Tackling Neuroinflammation After Traumatic Brain Injury:Complement Inhibition as a Therapy for Secondary Injury

Traumatic brain injury (TBI) is a leading cause of mortality, sensorimotor morbidity, and neurocognitive disability. Neuroinflammation is one of the key drivers causing secondary brain injury after TBI. Therefore, attenuation of the inflammatory response is a potential therapeutic goal. This review summarizes the most important neuroinflammatory pathophysiology resulting from TBI and the clinical trials performed to attenuate neuroinflammation. Studies show that non-selective attenuation of the inflammatory response, in the early phase after TBI, might be detrimental and that there is a gap in the literature regarding pharmacological trials targeting specific pathways. The complement system and its crosstalk with the coagulation system play an important role in the pathophysiology of secondary brain injury after TBI. Therefore, regaining control over the complement cascades by inhibiting overshooting activation might constitute useful therapy. Activation of the complement cascade is an early component of neuroinflammation, making it a potential target to mitigate neuroinflammation in TBI. Therefore, we have described pathophysiological aspects of complement inhibition and summarized animal studies targeting the complement system in TBI. We also present the first clinical trial aimed at inhibition of complement activation in the early days after brain injury to reduce the risk of morbidity and mortality following severe TBI.</p

Delirium in older COVID-19 patients:Evaluating risk factors and outcomes

Objectives: A high incidence of delirium has been reported in older patients with Coronavirus disease 2019 (COVID-19). We aimed to identify determinants of delirium, including the Clinical Frailty Scale, in hospitalized older patients with COVID-19. Furthermore, we aimed to study the association of delirium independent of frailty with in-hospital outcomes in older COVID-19 patients. Methods: This study was performed within the framework of the multi-center COVID-OLD cohort study and included patients aged ≥60 years who were admitted to the general ward because of COVID-19 in the Netherlands between February and May 2020. Data were collected on demographics, co-morbidity, disease severity, and geriatric parameters. Prevalence of delirium during hospital admission was recorded based on delirium screening using the Delirium Observation Screening Scale (DOSS) which was scored three times daily. A DOSS score ≥3 was followed by a delirium assessment by the ward physician In-hospital outcomes included length of stay, discharge destination, and mortality. Results: A total of 412 patients were included (median age 76, 58% male). Delirium was present in 82 patients. In multivariable analysis, previous episode of delirium (Odds ratio [OR] 8.9 [95% CI 2.3–33.6] p = 0.001), and pre-existent memory problems (OR 7.6 [95% CI 3.1–22.5] p < 0.001) were associated with increased delirium risk. Clinical Frailty Scale was associated with increased delirium risk (OR 1.63 [95%CI 1.40–1.90] p < 0.001) in univariable analysis, but not in multivariable analysis. Patients who developed delirium had a shorter symptom duration and lower levels of C-reactive protein upon presentation, whereas vital parameters did not differ. Patients who developed a delirium had a longer hospital stay and were more often discharged to a nursing home. Delirium was associated with mortality (OR 2.84 [95% CI1.71–4.72] p < 0.001), but not in multivariable analyses. Conclusions: A previous delirium and pre-existent memory problems were associated with delirium risk in COVID-19. Delirium was not an independent predictor of mortality after adjustment for frailty

The preservation of ancient DNA in archaeological fish bone

The field of ancient DNA is dominated by studies focusing on terrestrial vertebrates. This taxonomic bias limits our understanding of endogenous DNA preservation for species with different bone physiology, such as teleost fish. Teleost bone is typically brittle, porous, lightweight, and is characterized by a lack of bone remodeling during growth. All of these factors potentially affect DNA preservation. Using high-throughput shotgun sequencing, we here investigate the preservation of DNA in a range of different bone elements from over 200 archaeological Atlantic cod (Gadus morhua) specimens from 38 sites in northern Europe, dating up to 8000 years before present. We observe that the majority of archaeological sites (79%) yield endogenous DNA, with 40% of sites providing samples containing high levels (>20%). Library preparation success and levels of endogenous DNA depend mainly on excavation site and pre-extraction laboratory treatment. The use of pre-extraction treatments lowers the rate of libraries that can be sequenced, although — if successful — the fraction of endogenous DNA can be improved by several orders of magnitude. This trade-off between library preparation success and levels of endogenous DNA allows for alternative extraction strategies depending on the requirements of down-stream analyses and research questions. Finally, we do not find particular bone elements to yield higher levels of endogenous DNA, as is the case for denser bones in mammals. Our results highlight the potential of archaeological fish bone as a source for ancient DNA and suggest a possible role of bone remodeling in the preservation of endogenous DNA

Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history

The distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we first generate a de novo genome assembly of the black rat. We then sequence 67 ancient and three modern black rat mitogenomes, and 36 ancient and three modern nuclear genomes from archaeological sites spanning the 1st-17th centuries CE in Europe and North Africa. Analyses of our newly reported sequences, together with published mitochondrial DNA sequences, confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6th and 10th centuries CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.Peer reviewe

A remarkable collection of Late Pleistocene reindeer (Rangifer tarandus) remains from Woerden (The Netherlands)

Woerden, in the central part of The Netherlands, is a locality where the amateur-archaeologist Pieter Stoel collected several thousands of fossil mammalian remains of Pleistocene age. The stratigraphically-mixed assemblage includes a broad variety of taxa including species that are indicative of interglacial conditions such as Hippopotamus sp. as well as species that inhabited the area during glacial episodes e.g. Mammuthus primigenius and Coelodonta antiquitatis. The fossil remains have an early Middle Pleistocene - Late Pleistocene age. Rangifer tarandus is one of the species that is very well represented in the faunal assemblage from Woerden. Woerden yielded not only thousands of fossil bones but also Palaeolithic artefacts. A direct relationship between the reindeer bones and these artefacts could not be indicated. Most of the bones are complete and not a single reindeer bone or bone fragment shows traces of human interference such as clear impact or cut marks. This is remarkable considering the many European Palaeolithic sites where reindeer hunters left their traces. Detailed investigation of the reindeer remains indicates that the majority of the reindeer remains from Woerden represent one population with juvenile as well as adult individuals. The adult specimens show a female/male ratio of 2:1, which is characteristic for natural living reindeer populations. This ratio as well as the standard deviation of the size measurements suggests that the assemblage is one distinct population and not a mix of fossil assemblages with reindeer of different size and different geological ages. Further remarkable is that the dimensions of the limb bones indicate that the reindeer from Woerden were extremely slender; much more slender than the fossil Middle and Late Pleistocene reindeer assemblages from other localities in north-western and central Europe.

Treatment-limiting decisions in patients with severe traumatic brain injury in the Netherlands

Introduction: Treatment-limiting decisions (TLDs) can be inevitable severe traumatic brain injury (s-TBI) patients, but data on their use remain scarce. Research question: To investigate the prevalence, timing and considerations of TLDs in s-TBI patients. Material and methods: s-TBI patients between 2008 and 2017 were analysed retrospecively. Patient data, timing, location, involvement of proxies, and reasons for TLDs were collected. Baseline characteristics and in-hospital outcomes were compared between s-TBI patients with and without TLDs. Results: TLDs were reported in 117 of 270 s-TBI patients (43.3%) and 95.9% of deaths after s-TBI were preceded by a TLD. The majority of TLDs (68.4%) were categorized as withdrawal of therapy, of which withdrawal of organ-support in 64.1%. Neurosurgical intervention was withheld in 29.9%. The median time from admission to TLD was 2 days [IQR, 0–8] and 50.4% of TLDs were made within 3 days of admission. The main reason for a TLD was that the patients were perceived as unsalvageable (66.7%). Nearly all decisions were made multidisciplinary (99.1%) with proxies involvement (75.2%). The predicted mortality (CRASH-score) between patients with and without TLDs were 72.6 vs. 70.6%. The percentage of TLDs in s-TBI patients increased from 20.0% in 2008 to 42.9% in 2012 and 64.3% in 2017. Discussion and conclusion: TLDs occurred in almost half of s-TBI patients and were instituted more frequently over time. Half of TLDs were made within 3 days of admission in spite of baseline prognosis between groups being similar. Future research should address whether prognostic nihilism contributes to self-fulfilling prophecies

Tackling Neuroinflammation After Traumatic Brain Injury: Complement Inhibition as a Therapy for Secondary Injury

