Paediatric meningitis in the conjugate vaccine era and a novel clinical decision model to predict bacterial aetiology.

OBJECTIVES: The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes. METHODS: Children aged <16 years hospitalised with suspected meningitis/encephalitis were included, and prospectively recruited at 31 UK hospitals. Meningitis was defined as identification of bacteria/viruses from cerebrospinal fluid (CSF) and/or a raised CSF white blood cell count. New clinical decision rules were developed to distinguish bacterial from viral meningitis and those of alternative aetiology. RESULTS: The cohort included 3002 children (median age 2·4 months); 1101/3002 (36·7%) had meningitis, including 180 bacterial, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged <6 months and 10-16 years, with Neisseria meningitidis and/or Streptococcus pneumoniae commonest at age 6 months to 9 years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after lumbar puncture (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis. CONCLUSIONS: Bacterial meningitis comprised 6% of children with suspected meningitis/encephalitis. Our clinical decision rules provide potential novel approaches to assist with identifying children with bacterial meningitis. FUNDING: This study was funded by the Meningitis Research Foundation, Pfizer and the NIHR Programme Grants for Applied Research.

Earliest systematic coal exploitation for fuel extended to ~3600 B.P.

Coal has long fueled human civilizations. The history of systematic coal fuel exploitation has been traced back to the late third millennium before present (post-2500 B.P.). Although sporadic combustion of coal for fuel was reported in some prehistoric archaeological sites, evidence for the systematic exploitation of coal for fuel before 2500 B.P. remains lacking. Here, we report comprehensive understanding for the earliest systematic exploitation of coal for fuel at the Jirentaigoukou site in Xinjiang, northwestern China, at ~3600 B.P. The main body of the site witnessed systematic exploitation of bituminous coals, illustrating a complete chaîne opératoire with selective mining, planned storage, and extensive combustion. Our results transform the knowledge of energy history by extending the upper limit of the systematic exploitation of coal for fuel by approximately a millennium, and provide a precedent of energy transition under intense conflict between social demand and environmental deterioration.

Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults.

Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, 3- and 7-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at 3 days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.

A Retrospective Service- Evaluation of Implant Success, Survival, Periimplant Health and Prosthetic Complications in a Cohort of Head and Neck Cancer Patients.

OBJECTIVES: To determine the success, survival, peri-implant health and prosthetic complications in head and neck cancer patients receiving oral rehabilitation utilising dental implants between 2008 and the present day. MATERIALS AND METHODS: Service evaluation. Survival Group: Retrospective review of records to determine implant survival and prosthetic complications. Success Group: Examination to determine implant success and health. RESULTS: Survival Group: 260 implants in 81 individuals, median follow up 49.2 months. 89.3% implant survival at 96 months, no further failures up to 133 months. 40.9% individuals required repair or remake of prosthesis by 72 months - mostly denture re-lines. Success group: 164 implants in 48 individuals, median follow up 56 months. Peri-implant mucositis detected in 22% of fixtures (37.5% individuals); peri-implantitis in 12.8% (25% individuals); 33.3% fixtures exhibiting periimplantitis at 120 months. Previous smoking significantly associated with development of peri-implantitis (HR 2.372, p=0.032, 95CI:1.232, 93.317). Compromised survival (e.g. peri-implantitis), absolute (not in mouth) or clinical failure estimated to occur in 28.1% fixtures at 101 months, mostly due to peri-implantitis. CONCLUSIONS: There is a large burden of ongoing care in this cohort, requiring interventions to improve peri-implant health and maintain complex prostheses. Oral rehabilitation and ongoing maintenance in this cohort is complex and multi-disciplinary.

Diverse dietary practices across the Early Bronze Age 'Kura-Araxes culture' in the South Caucasus.

