A long-term view of tropical cyclone risk in Australia

Natural hazard risk is assessed by leveraging, among other things, the historical record. However, if the record is short then there is the danger that risk models are not capturing the true envelope of natural variability. In the case of tropical cyclones in Australia, the most reliable observational record spans less than 50 years. Here, we use a much longer (ca. 6000-year) chronology of intense paleo-cyclones and, for the first time, blend this information with a catastrophe loss model to reassess tropical cyclone wind risk in Northeast Australia. Results suggests that the past several decades have been abnormally quiescent compared to the long-term mean (albeit with significant temporal variability). Category 5 cyclones made landfall within a section of the northeast coast of Australia almost five times more frequently, on average, over the late Holocene period than at present. If the physical environment were to revert to the long-term mean state, our modelling suggests that under the present-day exposure setting, insured losses in the area would rise by over 200%. While there remain limitations in incorporating paleoclimate data into a present-day view of risk, the value of paleoclimate data lies in contextualizing the present-day risk environment, rather than complementing it, and supporting worst-case disaster planning

An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Using co-authorship networks to map and analyse global Neglected Tropical Disease research with an affiliation to Germany

Neglected tropical disease research has changed considerably in recent decades, and the German government is committed to addressing its past neglect of NTD research. Our aim was to use an innovative social network analysis of bibliometric data to map neglected tropical disease research networks that are inside of and affiliated with Germany, thereby enabling data-driven health policy decision-making. We created and analysed co-author networks from publications in the SCOPUS database, with a focus on five diseases. We found that Germany's share of global publication output for NTDs is approximately half that of other medical research fields. Furthermore, we identified institutions with prominent NTD research within Germany and strong research collaborations between German institutions and partners abroad, mostly in other high-income countries. This allowed an assessment of strong collaborations for further development, e.g., for research capacity strengthening in low-income-countries, but also for identifying missed opportunities for collaboration within the network. Through co-authorship network analysis of individual researcher networks, we identified strong performers by using classic bibliometric parameters, and we identified academic talent by social network analysis parameters on an individual level

Virosome-Formulated Plasmodium falciparum AMA-1 & CSP Derived Peptides as Malaria Vaccine: Randomized Phase 1b Trial in Semi-Immune Adults & Children

BACKGROUND\ud \ud This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.\ud \ud METHODS\ud \ud The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.\ud \ud RESULTS\ud \ud No serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR  = 0.50 [95%-CI: 0.29-0.88], p = 0.02).\ud \ud CONCLUSION\ud \ud These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.\ud \ud TRIAL REGISTRATION\ud \ud ClinicalTrials.gov NCT00513669

Evaluation of inhaler technique and achievement and maintenance of mastery of budesonide/formoterol Spiromax® compared with budesonide/formoterol Turbuhaler® in adult patients with asthma: the Easy Low Instruction Over Time (ELIOT) study

Background: Incorrect inhaler technique is a common cause of poor asthma control. This two-phase pragmatic study evaluated inhaler technique mastery and maintenance of mastery with DuoResp® (budesonide-formoterol [BF]) Spiromax® compared with Symbicort® (BF) Turbuhaler® in patients with asthma who were receiving inhaled corticosteroids/long-acting β2-agonists. Methods: In the initial cross-sectional phase, patients were randomized to a 6-step training protocol with empty Spiromax and Turbuhaler devices. Patients initially demonstrating ≥1 error with their current device, and then achieving mastery with both Spiromax and Turbuhaler (absence of healthcare professional [HCP]-observed errors), were eligible for the longitudinal phase. In the longitudinal phase, patients were randomized to BF Spiromax or BF Turbuhaler. Co-primary endpoints were the proportions of patients achieving device mastery after three training steps and maintaining device mastery (defined as the absence of HCP-observed errors after 12 weeks of use). Secondary endpoints included device preference, handling error frequency, asthma control, and safety. Exploratory endpoints included assessment of device mastery by an independent external expert reviewing video recordings of a subset of patients. Results: Four hundred ninety-three patients participated in the cross-sectional phase, and 395 patients in the longitudinal phase. In the cross-sectional phase, more patients achieved device mastery after three training steps with Spiromax (94%) versus Turbuhaler (87%) (odds ratio [OR] 3.77 [95% confidence interval (CI) 2.05–6.95], p < 0.001). Longitudinal phase data indicated that the odds of maintaining inhaler mastery at 12 weeks were not statistically significantly different (OR 1.26 [95% CI 0.80–1.98], p = 0.316). Asthma control improved in both groups with no significant difference between groups (OR 0.11 [95% CI -0.09–0.30]). An exploratory analysis indicated that the odds of maintaining independent expert-verified device mastery were significantly higher for patients using Spiromax versus Turbuhaler (OR 2.11 [95% CI 1.25–3.54]). Conclusions: In the cross-sectional phase, a significantly greater proportion of patients using Spiromax versus Turbuhaler achieved device mastery; in the longitudinal phase, the proportion of patients maintaining device mastery with Spiromax versus Turbuhaler was similar. An exploratory independent expert-verified analysis found Spiromax was associated with higher levels of device mastery after 12 weeks. Asthma control was improved by treatment with both BF Spiromax and BF Turbuhaler

