Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

In vitro killing of multidrug/extensively drug-resistant Pseudomonas aeruginosa by fosfomycin alone or in combination with antipseudomonal antibiotics

Pseudomonas aeruginosa is a leading cause of nosocomial infections. Given the constant rise in resistance, adequate therapy is increasingly demanding. Fosfomycin recently became an appealing treatment option of bacterial infections due to multidrug-resistant bacteria (MDR). So far, fosfomycin synergy with other antibiotics has been assessed in studies, but only a limited number focused on MDR P. aeruginosa and on the effect of these combinations on the duration of the postantibiotic effect (PAE). We investigated synergy of fosfomycin with an array of antipseudomonal antibiotics using gradient diffusion strip cross method and time-kill method, and their effect on the duration of PAE against 51 variously resistant P. aeruginosa isolates. The highest rate of synergy was observed for combination with ceftazidime (23.4%) and gentamicin (19.1%). The PAE of antibiotic combinations was superior to that of the drugs alone. Our findings indicate that fosfomycin combination therapy may be a valuable treatment alternative

Acceptability and feasibility of community-based provision of urine pregnancy tests to support linkages to reproductive health services in Western Kenya: a qualitative analysis

Background The majority of women living in rural Kenya access antenatal care (ANC) late in pregnancy, and approximately 20% have an unmet need for family planning (FP). This study aimed to determine whether training community health volunteers (CHVs) to deliver urine pregnancy testing (UPT), post-test counselling, and referral to care was an acceptable and feasible intervention to support timely initiation of ANC and uptake of FP. Methods We applied community-based participatory methods to design and implement the pilot intervention between July 2018 and May 2019. We conducted qualitative content analysis of 12 pre-intervention focus group discussions (FGDs) with women, men, and CHVs, and of 4 post-intervention FGDs with CHVs, each with 7–9 participants per FGD group. Using a pragmatic approach, we conducted inductive line-by-line coding to generate themes and subthemes describing factors that positively or negatively contributed to the intervention’s acceptability and feasibility, in terms of participants’ views and the intervention aims. Results We found that CHV-delivered point of care UPT, post-test counselling, and referral to care was an acceptable and feasible intervention to increase uptake of ANC, FP, and other reproductive healthcare services. Factors that contributed to acceptability were: (1) CHV-delivery made UPT more accessible; (2) UPT and counselling supported women and men to build knowledge and make informed choices, although not necessarily for women with unwanted pregnancies interested in abortion; (3) CHVs were generally trusted to provide counselling, and alternative counselling providers were available according to participant preference. A factor that enhanced the feasibility of CHV delivering UPT and counselling was CHV's access to appropriate supplies (e.g. carrying bags). However, factors that detracted from the feasibility of women actually accessing referral services after UPT and counselling included (1) downstream barriers like cost of travel, and (2) some male community members’ negative attitudes toward FP. Finally, improved financial, educational, and professional supports for CHVs would be needed to make the intervention acceptable and feasible in the long-term. Conclusion Training CHVs in rural western Kenya to deliver UPT, post-test counselling, and referral to care was acceptable and feasible to men, women, and CHVs in this context, and may promote early initiation of ANC and uptake of FP. Additional qualitative work is needed to explore implementation challenges, including issues related to unwanted pregnancies and abortion, the financial burden of volunteerism on CHVs, and educational and professional supports for CHVs.Medicine, Faculty ofNon UBCObstetrics and Gynaecology, Department ofReviewedFacultyResearche

Enabling Adherence to Treatment (EAT): a pilot study of a combination intervention to improve HIV treatment outcomes among street-connected individuals in western Kenya

