Development of a reliable surgical quality assurance tool for gastrectomy in oncological trials.

BACKGROUND: Despite its recognized importance, there is currently no reliable tool for surgical quality assurance (SQA) of gastrectomy in surgical oncology. The aim of this study was to develop an SQA tool for gastrectomy and to apply this tool within the ADDICT Trial in order to assess the extent and completeness of lymphadenectomy. METHODS: The operative steps for D1+ and D2 gastrectomy have been previously described in the literature and ADDICT trial manual. Two researchers also performed fieldwork in the UK and Japan to document key operative steps through photographs and semi-structured interviews with expert surgeons. This provided the steps that were used as the framework for the SQA tool. Sixty-two photographic cases from the ADDICT Trial were rated by three independent surgeons. Generalizability (G) theory determined inter-rater reliability. D-studies examined the effect of varying the number of assessors and photographic series they rated. Chi-square assessed intra-rater reliability, comparing how the individual assessor's responses corresponded to their global rating for extent of lymphadenectomy. RESULTS: The tool comprised 20 items, including 19 anatomical landmarks and a global rating score. Overall reliability had G-coefficient of 0.557. Internal consistency was measured with a Cronbach's alpha score of 0.869 and Chi-square confirmed intra-rater reliability for each assessor as < 0.05. CONCLUSIONS: A photographic surgical quality assurance tool is presented for gastrectomy. Using this tool, the assessor can reliably determine not only the quality but also the extent of the lymphadenectomy performed based on remaining anatomy rather than the excised specimen.

Equipping for risk: Lessons learnt from the UK shale-gas experience on assessing environmental risks for the future geoenergy use of the deep subsurface.

findings are presented from an investigation to improve understanding of the environmental risks associated with developing an unconventional-hydrocarbons industry in the UK. The EQUIPT4RISK project, funded by UK Research Councils, focused on investigations around Preston New Road (PNR), Fylde, Lancashire, and Kirby Misperton Site A (KMA), North Yorkshire, where operator licences to explore for shale gas by hydraulic fracturing (HF) were issued in 2016, although exploration only took place at PNR. EQUIPT4RISK considered atmospheric (greenhouse gases, air quality), water (groundwater quality) and solid-earth (seismicity) compartments to characterise and model local conditions and environmental responses to HF activities. Risk assessment was based on the source-pathway-receptor approach. Baseline monitoring of air around the two sites characterised the variability with meteorological conditions, and isotopic signatures were able to discriminate biogenic methane (cattle) from thermogenic (natural-gas) sources. Monitoring of a post-HF nitrogen-lift (well-cleaning) operation at PNR detected the release of atmospheric emissions of methane (4.2 ± 1.4 t CH4). Groundwater monitoring around KMA identified high baseline methane concentrations and detected ethane and propane at some locations. Dissolved methane was inferred from stable-isotopic evidence as overwhelmingly of biogenic origin. Groundwater-quality monitoring around PNR found no evidence of HF-induced impacts. Two approaches for modelling induced seismicity and associated seismic risk were developed using observations of seismicity and operational parameters from PNR in 2018 and 2019. Novel methodologies developed for monitoring include use of machine learning to identify fugitive atmospheric methane, Bayesian statistics to assess changes to groundwater quality, a seismicity forecasting model seeded by the HF-fluid injection rate and high-resolution monitoring of soil-gas methane. The project developed a risk-assessment framework, aligned with ISO 31000 risk-management principles, to assess the theoretical combined and cumulative environmental risks from operations over time. This demonstrated the spatial and temporal evolution of risk profiles: seismic and atmospheric impacts from the shale-gas operations are modelled to be localised and short-lived, while risk to groundwater quality is longer-term.

