University College London Qatar

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by progressive fibrofatty replacement of the right ventricular (RV) myocardium which may act as a substrate for ventricular arrhythmias and sudden cardiac death (SCD).1 , 2 The classic form of ARVC is a genetically determined cardiomyopathy caused by heterozygous or compound mutations in genes encoding proteins of desmosomes, which are specialized intercellular structures providing mechanical attachment of myocytes.3 However, there are other genetic (non-desmosomal) and non-genetic causes of the disease. Biventricular and left-dominant disease variants have been identified and have led some to use the term ‘arrhythmogenic cardiomyopathy’ (ACM) to define the broader spectrum of the disease phenotypic expressions.2–8 However, to avoid confusion of readers, in the present International Expert Report, the original designation of ARVC was maintained because the document is a critical appraisal of the 2010 International Task Force (ITF) criteria that were specifically designed to diagnose the ‘classic’ ARVC phenotype. The current classification of ARVC includes the following clinical variants: (i) the classic ARVC phenotype, i.e. the originally reported and most common disease variant, characterized by isolated RV involvement (Figure 1); (ii) the ‘biventricular disease variants’, i.e. ‘balanced’, ‘dominant-right’ or ‘dominant-left’, characterized by the parallel, predominant RV, and predominant left ventricular (LV) involvement, respectively; and (iii) the LV phenotype characterized by isolated LV involvement (i.e. without clinically demonstrable RV involvement) (Figure 2).1–8 Electrocardiographic and cardiac magnetic resonance features of a representative case of right-dominant (classic) phenotypic variant of arrhythmogenic right ventricular cardiomyopathy. (A) Basal electrocardiographic showing T-wave inversion in right precordial leads (V1–V4). (B) End-diastolic frame of cine cardiac magnetic resonance sequence in long-axis four-chamber view showing a dilated right ventricle (end-diastolic volume, 127 mL/m2) with a severely reduced ejection fraction (25%). The post-contrast orthogonal images in long-axis (C) and short-axis (D) views show late gadolinium enhancement as mid-wall stria in the mid-septum (white arrow). In C, late gadolinium enhancement is also visible in the anterolateral, mid, and apical regions of the right ventricular wall, with segmental transmural involvement (white arrowheads) associated with regional dyskinesia (not shown). From De Lazzari et al. 54 Electrocardiographic and cardiac magnetic resonance findings of a representative case of left-dominant phenotypic variant of arrhythmogenic right ventricular cardiomyopathy in a patient with a DSP-gene mutation and a history of sustained ventricular tachycardia. (A) Basal electrocardiographic showing low QRS voltages (<0.5 mV) in limb leads. (B) End-diastolic frame of cine cardiac magnetic resonance sequence in long-axis four-chamber view showing normal cavity size and function of both ventricles. (C) Post-contrast image showing myocardial fibrosis in the form of stria of late gadolinium enhancement in the epicardium of the left ventricular lateral wall (arrowheads) and mid-mural layer of the interventricular septum (arrows). From De Lazzari et al. 54 In 1994, an ITF proposed criteria for diagnosis of ARVC, in the form of a qualitative scoring system which encompassed familial, electrocardiographic, arrhythmic, morpho-functional, and disease features.9 The ITF criteria were revised in 2010 by international consensus with the intention to improve diagnostic accuracy, by providing quantitative criteria for diagnosing structural and functional RV abnormalities, improvement of electrocardiographic criteria, and adding molecular genetic criteria (Supplementary material online, Table S1).10 Clinical experience with the 2010 ITF diagnostic score system has identified limitations on the use of the criteria, potentially resulting in disease misdiagnosis.11 , 12 The following problems in the use of current ITF criteria have been identified: (i) overdiagnosis due to the inclusion of molecular genetic findings in the diagnostic criteria, misinterpretation of electrocardiographic (ECG) and imaging findings, and misdiagnosis with other diseases mimicking the ARVC phenotype; (ii) underdiagnosis due to absence of cardiac magnetic resonance (CMR) tissue characterization findings. In recent years, there have been evolving indications for the clinical and imaging tests for reaching definitive diagnosis of ARVC.13–15 Due to technological advances and increased experience in the interpretation of structural, functional and tissue characterization by contrast-enhanced CMR this has become an important imaging technique for the diagnosis of ARVC.14 In the era of CMR, some diagnostic tests have been abandoned because of the non-specific and limited accuracy, while others have been reserved for selected cases because of the invasive nature and the risk of serious complications. Since both the 1994 and 2010 guidelines were developed to diagnose the original right-dominant disease phenotype they did not include specific criteria for diagnosing LV involvement and the more recently recognized left-sided phenotypic variants.7 , 8 Moreover, peculiarities of diagnosis in the paediatric population, which represents approximately one-sixth of the overall ARVC-population, were not addressed.16 The present international expert report is not intended to redesign the 2010 ITF diagnostic criteria, which in the general view of the authors are still valid and do not need substantial changes. However, the increasing risk of misdiagnosis resulting from the inappropriate use of the criteria has prompted this international expert document aimed to critically review the clinical performance and highlight the potential limitations of current criteria, to propose some solutions for a better clinical use and to identify potential areas of improvement, with particular reference to diagnosis of left-sided phenotypes and identification of early disease in the paediatric population. (See Supplementary material online, Text). The following sections of the document focus on the critical evaluation of each group of current diagnostic criteria and provide key suggestions for improving their use in the clinical practice. Mutations in the genes encoding desmosomal proteins play a key role in the pathogenesis of fibrofatty replacement of the myocardium and the development of the disease phenotype.2 , 3 Pooled data from major studies on molecular genetic screening for desmosomal gene mutations showed that the overall rate of successful genotyping in patients meeting the ITF diagnostic criteria is approximately 50%.17 , 18 The most common mutant gene is PKP2 (10–45%), followed by DSP (10–15%), DSG2 (7–10%), and DSC2 (2%).19–21 Screening for non-desmosomal genes marginally increases the rate of detection of gene mutations, even though some mutations in specific genes such as TMEM43 p.P358L22 and PLN p.R14del23 can be highly prevalent in certain populations because of a founder effect (Supplementary material online, Table S2). Compound/digenic heterozygosity has been identified in up to 25% of patients and has been reported to account for both phenotypic variability and more malignant life-time arrhythmic outcome (‘dose-effect’).24–26 Different from all other forms of cardiomyopathy, the ARVC diagnostic criteria include the presence of a pathogenic variant in ARVC related genes as a major criterion to establish the diagnosis.10 However, it has not been defined which mutations have sufficient evidence to be considered as disease-causing and conferring pathogenicity to a variant can be challenging. Moreover, a negative genetic test does not exclude the possibility that the phenotype is due to a mutation in an unknown gene or that the molecular genetic screening technique does not detect all disease-causing variants, including large deletions or duplications.27 An increasingly emerging problem with the use of the current ITF criteria is that the incorrect classification of a desmomosal-gene variant as ‘pathogenic’ (major criterion) or the identification of a pathogenic variant in a gene with insufficient evidence for disease causation may lead to a (mis)-diagnosis of ARVC in probands who otherwise may not fulfil the ITF criteria for a (definite) phenotypic diagnosis (see Supplementary material online, Text). The limitations of current understanding of the genetic basis of ARVC and the high genetic noise due to frequent disease-associated genetic variants both in the normal population and other cardiomyopathies are associated with the risk of misdiagnosis if molecular genetic results are integral part of the diagnostic scoring to the general for molecular genetic in inherited genotyping is to identify a pathogenic or pathogenic mutation in a who phenotypic diagnostic criteria for ARVC, and to genetic for detection of gene genetic is for following the identification of a pathogenic or pathogenic mutation in the with a clinical diagnosis of ARVC, in to identify genetically a to a diagnosis in a patient with phenotypic may be considered in selected cases that the results are by on the disease molecular because the high of variants of may the genotyping results more screening can be also for arrhythmic risk In heterozygosity of variants a more serious arrhythmic outcome because of a gene is important to the of genes including specific non-desmosomal if founder mutations in genes are present in specific such as TMEM43 in and PLN in the or a with specific tissue characterization by has been part of the diagnostic evaluation of ARVC technique the potential for an in tissue characterization with of the disease i.e. the of myocardium with fibrofatty that has been considered the for the clinical diagnosis of ARVC diagnostic of the RV myocardium is not specific for ARVC, reported in normal in the and In this the revised ITF criteria the that the presence of fibrosis is also and quantitative for evaluation of on the of and fibrosis on of The diagnosis of ARVC that is for the or also probands and The diagnostic tissue characterization can be by of cardiac for other or in or cardiac The evidence of fibrofatty replacement of the ventricular myocardium with a or with transmural involvement in the absence of the is a diagnostic criterion for An of for the diagnosis of ARVC has been developed with the of in the of desmosomal (see Supplementary material online, Text). ventricular is an imaging technique which may be of for the diagnosis of ARVC it has the potential to identify and RV regions of with showing or ventricular is an and highly technique with a risk of interpretation of in areas of normal myocardium due to Moreover, a be also from the of RV, which a not for diagnostic is not as a diagnostic test for be reserved for selected patients such as probands with a form of ARVC and predominant LV involvement, in the diagnosis on of such as or other heart muscle In to of myocardial for evaluation of desmosomal the may provide diagnostic ventricular is not for diagnostic be reserved for selected ARVC patients cardiac for and in with a large experience in of the RV wall is not in the of and be proposed for structural and functional by imaging include ventricular reduced RV ejection regional wall abnormalities, and fibrofatty myocardial , 3 , , and CMR are the imaging for the diagnosis of magnetic resonance has become the for ventricular and regional wall as as to myocardial tissue Due to the of CMR and imaging that can be CMR the potential to regional wall abnormalities, and structural of the , CMR provide an of RV and However, have low and for the diagnosis of , and variability in the interpretation of segmental of the RV wall has been characterization findings by CMR and fibrofatty were not in the 2010 ITF criteria because of limited in the and low However, recent studies the of regional wall and tissue characterization by CMR for the diagnosis of The was present wall and LV and late gadolinium enhancement were considered The original of of which to the most regions of the RV, has to the current of a of which also includes the LV wall, which is the most LV In the early of ARVC, the and the LV wall may be the , , , imaging technique may diagnostic for ARVC, even in early by a myocardial in the LV wall, which otherwise by because it is to the and may not be large to a wall (Figure of criteria for characterization of myocardial fibrofatty replacement the potential (i) to the of the interpretation of RV wall has a high variability and by the myocardial (ii) to the for forms of ARVC which are more by with of the segmental in the LV wall which may be the imaging of left-dominant phenotypic variants of of high negative contrast-enhanced CMR has the potential to become the imaging test for evaluation of structural and functional ventricular of ARVC (see Supplementary material online, Text). the technological advances and improvement of interpretation of CMR tissue characterization and image evaluation of myocardial and contrast-enhanced CMR is for definitive diagnosis and better characterization of the disease phenotypic is as part of the evaluation of a patient with The of findings evaluation is important in view of the imaging evaluation be on the genetic and clinical avoid of structural and functional ventricular is to a diagnosis in a ventricular may be not in because clinical are more and may the disease due to the and and the phenotypic the large of and of the normal RV, the presence of both regional wall and be in orthogonal long-axis and short-axis magnetic resonance be in high with particular experience and in imaging and interpretation of ARVC CMR is and due to of data and with CMR studies is CMR be considered in patients with a diagnosis of ARVC who of clinical abnormalities, arrhythmic or findings. ventricular is not of diagnostic and be reserved to patients in is is is for diagnosis ARVC and heart diseases with a left to right The spectrum of ventricular arrhythmias in ARVC from isolated ventricular to sustained ventricular or ventricular to cardiac , , , 18 , The of the is patients and the of the , The of the of the arrhythmic QRS on may identification of the ventricular of and the of the to the 2010 ITF diagnostic criteria, the of has an on diagnosis.10 with a left right ventricular is considered a diagnostic criterion because of low which may lead to misdiagnosis of ARVC in patients with right ventricular However, with an and or RV wall is more specific for ARVC and this is as a diagnostic with a right may as a of or predominant LV with have that most ARVC patients have