Does respiratory drive modify the cerebral vascular response to changes in end‐tidal carbon dioxide?

What is the central question of this study? An interaction exists between the regulatory systems of respiration and cerebral blood flow (CBF), because of the same mediator (carbon dioxide, CO ) for both physiological systems. The present study examined whether the traditional method for determining cerebrovascular reactivity to CO (cerebrovascular reactivity; CVR) is modified by changes in respiration. What is the main finding and its importance? CVR was modified by voluntary changes in respiration during hypercapnia. This finding suggests that an alteration in the respiratory system may under- or over-estimate CVR determined by traditional methods in healthy adults.The cerebral vasculature is sensitive to changes in the arterial partial pressure of carbon dioxide (CO ). This physiological mechanism has been well established as a cerebrovascular reactivity to CO (CVR). However, arterial CO may not be an independent variable in the traditional method to assess CVR since the cerebral blood flow (CBF) response is partly affected by the activation of respiratory drive or higher centers in the brain. We hypothesized that CVR is modified by changes in respiration. To test our hypothesis, in the present study, ten young healthy subjects performed hyper- or hypo-ventilation to change end-tidal CO (P CO ) under different concentrations of CO gas inhalation (0, 2.0, 3.5%). We measured middle cerebral artery mean blood flow velocity (MCAVm) by transcranial Doppler to identify the CBF response to change in P CO during each condition. At each F CO condition, P CO was significantly altered by changes in ventilation, and MCA Vm changed accordingly. However, the relationship between changes in MCV Vm and P CO as a response curve of CVR was reset upwards and downwards by hypo- and hyper-ventilation, respectively, compared with CVR during normal-ventilation. The findings of the present study may provide the possibility that an alteration in respiration under- or over-estimates CVR determined by the traditional methods

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates. Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities

Gravitational Transitions Increase Posterior Cerebral Perfusion and Systemic Oxidative-nitrosative Stress: Implications for Neurovascular Unit Integrity

International audienceThe present study examined if repeated bouts of micro- and hypergravity during parabolic flight (PF) alter structural integrity of the neurovascular unit (NVU) subsequent to free radical-mediated changes in regional cerebral perfusion. Six participants (5♂, 1♀) aged 29 ± 11 years were examined before, during and after a 3h PF and compared to six sex and age-matched (27 ± 6 years) normogravity controls. Blood flow was measured in the anterior (middle cerebral artery, MCA; internal carotid artery, ICA) and posterior (vertebral artery, VA) circulation (duplex ultrasound) in-flight over the course of 15 parabolas. Venous blood was assayed for free radicals (electron paramagnetic resonance spectroscopy), nitric oxide (NO, ozone-based chemiluminescence) and NVU integrity (chemiluminescence/ELISA) in normogravity before and after exposure to 31 parabolas. While MCA velocity did not change (P > 0.05), a selective increase in VA flow was observed during the most marked gravitational transition from micro- to hypergravity (P 0.05). Collectively, these findings suggest that the cumulative effects of repeated gravitational transitions may promote minor blood-brain barrier disruption, potentially related to the combined effects of haemodynamic (posterior cerebral hyperperfusion) and molecular (systemic oxidative-nitrosative) stress

Clinical Characteristics of Osimertinib Responder in Non-Small Cell Lung Cancer Patients with EGFR-T790M Mutation

Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatment (p = 0.035), whereas osimertinib response was significantly related to the PFS and OS with osimertinib treatment (p = 0.016 and p = 0.006, respectively). Our retrospective observations indicate that PFS following the initial EGFR-TKI treatment and the response rate to osimertinib might be promising predictors for effective osimertinib treatment in NSCLC patients with the EGFR-T790M mutation

Cleaning Up the Internet of Evil Things: Real-World Evidence on ISP and Consumer Efforts to Remove Mirai

With the rise of IoT botnets, the remediation of infected devices has become a critical task. As over 87% of these devices reside in broadband networks, this task will fall primarily to consumers and the Internet Service Providers. We present the first empirical study of IoT malware cleanup in the wild -- more specifically, of removing Mirai infections in the network of a medium-sized ISP. To measure remediation rates, we combine data from an observational study and a randomized controlled trial involving 220 consumers who suffered a Mirai infection together with data from honeypots and darknets. We find that quarantining and notifying infected customers via a walled garden, a best practice from ISP botnet mitigation for conventional malware, remediates 92% of the infections within 14 days. Email-only notifications have no observable impact compared to a control group where no notifications were sent. We also measure surprisingly high natural remediation rates of 58-74% for this control group and for two reference networks where users were also not notified. Even more surprising, reinfection rates are low. Only 5% of the customers who remediated suffered another infection in the five months after our first study. This stands in contrast to our lab tests, which observed reinfection of real IoT devices within minutes -- a discrepancy for which we explore various different possible explanations, but find no satisfactory answer. We gather data on customer experiences and actions via 76 phone interviews and the communications logs of the ISP. Remediation succeeds even though many users are operating from the wrong mental model -- e.g., they run anti-virus software on their PC to solve the infection of an IoT device. While quarantining infected devices is clearly highly effective, future work will have to resolve several remaining mysteries. Furthermore, it will be hard to scale up the walled garden solution because of the weak incentives of the ISPs.Organisation and Governanc

Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR‐mutated non‐small cell lung cancer

Abstract Background Treatment with epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) leads to initial response in most patients with EGFR‐mutated non‐small cell lung cancer (NSCLC). In contrast, little is known of the subpopulation of patients with NSCLC with EGFR mutations who exhibit clinical outcomes that require treatment with immune checkpoint inhibitors (ICIs). Therefore, to identify eligible cases to treat with ICIs, we retrospectively analyzed the correlation between clinical features and the efficacy of ICIs in patients with EGFR mutations. Patients and Methods We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who were treated with ICIs after developing resistance to EGFR‐TKIs between February 2016 and April 2018 at 6 institutions in Japan. The association between clinical outcomes and the efficacy of ICIs was investigated. Results We enrolled 27 patients who harbored EGFR‐activating mutations. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (71% vs 35.7% and 57% vs 7%, P = 0.14 and P < 0.01, respectively). Patients with uncommon EGFR mutations or without T790M mutations exhibited a significantly longer median progression‐free survival than those with common EGFR mutations or with T790M mutations (P = 0.003 and P = 0.03, respectively). Conclusion Patients with uncommon EGFR mutations and without T790M mutations are associated with the best outcomes for treatment with immunotherapy among those with EGFR‐mutated NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders with EGFR mutations

Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project

Abstract Background Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. Results We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. Conclusions 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population’s genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago

Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries

Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5, and SMAD6. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates. Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.Peer reviewe