Age-dependent change and intraskeletal variability in secondary osteons of elderly Australians.

There is a need to fully understand intra-skeletal variability within different populations to develop and improve age-at-death estimation methods. This study evaluates age-related histomorphometric changes in three different bones intra-individually in a modern Australian sample. Four female and 13 male elderly Australian adult donors (67-93 years) were examined for osteon population density (OPD), osteon area (On.Ar), and Haversian canal area (H.Ar) of secondary osteons to compare between femora, ribs, and humeri and assess against age. In the pooled sex sample, no statistically significant correlations were observed between age and each histological variable. In the males, OPD of the femur increased significantly with age, as did porosity in the rib. In the male humeri, OPD increased moderately with age, while H.Ar was decreased moderately with age. Intra-bone comparisons showed that males had significantly higher osteon counts in their ribs compared to their femora, while their ribs showed statistically significantly less porosity than their humeri. When bone size was accounted for, by adjusting the femur and humerus histology data by robusticity indices, histology values were found to be similar between bones within the same individual. This is despite the upper and lower limbs receiving different ranges and types of biomechanical load. Our findings demonstrate that bone size influences histomorphometry, and this could confound age-at-death estimations that have not been adjusted for robusticity. Future studies would benefit from examining bone histomorphometry within a larger sample size and incorporating bone robusticity measures into histology analyses.

Evaluation of survival extrapolation in immuno-oncology using multiple pre-planned data cuts: learnings to aid in model selection.

BACKGROUND: Due to limited duration of follow up in clinical trials of cancer treatments, estimates of lifetime survival benefits are typically derived using statistical extrapolation methods. To justify the method used, a range of approaches have been proposed including statistical goodness-of-fit tests and comparing estimates against a previous data cut (i.e. interim data collected). In this study, we extend these approaches by presenting a range of extrapolations fitted to four pre-planned data cuts from the JAVELIN Merkel 200 (JM200) trial. By comparing different estimates of survival and goodness-of-fit as JM200 data mature, we undertook an iterative process of fitting and re-fitting survival models to retrospectively identify early indications of likely long-term survival. METHODS: Standard and spline-based parametric models were fitted to overall survival data from each JM200 data cut. Goodness-of-fit was determined using an assessment of the estimated hazard function, information theory-based methods and objective comparisons of estimation accuracy. Best-fitting extrapolations were compared to establish which one provided the most accurate estimation, and how statistical goodness-of-fit differed. RESULTS: Spline-based models provided the closest fit to the final JM200 data cut, though all extrapolation methods based on the earliest data cut underestimated the 'true' long-term survival (difference in restricted mean survival time [RMST] at 36 months: - 1.1 to - 0.5 months). Goodness-of-fit scores illustrated that an increasingly flexible model was favored as data matured. Given an early data cut, a more flexible model better aligned with clinical expectations could be reasonably justified using a range of metrics, including RMST and goodness-of-fit scores (which were typically within a 2-point range of the statistically 'best-fitting' model). CONCLUSIONS: Survival estimates from the spline-based models are more aligned with clinical expectation and provided a better fit to the JM200 data, despite not exhibiting the definitively 'best' statistical goodness-of-fit. Longer-term data are required to further validate extrapolations, though this study illustrates the importance of clinical plausibility when selecting the most appropriate model. In addition, hazard-based plots and goodness-of-fit tests from multiple data cuts present useful approaches to identify when a more flexible model may be advantageous. TRIAL REGISTRATION: JAVELIN Merkel 200 was registered with ClinicalTrials.gov as NCT02155647 on June 4, 2014.

The neolithic demographic transition and oral health: The Southeast Asian experience.

The purpose of this article is to present new oral health data from Neolithic An Son, southern Vietnam, in the context of (1) a reassessment of published data on other Neolithic, Bronze, and Iron Age Southeast Asian dental series, and (2) predictions of the Neolithic Demographic Transition (NDT). To this end, frequencies for three oral conditions (caries, antemortem tooth loss, and alveolar lesions) were investigated for seven Southeast Asian adult dental series from Thailand and Vietnam with respect to time period, age-at-death and sex. A clear pattern of elevated rates for oral disease in the Neolithic followed by a marked improvement in oral health during the Bronze and Iron Ages was observed. Moreover, rates of caries and antemortem tooth loss for females were almost without exception higher than that for males in all samples. The consensus view among Southeast Asian bioarchaeologists that oral health did not decline with the adoption/intensification of agriculture in Southeast Asia, can no longer be supported. In light of evidence for (1) the low cariogenicity of rice; (2) the physiological predisposition of females (particularly when pregnant) to poorer oral health; and (3) health predictions of the NDT model with respect to elevated levels of fertility, the most plausible chief explanation for the observed patterns in oral health in Southeast Asia is increased levels of fertility during the Neolithic, followed by a decline in fertility during the subsequent Bronze and Iron Ages.