Challenges to genetic testing for germline mutations associated with breast cancer among African Americans

Inequities in preventive cancer screening, diagnosis, treatment, and inferior cancer outcomes continue to pose challenges across the cancer continuum. While the exact reasons for these inferior outcomes are unknown, multiple barriers to various domains of social determinants of health (SDOH) play a vital role, leading to inequities in cancer care. These include barriers to transportation, housing, and food insecurities, contributing to delays in preventive screening and treatment. Furthermore, aggressive biologies also exist across various racial profiles with accompanying germline mutations. For example, African Americans (AAs) have a higher incidence of triple-negative breast cancer subtype and a high prevalence of BRCA1/2 gene mutations, increasing the risk of multiple cancers, warranting high-risk screening for these populations. Unfortunately, other barriers, such as financial insecurities, low health literacy rates, and lack of awareness, lead to delays in cancer screening and genetic testing, even with available high-risk screening and risk reduction procedures. In addition, physicians receive minimal interdisciplinary training to address genetic assessment, interpretation of the results, and almost no additional training in addressing the unique needs of racial minorities, leading to suboptimal delivery of genetic assessment provision resources among AAs. In this review, we discuss the confluence of factors and barriers limiting genetic testing among AAs and highlight the prevalence of germline mutations associated with increased risk of breast cancer among AAs, reflecting the need for multi-panel germline testing as well as education regarding hereditary cancer risks in underserved minorities.

Considerations for Colorectal Neoplasia Detection in Inflammatory Bowel Disease Clinical Trials.

BACKGROUND: High-quality colonoscopic surveillance can lead to earlier and increased detection of colorectal neoplasia in patients with inflammatory bowel disease (IBD). In IBD clinical trials, endoscopy is used to assess mucosal disease activity before and after treatment but also provides an opportunity to surveil for colorectal neoplasia during follow-up. SUMMARY: Best practices for colorectal cancer identification in IBD clinical trials require engagement and collaboration between the clinical trial sponsor, site endoscopist and/or principal investigator, and central read team. Each team member has unique responsibilities for maximizing dysplasia detection in IBD trials. KEY MESSAGES: Sponsors should work in accordance with scientific guidelines to standardize imaging procedures, design the protocol to ensure the trial population is safeguarded, and oversee trial conduct. The site endoscopist should remain updated on best practices to tailor sponsor protocol-required procedures to patient needs, examine the mucosa for disease activity and potential dysplasia during all procedures, and provide optimal procedure videos for central read analysis. Central readers may detect dysplasia or colorectal cancer and a framework to report these findings to trial sponsors is essential. Synergistic relationships between all team members in IBD clinical trials provide an important opportunity for extended endoscopic evaluation and colorectal neoplasia identification.

Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer.

BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis. CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.

Phylogenomic Analyses Reveal an Allopolyploid Origin of Core Didymocarpinae (Gesneriaceae) Followed by Rapid Radiation.

Allopolyploid plants have long been regarded as possessing genetic advantages under certain circumstances due to the combined effects of their hybrid origins and duplicated genomes. However, the evolutionary consequences of allopolyploidy in lineage diversification remain to be fully understood. Here, we investigate the evolutionary consequences of allopolyploidy using 138 transcriptomic sequences of Gesneriaceae, including 124 newly sequenced, focusing particularly on the largest subtribe Didymocarpinae. We estimated the phylogeny of Gesneriaceae using concatenated and coalescent-based methods based on five different nuclear matrices and 27 plastid genes, focusing on relationships among major clades. To better understand the evolutionary affinities in this family, we applied a range of approaches to characterize the extent and cause of phylogenetic incongruence. We found that extensive conflicts between nuclear and chloroplast genomes and among nuclear genes were caused by both incomplete lineage sorting (ILS) and reticulation, and we found evidence of widespread ancient hybridization and introgression. Using the most highly supported phylogenomic framework, we revealed multiple bursts of gene duplication throughout the evolutionary history of Gesneriaceae. By incorporating molecular dating and analyses of diversification dynamics, our study shows that an ancient allopolyploidization event occurred around the Oligocene-Miocene boundary, which may have driven the rapid radiation of core Didymocarpinae.

Artificial Intelligence in Inflammatory Bowel Disease Endoscopy: Implications for Clinical Trials.