frequent isolated or with a ITF criteria the of without the of the represents a because ventricular from the RV wall have for ARVC the of ventricular or ventricular from the is to on 12 leads by or The has a limited role in the diagnosis of The test can provide the by ventricular of or more with may be in ARVC from which is a and arrhythmic characterized by a and by ventricular , of RV may be of diagnostic for diagnosis with that is to and or to avoid inappropriate misdiagnosis from with a large of view may also the presence of the use of a to is to the of ventricular which may the ventricular of with ventricular and RV are not as integral part of the diagnostic evaluation of patients with studies be limited to selected patients an invasive evaluation to from tachycardia. is a diagnostic test in ARVC and in up to of patients with in the right precordial leads are the most common (Figure QRS voltages (<0.5 mV) in the limb leads are in ARVC patients with of the LV as by CMR (Figure an of RV low QRS voltages LV involvement of the RV disease and of voltages of the LV wall and replacement by fibrofatty The resulting from RV include and QRS of right precordial QRS with a and The of the presence of as a diagnostic has been are related to and to large can also be in the form of late in the of the QRS by The use of technique for diagnosis of ARVC in probands and has been abandoned by most because of non-specific findings and limited diagnostic (see Supplementary material online, Text). The presence of be with in patients without other diagnostic QRS with in right precordial leads is a specific diagnostic if followed by negative QRS voltages (<0.5 mV) in the limb leads can be an of LV to and be considered as a normal variant in who do not other diagnostic features of LV involvement in ARVC include T-wave inversion in the leads and low QRS voltages (<0.5 mV) in limb which the of myocardium and voltages of the LV , is with a which form the , The LV imaging phenotype is characterized by a ventricular of LV and or LV in with a of LV the wall (Figure The of LV related to the of which in disease and LV wall In variants of ARVC, clinically demonstrable RV involvement is an important criterion for diagnosis with dilated cardiomyopathy In the absence of clinically RV involvement, of a pathogenic mutation of such as and PLN may the diagnosis of ARVC (see Supplementary material online, Text). for diagnosis of left-sided ARVC phenotypes (i) such as low QRS voltages in limb leads and in the (ii) ventricular arrhythmias with a right and (iii) structural and functional imaging features with a and Clinical of some of or structural RV involvement be considered as an important criterion for diagnosis of or left-dominant In patients with clinical findings of left-sided ARVC and clinically RV involvement, genetic for the presence of pathogenic mutations in such as the DSP can the diagnosis (Supplementary material online, Table S2). Arrhythmogenic RV cardiomyopathy is a genetically determined heart muscle disease characterized by a which most clinically the and of Clinical of the disease are up to of patients are , Arrhythmogenic RV cardiomyopathy is a progressive heart muscle disease with and structural phenotypic is that of structural ventricular can be and by patients more present with sustained paediatric patients are more to experience or sudden cardiac , , cardiac death may be the clinical of the as it was reported by a in the of of in and were caused by The diagnosis of ARVC is in of in development as as in disease and the use of the current criteria for diagnosis of ARVC in this clinical be to this patient population due to the of some in paediatric patients and the low of disease in In and can be while is more 3 and cardiac CMR 8 in (see Supplementary material online, Text). An diagnostic clinical normal and imaging reference for be in the paediatric population, due to the low of of some and of clinical findings in this studies such as RV and be reserved to selected cases all studies have been genetic for of by ARVC is for identification of genetically as as for detection of who can be and not detection of genetically to establish a on including of which is the most important the disease phenotypic by clinical evaluation of gene or with unknown who have a history of ARVC be on a basis to for disease and that can the ARVC phenotype and diagnosis of ARVC include and structural heart muscle diseases the RV, the or both diagnosis of arrhythmogenic right ventricular cardiomyopathy which may ARVC include and (see Supplementary material online, Text). with have a normal normal imaging by and by ventricular of is more in in ARVC which the RV wall and the the diagnosis of while or substantial from ARVC with to absence of and of abnormalities, and of arrhythmias and outcome right ventricular arrhythmogenic right ventricular ventricular left ventricular RV, right right ventricular T-wave ventricular ventricular tachycardia. arrhythmogenic right ventricular cardiomyopathy left left right RV, right right ventricular T-wave ventricular ventricular tachycardia. of structural may clinical features of right-dominant ARVC including heart and heart (Figure 3 and Table (see Supplementary material online, Text). magnetic resonance features of heart diseases mimicking right-dominant (classic) phenotypic variant of arrhythmogenic right ventricular cardiomyopathy. and frame of cine cardiac magnetic resonance sequence in long-axis four-chamber view showing right ventricular cine view showing the of the right in the (white and frame of cine cardiac magnetic resonance sequence in short-axis view showing a right ventricular due to a large ventricular frame of cine cardiac magnetic resonance sequence in four-chamber view showing a apical of the of the (white and of cine cardiac magnetic resonance sequence in short-axis view showing of the right ventricular wall (white of the interventricular septum (white and (white heart and and of cine cardiac magnetic resonance sequence in four-chamber view (end-diastolic mL/m2) and normal function fraction in the absence of wall (not shown). of right heart in heart disease such as or and absence may and RV mimicking due to to a heart disease of RV and without regional wall that the diagnosis with the imaging findings of ARVC characterized by both and regional RV and with regional RV of are the of the of the that is normal or reduced in The clinical phenotype of heart from that of ARVC with to the absence of fibrofatty myocardial replacement which is clinically demonstrable as (i) or on and (ii) RV on (iii) and replacement heart arrhythmogenic right ventricular cardiomyopathy late gadolinium left RV, right right ventricular sudden cardiac mimicking clinical features of left-dominant ARVC include cardiac involvement in genetic ventricular and disease (see Supplementary material online, Text). with left-sided ARVC, more LV and which are to the of ventricular tissue as by on CMR (Figure with left-sided ARVC, to ventricular arrhythmias that late the disease and are related to the of LV may in patients with genetic and may or clinical evidence of muscle the myocardial involvement is most part of the spectrum of features of the ventricular and may the clinical or may the phenotypic of the gene (Figure diagnosis the cardiomyopathy in the of a disease and ARVC on of specific phenotypic features of