Liver organoids: from basic research to therapeutic applications.

Organoid cultures have emerged as an alternative in vitro system to recapitulate tissues in a dish. While mouse models and cell lines have furthered our understanding of liver biology and associated diseases, they suffer in replicating key aspects of human liver tissue, in particular its complex architecture and metabolic functions. Liver organoids have now been established for multiple species from induced pluripotent stem cells, embryonic stem cells, hepatoblasts and adult tissue-derived cells. These represent a promising addition to our toolbox to gain a deeper understanding of this complex organ. In this perspective we will review the advances in the liver organoid field, its limitations and potential for biomedical applications.Acknowledgements M.H. is a Wellcome Trust Sir Henry Dale Fellow and is jointly funded by the Wellcome Trust and the Royal Society (104151/Z/14/Z). This work was partially funded by a H2020 LSMF4LIFE awarded to M.H. PI is funded by the NC3Rs (NC/R001162/1). The authors acknowledge core funding to the Gurdon Institute from the Wellcome Trust (092096) and CRUK (C6946/A14492)

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

The influence of corporate social responsibility associations on consumers’ perceptions towards global brands

The key research question in this study concerns the effect of global brands corporate social responsibility (CSR) associations on corporate ability (CA) associations and consumer-company identification and their ultimate impact on brand loyalty. The study tests the hypotheses using Structural Equation Modelling (SEM) in the software PLS (Partial Least Squares) with a data-set composed of survey data from 344 consumers. One important finding is the empirical validation of the relationship between two important types of corporate associations (CSR and CA). CSR associations are a relevant precursor of CA associations and consumer-company identification, demonstrating that consumers’ perceptions regarding CSR can influence both the formation of other corporate associations and the construction of an emotional link and sense of attachment established with the brand. The findings also evidence that CSR associations lead to consumers’ brand loyalty mediated by CA associations and consumer-company identification. This research contributes to social identity theory by demonstrating that CSR is a mechanism that deepens the consumers’ strength of identification with the organization reinforcing brand loyalty through both CA associations and consumer-company identification. Another important finding of this research is the empirical validation of the impact of consumer psychological features on the construction of CA associations as result of CSR associations. Customers highly supportive of CSR are more prone to build favorable CA associations. The study finds evidence that CSR associations are essential for managing and for the differentiation of global brands.info:eu-repo/semantics/publishedVersio

Heart failure after conventional metal-on-metal hip replacements: A retrospective cohort study

Background and purpose — It is unclear whether metal particles and ions produced by mechanical wear and corrosion of hip prostheses with metal-on-metal (MoM) bearings have systemic adverse effects on health. We compared the risk of heart failure in patients with conventional MoM total hip arthroplasty (THA) and in those with metal-on-polyethylene (MoP) THA. Patients and methods — We conducted a retrospective cohort study using data from the Australian Government Department of Veterans’ Affairs health claims database on patients who received conventional THA for osteoarthritis between 2004 and 2012. The MoM THAs were classified into groups: Articular Surface Replacement (ASR) XL Acetabular System, other large-head (LH) (> 32 mm) MoM, and small-head (SH) (≤ 32 mm) MoM. The primary outcome was hospitalization for heart failure after THA. Results — 4,019 patients with no history of heart failure were included (56% women). Men with an ASR XL THA had a higher rate of hospitalization for heart failure than men with MoP THA (hazard ratio (HR) = 3.2, 95% CI: 1.6–6.5). No statistically significant difference in the rate of heart failure was found with the other LH MoM or SH MoM compared to MoP in men. There was no statistically significant difference in heart failure rate between exposure groups in women. Interpretation — An association between ASR XL and hospitalization for heart failure was found in men. While causality between ASR XL and heart failure could not be established in this study, it highlights an urgent need for further studies to investigate the possibility of systemic effects associated with MoM THA

Postoperative opioid use as an early indication of total hip arthroplasty failure

Background and purpose — A criticism of total hip arthroplasty (THA) survivorship analysis is that revisions are a late and rare outcome. We investigated whether prolonged opioid use is a possible indicator of early THA failure. Patients and methods — We conducted a cohort study of THAs registered in a total joint replacement registry from January 2008 to December 2011. 12,859 patients were evaluated. The median age was 67 years and 58% were women. Opioid use in the year after surgery was the exposure of interest, and the cumulative daily amounts of oral morphine equivalents (OMEs) were calculated. Post-THA OMEs per 90 day periods were categorized into quartiles. The endpoints were 1- and 5-year revisions. Results — After the first 90 days, 27% continued to use opioids. The revision rate was 0.9% within a year and 1.7% within 5 years. Use of medium-low (100–219 mg), medium-high (220–533 mg), and high (≥ 534 mg) amounts of OMEs in days 91–180 after surgery was associated with a 6 times (95% confidence interval (CI): 3–15), 5 times (CI: 2–13), and 11 times (CI: 2.9–44) higher adjusted risk of 1 year revision, respectively. The use of medium-low and medium-high amounts of OMEs in days 181–270 after surgery was associated with a 17 times (CI: 6–44) and 14 times (95% CI: 4–46) higher adjusted risk of 1-year revision. There was a similar higher risk of 5-year revision. Interpretation — Persistent postoperative use of opioids was associated with revision THA surgery in this cohort, and it may be an early indicator of potential surgical failures