High resolution imaging of the M​L​ 2.9 August 2019 earthquake in Lancashire, UK, induced by hydraulic fracturing during Preston New Road PNR-2 operations

Hydraulic fracturing (HF) at Preston New Road (PNR), Lancashire, United Kingdom, in August 2019, induced a number of felt earthquakes. The largest event (⁠ML 2.9) occurred on 26 August 2019, approximately three days after HF operations at the site had stopped. Following this, in November 2019, the United Kingdom Government announced a moratorium on HF for shale gas in England. Here we provide an analysis of the microseismic observations made during this case of HF‐induced fault activation. More than 55,000 microseismic events were detected during operations using a downhole array, the vast majority measuring less than Mw 0. Event locations revealed the growth of hydraulic fractures and their interaction with several preexisting structures. The spatiotemporal distribution of events suggests that a hydraulic pathway was created between the injection points and a nearby northwest–southeast‐striking fault, on which the largest events occurred. The aftershocks of the ML 2.9 event clearly delineate the rupture plane, with their spatial distribution forming a halo of activity around the mainshock rupture area. Across clusters of events, the magnitude distributions are distinctly bimodal, with a lower Gutenberg–Richter b‐value for events above Mw 0, suggesting a break in scaling between events associated with hydraulic fracture propagation, and events associated with activation of the fault. This poses a challenge for mitigation strategies that rely on extrapolating microseismicity observed during injection to forecast future behavior. The activated fault was well oriented for failure in the regional stress field, significantly more so than the fault activated during previous operations at PNR in 2018. The differing orientations within the stress field likely explain why this PNR‐2 fault produced larger events compared with the 2018 sequence, despite receiving a smaller volume of injected fluid. This indicates that fault orientation and in situ stress conditions play a key role in controlling the severity of seismicity induced by HF

Measuring the Impact of the COVID-19 Pandemic on Diagnostic Delay in Rare Disease

Rare diseases are individually rare but collectively common, with a combined prevalence of 3.5–5.9%. A common feature of many diseases is a substantial delay in patients receiving a correct diagnosis; this protracted path to diagnosis is termed ‘the diagnostic odyssey’. During the COVID-19 pandemic, significant concerns have emerged from both clinicians and patients regarding a disproportionate effect of the pandemic on diagnosis and management of rare disease. Such concerns prompted a study to explore this question further, the results of which are presented here. A cross-sector multi-stakeholder coalition was formed, Action for Rare Disease Empowerment (ARDEnt), with representation from patients with rare diseases and carers, patient advocacy groups, clinicians, academics, data scientists, and industry. A mixed methods approach was used to collect and collate information about the impact of the pandemic on diagnostic delay in rare disease. Currently, there is a lack of systematic recording and reporting of rare disease diagnosis in the UK, which created challenges in directly measuring diagnosis rates. Therefore, the group was dependent on a mix of data sources to reflect healthcare provided during 2020 compared with previous years. The findings were synthesised to describe the impact of the pandemic along the path to diagnosis, from the moment of first concern and engagement with health services, to the availability of definitive testing. In conclusion, evidence suggests the pandemic has exacerbated the problem of diagnostic delay for rare diseases, affecting all points on the path to diagnosis. The authors recommend three actions to help address this: optimising remote clinical consultations; enhancing the use of health informatics in rare diseases; and proactively identifying patients with undiagnosed rare diseases missed due to the pandemic. This study also highlights the need for better reporting of rare disease diagnoses, a core metric to measure the impact of health system changes that may be put into place to address the priorities of The UK Rare Diseases Framework, also published this year

A female advantage in the recognition of emotional facial expressions: Test of an evolutionary hypothesis

A set of computerized tasks was used to investigate sex differences in the speed and accuracy of emotion recognition in 62 men and women of reproductive age. Evolutionary theories have posited that female superiority in the perception of emotion might arise from women's near-universal responsibility for child-rearing. Two variants of the child-rearing hypothesis predict either across-the-board female superiority in the discrimination of emotional expressions ("attachment promotion" hypothesis) or a female superiority that is restricted to expressions of negative emotion ("fitness threat" hypothesis). Therefore, we sought to evaluate whether the expression of the sex difference is influenced by the valence of the emotional signal (Positive or Negative). The results showed that women were faster than men at recognizing both positive and negative emotions from facial cues, supporting the attachment promotion hypothesis. Support for the fitness threat hypothesis also was found, in that the sex difference was accentuated for negative emotions. There was no evidence that the female superiority was learned through previous childcare experience or that it was derived from a sex difference in simple perceptual speed. The results suggest that evolved mechanisms, not domain-general learning, underlie the sex difference in recognition of facial emotions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83923/1/A_female_advantage_in_the_recognition_of_emotional_facial_expressions_test_of_an_evolutionary_hyptothesis.pd

A Single Mutation in the PB1-F2 of H5N1 (HK/97) and 1918 Influenza A Viruses Contributes to Increased Virulence