the associated of isolated cardiomyopathy muscle involvement) of the specific genetic by molecular diagnosis or and ARVC clinical of and imaging RV involvement, and molecular genetic criteria to from inherited cardiomyopathy have not been LV CMR may is not diagnostic and history and screening are to exclude left-sided The diagnosis of cardiac in patients with involvement on clinical and imaging features of the disease (Figure in the presence of evidence of in or more cardiac is on the basis of by or , The segmental nature of with associated normal ventricular myocardium and the of myocardial fibrosis are not with the diagnosis of history and a to cardiac disease from magnetic resonance features of dilated cardiomyopathy left-dominant phenotypic variant of arrhythmogenic right ventricular cardiomyopathy. cardiomyopathy and frame of cine cardiac magnetic resonance sequence in four-chamber view showing left ventricular (A) with (not post-contrast inversion sequence in short-axis view showing limited mid-wall late gadolinium enhancement in the interventricular septum and the wall (white arrhythmogenic right ventricular cardiomyopathy and post-contrast inversion sequence in four-chamber view showing a (C) and (not left post-contrast inversion sequence in short-axis view showing a large of late gadolinium enhancement the interventricular septum and both and left ventricular and magnetic resonance features and findings of left ventricular of and post-contrast inversion sequence in short-axis view showing a stria of late gadolinium enhancement in the left ventricular wall (white view of the left ventricular wall showing fibrosis to the layer of the from et al. and post-contrast inversion sequence in short-axis view showing late gadolinium enhancement of the left ventricular wall view of the left ventricular wall showing tissue replacement in the layer of the From et al. left-sided arrhythmogenic right ventricular cardiomyopathy and post-contrast inversion sequence in short-axis view showing late gadolinium enhancement of the left ventricular wall in a DSP-gene mutation view showing myocardial replacement of the layer of the left ventricular wall in a sudden cardiac death a DSP-gene mutation From et al. resonance and cardiac features of cardiac Post-contrast inversion sequence in four-chamber view showing right ventricular and late gadolinium enhancement of the interventricular septum and lateral left ventricular wall (white the of late gadolinium enhancement the and left ventricular regions and the areas of on to cardiomyopathy left-dominant arrhythmogenic right ventricular cardiomyopathy left left ventricular ventricular right RV, right right ventricular T-wave ventricular ventricular tachycardia. In of ARVC is a genetic disease caused by a mutation of desmosomal of patients may have non-desmosomal phenotype to ARVC may also in other genetic or , 3 a of patients have non-genetic diseases with a phenotype ARVC and characterized by the to ventricular arrhythmias which the of ventricular related to the large of myocardial fibrosis which is an arrhythmogenic risk with current of other cardiomyopathies such as and dilated cardiomyopathy and in with the Expert on arrhythmogenic it is to propose a disease classification which the large of ‘arrhythmogenic a spectrum of of the RV, the LV or genetic or common is the ventricular myocardial and the ventricular arrhythmias (Figure with the phenotype are associated with a risk of because myocardial fibrosis as a substrate of malignant ventricular in patients by genetic or the of an for be considered in the presence of large arrhythmogenic ventricular even if the ventricular function is not severely classification of arrhythmogenic The most common of arrhythmogenic cardiomyopathy is a genetic of desmosomal there are other genetic and non-genetic causes (see the for more use of the current ITF diagnostic criteria and of the scoring system for diagnosis of ARVC (i) the of current understanding of the genetic of the disease that the risk of misdiagnosis if molecular genetic test is an integral part of the diagnostic scoring (ii) the advances of and improvement of interpretation of tissue characterization images by CMR which has become the imaging technique for characterization of the disease phenotype; (iii) the spectrum of the ARVC phenotype which includes left-dominant disease variants and specific diagnostic criteria from clinical and the peculiarities of clinical features and diagnostic tests of ARVC in the paediatric population which represents a of patients due to the increasing clinical and genetic screening of The focus on better understanding of the genetic improvement of clinical and imaging characterization of the phenotype, with particular reference to left-sided variants and of diagnostic The clinical of the proposed classification of arrhythmogenic cardiomyopathy to be by of is to the of recently and who a role in the development of the International Task Force criteria for diagnosis of arrhythmogenic right ventricular cardiomyopathy. 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Research over the last few decades has greatly enhanced our understanding of the production and distribution of glass across time and space, resulting in an almost kaleidoscopically colourful and complex picture. We now recognise several major ‘families’ of glass composition, including plant-ash based glass in Late Bronze Age Egypt and Mesopotamia, and the Islamic World; mineral natron glass in the Greek, Roman and Byzantine Empires; mineral-based lead- and lead–barium glass in Han period China and medieval Europe; and wood-ash and ash-lime glass in medieval Europe. Other glass groups include a peculiar granite-based glass in medieval Nigeria, and probably mineral-based glass in Bronze Age southern Europe. However, despite two centuries of research, we know very little about the actual production locations and technologies for most of these glass groups, and how and where glass making was invented. The early literature reflects the comparatively limited number of individuals and research groups working on glass; only recently there is a significant broadening of the research community and expansion and refinement of the data base. This enables us now to take stock of our current understanding and identify major lacunae and areas where additional work may make the most significant contributions to our understanding of the complex picture. Hopefully this will help moving from the traditional descriptive and often fragmented opportunistic data-gathering phase (asking ‘what’, ‘where’ and ‘when’) to a more interpretative period looking with fresh eyes at the ‘why’ and ‘how’ of compositional and technical developments. This opening of the research field includes addressing the relationship of the different glass industries to the societies that used glass, and how they organised its production and distribution. A major overarching issue remains the question of the initial invention of glass, and how the idea as well as the material itself spread. Major debates should ask whether there were multiple inventions of glass making; how best to identify and interpret long-distance trade; how to ensure data compatibility and quality; and how to integrate different types of data, from archaeology through craftsmanship and typology to chemistry and optical properties.

