Deformation processes, kinematics and conditions of the Grebe Mylonite Zone, Jaquiery Stream, central Fiordland, New Zealand.

Emplacement of the Median Batholith along the Gondwana margin has been argued to have resulted through magmatic and tectonic processes. Analysis of the Grebe Mylonite Zone (GMZ) an amphibolite facies Early Cretaceous ductile shear zone, provides new insight into the kinematics, conditions and processes that played a role in its deformation and exhumation. The GMZ forms the boundary between the Outboard Median Batholith and Eastern Province and the Inboard Median Batholith and the Western Province in Fiordland, New Zealand. Three units derived from Darran Suite magmas, (1) meta-diorite, (2) meta-granodiorite and (3) meta-granite dominate the GMZ and exhibit a north striking steeply west dipping foliation and moderately south plunging lineation. The grain boundary migration (GBM) mechanism dominates quartz recrystallisation and is inferred to represent deformation temperatures of ~ 600˚C and stresses of 6 to 22 MPa derived from paleopiezometry of recrystallised quartz size. Crystallographic preferred orientation (CPO) data of quartz, plagioclase and hornblende were obtained using electron backscatter diffraction (EBSD). Hornblende [100] a-axes align preferentially perpendicular to foliation with [001] c-axes aligned parallel to lineation, producing an orthorhombic symmetry that provides no information on shear sense. Plagioclase fabrics are sub divided into three groups: [a](c), hybrid-A and hybrid-B, from these fabrics it is interpreted that crystal plastic slip was accommodated on the (001), (010) and the previously unrecognised (011) planes. Weakening of the plagioclase CPO from east to west is thought to indicate a shift towards grain boundary sliding (GBS) diffusion creep deformation mechanisms. Quartz CPOs show predominantly Y-maxima fabrics, [0001] c-axis directions plot within the plane of foliation indicating prism slip at ~ 600˚C. Progressive rotation of quartz CPO fabrics towards the west are thought to represent an increasing temperature/strain rate gradient towards the western contact between the GMZ and the Puteketeke Pluton. Interpretation of quartz fabrics indicate an overall regional oblique sinistral west side down sense of motion relative to the Western Province. However, conflicting kinematics are observed between the units of the GMZ, strain partitioning in a dominantly coaxial strain geometry is proposed as the mechanism for the difference in kinematics

The Sociolinguistic Foundations of Language Modeling

In this paper, we introduce a sociolinguistic perspective on language modeling. We claim that large language models are inherently models of varieties of language, and we consider how this insight can inform the development and deployment of large language models. We begin by presenting a technical definition of the concept of a variety of language as developed in sociolinguistics. We then discuss how this perspective can help address five basic challenges in language modeling: social bias, domain adaptation, alignment, language change, and scale. Ultimately, we argue that it is crucial to carefully define and compile training corpora that accurately represent the specific varieties of language being modeled to maximize the performance and societal value of large language models

The sociolinguistic foundations of language modeling

In this article, we introduce a sociolinguistic perspective on language modeling. We claim that language models in general are inherently modeling varieties of language, and we consider how this insight can inform the development and deployment of language models. We begin by presenting a technical definition of the concept of a variety of language as developed in sociolinguistics. We then discuss how this perspective could help us better understand five basic challenges in language modeling: social bias, domain adaptation, alignment, language change, and scale. We argue that to maximize the performance and societal value of language models it is important to carefully compile training corpora that accurately represent the specific varieties of language being modeled, drawing on theories, methods, and descriptions from the field of sociolinguistics

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

Non-invasive vestibular nerve stimulation (VeNS) reduces visceral adipose tissue: results of a randomised controlled trial

Across multiple species, chronic vestibular stimulation activates hypothalamic regions involved in energy homeostasis and reduces body fat. This first-in-human randomised controlled trial evaluated the efficacy and safety of electrical vestibular nerve stimulation (VeNS) as a means of reducing excess body weight and fat. Overweight and obese adults were randomised 1:1 to receive 60 min of daily VeNS (n = 117) or sham stimulation (n = 124) for 6 months, together with a hypocaloric diet. The primary endpoints were weight loss based. Secondary endpoints included reduction in visceral adipose tissue (VAT). It is VAT, more than subcutaneous fat depots, which is particularly associated with the risks associated with obesity. The weight loss based primary endpoints were not met. However, mean change in VAT was significantly greater in the active (− 12.6%) versus the sham (− 4.7%) group (p = 0.03). This suggests that regular VeNS may cause a clinically meaningful reduction in VAT

Protocol for the stimulating β3-Adrenergic receptors for peripheral artery disease (STAR-PAD) trial: a double-blinded, randomised, placebo-controlled study evaluating the effects of mirabegron on functional performance in patients with peripheral arterial disease

Introduction: There is currently only one approved medication effective at improving walking distance in people with intermittent claudication. Preclinical data suggest that the β3-adrenergic receptor agonist (mirabegron) could be repurposed to treat intermittent claudication associated with peripheral artery disease. The aim of the Stimulating β3-Adrenergic Receptors for Peripheral Artery Disease (STAR-PAD) trial is to test whether mirabegron improves walking distance in people with intermittent claudication. Methods and analysis: The STAR-PAD trial is a Phase II, multicentre, double-blind, randomised, placebo-controlled trial of mirabegron versus placebo on walking distance in patients with PAD. A total of 120 patients aged ≥40 years with stable PAD and intermittent claudication will be randomly assigned (1:1 ratio) to receive either mirabegron (50 mg orally once a day) or matched placebo, for 12 weeks. The primary endpoint is change in peak walking distance as assessed by a graded treadmill test. Secondary endpoints will include: (i) initial claudication distance; (ii) average daily step count and total step count and (iii) functional status and quality of life assessment. Mechanistic substudies will examine potential effects of mirabegron on vascular function, including brachial artery flow-mediate dilatation; MRI assessment of lower limb blood flow, tissue perfusion and arterial stiffness and numbers and angiogenesis potential of endothelial progenitor cells. Given that mirabegron is safe and clinically available for alternative purposes, a positive study is positioned to immediately impact patient care. Ethics and dissemination: The STAR-PAD trial is approved by the Northern Sydney Local Health District Human Research Ethics Committee (HREC/18/HAWKE/50). The study results will be published in peer-reviewed medical or scientific journals and presented at scientific meetings, regardless of the study outcomes

Justify your alpha

Benjamin et al. proposed changing the conventional “statistical significance” threshold (i.e.,the alpha level) from p ≤ .05 to p ≤ .005 for all novel claims with relatively low prior odds. They provided two arguments for why lowering the significance threshold would “immediately improve the reproducibility of scientific research.” First, a p-value near .05provides weak evidence for the alternative hypothesis. Second, under certain assumptions, an alpha of .05 leads to high false positive report probabilities (FPRP2 ; the probability that a significant finding is a false positive

Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors JACC State-of-the-Art Review

Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed