Challenges in measuring measles case fatality ratios in settings without vital registration

Measles, a highly infectious vaccine-preventable viral disease, is potentially fatal. Historically, measles case-fatality ratios (CFRs) have been reported to vary from 0.1% in the developed world to as high as 30% in emergency settings. Estimates of the global burden of mortality from measles, critical to prioritizing measles vaccination among other health interventions, are highly sensitive to the CFR estimates used in modeling; however, due to the lack of reliable, up-to-date data, considerable debate exists as to what CFR estimates are appropriate to use. To determine current measles CFRs in high-burden settings without vital registration we have conducted six retrospective measles mortality studies in such settings. This paper examines the methodological challenges of this work and our solutions to these challenges, including the integration of lessons from retrospective all-cause mortality studies into CFR studies, approaches to laboratory confirmation of outbreaks, and means of obtaining a representative sample of case-patients. Our experiences are relevant to those conducting retrospective CFR studies for measles or other diseases, and to those interested in all-cause mortality studies

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis

Background: Cystic fibrosis (CF) is a chronic, life-limiting disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene leading to abnormal airway surface ion transport, chronic lung infections, inflammation and eventual respiratory failure. With the exception of the small-molecule potentiator, ivacaftor (Kalydeco®, Vertex Pharmaceuticals, Boston, MA, USA), which is suitable for a small proportion of patients, there are no licensed therapies targeting the basic defect. The UK Cystic Fibrosis Gene Therapy Consortium has taken a cationic lipid-mediated CFTR gene therapy formulation through preclinical and clinical development. Objective: To determine clinical efficacy of the formulation delivered to the airways over a period of 1 year in patients with CF. Design: This was a randomised, double-blind, placebo-controlled Phase IIb trial of the CFTR gene–liposome complex pGM169/GL67A. Randomisation was performed via InForm™ version 4.6 (Phase Forward Incorporated, Oracle, CA, USA) and was 1 : 1, except for patients in the mechanistic subgroups (2 : 1). Allocation was blinded by masking nebuliser chambers. Settings: Data were collected in the clinical and scientific sites and entered onto a trial-specific InForm, version 4.6 database. Participants: Patients with CF aged ≥ 12 years with forced expiratory volume in the first second (FEV1) between 50% and 90% predicted and any combination of CFTR mutations. The per-protocol group (≥ 9 doses) consisted of 54 patients receiving placebo (62 randomised) and 62 patients receiving gene therapy (78 randomised). Interventions: Subjects received 5 ml of nebulised pGM169/G67A (active) or 0.9% saline (placebo) at 28 (±5)-day intervals over 1 year. Main outcome measures: The primary end point was the relative change in percentage predicted FEV1 over the 12-month period. A number of secondary clinical outcomes were assessed alongside safety measures: other spirometric values; lung clearance index (LCI) assessed by multibreath washout; structural disease on computed tomography (CT) scan; the Cystic Fibrosis Questionnaire – Revised (CFQ-R), a validated quality-of-life questionnaire; exercise capacity and monitoring; systemic and sputum inflammatory markers; and adverse events (AEs). A mechanistic study was performed in a subgroup in whom transgene deoxyribonucleic acid (DNA) and messenger ribonucleic acid (mRNA) was measured alongside nasal and lower airway potential difference. Results: There was a significant (p = 0.046) treatment effect (TE) of 3.7% [95% confidence interval (CI) 0.1% to 7.3%] in the primary end point at 12 months and in secondary end points, including forced vital capacity (FVC) (p = 0.031) and CT gas trapping (p = 0.048). Other outcomes, although not reaching statistical significance, favoured active treatment. Effects were noted by 1 month and were irrespective of sex, age or CFTR mutation class. Subjects with a more severe baseline FEV1 had a FEV1 TE of 6.4% (95% CI 0.8% to 12.1%) and greater changes in many other secondary outcomes. However, the more mildly affected group also demonstrated benefits, particularly in small airway disease markers such as LCI. The active group showed a significantly (p = 0.032) greater bronchial chloride secretory response. No difference in treatment-attributable AEs was seen between the placebo and active groups. Conclusions: Monthly application of the pGM169/GL67A gene therapy formulation was associated with an improvement in lung function, other clinically relevant parameters and bronchial CFTR function, compared with placebo. Limitations: Although encouraging, the improvement in FEV1 was modest and was not accompanied by detectable improvement in patients’ quality of life. Future work: Future work will focus on attempts to increase efficacy by increasing dose or frequency, the coadministration of a CFTR potentiator, or the use of modified viral vectors capable of repeated administration. Trial registration: ClinicalTrials.gov NCT01621867. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership

Laser-activated fluoride treatment of enamel against an artificial caries challenge: comparison of five wavelengths

Background. Laser-activated fluoride (LAF) therapy with 488nm laser energy has been shown previously to increase the resistance of human enamel and dentine to acid dissolution in laboratory models of dental caries. The aims of this study were to examine whether LAF therapy, conducted using a range of wavelengths in the visible and near infrared regions, can protect human dental enamel from an artificial cariogenic challenge. Materials and methods: Buccal and lingual surfaces of extracted sound, molar and premolar teeth were used to prepare matched pairs of enamel slabs (N=10 per group). After application of neutral sodium fluoride gel (12300ppm F ion), slab surfaces were lased (energy density 15 J/cm(2); spot size 5mm, wavelength 532, 633, 670, 830 or 1064nm), then exposed to an artificial cariogenic challenge for a period of seven days. The Vicker's hardness number (VHN) was recorded before and after laser treatment and again following the cariogenic challenge. Negative controls did not receive laser exposure. Results: All wavelengths of laser light examined provided an effective LAF effect, compared with the unlased negative control surfaces. Conclusion: Using this in vitro model, we conclude that the action spectrum of the LAF effect extends across the visible and near-infrared regions of the spectrum

New gravimetric-only and hybrid geoid models of Taiwan for height modernisation, cross-island datum connection and airborne LiDAR mapping

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. This paper combines gravity data collected from airborne, shipborne and terrestrial surveys and those derived from satellite altimetry to determine a high-resolution gravimetric and hybrid geoid model (on a 30” × 30″ grid) in and around Taiwan. Some 6000 new land gravity values at a 0.03-mGal precision make a notable contribution to the geoid modeling. Shipborne gravity data in waters 20 km offshore Taiwan were collected to improve the coastal geoid precision. In a circular area of 50 km around each of the five major tide gauges in Taiwan, gravity data were measured to improve vertical datum connections between Taiwan and its four offshore islands. Height anomalies were computed first and then converted to geoid heights. At > 2000 benchmarks, we obtained measured geoid heights to assess the gravimetric-only geoid and to create a hybrid geoid. Our assessments and formal errors from least-squares collocation indicate few cm of standard deviations for both geoid models, but the gravimetric geoid has mean differences of up to 20 cm with the measured geoidal heights. The hybrid geoid is used in RTK-VBS orthometric heighting, achieving a 5-cm precision. The gravimetric geoid is used to determine the relative differences in the ocean’s mean dynamic topography (MDT) between Taiwan and the four offshore islands, which are also compared with those from oceanic and altimetric methods for estimating MDT. Differences in MDT help to identify 41.7 cm and 54.1 cm offsets in the current vertical datums of Penghu and Lanyu islands. In a low-lying, flood-prone region of southern Taiwan, the hybrid geoid improves LiDAR mapping of sub-zero elevation zones by 20 cm, corresponding to 70 years of sea level rise at an assumed rate of 0.286 cm/yr