The earliest known iron artefacts are nine small beads securely dated to circa 3200 BC, from two burials in Gerzeh, northern Egypt. We show that these beads were made from meteoritic iron, and shaped by careful hammering the metal into thin sheets before rolling them into tubes. The study demonstrates the ability of neutron and X-ray methods to determine the nature of the material even after complete corrosion of the iron metal. The iron beads were strung into a necklace together with other exotic minerals such as lapis lazuli, gold and carnelian, revealing the status of meteoritic iron as a special material on a par with precious metal and gem stones. The results confirm that already in the fourth millennium BC metalworkers had mastered the smithing of meteoritic iron, an iron–nickel alloy much harder and more brittle than the more commonly worked copper. This is of wider significance as it demonstrates that metalworkers had already nearly two millennia of experience to hot-work meteoritic iron when iron smelting was introduced. This knowledge was essential for the development of iron smelting, which produced metal in a solid state process and hence depended on this ability in order to replace copper and bronze as the main utilitarian metals.

Analysis of metal objects with portable and handheld X-ray fluorescence spectrometry has become increasingly popular in recent years. Here, methodological concerns that apply to non-destructive, surface examination with XRF instruments of ancient metal artefacts are discussed based on the comparative analyses of a set of copper-based objects by means of portable X-ray fluorescence (pXRF) and electron probe microanalyser (EPMA). The analytical investigation aims to explore issues of instrument comparability and reliability of the non-invasive pXRF results. The different analytical approaches produce a comparable pattern for the major element concentrations, but substantial variation is evident when it comes to the absolute values for major and minor/trace elements.