The proapoptotic PB1-F2 protein of influenza A viruses has been shown to contribute to pathogenesis in the mouse model. Expression of full-length PB1-F2 increases the pathogenesis of the influenza A virus, causing weight loss, slower viral clearance, and increased viral titers in the lungs. After comparing viruses from the Hong Kong 1997 H5N1 outbreak, one amino acid change (N66S) was found in the PB1-F2 sequence at position 66 that correlated with pathogenicity. This same amino acid change (N66S) was also found in the PB1-F2 protein of the 1918 pandemic A/Brevig Mission/18 virus. Two isogenic recombinant chimeric viruses were created with an influenza A/WSN/33 virus background containing the PB1 segment from the HK/156/97: WH and WH N66S. In mice infected with WH N66S virus there was increased pathogenicity as measured by weight loss and decreased survival, and a 100-fold increase in virus replication when compared to mice infected with the WH virus. The 1918 pandemic strain A/Brevig Mission/18 was reconstructed with a pathogenicity-reducing mutation in PB1-F2 (S66N). The resultant 1918 S66N virus was attenuated in mice having a 3-log lower 50% lethal dose and caused less morbidity and mortality in mice than the wild-type virus. Viral lung titers were also decreased in 1918 S66N–infected mice compared with wild-type 1918 virus–infected mice. In addition, both viruses with an S at position 66 (WH N66S and wt 1918) induced elevated levels of cytokines in the lungs of infected mice. Together, these data show that a single amino acid substitution in PB1-F2 can result in increased viral pathogenicity and could be one of the factors contributing to the high lethality seen with the 1918 pandemic virus

Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21,-200c, and-423

Drug-induced acute kidney injury (AKI) is often encountered in hospitalized patients. Although serum creatinine (SCr) is still routinely used for assessing AKI, it is known to be insensitive and nonspecific. Therefore, our objective was to evaluate kidney injury molecule 1 (KIM-1) in conjunction with microRNA (miR)-21, -200c, and -423 as urinary biomarkers for drug-induced AKI in humans. In a cross-sectional cohort of patients (n = 135) with acetaminophen (APAP) overdose, all 4 biomarkers were significantly (P < .004) higher not only in APAP-overdosed (OD) patients with AKI (based on SCr increase) but also in APAP-OD patients without clinical diagnosis of AKI compared with healthy volunteers. In a longitudinal cohort of patients with malignant mesothelioma receiving intraoperative cisplatin (Cp) therapy (n = 108) the 4 biomarkers increased significantly (P < .0014) over time after Cp administration, but could not be used to distinguish patients with or without AKI. Evidence for human proximal tubular epithelial cells (HPTECs) being the source of miRNAs in urine was obtained first, by in situ hybridization based confirmation of increase in miR-21 expression in the kidney sections of AKI patients and second, by increased levels of miR-21, -200c, and -423 in the medium of cultured HPTECs treated with Cp and 4-aminophenol (APAP degradation product). Target prediction analysis revealed 1102 mRNA targets of miR-21, -200c, and -423 that are associated with pathways perturbed in diverse pathological kidney conditions. In summary, we report noninvasive detection of AKI in humans by combining the sensitivity of KIM-1 along with mechanistic potentials of miR-21, -200c, and -423

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

How does large-scale genomic analysis shape our understanding of COVID variants in real time?

No abstract available

Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients

Organ-enriched blood proteins, those produced primarily in one organ and secreted or exported to the blood, potentially afford a powerful and specific approach to assessing diseases in their cognate organs. We demonstrate that quantification of organ-enriched proteins in the blood offers a new strategy to find biomarkers for diagnosis and assessment of drug-induced liver injury (and presumably the assessment of other liver diseases). We used selected reaction monitoring (SRM) mass spectrometry to quantify 81 liver-enriched proteins plus three aminotransferases (ALT1, AST1, and AST2) in plasma of C57BL/6J and NOD/ShiLtJ mice exposed to acetaminophen or carbon tetrachloride. Plasma concentrations of 49 liver-enriched proteins were perturbed significantly in response to liver injury induced by one or both toxins. We validated four of these toxin-responsive proteins (ALDOB, ASS1, BHMT, and GLUD1) by Western blotting. By both assays, these four proteins constitute liver injury markers superior to currently employed markers such as ALT and AST. A similar approach was also successful in human serum where we had analyzed 66 liver-enriched proteins in acetaminophen overdose patients. Of these, 23 proteins were elevated in patients; 15 of 23 overlapped with the concentration-increased proteins in the mouse study. A combination of 5 human proteins, AGXT, ALDOB, CRP, FBP1, and MMP9, provides the best diagnostic performance to distinguish acetaminophen overdose patients from controls (sensitivity: 0.85, specificity: 0.84, accuracy: 85%). These five blood proteins are candidates for detecting acetaminophen-induced liver injury using next-generation diagnostic devices (e.g, microfluidic ELISA assays)