Abstract Background Street-connected individuals (SCI) in Kenya experience barriers to accessing HIV care. This pilot study provides proof-of-concept for Enabling Adherence to Treatment (EAT), a combination intervention providing modified directly observed therapy (mDOT), daily meals, and peer navigation services to SCI living with HIV or requiring therapy for other conditions (e.g. tuberculosis). The goal of the EAT intervention was to improve engagement in HIV care and viral suppression among SCI living with HIV in an urban setting in Kenya. Methods This pilot study used a single group, pre/post-test design, and enrolled a convenience sample of self-identified SCI of any age. Participants were able to access free hot meals, peer navigation services, and mDOT 6 days per week. We carried out descriptive statistics to characterize participants’ engagement in EAT and HIV treatment outcomes. We used McNemar’s chi-square test to calculate unadjusted differences in HIV outcomes pre- and post-intervention among participants enrolled in HIV care prior to EAT. We compared unadjusted time to initiation of antiretroviral therapy (ART) and first episode of viral load (VL) suppression among participants enrolled in HIV care prior to EAT vs. concurrently with EAT using the Wilcoxon rank sum test. Statistical significance was defined as p < 0.05. We calculated total, fixed, and variable costs of the intervention. Results Between July 2018 and February 2020, EAT enrolled 87 participants: 46 (53%) female and 75 (86%) living with HIV. At baseline, 60 out of 75 participants living with HIV (80%) had previously enrolled in HIV care. Out of 60, 56 (93%) had initiated ART, 44 (73%) were active in care, and 25 (42%) were virally suppressed (VL < 1000 copies/mL) at their last VL measure in the 19 months before EAT. After 19 months of follow-up, all 75 participants living with HIV had enrolled in HIV care and initiated ART, 65 (87%) were active in care, and 44 (59%) were virally suppressed at their last VL measure. Among the participants who were enrolled in HIV care before EAT, there was a significant increase in the proportion who were active in HIV care and virally suppressed at their last VL measure during EAT enrollment compared to before EAT enrollment. Participants who enrolled in HIV care concurrently with EAT had a significantly shorter time to initiation of ART and first episode of viral suppression compared to participants who enrolled in HIV care prior to EAT. The total cost of the intervention over 19 months was USD $57,448.64. Fixed costs were USD$3623.04 and variable costs were USD $63.75/month/participant. Conclusions This pilot study provided proof of concept that EAT, a combination intervention providing mDOT, food, and peer navigation services, was feasible to implement and may support engagement in HIV care and achievement of viral suppression among SCI living with HIV in an urban setting in Kenya. Future work should focus on controlled trials of EAT, assessments of feasibility in other contexts, and cost-effectiveness studies

The opioid crisis is driving mortality among under-served people living with HIV in British Columbia, Canada

Introduction: Universal provision of effective antiretroviral medication has been essential to reduce mortality, increase longevity, and reduce onward transmission of HIV. This study aims to illuminate persistent threats to the health and longevity of under-served PLWH in British Columbia (BC), Canada. Methods: Between 2007 and 2010, 1000 PLWH across BC were enrolled in the Longitudinal Investigation into Supportive and Ancillary health services (LISA) study and completed a cross-sectional survey on their HIV-care experiences and healthcare engagement. The sample generally reflects an under-served population of PLWH. A linkage to the provincial Vital Statistics registry is used in this analysis in order to examine overall mortality and cause-specific mortality trends; probability of death was modeled using logistic regression for participants with ongoing clinical monitoring (n = 910). Results: By June 2017, 208 (20.8%) participants had died. The majority of deaths 57 (27.4%) were attributed to drug-related complications or overdoses, 39 (18.8%) were attributed to HIV-related complications, and 36 (17.3%) to non-AIDS-defining malignancies. We observed elevated odds of death among PLWH who smoked tobacco (aOR: 2.11, 95% CI: 1.38, 3.23), were older (aOR: 1.06 per one-year increase, 95% CI: 1.04, 1.08), indicated heavy alcohol consumption (aOR: 1.57, 95% CI: 1.11, 2.22), and reported unstable housing (aOR: 1.96, 95% CI: 1.37, 2.80); while higher CD4 cell count was protective (aOR: 0.87 per 100-unit increase, 95% CI: 0.79, 0.94) as was male gender), though non-significant (aOR: 0.73, 95% CI: 0.49, 1.07). Conclusions: Overdose is - the leading cause of mortality among a cohort of under-served PLWH in BC, Canada. Public health efforts to end the HIV epidemic and support the health and well-being of PLWH are being thwarted by persistent health inequities and the enormous and persistent risks facing people who use drugs. Integrated low-barrier primary care is essential for supporting under-served PLWH, and safe drug supply is needed to support PLWH who use drugs.Medicine, Faculty ofOther UBCNon UBCPopulation and Public Health (SPPH), School ofReviewedFacult

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (