Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Pregnancy-associated gynecological cancer in New South Wales, Australia 1994–2013: A population-based historical cohort study

Introduction: Pregnancy-associated gynecological cancer (PAGC) refers to cancers of the ovary, uterus, fallopian tube, cervix, vagina, and vulva diagnosed during pregnancy or within 12 months postpartum. We aimed to describe the incidence of, and perinatal outcomes associated with, invasive pregnancy-associated gynecological cancer. Material and methods: We conducted a population-based historical cohort study using linked data from New South Wales, Australia. We included all women who gave birth between 1994 and 2013, with a follow-up period extending to September 30, 2018. Three groups were analyzed: a gestational PAGC group (women diagnosed during pregnancy), a postpartum PAGC group (women diagnosed within 1 year of giving birth), and a control group (women with control diagnosis during pregnancy or within 1 year of giving birth). We used generalized estimation equations to compare perinatal outcomes between study groups. Results: There were 1 786 137 deliveries during the study period; 70 women were diagnosed with gestational PAGC and 191 with postpartum PAGC. The incidence of PAGC was 14.6/100 000 deliveries and did not change during the study period. Women with gestational PAGC (adjusted odds ratio [aAOR] 6.81, 95% confidence interval [CI] 2.97–15.62) and with postpartum PAGC (aOR 2.65, 95% CI 1.25–5.61) had significantly increased odds of a severe maternal morbidity outcome compared with the control group. Babies born to women with gestational PAGC were more likely to be born preterm (aOR 3.11, 95% CI 1.47–6.59) and were at increased odds of severe neonatal complications (aOR 3.47, 95% CI 1.45–8.31) compared with babies born to women without PAC. Conclusions: The incidence of PAGC has not increased over time perhaps reflecting, in part, the effectiveness of cervical screening and early impacts of human papillomavirus vaccination programs in Australia. The higher rate of preterm birth among the gestational PAGC group is associated with adverse outcomes in babies born to these women

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose finding for future psychedelic research.Trial registration: ClinicalTrials.gov identifier: NCT03604744

Age-related appearance of muscle trauma in primary total hip arthroplasty and the benefit of a minimally invasive approach for patients older than 70 years

Old age is frequently associated with a poorer functional outcome after THA. This might be based upon muscular damage resulting from surgical trauma. Minimally invasive approaches have been widely promoted on the basis of the muscle sparing effect. The aim of the study was to evaluate of the functional outcome and the grade of fatty muscle atrophy of the gluteus medius muscle by magnetic-resonance-imaging (MRI) in patients undergoing minimally invasive or traditional THA. Forty patients (21 female, 19 male) underwent THA either via a modified direct lateral (mDL) or a minimally invasive anterolateral (ALMI) approach. Patients were evaluated clinically and by MRI in terms of age (< or ≥70 y) preoperatively and at three and 12 months postoperatively. The Harris hip score and Trendelenburg’s sign were recorded and a survey of a pain (using a numeric rating scale of 0–10) and satisfaction score (using a numeric rating scale of 1–6) was performed. Fatty atrophy (FA) of gluteus medius muscle was rated by means of a five-point rating scale (0 indicates no fat and 4 implies more fat than muscle). Younger patients reached a significantly higher Harris hip score, lower pain score and lower rate of positive Trendelenburg’s sign accompanied by a significantly lower rate of postoperative FA (P = 0.03; young: FA (MW) = (preop. / 3 / 12 months), 0.15 / 0.7 / 0.7; old: FA (MW) = 0.18 / 1.3 / 1.36). Older patients with an mDL-approach had the significantly lowest clinical scores, the highest rate of positive Trendelenburg’s sign and also the highest rate of fatty atrophy (P = 0.03; FA (old) mDL: 1.8; ALMI: 0.7). Interestingly, no influence of the approach could be detected within the younger group. Patients older than 70 years had a poorer functional outcome and a higher postoperative extent of FA when compared to younger patients, which must be based upon a higher vulnerability and a reduced regenerative capacity of their skeletal muscle. Through a minimally invasive approach the muscle trauma in older patients can be effectively reduced and thus the functional outcome significantly improved. Incision and detachment of tendons and muscles should be strictly avoided