We present compositional data for nearly 100 glass samples from Pergamon, western Turkey, spanning 1500 years from the Hellenistic to Late Byzantine and Islamic periods. The data shows the use of already-known Roman glass groups during the first half of the time frame, for imported vessels as well as locally worked glass. No compositional change is seen related to the introduction of glass blowing for either of the glass groups in use during this time. During the first half of the 1st millennium AD, two previously little-known boron- and alumina-rich compositional groups emerge. These glass groups, thought to be regionally produced, dominate glass compositions in Pergamon during the mid-to late Byzantine and Islamic periods, indicating a major shift in glass supply and a fragmentation of the economy into more regional units. Plant-ash glass, from the 9th century AD replacing mineral natron glass in the Levant , plays only a minor role in Byzantine and Islamic Pergamon.

Eighty-seven glass fragments from Roman and Late Antique layers at Tell Basta/Bubastis in the Eastern Nile Delta were typologically evaluated and chemically analysed to determine chronological and compositional patterns of glass use at this important Egyptian city, and how this relates to larger pattern of glass production and consumption in the first half of the first millennium AD. Bubastis is situated in geographical proximity to Alexandria, an important seaport, and at the same time close to the raw glass production areas in the Wadi Natrun and Sinai peninsula. This paper reports the first substantial set of compositional data of Roman to Late Antique glass from a settlement in northern Egypt, filling an important gap in our knowledge of glass consumption pattern in the first half of the first millennium AD. The glass from Bubastis falls into several compositional groups known already from elsewhere in the Roman and Late Antique world, including antimony- and manganese-decoloured glass and two varieties of HIMT glass. Changes in glass composition over more than 500 years are in line with earlier observations concerning changes in prevalence of these glass groups. However, compositional groups known to dominate archaeological glass assemblages elsewhere, such as Roman blue/green during the earlier part of the period under study, or Levantine I in the later period, are notably absent. For the later period, this is probably due to the proximity of Tell Basta to the suspected production region of HIMT glass in northern Sinai/Egypt. By analogy, this might indicate that the earlier Roman blue/green glass has a production origin further away from the Delta than the decolourised glasses prevailing in Bubastis. A particular vessel type, small-volume thick-walled dark green unguentaria, is made of probably Egyptian plant ash glass, indicating the existence of a specialised glassmaker during the early first millennium AD.

Elemental analysis of ancient ceramics is primarily used in provenance research, where defined compositional groups are attributed to particular raw materials sources or production locations. Requirements in data quality and analytical performance are high, as is the need for clear and reproducible methodologies and the availability of information on the above to ensure interlaboratory comparability and long‐term data validity. This paper outlines the measurement parameters of a dedicated calibration set‐up for the analysis of ancient ceramics using wavelength‐dispersive X‐ray fluorescence spectrometry. The specimens are prepared as concentrated glass beads, allowing the measurement of 26 elements from a single sample, thus minimising sample size requirements. Certified and non‐commercial standards are used to evaluate the performance of the method in terms of detection limits, precision, repeatability and accuracy. The materials used cover a range of compositions in line with the matrix variability encountered in archaeological ceramics. The data confirm the high standard of the method and highlight specific limitations. An initial assessment of comparability with other set‐ups used in ceramic analyses, primarily neutron activation analysis, is given through a discussion of performance on commonly analysed materials. The advantages of the proposed method include excellent analytical performance, analysis of a large suite of elements including all major, minor and a good range of traces, relatively small sample sizes and preparation of samples that can be stored and reanalysed. Copyright © 2017 John Wiley & Sons, Ltd.

Background and Objectives Robust biomarkers that can mirror Parkinson disease (PD) are of great significance. In this study, we present a novel approach to investigate disease-associated α-synuclein (αSyn) aggregates as biomarkers of PD clinical stage. Methods We combined both seed amplification assay (SAA) and ELISA to provide a quantitative test readout that reflects the clinical severity of patients with PD. To attain this goal, we initially explored the potential of our test using 2 sets of human brain homogenates (pilot and validation sets) and then verified it with 2 independent human CSF cohorts; discovery (62 patients with PD and 34 controls) and validation (49 patients with PD and 48 controls) cohorts. Results We showed that oligomers-specific ELISA robustly quantified SAA end product from patients with PD or dementia with Lewy bodies with high sensitivity and specificity scores (100%). Analysis also demonstrated that seeding activity could be detected earlier with oligomeric ELISA as the test readout rather than SAA alone. Of more importance, multiplexing the assays provided robust information about the patients9 clinical disease stage. In the discovery cohort, levels of CSF-seeded αSyn oligomers correlated with the severity of the clinical symptoms of PD as measured by the Unified Parkinson Disease Rating Scale (UPDRS) motor (r = 0.58, p < 0.001) and Hoehn and Yahr (H&Y) scores (r = 0.43, p < 0.01). Similar correlations were observed in the validation cohort between the concentrations of CSF-seeded αSyn oligomers and both UPDRS motor (r = 0.50, p < 0.01) and H&Y scores (r = 0.49, p < 0.01). At 20 hours, receiver operating characteristic curves analysis yielded a sensitivity of 91.9% (95% CI 82.4%–96.5%) and a specificity of 85.3% (95% CI 69.8%–93.5%), with an area under the curve of 0.969 for CSF-seeded αSyn oligomers differentiating those with PD from controls in the discovery CSF cohort, whereas, a sensitivity of 80.7% (95% CI 69.1%–88.5%), a specificity of 76.5% (95% CI 60.0%–87.5%), and area under the curve of 0.860 were generated with thioflavin T maximum intensity of fluorescence at the same time point. Discussion We showed that combining SAA and ELISA assays is a more promising diagnostic tool than SAA alone, providing information about the disease stage by correlating with clinical measures of disease severity. Classification of Evidence This study provides Class III evidence that CSF-seeded αSyn oligomers can accurately discriminate patients with PD and normal controls and CSF-seeded αSyn oligomers levels correlate with PD severity.

