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

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Aging attractively: Women\u27s learning experiences in a beauty salon

The purpose of the present study was to explore how attitude formation and learning change throughout adulthood to include new models of attractiveness as aging occurs. American culture continues to present youth-based images of attractiveness that hold men and women to a standard impossible to achieve as they age, contributing to perceptions of failure, loss and depression (Thorson, 1995). The present research focused on identifying and clarifying how women are socialized and what standards of attractiveness are in fact used by aging women. This study is intended to help clarify how aging adults find and use models for maintaining attractiveness. The study used a qualitative grounded theory approach, which affords a method to investigate perceptions of attractiveness in aging. The setting, a beauty salon, was considered an appropriate place to investigate the role the image professional plays as aging women focus on their physical attractiveness. As people in mid-life move into their senior years, they are changing programs and services in every area of the culture (Dychtwald & Flower, 1990). One such service, devoted entirely to socialization about body image, is the beauty salon. The beauty salon provided an appropriate setting in which to study how older people form attitudes and perceive their own and others\u27 attractiveness. The study was limited to women participants who are all clients of the same beauty salon. Ultimately, the lack of information on women, aging and attractiveness led directly to the qualitative design of the present study and the following research questions: (1) Where do women find social comparisons for attractiveness as they age? (2) How do women\u27s images of attractiveness change as they age? (3) Are personal appearance preferences in women resistant to change over time? (4) Is there an appropriate mature image for women as they age & what does it look like

Effects of halothane on the transient outward K(+) current in rat ventricular myocytes

1. Halothane has been shown to affect several membrane currents in cardiac tissue including the L-type calcium current (I(Ca)), sodium current and a variety of potassium currents. However, little is known about the effects of halothane on the transient outward K(+) current (I(to)). 2. Single ventricular myocytes from rat hearts were voltage clamped using the whole cell patch configuration and an EGTA-containing pipette solution to record the Ca(2+)-independent, 4-aminopyridine sensitive component of I(to). 300 μM Cd(2+) or 10 μM nifedipine was used to block I(Ca). 3. At +80 mV, I(to) (peak current minus current at the end of the pulse) was 1.8±0.2 nA under control conditions which was reduced to 1.3±0.2 nA by 1 mM halothane (P<0.001, mean±s.e.mean, n=9). The inhibition of I(to) by halothane was concentration-dependent (K(0.5), 1.1±0.2 mM). One mM halothane led to a 16 mV shift in the steady-state inactivation curve towards negative membrane potentials (P=0.005, n=8) but had no significant effect on the activation-voltage relationship (P=0.724). 4. One mM halothane also increased the rate of inactivation of I(to); the dominant time constant of inactivation was reduced from 14±1 to 9±1 ms (P=0.017, mean±s.e.mean, n=6). 5. These data show that halothane reduced I(to); 0.3 mM, close to the MAC(50) value for halothane, inhibited the current by 15% and as such, the inhibition of I(to) will be relevant to the clinical situation. Halothane induced a shift in the steady-state inactivation curve and accelerated the inactivation process of I(to) which could be responsible for its inhibitory effect. 6. Due to the differential transmural expression of I(to) in ventricular tissue, inhibition of I(to) would reduce the transmural dispersion of refractoriness which could contribute to the arrhythmogenic properties of halothane