Artificial intelligence shows promise for clinical research in inflammatory bowel disease endoscopy. Accurate assessment of endoscopic activity is important in clinical practice and inflammatory bowel disease clinical trials. Emerging artificial intelligence technologies can increase efficiency and accuracy of assessing the baseline endoscopic appearance in patients with inflammatory bowel disease and the impact that therapeutic interventions may have on mucosal healing in both of these contexts. In this review, state-of-the-art endoscopic assessment of mucosal disease activity in inflammatory bowel disease clinical trials is described, covering the potential for artificial intelligence to transform the current paradigm, its limitations, and suggested next steps. Site-based artificial intelligence quality evaluation and inclusion of patients in clinical trials without the need for a central reader is proposed; for following patient progress, a second reading using AI alongside a central reader with expedited reading is proposed. Artificial intelligence will support precision endoscopy in inflammatory bowel disease and is on the threshold of advancing inflammatory bowel disease clinical trial recruitment.

Declining Enrolment and Other Challenges in IBD Clinical Trials: Causes and Potential Solutions.

BACKGROUND: Rates of enrolment in clinical trials in inflammatory bowel disease [IBD] have decreased dramatically in recent years. This has led to delays, increased costs and failures to develop novel treatments. AIMS: The aim of this work is to describe the current bottlenecks of IBD clinical trial enrolment and propose solutions. METHODS: A taskforce comprising experienced IBD clinical trialists from academic centres and pharmaceutical companies involved in IBD clinical research predefined the four following levels: [1] study design, [2] investigative centre, [3] physician and [4] patient. At each level, the taskforce collectively explored the reasons for declining enrolment rates and generated an inventory of potential solutions. RESULTS: The main reasons identified included the overall increased demands for trials, the high screen failure rates, particularly in Crohn's disease, partly due to the lack of correlation between clinical and endoscopic activity, and the use of complicated endoscopic scoring systems not reflective of the totality of inflammation. In addition, complex trial protocols with restrictive eligibility criteria, increasing burden of procedures and administrative tasks enhance the need for qualified resources in study coordination. At the physician level, lack of dedicated time and training is crucial. From the patients' perspective, long washout periods from previous medications and protocol requirements not reflecting clinical practice, such as prolonged steroid management and placebo exposures, limit their participation in clinical trials. CONCLUSION: This joint effort is proposed as the basis for profound clinical trial transformation triggered by investigative centres, contract research organizations, sponsors and regulatory agencies.

Endoscopic stapler versus laser diverticulotomy for Zenker's diverticulum: a systematic review and meta-analysis.

OBJECTIVE: A literature review and meta-analysis was performed to assess for difference in rate of complications and need for revision surgery between endoscopic stapler-assisted diverticulotomy and endoscopic carbon dioxide laser diverticulotomy. The hypothesis was that endoscopic stapler-assisted diverticulotomy has a lower complication rate but endoscopic carbon dioxide laser diverticulotomy has a lower need for revision surgery. METHOD: This was a systematic review of English-language studies comparing endoscopic stapler-assisted diverticulotomy and endoscopic carbon dioxide laser diverticulotomy for the treatment of Zenker's diverticulum. Meta-analysis of results with regard to rate of pharyngeal perforation, major post-operative complication and need for re-operation was performed. RESULTS: Nine retrospective studies were included with pooled analysis of 417 endoscopic stapler-assisted diverticulotomy and 413 endoscopic carbon dioxide laser diverticulotomy cases. Meta-analysis found no significant difference in rate of pharyngeal perforation, major complication or need for re-operation between the two groups. CONCLUSION: This study demonstrated both endoscopic stapler-assisted diverticulotomy and endoscopic carbon dioxide laser diverticulotomy to be a safe alternative to open surgery for Zenker's diverticulum. Both appear to be similar in terms of adverse events and efficacy. The authors recommend either approach, guided by surgeon's preference and experience, where patients are unsuitable for an open surgery approach.

Adaptive radiation in Orinus, an endemic alpine grass of the Qinghai-Tibet Plateau, based on comparative transcriptomic analysis.