A group of finds (vessels, raw glass chunks, window panes) from three sites in present-day Bulgaria was selected as representative of the circulation and usage of glass in the Lower Danube region during the 6th c. AD. In total, 79 samples were analysed by EPMA and/or LA-ICP-MS techniques. The data quality was assessed for each analytical run according to the measurement of reference glasses and to pairs of results obtained from representative samples of archaeological glass analysed by both techniques. Combining EPMA and LA-ICP-MS data allowed a sufficiently consistent and unified set of primary results to be formed. As already suggested in an earlier preliminary paper, only a single glass composition was found to dominate the 6th c. contexts in the region. The current study recognises this 6th c. glass from the Lower Danube as identical with the so called ‘Serie 2.1.’ defined by D. Foy and co-workers (2003) in various assemblages in Southern France and North Africa. The major, minor and trace oxide evidence presented here indicates that this is a distinct primary glass composition, with an iron-rich sub-group tentatively differentiated within the main group. Accordingly, an attempt is made to situate it relative to the other main primary compositions in the region. The proposed interpretation is that the 6th c. glass should not be linked to the HIMT glass despite the nominal similarity between them due to their elevated iron oxide, manganese, and titania concentrations. Instead, a possible link between the geochemical characteristics of the 6th c. glass and an earlier group of manganese decolourised glass, equivalent to ‘Serie 3.2.’ outlined by D. Foy and co-workers (2003) is suggested. This may imply the use of sand from a broadly identical geological area, hence it is possible that both the 6th c. glass and the manganese decolourised composition are likely to share a common origin.

Abstract

The Antikythera Mechanism, an ancient Greek astronomical calculator, has challenged researchers since its discovery in 1901. Now split into 82 fragments, only a third of the original survives, including 30 corroded bronze gearwheels. Microfocus X-ray Computed Tomography (X-ray CT) in 2005 decoded the structure of the rear of the machine but the front remained largely unresolved. X-ray CT also revealed inscriptions describing the motions of the Sun, Moon and all five planets known in antiquity and how they were displayed at the front as an ancient Greek Cosmos. Inscriptions specifying complex planetary periods forced new thinking on the mechanization of this Cosmos, but no previous reconstruction has come close to matching the data. Our discoveries lead to a new model, satisfying and explaining the evidence. Solving this complex 3D puzzle reveals a creation of genius-combining cycles from Babylonian astronomy, mathematics from Plato's Academy and ancient Greek astronomical theories.

Structure-from-motion and multiview-stereo together offer a computer vision technique for reconstructing detailed 3D models from overlapping images of anything from large landscapes to microscopic features. Because such models can be generated from ordinary photographs taken with standard cameras in ordinary lighting conditions, these techniques are revolutionising digital recording and analysis in archaeology and related subjects such as palaeontology, museum studies and art history. However, most published treatments so far have focused merely on this technique's ability to produce low-cost, high quality representations, with one or two also suggesting new opportunities for citizen science. However, perhaps the major artefact scale advantage comes from significantly enhanced possibilities for 3D morphometric analysis and comparative taxonomy. We wish to stimulate further discussion of this new research domain by considering a case study using a famous and contentious set of archaeological objects: the terracotta warriors of China's first emperor.

Tadmekka, a town at the southern edge of the Sahara desert, has produced good evidence for making gold coins in the ninth–tenth century AD, the first concrete proof of coinage in pre-colonial West Africa. These were produced by melting gold dust or nuggets in ceramic moulds, similar to those used for the first pellet-like coinage of the European Iron Age. The authors suggest these coins were not political statements, but were probably blank and intended to facilitate the busy early Islamic caravan trade to destinations north, south or east. On arrival at the Mediterranean coast, these blank pieces would have been melted down or converted into inscribed coins by the local authorities.

The trace element boron is present in most ancient glasses as an impurity, and high boron (≥ 300 ppm) marks raw material sources that are geologically specific and relatively uncommon. Recent analyses of Byzantine glass with high boron contents suggest that glass‐making was not limited to the traditional regions of the Levant and Egypt, and a production origin in or near western Anatolia is proposed. Glass bracelets from Ḥiṣn al‐Tīnāt in southern Turkey give fresh evidence for the production and circulation of high‐boron glasses that closely correlates with object typology. The patterning of findspots suggests that high‐boron glass was closely connected to the Byzantine world.