Traumatic brain injury (TBI) is a leading cause of mortality, sensorimotor morbidity, and neurocognitive disability. Neuroinflammation is one of the key drivers causing secondary brain injury after TBI. Therefore, attenuation of the inflammatory response is a potential therapeutic goal. This review summarizes the most important neuroinflammatory pathophysiology resulting from TBI and the clinical trials performed to attenuate neuroinflammation. Studies show that non-selective attenuation of the inflammatory response, in the early phase after TBI, might be detrimental and that there is a gap in the literature regarding pharmacological trials targeting specific pathways. The complement system and its crosstalk with the coagulation system play an important role in the pathophysiology of secondary brain injury after TBI. Therefore, regaining control over the complement cascades by inhibiting overshooting activation might constitute useful therapy. Activation of the complement cascade is an early component of neuroinflammation, making it a potential target to mitigate neuroinflammation in TBI. Therefore, we have described pathophysiological aspects of complement inhibition and summarized animal studies targeting the complement system in TBI. We also present the first clinical trial aimed at inhibition of complement activation in the early days after brain injury to reduce the risk of morbidity and mortality following severe TBI

Animals and people in the Netherlands’ past: >50 years of archaeozoology in the Netherlands

More than fifty years ago, Anneke T. Clason published the first English-language archaeozoological study on Dutch faunal assemblages. Inspired by the anniversary of this landmark publication, this paper presents a status overview of Dutch archaeozoology organized in twelve themes (e.g. rituals, Mesolithic-Neolithic transition, medieval period). The paper also discusses the common methods applied in Dutch archaeozoology, and includes extensive supplementary material that summarizes data from gray literature in Dutch. Our aim is to provide a guide to archaeozoological questions pertaining to the Netherlands and open a window for researchers working outside the Netherlands to the highly active world of Dutch archaeozoology

Ancient DNA sequence quality is independent of fish bone weight

The field of ancient DNA (aDNA) typically uses between 50 and 200 mg of minimum input weight of bone material for the extraction of DNA from archaeological remains. While laboratory and analysis techniques have focused on improved efficiency of extracting useable sequence data from older and poorer quality remains, bone material input requirements have rarely been critically evaluated. Here, we present the aDNA analysis of 121 size-constrained Atlantic herring remains – weighing between <10 and 70 mg – that were individually sequenced to explore the capacity of successful aDNA retrieval from small archaeological remains. We statistically evaluate the relationship between bone weight and several response variables, including library success, endogenous DNA content, and library complexity, i.e., the number of unique molecules that are obtained. Remarkably, we find no relationship between bone weight and library success, levels of endogenous DNA, or library complexity. Our results imply that – at least in the case of fish bone – even minute bones can yield positive results and that the presumed minimum sample size required should be re-evaluated. Archaeological site, instead of bone size, is the primary driver of DNA sequence quality. Our work expands the number of specimens considered suitable for aDNA analyses, and therefore facilitates efforts to minimize the destructive impact of aDNA research and mediate some of the ethical concerns surrounding destructive analysis.publishedVersio

The preservation of ancient DNA in archaeological fish bone

The field of ancient DNA is dominated by studies focusing on terrestrial vertebrates. This taxonomic bias limits our understanding of endogenous DNA preservation for species with different bone physiology, such as teleost fish. Teleost bone is typically brittle, porous, lightweight, and is characterized by a lack of bone remodeling during growth. All of these factors potentially affect DNA preservation. Using high-throughput shotgun sequencing, we here investigate the preservation of DNA in a range of different bone elements from over 200 archaeological Atlantic cod (Gadus morhua) specimens from 38 sites in northern Europe, dating up to 8000 years before present. We observe that the majority of archaeological sites (79%) yield endogenous DNA, with 40% of sites providing samples containing high levels (>20%). Library preparation success and levels of endogenous DNA depend mainly on excavation site and pre-extraction laboratory treatment. The use of pre-extraction treatments lowers the rate of libraries that can be sequenced, although — if successful — the fraction of endogenous DNA can be improved by several orders of magnitude. This trade-off between library preparation success and levels of endogenous DNA allows for alternative extraction strategies depending on the requirements of down-stream analyses and research questions. Finally, we do not find particular bone elements to yield higher levels of endogenous DNA, as is the case for denser bones in mammals. Our results highlight the potential of archaeological fish bone as a source for ancient DNA and suggest a possible role of bone remodeling in the preservation of endogenous DNA