The Kura-Araxes (KA) cultural phenomenon (dated to the Early Bronze Age, c. 3500/3350-2500 BCE) is primarily characterised by the emergence of a homogeneous pottery style and a uniform 'material culture package' in settlements across the South Caucasus, as well as territories extending to the Ancient Near East and the Levant. It has been argued that KA societies practised pastoralism, despite a lack of direct examination of dietary and culinary practices in this region. Here, we report the first analyses of absorbed lipid residues from KA pottery to both determine the organic products produced and consumed and to reconstruct subsistence practices. Our results provide compelling evidence for a diversified diet across KA settlements in Armenia, comprising a mixed economy of meat and plant processing, aquatic fats and dairying. The preservation of diagnostic plant lipid biomarkers, notably long-chain fatty acids (C20 to C28) and n-alkanes (C23 to C33) has enabled the identification of the earliest processing of plants in pottery of the region. These findings suggest that KA settlements were agropastoral exploiting local resources. Results demonstrate the significance of applying biomolecular methods for examining dietary inferences in the South Caucasus region.

Unlocking the organic residues preserved in the corrosion from the Pewsey Hoard vessels.

The characterization of archaeological metal corrosion has traditionally been limited to the identification of inorganic compounds usually by X-ray diffraction (XRD), thought to result from the interaction between the metal object and the deposition environment. The discovery of a hoard of Late Roman copper-alloy vessels in Wiltshire, UK presented an unique opportunity to adopt a multi-analytical approach to characterize corrosion combining XRD with Fourier-transform infrared (FTIR) and gas chromatography with quadrupole time-of-flight mass spectrometry using a thermal separation probe (GC-QTOF-MS with TSP). This approach revealed organic compounds potentially historical preserved within crystalline inorganic matrices. It has been known for some time that ceramics can harbour organic residues, which provide crucial evidence about the use of these vessels in the past. Our results confirms that similar residues appear to survive in metal corrosion thus extending the potential for identification of biomaterials used in the past.

The influence of pesticides on the corrosion of a Roman bowl excavated in Kent, UK.

We analysed corrosion from a copper bowl dating from the Roman period (43-410 AD) found in a farm in Kent, UK. Despite its relatively good condition, the interior and exterior surface of the object had areas of deterioration containing green and brown-coloured corrosion which were sampled for characterization by a multi-analytical protocol. Basic copper chlorides atacamite and paratacamite were identified in the context of mineral phases along with chlorobenzenes in the green corrosion. Chlorobenzenes are common soil contaminants in rural areas from the use of pesticides, many of which were banned more than 50 years ago. Here we show that their presence is associated with accelerated corrosion, and this provides a threat to the preservation of archaeological metal objects in the ground.

New scientific analyses reveal mixing of copper sources in the early Iron Age metal production at Ili, western China.

The crucial role that Xinjiang played in cultural communication across the Eurasian steppe in prehistory is evidenced by the large number of copper-based objects that represent the early metallurgical technologies found across this region. Our research adds new chemical and isotopic analyses of 44 copper-based objects dated to the early Iron Age of Ili in Xinjiang, western China. As noted in a number of publications, tin bronze and arsenic copper/bronze were the dominant alloying types across Xinjiang during the second and first millennium BC, whereas some specific types of objects such as cauldrons are often made from pure copper. The western Tianshan Mountain, including the well-known mining site Nulasai, is the most likely copper source for the Ili metalworking. Meanwhile, a combination of lead isotopes, lead concentrations and trace elemental data reveals new evidence for the mixing and recycling of different sources of copper.

Species identification of silks by protein mass spectrometry reveals evidence of wild silk use in antiquity.

Silk has been a luxurious commodity throughout modern human history and sericulture has played an important role in ancient global trade as well as technological and cultural developments. Archaeological findings suggest that prior to domestication of the mulberry silkworm (Bombyx mori) silks were obtained from a range of silk-producing moth species with regional specificity. However, investigating the origins of sericulture is difficult as classification of silks by species-type has proved technically challenging. We therefore investigated a range of methods for solubilising modern and archaeological silks and developed a mass spectrometry-based proteomics method that was able to successfully differentiate modern Bombyx, Antheraea, and Samia-produced silks down to the species level. We subsequently analysed archaeological silk materials excavated from the ancient city of Palmyra. Solubilisation behaviour and proteomic analysis provided evidence that the Palmyra silks were constructed from wild silk derived from Antheraea mylitta, the Indian Tasar silkworm. We believe this is the first species-level biochemical evidence that supports archaeological theories about the production and trade of Indian wild silks in antiquity.

