Prevalence and correlates of alexithymia in older persons with medically (un)explained physical symptoms

Objectives: Much is unknown about the combination of Medically Unexplained Symptoms (MUS) and alexithymia in later life, but it may culminate in a high disease burden for older patients. In the present study we assess the prevalence of alexithymia in older patients with either MUS or Medically Explained Symptoms (MES) and we explore physical, psychological and social correlates of alexithymia.  Methods and Design: A case control study was performed. We recruited older persons (>60 years) with MUS (N = 118) or MES (N = 154) from the general public, general practitioner clinics and hospitals. Alexithymia was measured by the 20-item Toronto Alexithymia Scale, correlates were measured by various questionnaires. Results: Prevalence and severity of alexithymia were higher among older persons with MUS compared to MES. Alexithymia prevalence in the MUS subgroup was 23.7%. We found no association between alexithymia and increasing age. Alexithymia was associated with depressive symptoms, especially in the MUS population. Conclusions: Alexithymia prevalence was lower than generally found in younger patients with somatoform disorder, but comparable to studies with similar diagnostic methods for MUS. Considering the high prevalence and presumed etiological impact of alexithymia in older patients with MUS, as well as its association with depression, this stresses the need to develop better understanding of the associations between alexithymia, MUS and depression in later life

A seventeenth-centuryMycobacterium tuberculosisgenome supports a Neolithic emergence of theMycobacterium tuberculosiscomplex

BACKGROUND: Although tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modern Mycobacterium tuberculosis complex (MTBC) genomes suggests their most recent common ancestor followed human migrations out of Africa approximately 70,000 years before present. However, studies using ancient genomes as calibration points have yielded much younger dates of less than 6000 years. Here, we aim to address this discrepancy through the analysis of the highest-coverage and highest-quality ancient MTBC genome available to date, reconstructed from a calcified lung nodule of Bishop Peder Winstrup of Lund (b. 1605-d. 1679). RESULTS: A metagenomic approach for taxonomic classification of whole DNA content permitted the identification of abundant DNA belonging to the human host and the MTBC, with few non-TB bacterial taxa comprising the background. Genomic enrichment enabled the reconstruction of a 141-fold coverage M. tuberculosis genome. In utilizing this high-quality, high-coverage seventeenth-century genome as a calibration point for dating the MTBC, we employed multiple Bayesian tree models, including birth-death models, which allowed us to model pathogen population dynamics and data sampling strategies more realistically than those based on the coalescent. CONCLUSIONS: The results of our metagenomic analysis demonstrate the unique preservation environment calcified nodules provide for DNA. Importantly, we estimate a most recent common ancestor date for the MTBC of between 2190 and 4501 before present and for Lineage 4 of between 929 and 2084 before present using multiple models, confirming a Neolithic emergence for the MTBC

Barriers and facilitators to implementing interventions for medically unexplained symptoms in primary and secondary care: A systematic review

Objective: To integrate existing literature on barriers and facilitators to implementing interventions for Medically Unexplained Symptoms (MUS) in primary and secondary care. Method: Systematic review following PRISMA guidelines. A search of PsychINFO/Pubmed/Web of Science was performed to select studies focusing on MUS-interventions and implementation. All included papers were checked for quality and bias. A narrative synthesis approach was used to describe the included papers by implementation level, ranging from the specific intervention to the broader economic/political context. Results: 20 (quantitative/qualitative/mixed design) papers were included, but the quantitative studies especially, lacked methodological quality, with possible publication bias as a result. Results showed that the intervention needs to be acceptable and in line with daily practice routines. The professional's attitude and skills are important for implementation success, as well as for overcoming problems in the professional-patient interaction. If patients stick to finding a somatic cause, this hampers implementation. A lack of time is a frequently mentioned barrier at the organizational level. Barriers/facilitators at the social context level and at the economic/political level were barely reported on in the included papers. Conclusion: Results were integrated into an existing implementation model, as an example of how MUS-interventions can be successfully implemented in practice

