Genome sequencing reveals underdiagnosed cause of long-term lung condition
Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60–80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia . Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments.
Author contributions: Study conception and design: A. Shoemark, H. Griffin, G. Wheway, C. Hogg, J.S. Lucas, J.D. Chalmers, D. Morris-Rosendahl, H.M. Mitchison and A. De Soyza. Data collection: A. Shoemark, C. Hogg, J.S. Lucas, M. Carroll, M.R. Loebinger, D. Morris-Rosendahl and A. De Soyza. Data analysis: A. Shoemark, H. Griffin, G. Wheway, C. Camps, J.D. Chalmers, D. Morris-Rosendahl and H.M. Mitchison. Writing of the manuscript: A. Shoemark, H. Griffin, G. Wheway, C. Hogg, J.S. Lucas, J.D.
Conflict of interest: A. Shoemark has received grants from AstraZeneca. G. Wheway is currently employed by Illumina Inc. M.R. Loebinger has received consultancy or speaker fees from Insmed, AstraZeneca, Parion, Grifols and Armata. J.D.
Support statement: H.M. Mitchison acknowledges funding from the NIHR Biomedical Research Centre at Great Ormond Street Hospital and the Ministry of Higher Education in Egypt. The National PCD Service is commissioned and funded by NHS England; PCD research in Southampton is supported by NIHR Southampton Biomedical Research Centre, NIHR Clinical Research Facility, National Institute for Health Research and The AAIR Charity .
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Pathogen genomics study of an early medieval community in Germany reveals extensive co-infections - Genome BiologyBackground The pathogen landscape in the Early European Middle Ages remains largely unexplored. Here, we perform a systematic pathogen screening of the rural community Lauchheim “Mittelhofen,” in present-day Germany, dated to the Merovingian period, between fifth and eighth century CE. Skeletal remains of individuals were subjected to an ancient DNA metagenomic analysis. Genomes of the detected pathogens were reconstructed and analyzed phylogenetically. Results Over 30% of the individuals exhibit molecular signs of infection with hepatitis B virus (HBV), parvovirus B19, variola virus (VARV), and Mycobacterium leprae. Seven double and one triple infection were detected. We reconstructed four HBV genomes and one genome each of B19, VARV, and M. leprae. All HBV genomes are of genotype D4 which is rare in Europe today. The VARV strain exhibits a unique pattern of gene loss indicating that viruses with different gene compositions were circulating in the Early Middle Ages. The M. leprae strain clustered in branch 3 together with the oldest to-date genome from the UK. Conclusions The high burden of infectious disease, together with osteological markers of physiological stress, reflect a poor health status of the community. This could have been an indirect result of the climate decline in Europe at the time, caused by the Late Antique Little Ice Age (LALIA). Our findings suggest that LALIA may have created an ecological context in which persistent outbreaks set the stage for major epidemics of severe diseases such as leprosy and smallpox hundreds of years later.
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Gaseous nitric oxide tumor ablation induces an anti-tumor abscopal effect - Cancer Cell InternationalBackground In-situ tumor ablation provides the immune system with the appropriate antigens to induce anti-tumor immunity. Here, we present an innovative technique for generating anti-tumor immunity by delivering exogenous ultra-high concentration (| 10,000 ppm) gaseous nitric oxide (UHCgNO) intratumorally. Methods The capability of UHCgNO to induce apoptosis was tested in vitro in mouse colon (CT26), breast (4T1) and Lewis lung carcinoma (LLC-1) cancer cell lines. In vivo, UHCgNO was studied by treating CT26 tumor-bearing mice in-situ and assessing the immune response using a Challenge assay. Results Exposing CT26, 4T1 and LLC-1 cell lines to UHCgNO for 10 s–2.5 min induced cellular apoptosis 24 h after exposure. Treating CT26 tumors in-situ with UHCgNO followed by surgical resection 14 days later resulted in a significant secondary anti-tumor effect in vivo. 100% of tumor-bearing mice treated with 50,000 ppm UHCgNO and 64% of mice treated with 20,000 ppm UHCgNO rejected a second tumor inoculation, compared to 0% in the naive control for 70 days. Additionally, more dendrocytes infiltrated the tumor 14 days post UHCgNO treatment versus the nitrogen control. Moreover, T-cell penetration into the primary tumor was observed in a dose-dependent manner. Systemic increases in T- and B-cells were seen in UHCgNO-treated mice compared to nitrogen control. Furthermore, polymorphonuclear-myeloid-derived suppressor cells were downregulated in the spleen in the UHCgNO-treated groups. Conclusions Taken together, our data demonstrate that UHCgNO followed by the surgical removal of the primary tumor 14 days later induces a strong and potent anti-tumor response.
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Frontiers | Loss of perceived social role, an index of social frailty, is an independent predictor of future adverse events in hospitalized patients with heart failureAims Although the impact of physical frailty on prognosis and the effect of cardiac rehabilitation in HF patients has been well established, data for the prognostic impact of social frailty (SF) in HF patients are limited. In addition, the relative importance of each SF domain in clinical outcomes remains unclear. We aimed to get a new insight into the associations of SF with clinical outcomes in elderly hospitalized HF patients. Methods A single-center, retrospective cohort study was conducted using data from 310 in-hospital HF patients aged ≥ 65 years (mean age of 78 ± 8 years; 49% women). Makizako’s five questions, a self-reported questionnaire, were used to define SF. The primary outcome was composite events defined by all-cause death and cardiovascular events. Results Of the 310 elderly HF patients, 189 patients (61%) had SF. Seventy-five patients (24%) had composite events during a mean follow-up period of 1.93 ± 0.91 years. Kaplan-Meier curves showed that patients with SF had a significantly higher composite event rate than patients without SF. In multivariate Cox regression analyses, SF was independently associated with a higher composite event rate after adjusting for prognostic markers [adjusted hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.07 to 3.78; p=0.04]. Of the 5 questions for defining SF, an answer of yes to the question about not feeling helpful toward friends or family, which indicates loss of perceived social role, was an independent predictor of composite events (adjusted HR, 2.28; 95% CI, 1.36 to 3.82; p | 0.01). Inclusion of loss of perceived social role into the baseline prognostic model improved both the continuous net reclassification improvement (0.562; 95% CI, 0.298 to 0.827; p | 0.01) and integrated discrimination improvement (0.031; 95% CI, 0.006 to 0.056; p=0.02). Conclusion Loss of perceived social role is associated with increased adverse event risk and provides additive prognostic information in elderly HF patients.
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