We describe two crucible fragments from an early Islamic context at the West African site of Tadmekka, in the Republic of Mali. They are made from a very sandy fabric and contain numerous gold particles and mineral grains in a matrix of lightly-coloured glass-based crucible slag. We interpret these as remains of a process separating freshly-panned gold concentrate from residual mineral inclusions, by melting the concentrate together with crushed glass beads. The process has similarities in modern artisanal practice, and shows the versatility of craftspeople in this major urban trading centre famous for its gold wealth. © 2014 The Authors.

The term "bilateral deficit" (BLD) has been used to describe a reduction in performance during bilateral contractions when compared to the sum of identical unilateral contractions. In old age, maximal isometric force production (MIF) decreases and BLD increases indicating the need for training interventions to mitigate this impact in seniors. In a cross-sectional approach, we examined age-related differences in MIF and BLD in young (age: 20-30 years) and old adults (age: >65 years). In addition, a randomized-controlled trial was conducted to investigate training-specific effects of resistance vs. balance training on MIF and BLD of the leg extensors in old adults. Subjects were randomly assigned to resistance training (n = 19), balance training (n = 14), or a control group (n = 20). Bilateral heavy-resistance training for the lower extremities was performed for 13 weeks (3 × / week) at 80% of the one repetition maximum. Balance training was conducted using predominately unilateral exercises on wobble boards, soft mats, and uneven surfaces for the same duration. Pre- and post-tests included uni- and bilateral measurements of maximal isometric leg extension force. At baseline, young subjects outperformed older adults in uni- and bilateral MIF (all p < .001; d = 2.61-3.37) and in measures of BLD (p < .001; d = 2.04). We also found significant increases in uni- and bilateral MIF after resistance training (all p < .001, d = 1.8-5.7) and balance training (all p < .05, d = 1.3-3.2). In addition, BLD decreased following resistance (p < .001, d = 3.4) and balance training (p < .001, d = 2.6). It can be concluded that both training regimens resulted in increased MIF and decreased BLD of the leg extensors (HRT-group more than BAL-group), almost reaching the levels of young adults.

The Royal City of Meroe, ca. 200 km north of Khartoum in the modern-day Republic of the Sudan, was an ancient capital of the Kingdom of Kush. From the 3rd century b.c. to the 4th century a.d., Kushite rulers controlled significant territory from the banks of the Nile at Meroe, in part through their ability to ensure the production of significant quantities of iron. The extensive archaeological remains of Meroitic iron production have been investigated over decades, and recently a series of experimental iron smelts in a replica Meroitic furnace has shed new light on the archaeometallurgical evidence. The data generated during the smelting campaigns has provided an understanding of the type of iron ore used, the construction and operating parameters of the furnace, and the workshop space created by the ancient iron smelters during the later and post-Meroitic times.

This paper describes a multifaceted approach to the investigation of iron slag heaps, focusing on one of the slag heaps at the Royal City of Meroe in Sudan. This study marries together geoprospection data (gradiometry and electrical resistivity transects), topographic data and quantitative excavation data, to provide an analysis and comparison of the total volume, slag component and slag composition of a slag-heap. Significantly, the results demonstrate the limitations of using a topographic only model, but also demonstrate how volumetric modelling must be integrated within quantitative characterisation of slag-heap composition. In this case, quantitative sampling of the slag deposits revealed the composition of the slag assemblage was dominated by a newly defined category of slag which has major implications for reconstructing iron technologies in the Meroitic civilisation. This research highlights the dangers of applying simplistic models and basic investigative strategies to iron slag heaps and furthers the debate on applying volumetric modelling and excavation sampling to unexcavated areas of the finite and important resource of archaeometallurgical deposit sequences.

This paper discusses what it means to label heritage as being ‘at risk’ in post-disaster landscapes in the city of Banda Aceh, Indonesia, following the 2004 Indian Ocean tsunami. It questions the relevance of a ‘heritage at risk’ framework, pointing out the issues associated with starting from this popular threat-based model of preservation in the aftermath of near or total destruction. By challenging the hegemony of a ‘heritage at risk’ rhetorical device that constructs heritage typologies, this debate focuses instead on the emergence and mastering of new heritage in post-tsunami Aceh, and the ways in which a shift in focus is able to document and preserve the emergence of unique heritage constructs and priorities. This paper promotes the study of heritage as a performance that transcends an emphasis on victimhood, toward framing a heritage construct that is productive and dynamic, a steward for post-disaster identities.

Very little is known about early metallurgical activity in the north-western part of the Arabian Peninsula, despite the region's cultural importance. To begin to address this research lacuna, metallurgical remains including crucible fragments, metal dross and a copper artefact were sampled from two oases in northwest Arabia, Qurayyah and Tayma. The metallurgical activity in Qurayyah is dated to the Late Bronze Age, and in Tayma to the Roman/Late Roman period. At both sites we identified evidence for copper alloying and refining. Small scale copper smelting might also have been practiced in Qurayyah. Arsenical copper was processed at both sites, but in Tayma tin bronze and leaded tin bronze dominated. The chemical analysis of metal prills in crucible linings showed that fresh copper and tin instead of scrap metal were employed in these processes. Lead isotope analysis indicates that at least some of the Tayma metal was imported. Access to raw materials from remote areas is consistent with the importance of Tayma in the trading network of northwest Arabia.