Chronology

• For centuries, our main sources of information have been pottery sherds, burial sites and ancient texts.
• But the study of ancient DNA is changing what we know about the human past, and what we can know.

Who were the Avars?

The Avars were a nomadic people originating from eastern central Asia. From the 6th to the 9th century CE, they wielded power over much of eastern central Europe.

• The Avars are renowned among archaeologists for their distinctive belt garnitures, but their broader legacy has been overshadowed by predecessors such as the Huns.
• Nevertheless, Avar burial sites provide invaluable insights into their customs and way of life.

Kinship patterns, social practices and population dynamics

• We combined ancient DNA data with archaeological, anthropological and historical context.
• As a result, we have been able to reconstruct extensive pedigrees, shedding light on kinship patterns, social practices and population dynamics of this enigmatic period.

We sampled all available human remains from four fully excavated Avar-era cemeteries, including those at Rákóczifalva and Hajdúnánás in what is now Hungary. This resulted in a meticulous analysis of 424 individuals. Around 300 of these individuals had close relatives buried in the same cemetery. This allowed us to reconstruct multiple extensive pedigrees spanning up to nine generations and 250 years.

Communities were organised around main fathers’ lines

• Our results suggest Avar society ran on a strict system of descent through the father’s line (patrilineal descent).
• In contrast, women played a crucial role in fostering social ties by marrying outside their family’s community.
• Our study also revealed a transition in the main line of descent within Rákóczifalva, when one pedigree took over from another.
• Our results show an apparent genetic continuity can mask the replacement of entire communities.

Future direction of research

Our study, carried out with researchers from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany and at Eötvös Loránd University in Budapest, Hungary, is part of a larger project called HistoGenes funded by the European Research Council. This project shows we can use ancient DNA to examine entire communities, rather than just individuals. We think there is a lot more we can learn.

• Now we aim to deepen our understanding of ancestral Avar society by expanding our research over a wider geographical area within the Avar realm.
• Additionally, we plan to study evidence of pathogens and disease among the individuals in this research, to understand more about their health and lives.
• Another avenue of research is improving the dating of Avar sites.

• Bunbury receives funding from the Australian Research Council (ARC) (project number CE170100015).
• Guido Alberto Gnecchi-Ruscone receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement No 856453.

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  *For more information please refer to Public consultation explanatory note: Proposed E2B(R3) updates
  to align with ICH E2D(R1) guideline.
• 18
  July 2003

  E2D

  Approval by the Steering Committee under Step 4 and
  recommendation for adoption to the three ICH
  regulatory bodies.

• 12
  November 2003

  New
  Codification
  November
  2005
  E2D

  E2D

  Revision of E2D
  Code

  History

  E2D(R1) Endorsement by the Members of the ICH Assembly
  under Step 2 and release for public consultation.

• Date

  New
  Codification

  5 February 2024

  E2D(R1)

  POST-APPROVAL SAFETY DATA:
  DEFINITIONS AND STANDARDS FOR MANAGEMENT AND
  REPORTING OF INDIVIDUAL CASE SAFETY REPORTS
  E2D(R1)
  ICH Consensus Guideline
  Table of Contents
  1.

• The ICH E2D guideline provides guidance on definitions and standards for post-

  5

  approval individual case safety reporting, as well as good case management practices.

• Detailed guidance on the

  9

  specific structure, format, standards, and data elements for transmitting Individual Case Safety

  10

  Reports (ICSRs) is provided in the ICH E2B guideline.

• Guidance on periodic reporting of

  11

  aggregated safety data is covered in the ICH E2C guideline.

• 12

  This guideline provides recommendations that are harmonised to the extent possible given

  13

  differences in post-market safety reporting requirements among ICH regions.

• 25

  2.1.2

  Adverse Drug Reaction (ADR)

  26

  Adverse drug reactions, as defined by local and regional requirements, concern noxious and

  27

  unintended responses to a medicinal product.

• 66

  Product labelling may include information related to ADRs for the pharmaceutical class to

  67

  which the medicinal product belongs.

• In some cases, ?other observations? can occur

  78

  without any associated AEs/ADRs, while in other cases ?other observations? can occur with

  79

  an associated AE/ADR.

• 84

  For the purpose of reporting, requirements in some regions refer only to ADRs, whereas other

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  regions refer to AEs.

• 86

  Refer to local and regional requirements for specifications and requirements on the reporting

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  of AEs or ADRs to each Regulatory Authority.