Intraspecific Variation in Nickel Tolerance and Hyperaccumulation among Serpentine and Limestone Populations of Odontarrhena serpyllifolia (Brassicaceae: Alysseae) from the Iberian Peninsula.

Odontarrhena serpyllifolia (Desf.) Jord. & Fourr. (=Alyssum serpyllifolium Desf.) occurs in the Iberian Peninsula and adjacent areas on a variety of soils including both limestone and serpentine (ultramafic) substrates. Populations endemic to serpentine are known to hyperaccumulate nickel, and on account of this remarkable phenotype have, at times, been proposed for recognition as taxonomically distinct subspecies or even species. It remains unclear, however, to what extent variation in nickel hyperaccumulation within this taxon merely reflects differences in the substrate, or whether the different populations show local adaptation to their particular habitats. To help clarify the physiological basis of variation in nickel hyperaccumulation among these populations, 3 serpentine accessions and 3 limestone accessions were cultivated hydroponically under common-garden conditions incorporating a range of Ni concentrations, along with 2 closely related non-accumulator species, Clypeola jonthlaspi L. and Alyssum montanum L. As a group, serpentine accessions of O. serpyllifolia were able to tolerate Ni concentrations approximately 10-fold higher than limestone accessions, but a continuous spectrum of Ni tolerance was observed among populations, with the least tolerant serpentine accession not being significantly different from the most tolerant limestone accession. Serpentine accessions maintained relatively constant tissue concentrations of Ca, Mg, K, and Fe across the whole range of Ni exposures, whereas in the limestone accessions, these elements fluctuated widely in response to Ni toxicity. Hyperaccumulation of Ni, defined here as foliar Ni concentrations exceeding 1g kg-1 of dry biomass in plants not showing significant growth reduction, occurred in all accessions of O. serpyllifolia, but the higher Ni tolerance of serpentine accessions allowed them to hyperaccumulate more strongly. Of the reference species, C. jonthlaspi responded similarly to the limestone accessions of O. serpyllifolia, whereas A. montanum displayed by far the lowest degree of Ni tolerance and exhibited low foliar Ni concentrations, which only exceeded 1 g kg-1 in plants showing severe Ni toxicity. The continuous spectrum of physiological responses among these accessions does not lend support to segregation of the serpentine populations of O. serpyllifolia as distinct species. However, the pronounced differences in degrees of Ni tolerance, hyperaccumulation, and elemental homeostasis observed among these accessions under common-garden conditions argues for the existence of population-level adaptation to their local substrates.

Cracked Tooth Syndrome: Assessment, Prognosis and Predictable Management Strategies.

Cracked tooth syndrome (CTS) is a common presentation in general practice. The diagnosis and management of teeth with CTS may be difficult due to the unknown extent of the crack. This article reviews the aetiology, diagnosis, management and prognosis of teeth with CTS. A thorough examination is required to effectively assess CTS. Intervention should aim to relieve symptoms and brace the remaining tooth structure effectively against further flexion. Restored teeth with CTS have a guarded prognosis due to the risk of further crack propagation, but the chances of survival at 5-years is acceptable (74.1-96.8%).

Routes to diagnosis and missed opportunities in the detection of renal cancer.