Change in basic motor abilities, quality of movement and everyday activities following intensive, goal-directed, activity-focused physiotherapy in a group setting for children with cerebral palsy

Background: The effects of intensive training for children with cerebral palsy (CP) remain uncertain. The aim of the study was to investigate the impact on motor function, quality of movements and everyday activities of three hours of goal-directed activity-focused physiotherapy in a group setting, five days a week for a period of three weeks. Methods: A repeated measures design was applied with three baseline and two follow up assessments; immediately and three weeks after intervention. Twenty-two children with hemiplegia (n = 7), diplegia (n = 11), quadriplegia (n = 2) and ataxia (n = 2) participated, age ranging 3-9 y. All levels of Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) were represented. Parents and professionals participated in goal setting and training. ANOVA was used to analyse change over repeated measures. Results: A main effect of time was shown in the primary outcome measure; Gross Motor Function Measure-66 (GMFM- 66), mean change being 4.5 (p < 0.01) from last baseline to last follow up assessment. An interaction between time and GMFCS-levels was found, implying that children classified to GMFCS-levels I-II improved more than children classified to levels III-V. There were no main or interaction effects of age or anti-spastic medication. Change scores in the Pediatric Evaluation of Disability Inventory (PEDI) ranged 2.0-6.7, p < 0.01 in the Self-care domain of the Functional Skills dimension, and the Self-care and Mobility domains of the Caregiver Assistance dimension. The children's individual goals were on average attained, Mean Goal Attainment Scaling (GAS) T-score being 51.3. Non-significant improved scores on the Gross Motor Performance Measure (GMPM) and the Quality of Upper Extremities Skills Test (QUEST) were demonstrated. Significant improvement in GMPM scores were found in improved items of the GMFM, not in items that maintained the same score. Conclusions: Basic motor abilities and self-care improved in young children with CP after goal-directed activityfocused physiotherapy with involvement of their local environment, and their need for caregiver assistance in self-care and mobility decreased. The individualized training within a group context during a limited period of time was feasible and well-tolerated. The coherence between acquisition of basic motor abilities and quality of movement should be further examined

The effects of improving sleep on mental health (OASIS): a randomised controlled trial with mediation analysis

BACKGROUND: Sleep difficulties might be a contributory causal factor in the occurrence of mental health problems. If this is true, improving sleep should benefit psychological health. We aimed to determine whether treating insomnia leads to a reduction in paranoia and hallucinations. METHODS: We did this single-blind, randomised controlled trial (OASIS) at 26 UK universities. University students with insomnia were randomly assigned (1:1) with simple randomisation to receive digital cognitive behavioural therapy (CBT) for insomnia or usual care, and the research team were masked to the treatment. Online assessments took place at weeks 0, 3, 10 (end of therapy), and 22. The primary outcome measures were for insomnia, paranoia, and hallucinatory experiences. We did intention-to-treat analyses. The trial is registered with the ISRCTN registry, number ISRCTN61272251. FINDINGS: Between March 5, 2015, and Feb 17, 2016, we randomly assigned 3755 participants to receive digital CBT for insomnia (n=1891) or usual practice (n=1864). Compared with usual practice, the sleep intervention at 10 weeks reduced insomnia (adjusted difference 4·78, 95% CI 4·29 to 5·26, Cohen's d=1·11; p<0·0001), paranoia (-2·22, -2·98 to -1·45, Cohen's d=0·19; p<0·0001), and hallucinations (-1·58, -1·98 to -1·18, Cohen's d=0·24; p<0·0001). Insomnia was a mediator of change in paranoia and hallucinations. No adverse events were reported. INTERPRETATION: To our knowledge, this is the largest randomised controlled trial of a psychological intervention for a mental health problem. It provides strong evidence that insomnia is a causal factor in the occurrence of psychotic experiences and other mental health problems. Whether the results generalise beyond a student population requires testing. The treatment of disrupted sleep might require a higher priority in mental health provision. FUNDING: Wellcome Trust