Enabling FrodoKEM on Embedded Devices

FrodoKEM is a lattice-based Key Encapsulation Mechanism (KEM) based on unstructured lattices. From a security point of view this makes it a conservative option to achieve post-quantum security, hence why it is favored by several European authorities (e.g., German BSI and French ANSSI). Relying on unstructured instead of structured lattices (e.g., CRYSTALS-Kyber) comes at the cost of additional memory usage, which is particularly critical for embedded security applications such as smart cards. For example, prior FrodoKEM-640 implementations (using AES) on Cortex-M4 require more than 80 kB of stack making it impossible to run on some embedded systems. In this work, we explore several stack reduction strategies and the resulting time versus memory trade-offs. Concretely, we reduce the stack consumption of FrodoKEM by a factor 2–3× compared to the smallest known implementations with almost no impact on performance. We also present various time-memory trade-offs going as low as 8 kB for all AES parameter sets, and below 4 kB for FrodoKEM-640. By introducing a minor tweak to the FrodoKEM specifications, we additionally reduce the stack consumption down to 8 kB for all the SHAKE versions. As a result, this work enables FrodoKEM on more resource constrained embedded systems

Analysis of 3800-year-old Yersinia pestis genomes suggests Bronze Age origin for bubonic plague

该论文通过对青铜器时代的两个鼠疫杆菌分离株进行测序，深入剖析了鼠疫杆菌的历史。德国、俄罗斯、中国和瑞士等多国研究员共同参与了研究。这篇论文的第一作者是德国马克斯-普朗克研究所的考古遗传学专家Maria Spyrou。她和同事从俄罗斯墓穴中埋葬的九名古代人的牙齿样本入手，发现有两人感染鼠疫杆菌。之后，他们从这些个体中分离出距今约3800年的病原菌。在这项新研究中，研究人员利用液相捕获和Illumina鸟枪法测序技术，对青铜器时代的一名男子（RT5）的鼠疫杆菌和人类宿主序列进行测序，其中鼠疫杆菌基因组的平均覆盖度达到32倍。同时，他们还对另一名感染个体（RT6）的分离株进行测序，平均覆盖度为1.9倍。系统发育分析表明，RT5和RT6分离株是共同谱系的一部分，这个谱系的祖先是史上三次瘟疫大流行的罪魁祸首。除了众所周知的中世纪欧洲瘟疫大流行，鼠疫杆菌还曾造成公元6世纪的查士丁尼瘟疫和19世纪的中国大规模鼠疫。 马克斯-普朗克人类历史科学研究所的古病理学专家Kirsten Bos表示，这些结果表明“具有传播潜力的瘟疫存在的时间比我们想象得更久。”Bos是这篇论文的通讯作者之一。【Abstract】The origin of Yersinia pestis and the early stages of its evolution are fundamental subjects of investigation given its high virulence and mortality that resulted from past pandemics. Although the earliest evidence of Y. pestis infections in humans has been identified in Late Neolithic/Bronze Age Eurasia (LNBA 5000–3500y BP), these strains lack key genetic components required for flea adaptation, thus making their mode of transmission and disease presentation in humans unclear. Here, we reconstruct ancient Y. pestis genomes from individuals associated with the Late Bronze Age period (~3800 BP) in the Samara region of modern-day Russia. We show clear distinctions between our new strains and the LNBA lineage, and suggest that the full ability for flea-mediated transmission causing bubonic plague evolved more than 1000 years earlier than previously suggested. Finally, we propose that several Y. pestis lineages were established during the Bronze Age, some of which persist to the present day.We thank Cosimo Posth, Marcel Keller, Michal Feldman and Wolfgang Haak for useful insights to the manuscript, as well as Alexander Immel and Stephen Clayton for computational support. In addition, we are thankful to Guido Brandt, Antje Wissgott and Cäcilia Freund for laboratory support. M.A.S., A.H., K.I.B. and J.K. were supported by the ERC starting grant APGREID, and by the Max Planck Society. C.C.W. was supported by the Max Planck Society and the Nanqiang Outstanding Young Talents Program of Xiamen University. D.K. was supported by a Marie Heim-Vögtlin grant from the Swiss National Science Foundation

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.</p

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275

Stone Age Yersinia pestis genomes shed light on the early evolution, diversity, and ecology of plague