Paleoepidemiology of cribra orbitalia: Insights from early seventh millennium BP Con Co Ngua, Vietnam.

OBJECTIVES: We test the hypothesis that the condition(s) leading to the development of cribra orbitalia at Con Co Ngua, an early seventh millennium sedentary foraging community in Vietnam, effectively reduced the resilience of the population to subsequent health/disease impacts. An assessment of both the implications and potential etiology of cribra orbitalia in this specific population is carried out. METHODS: The effective sample included 141 adults aged ≥15 years (53 females, 71 males, and 17 unknown sex) and 15 pre-adults aged ≤14 years. Cribra orbitalia was identified by way of cortical bone porosity of the orbital roof initiated within the diplöic space, rather than initiated subperiosteally. The approach is also robust to the misidentification of various pseudo-lesions. Resultant data was analyzed using Kaplan-Meier survival analysis. RESULTS: Median survival is higher in adults aged ≥15 years without cribra orbitalia than those with this lesion. For the pre-adult cohort, the opposite pattern is seen where median survival is higher in those with cribra orbitalia than those without. CONCLUSION: Adults displayed increased frailty and pre-adults increased resilience with respect to cribra orbitalia. The differential diagnosis for a survival analysis of adults and pre-adults with and without cribra orbitalia included iron deficiency anemia and B12/folate deficiency, parasitism (including hydatid disease and malaria) in addition to thalassemia. The most parsimonious explanation for observed results is for both thalassemia and malaria being the chief etiological agents, while appreciating these conditions interact with, and can cause, other forms such as hematinic deficiency anemias.

IL-33 Induces an Antiviral Signature in Mast Cells but Enhances Their Permissiveness for Human Rhinovirus Infection.

Mast cells (MCs) are classically associated with allergic asthma but their role in antiviral immunity is unclear. Human rhinoviruses (HRVs) are a major cause of asthma exacerbations and can infect and replicate within MCs. The primary site of HRV infection is the airway epithelium and MCs localise to this site with increasing asthma severity. The asthma susceptibility gene, IL-33, encodes an epithelial-derived cytokine released following HRV infection but its impact on MC antiviral responses has yet to be determined. In this study we investigated the global response of LAD2 MCs to IL-33 stimulation using RNA sequencing and identified genes involved in antiviral immunity. In spite of this, IL-33 treatment increased permissiveness of MCs to HRV16 infection which, from the RNA-Seq data, we attributed to upregulation of ICAM1. Flow cytometric analysis confirmed an IL-33-dependent increase in ICAM1 surface expression as well as LDLR, the receptors used by major and minor group HRVs for cellular entry. Neutralisation of ICAM1 reduced the IL-33-dependent enhancement in HRV16 replication and release in both LAD2 MCs and cord blood derived MCs. These findings demonstrate that although IL-33 induces an antiviral signature in MCs, it also upregulates the receptors for HRV entry to enhance infection. This highlights the potential for a gene-environment interaction involving IL33 and HRV in MCs to contribute to virus-induced asthma exacerbations.

Hydatid disease (Echinococcosis granulosis) diagnosis from skeletal osteolytic lesions in an early seventh-millennium BP forager community from preagricultural northern Vietnam.

OBJECTIVES: Con Co Ngua is a complex, sedentary forager site from northern Vietnam dating to the early seventh millennium BP. Prior research identified a calcified Echinococcus granulosis cyst, which causes hydatid disease. Osteolytic lesions consistent with hydatid disease were also present in this individual and others. Hydatid disease is observed in high frequencies in pastoralists, and its presence in a hunter-gatherer community raises questions regarding human-animal interaction prior to farming. The objective of this article is to identify and describe the epidemiology of hydatid disease in the human skeletal assemblage at Con Co Ngua. MATERIALS AND METHODS: One hundred and fifty-five individuals were macroscopically assessed for lesions. Of these, eight individuals were radiographed. Hydatid disease was diagnosed using a new threshold criteria protocol derived from clinical literature, which prioritizes lesions specific to the parasite. RESULTS: Twenty-two individuals (14.2%) presented with osteolytic lesions consistent with hydatid disease, affecting the distal humerus, proximal femur and forearm, and pelvis. Seven individuals radiographed (4.5%) had multilocular cystic lesions strongly diagnostic for hydatid disease. All probable cases had lesions of the distal humerus. The remaining lesions were macroscopically identical to those radiographed and were considered possible cases. DISCUSSION: While hydatid disease has previously been found in pre-agricultural communities, the high prevalence at Con Co Ngua is non-incidental. We propose that the presence of wild canids and management of wild buffalo and deer increased the risk of disease transmission. These findings further reveal subsistence complexity among hunter-gatherers living millennia prior to the adoption of farming in Southeast Asia.