The species of Orinus (Poaceae) are important alpine plants with a variety of phenotypic traits and potential usages in molecular breeding toward drought-tolerant forage crops. However, the genetic basis of evolutionary adaption and diversification in the genus is still unclear. In the present study, we obtained transcriptomes for the two most divergent species, O. thoroldii and O. kokonoricus, using the Illumina platform and de novo assembly. In total, we generated 23,029 and 24,086 unigenes with N50 values of 1188 and 1203 for O. thoroldii and O. kokonoricus respectively, and identified 19,005 pairs of putative orthologs between the two species of Orinus. For these orthologs, estimations of non-synonymous/synonymous substitution rate ratios indicated that 568 pairs may be under strongly positive selection (Ka/Ks > 1), and Gene Ontogeny (GO) enrichment analysis revealed that significantly enriched pathways were in DNA repair and resistance to abiotic stress. Meanwhile, the divergence times of species between O. thoroldii and O. kokonoricus occurred 3.2 million years ago (Mya), and the recent evolutionary branch is an allotetraploid species, Cleistogenes songorica. We also detected a Ks peak of ∼0.60 for Orinus. Additionally, we identified 188 pairs of differentially expressed genes (DEGs) between the two species of Orinus, which were significantly enrich in stress resistance and lateral root development. Thus, we considered that the species diversification and evolutionary adaption of this genus was initiated by environmental selection, followed by phenotypic differentiation, finally leading to niche separation in the Qinghai-Tibet Plateau.

Genome size evolution of the extant lycophytes and ferns.

Ferns and lycophytes have remarkably large genomes. However, little is known about how their genome size evolved in fern lineages. To explore the origins and evolution of chromosome numbers and genome size in ferns, we used flow cytometry to measure the genomes of 240 species (255 samples) of extant ferns and lycophytes comprising 27 families and 72 genera, of which 228 species (242 samples) represent new reports. We analyzed correlations among genome size, spore size, chromosomal features, phylogeny, and habitat type preference within a phylogenetic framework. We also applied ANOVA and multinomial logistic regression analysis to preference of habitat type and genome size. Using the phylogeny, we conducted ancestral character reconstruction for habitat types and tested whether genome size changes simultaneously with shifts in habitat preference. We found that 2C values had weak phylogenetic signal, whereas the base number of chromosomes (x) had a strong phylogenetic signal. Furthermore, our analyses revealed a positive correlation between genome size and chromosome traits, indicating that the base number of chromosomes (x), chromosome size, and polyploidization may be primary contributors to genome expansion in ferns and lycophytes. Genome sizes in different habitat types varied significantly and were significantly correlated with habitat types; specifically, multinomial logistic regression indicated that species with larger 2C values were more likely to be epiphytes. Terrestrial habitat is inferred to be ancestral for both extant ferns and lycophytes, whereas transitions to other habitat types occurred as the major clades emerged. Shifts in habitat types appear be followed by periods of genomic stability. Based on these results, we inferred that habitat type changes and multiple whole-genome duplications have contributed to the formation of large genomes of ferns and their allies during their evolutionary history.

Radiogenomic analysis of primary breast cancer reveals [18F]-fluorodeoxglucose dynamic flux-constants are positively associated with immune pathways and outperform static uptake measures in associating with glucose metabolism.

BACKGROUND: PET imaging of 18F-fluorodeoxygucose (FDG) is used widely for tumour staging and assessment of treatment response, but the biology associated with FDG uptake is still not fully elucidated. We therefore carried out gene set enrichment analyses (GSEA) of RNA sequencing data to find KEGG pathways associated with FDG uptake in primary breast cancers. METHODS: Pre-treatment data were analysed from a window-of-opportunity study in which 30 patients underwent static and dynamic FDG-PET and tumour biopsy. Kinetic models were fitted to dynamic images, and GSEA was performed for enrichment scores reflecting Pearson and Spearman coefficients of correlations between gene expression and imaging. RESULTS: A total of 38 pathways were associated with kinetic model flux-constants or static measures of FDG uptake, all positively. The associated pathways included glycolysis/gluconeogenesis ('GLYC-GLUC') which mediates FDG uptake and was associated with model flux-constants but not with static uptake measures, and 28 pathways related to immune-response or inflammation. More pathways, 32, were associated with the flux-constant K of the simple Patlak model than with any other imaging index. Numbers of pathways categorised as being associated with individual micro-parameters of the kinetic models were substantially fewer than numbers associated with flux-constants, and lay around levels expected by chance. CONCLUSIONS: In pre-treatment images GLYC-GLUC was associated with FDG kinetic flux-constants including Patlak K, but not with static uptake measures. Immune-related pathways were associated with flux-constants and static uptake. Patlak K was associated with more pathways than were the flux-constants of more complex kinetic models. On the basis of these results Patlak analysis of dynamic FDG-PET scans is advantageous, compared to other kinetic analyses or static imaging, in studies seeking to infer tumour-to-tumour differences in biology from differences in imaging. Trial registration NCT01266486, December 24th 2010.

