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Background and purpose: Although sporadic Creutzfeldt–Jakob disease (sCJD) is a rare cause of dementia, it is critical to understand its functional networks as the prion protein spread throughout the brain may share similar mechanisms with other more common neurodegenerative disorders. In this study, the metabolic brain network associated with sCJD was investigated and its internal network organization was explored. Methods: We explored 2-[$^{18}$F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) brain scans of 29 sCJD patients, 56 normal controls (NCs) and 46 other dementia patients from two independent centers. sCJD-related pattern (CJDRP) was identified in a cohort of 16 pathologically proven sCJD patients and 16 age-matched NCs using scaled subprofile modeling/principal component analysis and was prospectively validated in an independent cohort of 13 sCJD patients and 20 NCs. The pattern's specificity was tested on other dementia patients and its clinical relevance by clinical correlations. The pattern's internal organization was further studied using graph theory methods. Results: The CJDRP was characterized by relative hypometabolism in the bilateral caudate, thalami, middle and superior frontal gyri, parietal lobe and posterior cingulum in association with relative hypermetabolism in the hippocampi, parahippocampal gyri and cerebellum. The pattern's expression significantly discriminated sCJD from NCs and other dementia patients (p < 0.005 receiver operating characteristic analysis CJD vs. NCs area under the curve [AUC] 0.90–0.96, sCJD vs. Alzheimer's disease AUC 0.78, sCJD vs. behavioral variant of frontotemporal dementia AUC 0.84). The pattern's expression significantly correlated with cognitive, functional decline and disease duration. The metabolic connectivity analysis revealed inefficient information transfer with specific network reorganization. Conclusions: The CJDRP is a robust metabolic biomarker of sCJD. Due to its excellent clinical correlations it has the potential to monitor disease in emerging disease-modifying trials.

Background Immune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients. Methods irAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software. Results irAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. ‘Respiratory, thoracic and mediastinal disorders’ and ‘gastrointestinal disorders’ were the two most common groups of disorders caused by the seven ICIs studied. ‘Cardiac disorders’ was the main type of disorders caused by these ICIs in cancer patients aged 65–85, while ‘reproductive system and breast disease’ was the main type of disorder in cancer patients aged 18–64. ‘Respiratory, thoracic, mediastinal diseases’ and ‘reproductive system and breast diseases’ were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively. Conclusion Tissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies.

Radiotherapy plays an essential role in cancer treatment, yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. PKM2, an enzyme that regulates the final rate-limiting step of glycolysis, has different functions in the occurrence, progression and metastasis of cancer. However, whether PKM2 plays a vital role in radioresistance is unclear, especially in head and neck squamous cell carcinoma (HNSCC). Here we report the upregulation of PKM2 in primary post-radiotherapy tumor tissues collected from radioresistant HNSCC patients. Using multidisciplinary approaches, we found elevated PKM2 in response to radiation, which confers radioresistance in HNSCC cells via extracellular matrix protein 1 (ECM1). Mechanistically, PKM2 activates STAT5 signaling pathway in HNSCC cells upon radiation, which enhances ECM1 expression. Moreover, ECM1 upregulation mediated by PKM2 prevents effector T cells from migrating to radioresistant head and neck tumors. While depletion of ECM1 overcomes PKM2-mediated radioresistance in orthotopic xenograft mice through altering the profile of chemo-attractants, which in turn remodels the tumor microenvironment to promote more cytotoxic T cells home to tumors. These novel and significant findings not only demonstrate a novel mechanism underpinning the interaction between tumor-derived PKM2 and immune cells in radioresistance but also provide a possible therapeutic strategy to overcome the failure of radiotherapy in HNSCC patients. Citation Format: Fanghui Chen, Yang Fan, Chris Tang, Qin Richard, Zheng Wei, Yong Teng. Pyruvate kinase M2 confers radioresistance in head and neck cancer through reprograming the tumor-immune microenvironment via ECM1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2813.