AIM: To determine the proportion of renal cancers for which incidental detection was the route to diagnosis, the characteristics of tumours identified in this way, and the frequency with which opportunities to make this diagnosis were missed. MATERIALS AND METHODS: Consecutive patients with renal cancers treated at Royal Cornwall Hospitals NHS Trust (April 2011 and July 2018 inclusive) were identified from the Trust's cancer registry database, and a retrospective review of the imaging and electronic case notes was undertaken. Mann-Whitney U-tests for comparison of patient age and tumour size at diagnosis, and chi-squared tests for comparing cell type distribution and grade were performed. Logistic regression was then used to identify the characteristics of patients in whom a renal tumour was missed initially. RESULTS: Of 327 patients, 194 (63%) presented incidentally, and 133 (37%) symptomatically. Incidentally detected cancers were found in younger patients, (median of 65 years versus 69 p=0.01) and were smaller at presentation (median of 5.5 versus 7.2 cm, p<0.00001). Thirty-six different reporters missed opportunities to diagnose renal cancer in 50 (16%) patients on 78 occasions, 28 lesions (35%) being missed more than once. Thirty were imaged incompletely; four were visible only on a single image and three on a scout view at magnetic resonance imaging. CONCLUSION: The commonest route to diagnosis of renal cancer is by incidental detection of a mass. In 16% of patients in whom renal cancer is diagnosed, there is at least one prior examination on which the lesion is visible at an earlier date. The clinical impact of these missed diagnostic opportunities remains uncertain.

Social hierarchy and the choice of metal recycling at Anyang, the last capital of Bronze Age Shang China.

Anyang, the last capital of the Chinese Shang dynasty, became one of the largest metal consumers in Eurasia during the second millennium BCE. However, it remains unclear how Anyang people managed to sustain such a large supply of metal. By considering the chemical analysis of bronze objects within archaeological contexts, this paper shows that the casting and circulation of metal at Anyang was effectively governed by social hierarchy. Objects belonging to the high elites such as Fuhao, particularly the bronze ritual vessels, were made by carefully controlled alloying practice (primary) using very pure copper, whereas the lower elites only had access to bronzes made by secondary alloying practice and copper with more impurities. Such contrasts allow scholars to identify those objects which are less likely to have been made by mixing and recycling, which has very important implications for the chemical and isotopic determination of provenance for future studies.

Phylogenetic and geographic distribution of nickel hyperaccumulation in neotropical Psychotria.

PREMISE: Hyperaccumulation of heavy metals in plants has never been documented from Central America or Mexico. Psychotria grandis, P. costivenia, and P. glomerata (Rubiaceae) have been reported to hyperaccumulate nickel in the Greater Antilles, but they also occur widely across the neotropics. The goals of this research were to investigate the geographic distribution of hyperaccumulation in these species and explore the phylogenetic distribution of hyperaccumulation in this clade by testing related species. METHODS: Portable x-ray fluorescence (XRF) spectroscopy was used to analyze 565 specimens representing eight species of Psychotria from the Missouri Botanical Garden herbarium. RESULTS: Nickel hyperaccumulation was found in specimens of Psychotria costivenia ranging from Mexico to Costa Rica and in specimens of P. grandis from Guatemala to Ecuador and Venezuela. Among related species, nickel hyperaccumulation is reported for the first time in P. lorenciana and P. papantlensis, but no evidence of hyperaccumulation was found in P. clivorum, P. flava, or P. pleuropoda. Previous reports of hyperaccumulation in P. glomerata appear to be erroneous, resulting from taxonomic synonymy and specimen misidentification. CONCLUSIONS: Hyperaccumulation of nickel by Psychotria is now known to occur widely from southern Mexico through Central America to northwestern South America, including some areas not known to have ultramafic soils. Novel aspects of this research include the successful prediction of new hyperaccumulator species based on molecular phylogeny, use of XRF technology to nondestructively obtain elemental data from herbarium specimens, and documentation of previously unknown areas of ultramafic or nickel-rich soil based on such data.

X-Ray Fluorescence Ionomics of Herbarium Collections.

Global herbaria are the greatest repositories of information on the plant kingdom. Discoveries of trace element hyperaccumulator plants have historically required time-consuming destructive chemical analysis of fragments from herbarium specimens, which severely constrains the collection of large datasets. Recent advances in handheld X-Ray Fluorescence spectroscopy (XRF) systems have enabled non-destructive analysis of plant samples and here we propose a new method, which we term "Herbarium XRF Ionomics", to extract elemental data from herbarium specimens. We present two case studies from major tropical herbaria where Herbarium XRF Ionomics has led to the discovery of new hyperaccumulator plants and provided valuable insights into phylogenetic patterns of trace element hyperaccumulation. Herbarium XRF Ionomics is a new value proposition for continued funding and retention of herbarium specimens globally.

