (LNG) and 30 Ag of EE. Subjects received NuvaRing or a COC for 13 cycles (3 weeks of ring/pill treatment followed by a 1-week ring-/pill-free period). A total of 1030 subjects (NuvaRing, n = 512; COC, n = 518) was randomized and started treatment (intent-to-treat [ITT] population). The percentage of women in the ITT population who completed the trial was 70.9% for the NuvaRing group and 71.2% for the COC group. Five in-treatment pregnancies occurred in each group, giving Pearl indices of 1.23 for NuvaRing and 1.19 for the COC. Compliance with both treatments was excellent and both were well tolerated. In conclusion, NuvaRing has comparable efficacy and tolerability with a COC containing 150 Ag of LNG and 30 Ag of EE and does not require daily dosing.

The sequences of 150,119 genomes in the UK Biobank

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data(1,2). Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank(3). This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation

Genetic insight into sick sinus syndrome

Aims. The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results. We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10⁻²⁰), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion. We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.publishedVersio

The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadAge-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10-22 and OR = 4.2 for heterozygotes, P = 5.7 × 10-27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.</p

Genetic architecture of band neutrophil fraction in Iceland

Publisher Copyright: © 2022, The Author(s).The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huët anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huët anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huët anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology.Peer reviewe

Rare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBack pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.European Commission European Commission Joint Research Centre Novo Nordisk Foundation Novocure Limite

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

What is meant by "balance" and "balance skill"? : Balance skill among school children

Aim The specific questions in the theoretic part were: What is contained in the terms "balance and balance skill" and how can this skill be measured? The specific questions in the empirical part were: How does balance skill in different age categories of children correlate with biological and physiological parameters such as age, gender, body height, weight and level of physical activity? Methods Literature search based on books and scientific papers related to the questions posed above. Selection was made at libraries and on–line through "Pubmed". Specific search words were used. Data collected during the SIH-project, including balance tests of approximately 1700 children 10-, 13- and 16 years old, were used for the empirical part of the project. Results The literature search concluded that there is little consensus about terms such as "balance" and "balance skill". Several scientific disciplines have "their own" definition of these terms depending on whether the interpretation is purely mechanical/biomechanical, neurophysiological or from a more behaviouristic point of view. There are a number of clinical/functional as well as more "lab based" test procedures of balance function that are considered to be reliable. The empirical study showed that balance skill varies in school children 10-, 13- and 16 years of age such that the older children display better balance skills that the younger ones. There was no effect of gender on balance skill. Overweight and obese children display lower balance skill than those of normal body weight. Body height appears to have little influence on balance skill. Children with high level of physical activity seem to display better balance skills than more inactive ones. Conclusion Definitions of terms used in balance related research have not been standardized and are therefore both difficult to interpret and to implement. Balance skill in children correlates with age, body weight and level of physical activity.Syfte och frågeställningar De specifika frågeställningarna i den teoretiska delen löd: Vad innefattas i begreppen balans och balansförmåga och hur kan dessa förmågor mätas? De specifika frågeställningarna i den empiriska delen löd: Hur är balansförmågan hos barn relaterad till ålder och kön, längd och kroppsvikt samt till graden av fysisk aktivitet? Metod Inledningsvis genomfördes en systematisk litteraturgenomgång av böcker och vetenskapliga artiklar med anknytningar till frågeställningarna. Urval av litteratur gjordes på bibliotek och via "Pubmed" där vissa specifika sökord användes. Till den empiriska delen användes data insamlade under SIH-projektet, där bland annat balanstester genomfördes på ca 1700 barn i åldrarna 10-, 13- och 16 år. Data analyserades i SPSS 11.0. Skillnader i balansförmåga mellan kön, ålderskategorier och andra relevanta variabler beräknades med chi2-test, där signifikansnivån sattes till p&lt;0,05. Resultat Litteraturgenomgången visade att det inte råder någon egentlig konsensus kring begrepp som "balans" och "balansförmåga". Olika vetenskapliga discipliner har "sin egen" definition beroende på om begreppen skall tolkas som rent mekaniska/biomekaniska, neurofysiologiska eller mera beteendevetenskapliga. Det finns ett flertal både kliniska/funktionella och mera laboratorieanpassade mätmetoder som anses vara reliabla. Den empiriska studien visade att balansförmågan varierade hos skolbarn 10-, 13- och 16 år gamla, så att de äldre balanserade bättre än de yngre. Ingen könsskillnad i balansförmåga erhölls. Överviktiga och feta barn balanserade sämre än normalviktiga. Kroppslängd hade mindre inverkan på balansförmågan. Mycket fysiskt aktiva barn tycks ha bättre balansförmåga än mindre aktiva. Slutsats Det är svårt att finna enhetliga definitioner på flera inom balansforskningen förekommande termer och uttryck. Barns balansförmåga var relaterad till ålder, kroppsvikt och grad av fysisk aktivitet