Previous multicenter imaging studies with (18)F-FDG PET have established the presence of motor-related and cognition-related metabolic patterns of Parkinson disease (PD), termed the PD-related pattern (PDRP) and the PD cognition–related pattern (PDCP), respectively, in patients with this disorder. Given that in PD cerebral perfusion and glucose metabolism are typically coupled in the absence of medication, we determined whether subject expression of these disease networks can be quantified in early-phase images from dynamic (18)F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl)nortropane ((18)F-FPCIT) PET scans acquired to assess striatal dopamine transporter (DAT) binding. Methods: We studied a cohort of early-stage PD patients and age-matched healthy control subjects who underwent (18)F-FPCIT at baseline; scans were repeated 4 y later in a smaller subset of patients. The early (18)F-FPCIT frames, which reflect cerebral perfusion, were used to compute PDRP and PDCP expression (subject scores) in each subject and were compared with analogous measures computed on the basis of the (18)F-FDG PET scan when additionally available. The late (18)F-FPCIT frames were used to measure caudate and putamen DAT binding in the same individuals. Results: PDRP subject scores from early-phase (18)F-FPCIT and (18)F-FDG scans were elevated and striatal DAT binding was reduced in PD versus healthy subjects. The PDRP scores from (18)F-FPCIT correlated with clinical motor ratings, disease duration, and corresponding measures from (18)F-FDG PET. In addition to correlating with disease duration and analogous (18)F-FDG PET values, PDCP scores correlated with DAT binding in the caudate or anterior putamen. PDRP and PDCP subject scores using either method rose over 4 y, whereas striatal DAT binding declined over the same period. Conclusion: Early-phase images obtained with (18)F-FPCIT PET can provide an alternative to (18)F-FDG PET for PD network quantification. This technique therefore allows PDRP/PDCP expression and caudate/putamen DAT binding to be evaluated with a single tracer in a single scanning session.

Inflammatory bowel disease, encompassing both ulcerative colitis and Crohn’s disease, is characterized by chronic, relapsing-remitting gastrointestinal inflammation of unknown etiology. SHIP deficient mice develop fully penetrant, spontaneous ileitis at 6 weeks of age, and thus offer a tractable model of Crohn’s disease-like inflammation. Since disruptions to the microbiome are implicated in the pathogenesis of Crohn’s disease, we conducted a 16S rRNA gene survey of the ileum, cecum, colon, and stool contents of SHIP+/+ and SHIP−/− mice. We predicted that diversity and compositional changes would occur after, and possibly prior to, the onset of overt disease. No differences were found in alpha diversity, but significant changes in beta diversity and specific commensal populations were observed in the ileal compartment of SHIP deficient mice after the onset of overt disease. Specifically, reductions in the Bacteroidales taxa, Muribaculum intestinale, and an expansion in Lactobacillus were most notable. In contrast, expansions to bacterial taxa previously associated with inflammation, including Bacteroides, Parabacteroides, and Prevotella were observed in the ilea of SHIP deficient mice prior to the onset of overt disease. Finally, antibiotic treatment reduced the development of intestinal inflammation in SHIP−/− mice. Thus, our findings indicate that SHIP is involved in maintaining ileal microbial homeostasis. These results have broader implications for humans, since reduced SHIP protein levels have been reported in people with Crohn’s disease.

The mass media has an important role in informing the general public about emerging health risks. Content-based studies of risk communication in the media have revealed a tendency to exaggerate risks or simplify science, but linguistic studies in this area are still scarce. This paper outlines a corpus based investigation of media reporting on the discovery of minute amounts of Endocrine Disrupting Compounds (EDCs) and Pharmaceuticals and Personal Care Products (PPCPs) in drinking water. There is no concrete evidence that these residuals pose any threat to human health in such minute amounts, but the natural scientific uncertainty and professional risk language surrounding contaminants have sparked considerable media attention in both the US and the UK. In fact, these have lead to Congress-level discussions about changes to the way contaminants are regulated in the US. Comparing media reports that appeared in newspaper articles, magazines and web-based media in the UK and the US with those to appear on water company and public health organisation websites, our use of quantitative and qualitative corpus linguistic techniques revealed strikingly different patterns for the language used to represent contaminants and their risks. While water organisation reports demonstrated a clear tendency to downplay the probability and severity of the risk posed by contaminants, the linguistic and rhetorical features identified in media texts place the focus on the potentiality of contaminants as an unconfirmed threat to public and environmental health. We discuss the implications of these findings for the role of the media in the communication of health risks, and for communication about water contaminants.

Cancer symptoms usually arise from a direct effect of a primary tumour or its metastases. Uncommonly, malignancies may present through paraneoplastic syndromes (PNS). These are a heterogeneous group of disorders in which symptoms are caused by an indirect effect of the cancer. The relevance of these conditions is twofold: they may aid earlier diagnosis of malignancies, and may contribute to patient morbidity and mortality.