• 89

  2.2

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  An ICSR is a description of an AE/ADR or other observation in an individual patient at a specific

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  point of time.

• Cases missing any of the above criteria do not qualify for reporting; due diligence

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  should be exercised to collect the missing criteria.

• 6

  104

  An ICSR can be a description of at least one AE/ADR, or other observation (see Section 5.1.3,

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  Other Observations), or both.

• Primary sources, often referred

  112

  to as ?reporters?, include healthcare professionals and consumers who provide facts about a case

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  to the MAH or regulatory authority.

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  2.7

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  A digital platform is the software and technology used to enable transmission of information

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  between users (see Section 4.3, Digital Platforms).

• Expedited Report

  Primary Source

  Healthcare Professional (HCP)

  Consumer

  Digital Platform

  7

  130

  2.8

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  An organised data collection system (ODCS) is an activity that gathers data in a planned manner,

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  thereby enabling review to be performed.

• MAHs should also follow the

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  advice in Section 5.1.2, Important Safety Findings, about communicating safety findings to

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  regulatory authorities.

• MAHs may conduct an MRP

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  using a digital platform; in this situation the ICH E2B data element value for ?MRP? should be

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  selected.

• 564

  Terms (e.g., AEs/ADRs, indication, and medical conditions) in the narrative should be accurately

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  reflected in appropriate ICH E2B data elements.

• 638

  Regulatory Authorities and MAHs should consider and manage duplicates when reviewing

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  pharmacovigilance data, as duplicates negatively impact signal detection.

• 651

  Duplicate detection relies on good quality data and is generally based on similarities but should

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  take into account that information in ICSRs may differ between reporters.

• The idea that two different human species, Homo sapiens (us) and Neanderthals, co-existed in western Eurasia 50–40,000 years ago has long captured the imagination of academics and the public alike.
• It is therefore not surprising that this time period – the Middle-to-Upper Palaeolithic transition – has been a focus of research for many archaeologists, physical anthropologists and, more recently, geneticists.
• Human skeletal remains are comparatively rare, with many of the best-known fossils having been excavated under less than ideal conditions in the 19th and early 20th centuries.

Major revisions

• This means the smallest amounts of more recent contamination from the burial environment, or from museum conservation materials, can make dating finds from these sites extremely challenging.
• This has resulted in major revisions to the chronology of early human occupation over the past decade, shifting some dates on Neanderthal and modern human remains by many thousands of years.
• This is obviously crucial to the debate, since it is impossible to speak of overlap or replacement without a robust chronology.

• These teeth came from the same sediment levels as the human remains.
• The results place the people in a particularly cold snap around 45–43,000 years ago.
• The H. sapiens remains are associated with what was previously considered an ambiguous stone tool industry (a particular way of making tools) called the Lincombian–Ranisian–Jerzmanowician (LRJ).

Mystery toolmakers

• Most notable is the Châtelperronian of southern France and northern Spain: do the Neanderthal remains accompanying some of these “modern-looking” tool industries mean they were the toolmakers, or is the association fortuitous?
• Most caves with Palaeolithic deposits saw intermittent occupation, often by both Neanderthals and H. sapiens, over millennia.
• The dates for the levels under consideration still span several millennia, during which there may well have been short-term visits by both camps.

New archaeological techniques

• The results from Ranis, as well as contributing important new data to our understanding of the Middle-Upper Palaeolithic transition, highlight the contributions of recent developments in archaeological science.
• This technique was also applied to the site’s fauna in another companion paper.
• Then, relatively high-precision radiocarbon dates were obtained for both the sediment level and the human remains themselves.
• But most importantly for the question at hand, ancient DNA analysis – in this case, mitochondrial DNA (mtDNA) – confirmed the identification as H. sapiens.

Rick Schulting does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

• In addition to 685 building materials which weigh 87 kg, as well as 187 glass artifacts which weigh 5kg and 71 metal artifacts of 7kg.
• The wood's origin has been identified to be Ceylon Island in the Indian Ocean which highlights the far-reaching trade connections of Historic Jeddah.
• Moreover, several tombstones of Mangabi stone, marble, and granite were also found in different locations in Historic Jeddah.
• Jeddah Historic District Program in cooperation with the Heritage Commission supervised the documentation, registration, and preservation of archaeological artifacts discovered in Historic Jeddah, and listed the finds in the National Archaeological Register.