A Rapid, Handheld Device to Assess Respiratory Resistance: Clinical and Normative Evidence

Introduction: Following reports of respiratory symptoms among service members returning from deployment to South West Asia (SWA), an expert panel recommended pre-deployment spirometry be used to assess disease burden. Unfortunately, testing with spirometry is high cost and time-consuming. The airflow perturbation device (APD) is a handheld monitor that rapidly measures respiratory resistance (APD-Rr) and has promising but limited clinical data. Its speed and portability make it ideally suited for large volume pre-deployment screening. We conducted a pilot study to assess APD performance characteristics and develop normative values. Materials and Methods: We prospectively enrolled subjects and derived reference equations for the APD from those without respiratory symptoms, pulmonary disease, or tobacco exposure. APD testing was conducted by medical technicians who received a 10-min in-service on its use. A subset of subjects performed spirometry and impulse oscillometry (iOS), administered by trained respiratory therapists. APD measures were compared with spirometry and iOS. Results: The total study population included 199 subjects (55.8% males, body mass index 27.7 ± 6.0 kg/m2, age 49.9 ± 18.7 yr). Across the three APD trials, mean inspiratory (APD-Ri), expiratory (APD-Re), and average (APD-Ravg) resistances were 3.30 ± 1.0, 3.69 ± 1.2, and 3.50 ± 1.1 cm H2O/L/s. Reference equations were derived from 142 clinically normal volunteers. Height, weight, and body mass index were independently associated with APD-Ri, APD-Re, and APD-Ravg and were combined with age and gender in linear regression models. APD-Ri, APD-Re, and APD-Ravg were significantly inversely correlated with FEV1 (r = −0.39 to −0.42), FVC (r = −0.37 to −0.40), and FEF25–75 (r = −0.31 to −0.35) and positively correlated with R5 (r = 0.61–0.62), R20 (r = 0.50–0.52), X5 (r = −0.57 to −0.59), and FRES (r = 0.42–0.43). Bland–Altman plots showed that the APD-Rr closely approximates iOS when resistance is normal. Conclusion: Rapid testing was achieved with minimal training required, and reference equations were constructed. APD-Rr correlated moderately with iOS and weakly with spirometry. More testing is required to determine whether the APD has value for pre- and post-deployment respiratory assessment

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Severe Respiratory Syncytial Virus Bronchiolitis in Infants Is Associated with Reduced Airway Interferon Gamma and Substance P

Severe human respiratory syncytial virus (hRSV) bronchiolitis in previously well infants may be due to differences in the innate immune response to hRSV infection. Aim: to determine if factors mediating proposed mechanisms for severe bronchiolitis differ with severity of disease

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Induced intra- and intermolecular template switching as a therapeutic mechanism against RNA viruses

Viral RNA-dependent RNA polymerases (RdRps) are a target for broad-spectrum antiviral therapeutic agents. Recently, we demonstrated that incorporation of the T-1106 triphosphate, a pyrazine-carboxamide ribonucleotide, into nascent RNA increases pausing and backtracking by the poliovirus RdRp. Here, by monitoring enterovirus A-71 RdRp dynamics during RNA synthesis using magnetic tweezers, we identify the ‘‘backtracked’’ state as an intermediate used by the RdRp for copy-back RNA synthesis and homologous recombination. Cell-based assays and RNA sequencing (RNA-seq) experiments further demonstrate that the pyrazine-carboxamide ribonucleotide stimulates these processes during infection. These results suggest that pyrazine-carboxamide ribonucleotides do not induce lethal mutagenesis or chain termination but function by promoting template switching and formation of defective viral genomes. We conclude that RdRp-catalyzed intra- and intermolecular template switching can be induced by pyrazine-carboxamide ribonucleotides, defining an additional mechanistic class of antiviral ribonucleotides with potential for broad-spectrum activity

Dynamic Chromatin Localization of Sirt6 Shapes Stress- and Aging-Related Transcriptional Networks

