Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Mid to late Paleozoic shortening pulses in the Lachlan Orogen, southeastern Australia: a review

In the late Silurian, the Lachlan Orogen of southeastern Australia had a varied paleogeography with deep-marine, shallow-marine, subaerial environments and widespread igneous activity reflecting an extensional backarc setting. This changed to a compressional-extensional regime in the Devonian associated with episodic compressional events, including the Bindian, Tabberabberan and Kanimblan orogenies. The Early Devonian Bindian Orogeny was associated with SSE transport of the Wagga-Omeo Zone that was synchronous with thick sedimentation in the Cobar and Darling basins in central and western New South Wales. Shortening has been controlled by the margins of the Wagga-Omeo Zone with partitioning along strike-slip faults, such as along the Gilmore Fault, and inversion of pre-existing extensional basins including the Limestone Creek Graben and the Canbelego-Mineral Hill Volcanic Belt. Shortening was more widespread in the late Early Devonian to Middle Devonian Tabberabberan Orogeny, with major deformation in the Melbourne Zone, Cobar Basin and eastern Lachlan Orogen. In the eastern Melbourne Zone, structural trends have been controlled by the pre-existing structural grain in the adjacent Tabberabbera Zone. Elsewhere Tabberabberan deformation involved inversion of pre-existing rifts resulting in a variation in structural trends. In the Early Carboniferous, the Lachlan Orogen was in a compressional backarc setting west of the New England continental margin arc with Kanimblan deformation most evident in Upper Devonian units in the eastern Lachlan Orogen. Kanimblan structures include major thrusts and associated fault-propagation folds indicated by footwall synclines with a steeply dipping to overturned limb adjacent to the fault. Ongoing deformation and sedimentation have been documented in the Mt Howitt Province of eastern Victoria. Overall, structural trends reflect a combination of controls provided by reactivation of pre-existing contractional and extensional structures in dominantly E-W shortening operating intermittently from the earliest Devonian to Early Carboniferous