Humoral and cellular immunity to RSV in infants, children and adults.

BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory disease throughout life. Here we report differences in naturally acquired immunity with age and presumed exposure. METHODS: A longitudinal, non-interventional, observational study was performed in healthy adults (20 paediatric healthcare workers and 10 non-healthcare workers), children (10 aged 3-6 years) and infants (5 aged 2-4 months and 20 aged 6-12 months). Blood samples were analysed for RSV-neutralising antibody titre, F/Ga/Gb-specific antibody titres, F-specific IgG/IgA memory B-cell frequencies and T-cell production of IFNγ, IL-4, IL-13 and IL-17. RESULTS: Serum G-specific antibody titres were significantly lower in infants and children than adults. However, serum titres of F-specific and RSV-neutralising antibody and IFNγ-producing T-cell frequencies were low or absent in the infants, but comparable between children and adults. Interestingly, F-specific memory IgA B-cells could not be detected in paediatric samples and in samples from non-healthcare workers, but recordable IgA memory B-cells were found in 9/18 paediatric healthcare workers and 2/8 non-healthcare workers at the end of the RSV season. These responses waned 4-6 months later. By contrast, F-specific IgG memory B-cells were detectable in samples from all adults without significant variation across time points. T-cells producing IL-4, IL-13 and IL-17 responses were not detectable in peripheral blood from a subset of volunteers. CONCLUSIONS: Repeated RSV exposure in early life generates immune responses that are inversely related to frequency of severe disease. Induction of F-specific antibody and cellular immune responses through infant vaccination might help to accelerate the development of protective immune responses at an early age. Clinicaltrials.gov reference NCT01563692 and NCT01640652.

Beyond ritual bronzes: identifying multiple sources of highly radiogenic lead across Chinese history.

One of the greatest enigmas in the study of Bronze Age China is the source of highly radiogenic lead discovered in the copper-based objects of the Shang period (ca. 1500-1046 BC). Although being relatively rare in nature, such lead contributed over half of the lead consumed across a vast area from the Yellow River to the Yangtze. Identifying its source and supply network would significantly contribute to our understanding of how China achieved the largest metal production across Eurasia. The past thirty years of research have seen various proposals for the origin of this lead, including south-western China, the middle Yangtze River valley, the Qinling and Zhongtiao mountains, and even Africa. This paper attempts to illustrate the tempero-spatial pattern of this highly radiogenic lead using the largest possible databank. Furthermore, by going beyond the bronze data and investigating lead isotopes in non-metal objects, we confirm that multiple sources of highly radiogenic lead must have been used across Chinese history. In turn, this implies the feasibility of a multi-source model for the lead in the Shang bronzes.

Lead pollution recorded in Greenland ice indicates European emissions tracked plagues, wars, and imperial expansion during antiquity.

Lead pollution in Arctic ice reflects midlatitude emissions from ancient lead-silver mining and smelting. The few reported measurements have been extrapolated to infer the performance of ancient economies, including comparisons of economic productivity and growth during the Roman Republican and Imperial periods. These studies were based on sparse sampling and inaccurate dating, limiting understanding of trends and specific linkages. Here we show, using a precisely dated record of estimated lead emissions between 1100 BCE and 800 CE derived from subannually resolved measurements in Greenland ice and detailed atmospheric transport modeling, that annual European lead emissions closely varied with historical events, including imperial expansion, wars, and major plagues. Emissions rose coeval with Phoenician expansion, accelerated during expanded Carthaginian and Roman mining primarily in the Iberian Peninsula, and reached a maximum under the Roman Empire. Emissions fluctuated synchronously with wars and political instability particularly during the Roman Republic, and plunged coincident with two major plagues in the second and third centuries, remaining low for >500 years. Bullion in silver coinage declined in parallel, reflecting the importance of lead-silver mining in ancient economies. Our results indicate sustained economic growth during the first two centuries of the Roman Empire, terminated by the second-century Antonine plague.