A volumetric technique for fossil body mass estimation applied to Australopithecus afarensis

Fossil body mass estimation is a well established practice within the field of physical anthropology. Previous studies have relied upon traditional allometric approaches, in which the relationship between one/several skeletal dimensions and body mass in a range of modern taxa is used in a predictive capacity. The lack of relatively complete skeletons has thus far limited the potential application of alternative mass estimation techniques, such as volumetric reconstruction, to fossil hominins. Yet across vertebrate paleontology more broadly, novel volumetric approaches are resulting in predicted values for fossil body mass very different to those estimated by traditional allometry. Here we present a new digital reconstruction of Australopithecus afarensis (A.L. 288-1; ‘Lucy’) and a convex hull-based volumetric estimate of body mass. The technique relies upon identifying a predictable relationship between the ‘shrink-wrapped’ volume of the skeleton and known body mass in a range of modern taxa, and subsequent application to an articulated model of the fossil taxa of interest. Our calibration dataset comprises whole body computed tomography (CT) scans of 15 species of modern primate. The resulting predictive model is characterized by a high correlation coefficient (r2 = 0.988) and a percentage standard error of 20%, and performs well when applied to modern individuals of known body mass. Application of the convex hull technique to A. afarensis results in a relatively low body mass estimate of 20.4 kg (95% prediction interval 13.5–30.9 kg). A sensitivity analysis on the articulation of the chest region highlights the sensitivity of our approach to the reconstruction of the trunk, and the incomplete nature of the preserved ribcage may explain the low values for predicted body mass here. We suggest that the heaviest of previous estimates would require the thorax to be expanded to an unlikely extent, yet this can only be properly tested when more complete fossils are available

Suicide trends in the early months of the COVID-19 pandemic: an interrupted time-series analysis of preliminary data from 21 countries

BackgroundThe COVID-19 pandemic is having profound mental health consequences for many people. Concerns have been expressed that at its most extreme, this may manifest itself in increased suicide rates.MethodsWe sourced real-time suicide data from around the world via a systematic internet search and recourse to our networks and the published literature. We used interrupted time series analysis to model the trend in monthly suicides prior to COVID-19 in each country/area-within-country, comparing the expected number of suicides derived from the model with the observed number of suicides in the early months of the pandemic. Countries/areas-within countries contributed data from at least 1 January 2019 to 31 July 2020 and potentially from as far back as 1 January 2016 until as recently as 31 October 2020. We conducted a primary analysis in which we treated 1 April to 31 July 2020 as the COVID-19 period, and two sensitivity analyses in which we varied its start and end dates (for those countries/areas-within-countries with data beyond July 2020).OutcomesWe sourced data from 21 countries (high income [n=16], upper-middle income [n=5]; whole country [n=10], area(s)-within-the-country [n=11]). In general, there does not appear to have been a significant increase in suicides since the pandemic began in the countries for which we had data. In fact, in a number of countries/areas-within-countries there appears to have been a decrease.InterpretationThis is the first study to examine suicides occurring in the context of the COVID-19 pandemic in multiple countries. It offers a consistent picture, albeit from high- and upper-middle income countries, of suicide numbers largely remaining unchanged or declining in the early months of the pandemic. We need to remain vigilant and be poised to respond if the situation changes as the longer-term mental health and economic impacts of the pandemic unfold