"Lest we forget": An overview of Australia's response to the recovery and identification of unrecovered historic military remains.

The Australian Defence Force (ADF) is responsible for the recovery and identification of its historic casualties. With over 30,000 still unrecovered from past conflicts including World War One (WW1) and World War Two (WWII), the Australian Army and Royal Australian Air Force have teams that research, recover, identify and oversee the burial (or reburial) of the remains of soldiers and airmen who continue to be found each year. The Royal Australian Navy is also responsible for its unrecovered casualties. Collectively the priorities of the various services within the ADF are the respectful recovery and treatment of the dead, thorough forensic identification efforts, resolution for families and honouring the ADF's proud history of service and sacrifice. What is unique about the approach of the ADF is that the respective services retain responsibility for their historic losses, while a joint approach is taken on policies and in the utilisation of the pool of forensic specialists. Section One describes the process undertaken by the Australian Army in the recovery, identification and burial or repatriation of soldiers through its specialised unit Unrecovered War Casualties - Army (UWC-A). Section Two describes the role of the Royal Australian Air Force in the recovery of aircraft and service personnel through their specialised unit Historic Unrecovered War Casualties - Air Force (HUWC-AF). An overview of the operations of each service and case studies is presented for each section.

Forager and farmer evolutionary adaptations to malaria evidenced by 7000 years of thalassemia in Southeast Asia.

Thalassemias are inherited blood disorders that are found in high prevalences in the Mediterranean, Southeast Asia and the Pacific. These diseases provide varying levels of resistance to malaria and are proposed to have emerged as an adaptive response to malaria in these regions. The transition to agriculture in the Holocene has been suggested to have influenced the selection for thalassemia in the Mediterranean as land clearance for farming encouraged interaction between Anopheles mosquitos, the vectors for malaria, and human groups. Here we document macroscopic and microscopic skeletal evidence for the presence of thalassemia in both hunter-gatherer (Con Co Ngua) and early agricultural (Man Bac) populations in northern Vietnam. Firstly, our findings demonstrate that thalassemia emerged prior to the transition to agriculture in Mainland Southeast Asia, from at least the early seventh millennium BP, contradicting a long-held assumption that agriculture was the main driver for an increase in malaria in Southeast Asia. Secondly, we describe evidence for significant malarial burden in the region during early agriculture. We argue that the introduction of farming into the region was not the initial driver of the selection for thalassemia, as it may have been in other regions of the world.

Domestication and large animal interactions: Skeletal trauma in northern Vietnam during the hunter-gatherer Da But period.

The aim of this paper is to test the hypothesis that healed traumatic injuries in the pre-Neolithic assemblage of Con Co Ngua, northern Vietnam (c. 6800-6200 cal BP) are consistent with large wild animal interactions prior to their domestication. The core sample included 110 adult (aged ≥ 18 years) individuals, while comparisons are made with an additional six skeletal series from Neolithic through to Iron Age Vietnam, Thailand, and Mongolia. All post cranial skeletal elements were assessed for signs of healed trauma and identified cases were further x-rayed. Crude trauma prevalence (14/110, 12.7%) was not significantly different between males (8/52) and females (5/37) (χ2 = 0.061, p = 0.805). Nor were there significant differences in the prevalence of fractured limbs, although males displayed greater rates of lower limb bone trauma than females. Further, distinct from females, half the injured males suffered vertebral fractures, consistent with high-energy trauma. The first hypothesis is supported, while some support for the sexual divisions of labour was found. The prevalence and pattern of fractured limbs at CCN when compared with other Southeast and East Asian sites is most similar to the agropastoral site of Lamadong, China. The potential for skeletal trauma to assess animal trapping and herding practices prior to domestication in the past is discussed.

Cost Effectiveness of Avelumab for Metastatic Merkel Cell Carcinoma.

BACKGROUND: Metastatic Merkel cell carcinoma (mMCC) is a rare and aggressive skin cancer. Until recently, there were no licensed treatment options for patients with mMCC, and prognosis was poor. A cost-effectiveness analysis was conducted for avelumab, a newly available treatment option for mMCC, versus standard care (SC), from a UK National Health Service perspective. METHODS: A partitioned survival model was developed to assess the lifetime costs and effects of avelumab versus SC. Data from the JAVELIN Merkel 200 trial (NCT02155647) were used to inform estimates of quality-adjusted life-years (QALYs). Unit costs and associated frequencies of use were informed by published literature and clinical expert opinion. Results were presented as incremental cost-effectiveness ratios (ICERs, i.e. the cost per QALY gained) for treatment-experienced (TE) and treatment-naïve (TN) patients. Uncertainty was explored through a range of sensitivity analyses. RESULTS: Discounting costs and QALYs at 3.5% per annum, avelumab was associated with ICERs of £35,274 (TE)/£39,178 (TN) per QALY gained. Probabilistic sensitivity analysis results demonstrated that avelumab was associated with an 88.3% (TE)/69.3% (TN) probability of being cost effective at a willingness-to-pay threshold for end-of-life treatments of £50,000 per QALY gained. Results were most sensitive to alternative survival extrapolations and dosing assumptions. CONCLUSIONS: The analysis results suggest that avelumab is likely to be a cost-effective treatment option for UK mMCC patients. The results for TN patients are subject to some uncertainty, and a confirmatory analysis will be conducted with more mature data.