The sirtuin Sirt6 is a NAD-dependent histone deacetylase that is implicated in gene regulation and lifespan control. Sirt6 can interact with the stress-responsive transcription factor NF-κB and regulate some NF-κB target genes, but the full scope of Sirt6 target genes as well as dynamics of Sirt6 occupancy on chromatin are not known. Here we map Sirt6 occupancy on mouse promoters genome-wide and show that Sirt6 occupancy is highly dynamic in response to TNF-α. More than half of Sirt6 target genes are only revealed upon stress-signaling. The majority of genes bound by NF-κB subunit RelA recruit Sirt6, and dynamic Sirt6 relocalization is largely driven in a RelA-dependent manner. Integrative analysis with global gene expression patterns in wild-type, Sirt6−/−, and double Sirt6−/− RelA−/− cells reveals the epistatic relationships between Sirt6 and RelA in shaping diverse temporal patterns of gene expression. Genes under the direct joint control of Sirt6 and RelA include several with prominent roles in cell senescence and organismal aging. These data suggest dynamic chromatin relocalization of Sirt6 as a key output of NF-κB signaling in stress response and aging

Low-Pathogenic Avian Influenza Viruses in Wild House Mice

Background: Avian influenza viruses are known to productively infect a number of mammal species, several of which are commonly found on or near poultry and gamebird farms. While control of rodent species is often used to limit avian influenza virus transmission within and among outbreak sites, few studies have investigated the potential role of these species in outbreak dynamics. Methodology/Principal Findings: We trapped and sampled synanthropic mammals on a gamebird farm in Idaho, USA that had recently experienced a low pathogenic avian influenza outbreak. Six of six house mice (Mus musculus) caught on the outbreak farm were presumptively positive for antibodies to type A influenza. Consequently, we experimentally infected groups of naïve wild-caught house mice with five different low pathogenic avian influenza viruses that included three viruses derived from wild birds and two viruses derived from chickens. Virus replication was efficient in house mice inoculated with viruses derived from wild birds and more moderate for chicken-derived viruses. Mean titers (EID50 equivalents/mL) across all lung samples from seven days of sampling (three mice/day) ranged from 103.89 (H3N6) to 105.06 (H4N6) for the wild bird viruses and 102.08 (H6N2) to 102.85 (H4N8) for the chicken-derived viruses. Interestingly, multiple regression models indicated differential replication between sexes, with significantly (p\u3c0.05) higher concentrations of avian influenza RNA found in females compared with males. Conclusions/Significance: Avian influenza viruses replicated efficiently in wild-caught house mice without adaptation, indicating mice may be a risk pathway for movement of avian influenza viruses on poultry and gamebird farms. Differential virus replication between males and females warrants further investigation to determine the generality of this result in avian influenza disease dynamics

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Methods: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. Results: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. Conclusions: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses

Secretion of Novel SEL1L Endogenous Variants Is Promoted by ER Stress/UPR via Endosomes and Shed Vesicles in Human Cancer Cells

We describe here two novel endogenous variants of the human endoplasmic reticulum (ER) cargo receptor SEL1LA, designated p38 and p28. Biochemical and RNA interference studies in tumorigenic and non-tumorigenic cells indicate that p38 and p28 are N-terminal, ER-anchorless and more stable relative to the canonical transmembrane SEL1LA. P38 is expressed and constitutively secreted, with increase after ER stress, in the KMS11 myeloma line and in the breast cancer lines MCF7 and SKBr3, but not in the non-tumorigenic breast epithelial MCF10A line. P28 is detected only in the poorly differentiated SKBr3 cell line, where it is secreted after ER stress. Consistently with the presence of p38 and p28 in culture media, morphological studies of SKBr3 and KMS11 cells detect N-terminal SEL1L immunolabeling in secretory/degradative compartments and extracellularly-released membrane vesicles. Our findings suggest that the two new SEL1L variants are engaged in endosomal trafficking and secretion via vesicles, which could contribute to relieve ER stress in tumorigenic cells. P38 and p28 could therefore be relevant as diagnostic markers and/or therapeutic targets in cancer

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research