[Significance] The bacterium Yersinia pestis has caused numerous historically documented outbreaks of plague and research using ancient DNA could demonstrate that it already affected human populations during the Neolithic. However, the pathogen’s genetic diversity, geographic spread, and transmission dynamics during this early period of Y. pestis evolution are largely unexplored. Here, we describe a set of ancient plague genomes up to 5,000 y old from across Eurasia. Our data demonstrate that two genetically distinct forms of Y. pestis evolved in parallel and were both distributed across vast geographic distances, potentially occupying different ecological niches. Interpreted within the archeological context, our results suggest that the spread of plague during this period was linked to increased human mobility and intensification of animal husbandry.The bacterial pathogen Yersinia pestis gave rise to devastating outbreaks throughout human history, and ancient DNA evidence has shown it afflicted human populations as far back as the Neolithic. Y. pestis genomes recovered from the Eurasian Late Neolithic/Early Bronze Age (LNBA) period have uncovered key evolutionary steps that led to its emergence from a Yersinia pseudotuberculosis-like progenitor; however, the number of reconstructed LNBA genomes are too few to explore its diversity during this critical period of development. Here, we present 17 Y. pestis genomes dating to 5,000 to 2,500 y BP from a wide geographic expanse across Eurasia. This increased dataset enabled us to explore correlations between temporal, geographical, and genetic distance. Our results suggest a nonflea-adapted and potentially extinct single lineage that persisted over millennia without significant parallel diversification, accompanied by rapid dispersal across continents throughout this period, a trend not observed in other pathogens for which ancient genomes are available. A stepwise pattern of gene loss provides further clues on its early evolution and potential adaptation. We also discover the presence of the flea-adapted form of Y. pestis in Bronze Age Iberia, previously only identified in in the Caucasus and the Volga regions, suggesting a much wider geographic spread of this form of Y. pestis. Together, these data reveal the dynamic nature of plague’s formative years in terms of its early evolution and ecology.This study was funded by the Max Planck Society, Max Planck Harvard Research Center for the Archaeoscience of the Ancient Mediterranean and the European Research Council under the European Union’s Horizon 2020 research and innovation program under Grant Agreement 771234 – PALEoRIDER (to W.H.), 856453 – HistoGenes (to J.K.), and 834616 – ARCHCAUCASUS (to S.H.). The Heidelberg Academy of Science financed the genetic and archeological research on human individuals from the Augsburg region within the project WIN Kolleg: “Times of Upheaval: Changes of Society and Landscape at the Beginning of the Bronze Age. M.E. was supported by the award “Praemium Academiae” of the Czech Academy of Sciences. M.D. was supported by the project RVO 67985912 of the Institute of Archaeology of the Czech Academy of Sciences, Prague. I.O. was supported by the Ramón y Cajal grant from Ministerio de Ciencia e Innovación, Spanish Government (RYC2019-027909-I). A. H€ubner was supported by the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (EXC 2051 – Project-ID 390713860). J.F.-E. and J.A.M.-A. were supported by the Diputación Foral de Alava, IT 1223-19, Gobierno Vasco. A. Buzhilova was supported by the Center of Information Technologies and Systems (CITIS), Moscow, Russia 121041500329-0. L. M., L.B.D., and E. Khussainova were supported by the Grant AP08856654, Ministry of Education and Science of the Republic of Kazakhstan. A. Beisenov was supported by the Grant AP08857177, Ministry of Education and Science of the Republic of Kazakhstan.Peer reviewe

Ten millennia of hepatitis B virus evolution

Hepatitis B virus (HBV) has been infecting humans for millennia and remains a global health problem, but its past diversity and dispersal routes are largely unknown. We generated HBV genomic data from 137 Eurasians and Native Americans dated between ~10,500 and ~400 years ago. We date the most recent common ancestor of all HBV lineages to between ~20,000 and 12,000 years ago, with the virus present in European and South American hunter-gatherers during the early Holocene. After the European Neolithic transition, Mesolithic HBV strains were replaced by a lineage likely disseminated by early farmers that prevailed throughout western Eurasia for ~4000 years, declining around the end of the 2nd millennium BCE. The only remnant of this prehistoric HBV diversity is the rare genotype G, which appears to have reemerged during the HIV pandemic