Cranio-morphometric and aDNA corroboration of the Austronesian dispersal model in ancient Island Southeast Asia: Support from Gua Harimau, Indonesia.

The Austronesian language is spread from Madagascar in the west, Island Southeast Asia (ISEA) in the east (e.g. the Philippines and Indonesian archipelagoes) and throughout the Pacific, as far east as Easter Island. While it seems clear that the remote ancestors of Austronesian speakers originated in Southern China, and migrated to Taiwan with the development of rice farming by c. 5500 BP and onto the northern Philippines by c. 4000 BP (the Austronesian Dispersal Hypothesis or ADH), we know very little about the origins and emergence of Austronesian speakers in the Indonesian Archipelago. Using a combination of cranial morphometric and ancient mtDNA analyses on a new dataset from Gua Hairmau, that spans the pre-Neolithic through to Metal Period (5712-5591cal BP to 1864-1719 cal BP), we rigorously test the validity of the ADH in ISEA. A morphometric analysis of 23 adult male crania, using 16 of Martin's standard measurements, was carried out with results compared to an East and Southeast Asian dataset of 30 sample populations spanning the Late Pleistocene through to Metal Period, in addition to 39 modern samples from East and Southeast Asia, near Oceania and Australia. Further, 20 samples were analyzed for ancient mtDNA and assigned to identified haplogroups. We demonstrate that the archaeological human remains from Gua Harimau cave, Sumatra, Indonesia provide clear evidence for at least two (cranio-morphometrically defined) and perhaps even three (in the context of the ancient mtDNA results) distinct populations from two separate time periods. The results of these analyses provide substantive support for the ADH model in explaining the origins and population history of ISEA peoples.

Ancient genomes document multiple waves of migration in Southeast Asian prehistory.

Southeast Asia is home to rich human genetic and linguistic diversity, but the details of past population movements in the region are not well known. Here, we report genome-wide ancient DNA data from 18 Southeast Asian individuals spanning from the Neolithic period through the Iron Age (4100 to 1700 years ago). Early farmers from Man Bac in Vietnam exhibit a mixture of East Asian (southern Chinese agriculturalist) and deeply diverged eastern Eurasian (hunter-gatherer) ancestry characteristic of Austroasiatic speakers, with similar ancestry as far south as Indonesia providing evidence for an expansive initial spread of Austroasiatic languages. By the Bronze Age, in a parallel pattern to Europe, sites in Vietnam and Myanmar show close connections to present-day majority groups, reflecting substantial additional influxes of migrants.

Childhood long-term conditions in primary care: a qualitative study of practitioners' views.

BACKGROUND: Improving child health and wellbeing in England was the key focus of the Chief Medical Officer's Annual Report 2012, which recommended that all children with long-term conditions (LTCs) have a named GP responsible for their care. Little is known, however, about practitioners' views and experiences of supporting children with LTCs in primary care. AIM: To explore practitioners' views of supporting children with LTCs and their families in primary care. DESIGN AND SETTING: Qualitative interview study in primary care settings in South Yorkshire, England. METHOD: Interviews explored practitioners' views and experiences of supporting children with asthma, cystic fibrosis, type 1 diabetes, and epilepsy. Interviews were audiotaped, transcribed verbatim, and analysed using the framework approach. RESULTS: Nineteen practitioners were interviewed: 10 GPs, five practice nurses, and four nurse practitioners. The GPs' clinical roles included prescribing and concurrent illness management; nurse practitioners held minor illness clinics; and practice nurses conduct asthma clinics and administer immunisations. GPs were coordinators of care and provided a holistic service to the family. GPs were often unsure of their role with children with LTCs, and did not feel they had overall responsibility for these patients. Confidence was dependent on experience; however, knowledge of GPs' own limits and accessing help were felt to be more important than knowledge of the condition. CONCLUSION: Primary care has a valuable role in the care of children with LTCs and their families. This study suggests that improving communication between services would clarify roles and help improve the confidence of primary care practitioners.