Implementation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System in a randomized phase IIb study of abatacept in psoriatic arthritis.

OBJECTIVES: To investigate if the OMERACT PsA MRI Scoring System (PsAMRIS), including a novel total inflammation score, shows sensitivity to change with an agent (abatacept) known to impact clinical outcomes in PsA. METHODS: We performed a post hoc analysis of a randomized phase IIb study of abatacept in patients with PsA and inadequate DMARD response. Participants received one of three abatacept dosing regimens [ABA3, ABA10 or ABA30/10 mg/kg (30 mg/kg switched to 10 mg/kg after two doses)] or placebo until day 169, then ABA10 through day 365. MRIs at baseline and days 85, 169 and 365 were centrally evaluated by two readers blinded to chronological order and treatment arm. Synovitis, osteitis, tenosynovitis, periarticular inflammation, bone erosions, joint space narrowing and bone proliferation were assessed using the PsAMRIS. A novel total inflammation score was tested. RESULTS: MRIs for 123 patients were included. On day 169, ABA10 and ABA30/10 significantly reduced MRI synovitis and tenosynovitis, respectively, vs placebo [differences -0.966 (P = 0.039) and -1.652 (P = 0.014), respectively]. Synovitis in the placebo group increased non-significantly from baseline to day 169, total inflammation and tenosynovitis decreased non-significantly and all measures improved significantly after a switch to ABA10 [-1.019, -0.940, -2.275 (P < 0.05), respectively, day 365 vs day 169]. Structural outcomes changed minimally across groups. CONCLUSION: Adults with PsA receiving ABA10 and ABA30/10 demonstrated significant resolution of inflammatory components of disease, confirmed by MRI, with synovitis and tenosynovitis improvements consistent with previously reported clinical responses for these doses. Results indicate that a reduction in OMERACT PsAMRIS inflammation scores may provide proof of tissue-level efficacy in PsA clinical trials. REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT00534313.

Characterising 18F-fluciclovine uptake in breast cancer through the use of dynamic PET/CT imaging.

BACKGROUND: 18F-fluciclovine is a synthetic amino acid positron emission tomography (PET) radiotracer that is approved for use in prostate cancer. In this clinical study, we characterised the kinetic model best describing the uptake of 18F-fluciclovine in breast cancer and assessed differences in tracer kinetics and static parameters for different breast cancer receptor subtypes and tumour grades. METHODS: Thirty-nine patients with pathologically proven breast cancer underwent 20-min dynamic PET/computed tomography imaging following the administration of 18F-fluciclovine. Uptake into primary breast tumours was evaluated using one- and two-tissue reversible compartmental kinetic models and static parameters. RESULTS: A reversible one-tissue compartment model was shown to best describe tracer uptake in breast cancer. No significant differences were seen in kinetic or static parameters for different tumour receptor subtypes or grades. Kinetic and static parameters showed a good correlation. CONCLUSIONS: 18F-fluciclovine has potential in the imaging of primary breast cancer, but kinetic analysis may not have additional value over static measures of tracer uptake. CLINICAL TRIAL REGISTRATION: NCT03036943.

Management of haematoma after thyroid surgery: systematic review and multidisciplinary consensus guidelines from the Difficult Airway Society, the British Association of Endocrine and Thyroid Surgeons and the British Association of Otorhinolaryngology, Head and Neck Surgery.

Haematoma after thyroid surgery can lead to airway obstruction and death. We therefore developed guidelines to improve the safety of peri-operative care of patients undergoing thyroid surgery. We conducted a systematic review to inform recommendations, with expert consensus used in the absence of high-quality evidence, and a Delphi study was used to ratify recommendations. We highlight the importance of multidisciplinary team management and make recommendations in key areas including: monitoring; recognition; post-thyroid surgery emergency box; management of suspected haematoma following thyroid surgery; cognitive aids; post-haematoma evacuation care; day-case thyroid surgery; training; consent and pre-operative communication; postoperative communication; and institutional policies. The guidelines support a multidisciplinary approach to the management of suspected haematoma following thyroid surgery through oxygenation and evaluation; haematoma evacuation; and tracheal intubation. They have been produced with materials to support implementation. While these guidelines are specific to thyroid surgery, the principles may apply to other forms of neck surgery. These guidelines and recommendations provided are the first in this area and it is hoped they will support multidisciplinary team working, improving care and outcomes for patients having thyroid surgery.

Phylogenomic and Macroevolutionary Evidence for an Explosive Radiation of a Plant Genus in the Miocene.

Mountain systems harbor a substantial fraction of global biodiversity and, thus, provide excellent opportunities to study rapid diversification and to understand the historical processes underlying the assembly of biodiversity hotspots. The rich biodiversity in mountains is widely regarded as having arisen under the influence of geological and climatic processes as well as the complex interactions among them. However, the relative contribution of geology and climate in driving species radiation is seldom explored. Here, we studied the evolutionary radiation of Oreocharis (Gesneriaceae), which has diversified extensively throughout East Asia, especially within the Hengduan Mountains (HDM), using transcriptomic data and a time calibrated phylogeny for 88% (111/126) of all species of the genus. In particular, we applied phylogenetic reconstructions to evaluate the extent of incomplete lineage sorting accompanying the early and rapid radiation in the genus. We then fit macroevolutionary models to explore its spatial and diversification dynamics in Oreocharis and applied explicit birth-death models to investigate the effects of past environmental changes on its diversification. Evidence from 574 orthologous loci suggest that Oreocharis underwent an impressive early burst of speciation starting ca. 12 Ma in the Miocene, followed by a drastic decline in speciation toward the present. Although we found no evidence for a shift in diversification rate across the phylogeny of Oreocharis, we showed a difference in diversification dynamics between the HDM and non-HDM lineages, with higher diversification rates in the HDM. The diversification dynamic of Oreocharis is most likely positively associated with temperature-dependent speciation and dependency on the Asian monsoons. We suggest that the warm and humid climate of the mid-Miocene was probably the primary driver of the rapid diversification in Oreocharis, while mountain building of the HDM might have indirectly affected species diversification of the HDM lineage. This study highlights the importance of past climatic changes, combined with mountain building, in creating strong environmental heterogeneity and driving diversification of mountain plants, and suggests that the biodiversity in the HDM cannot directly be attributed to mountain uplift, contrary to many recent speculations.[East Asian monsoons; environmental heterogeneity; Hengduan Mountains; incomplete lineage sorting; Oreocharis; past climate change; rapid diversification; transcriptome.].

Matters of size: Roles of hyaluronan in CNS aging and disease.

Involvement of extracellular matrix (ECM) components in aging and age-related neurodegeneration is not well understood. The role of hyaluronan (HA), a major extracellular matrix glycosaminoglycan, in malignancy and inflammation is gaining new understanding. In particular, the differential biological effects of high molecular weight (HMW-HA) and low molecular weight hyaluronan (LMW-HA), and the mechanism behind such differences are being uncovered. Tightly regulated in the brain, HA can have diverse effects on cellular development, growth and degeneration. In this review, we summarize the homeostasis and signaling of HA in healthy tissue, discuss its distribution and ontogeny in the central nervous system (CNS), summarize evidence for its involvement in age-related neurodegeneration and Alzheimer Disease (AD), and assess the potential of HA as a therapeutic target in the CNS.