Library 2.0 advocates a socially rich, multimedia enabled, user originated and communally innovative environment that poses significant opportunities for the libraries to evolve and make themselves even more relevant and significant for her users. This paper presents a case study of the National Library Board of Singapore, in playing a vital role to facilitate the realisation of a long-term key national program. The Singapore Memory (SM) Project. SM embraces the attributes of the Library 2.0 environment to enable the nation's memory to be collected, organised, preserved, discovered, researched, augmented and created. The output of is an evolving collection of knowledge assets on Singapore along a Singapore Memory Content Continuum of existing content that is steadily augmented with new content. The content will be collected across all formats, in any language, from Singaporeans and non-Singaporeans, from any institution and agency, from Singapore and abroad, and from official and unofficial sources. The utopian scenario of SM Project is that any person, community, group or institution who has ever experienced Singapore in any way or has any material on Singapore will engage actively in the contribution, discovery and creation of content for the project, and thus become advocates to further encourage and catalyse more contribution, discovery and creation. The paper outlines the key approaches, concepts and ideas for the project. An important element is the proliferation, exposure and accessibility of the rich contents envisaged in the project. The SM proliferation plan along with examples of how two existing resources, namely, the Singapore Infopedia, a database of articles on Singapore's history, culture, people and events and NewspaperSG, an online resource of current and historic Singapore and Malayan newspapers, have been designed are presented to demonstrate how content can be exposed, searched and discovered.

The health risks posed by heatwaves have been well documented. In the UK, before and during a heatwave, alerts are issued to the general public based on a tiered warning system integrating the use of colour and number sequences. There has of yet been no formal assessment of the public response to these messages. Cultural and language barriers make some members of ethnic minority communities particularly hard to reach. These may be less challenging amongst younger community members, who may be well placed to instigate the circulation of warning information to those less able or willing to use conventional channels.This qualitative study assesses the role of age and ethnic and cultural background in the conceptualisation of the number and colour systems used as part of the Heat-Health Watch System (HHWS) and the National Severe Weather Warning Service (NSWWS). Young and older participants were recruited from the Bangladeshi and white British populations of Tower Hamlets. All participants were given a cognitive task that required them to identify and draw associations between 12 cards depicting the four colours and numbers used in the warning system and four pictures providing contextualisation in terms of heatwave risk. A qualitative analysis of the heuristics used in the group discussions provided insights into the conceptualisations basic to interpreting colour and number sequences as representations of risk graduations, and how interpretation might be influenced by age and ethnic and cultural background.There were considerable differences in the interpretation of young Bangladeshi and older white British participants, on the one hand, and older Bangladeshi participants, on the other. Young Bangladeshis and older white British participants conceptualised the colours and numbers as a vertical scale, with the numbers/colours at “the top” corresponding to representations of higher temperature. This conceptualisation was mainly based on strong associations between colour and temperature, with risk only associated with the upper limit of the scale. Older Bangladeshi participants, on the other hand, conceptualised the numbers and pictures as a narrative sequence and disassociated the colours from the other cards. The differences between groups suggest potential cultural barriers to the “intended” interpretation of the colour and number sequences for older Bangladeshis but not for young Bangladeshis. The fact that the predominant association for the colour sequence for both young Bangladeshis and older white British participants was with graduations of temperature rather than risk raises questions about the applicability of using colours in a tiered warning system.

Study Design. A retrospective review of charts and radiographs of ail consecutive patients who underwent kyphoplasty at the authors' center from the initial procedure in September 2000 to the end of the collection period in July 2002. Summary of Background Data. The best available natural history data would suggest that after experiencing an osteoporotic vertebral compression fracture, patients have a 19% incidence of subsequent fracture in the following year when no surgical intervention is performed. When kyphoplasty is performed, there are conflicting data regarding the incidence of subsequent fracture, ranging anywhere from 3 to 29%. These fractures occur at adjacent levels between 30 and 90% of the time, with no clear explanation for the wide variation in the results of three different studies. There are biomechanical data to suggest that injection of cement does increase the stiffness of the treated vertebra and that this increases strain on adjacent vertebrae, especially in forward bending. Methods. A database was created containing patient age, gender, height, weight, medication history, comorbidities, fracture levels, and pain level before and after surgery. Subsequent fractures were confirmed with radiographs and MRI. Statistical analysis was performed. Results. Thirty-eight patients (10 men and 28 women) were treated for 47 levels initially. L1 and L2 were the most common level of fracture managed initially. The gender, smoking and medication history, location of fracture, and number of fracture ieveis of the patients did not correlate with the risk of subsequent fracture. Over the follow-up period (average, 8 months), 10 patients sustained 17 subsequent fractures. Eight patients sustained fractures in the first 2 months after the index procedure, all with at least one fracture at an adjacent level. Of the 17 subsequent fractures, there were nine at the adjacent-above levels, four at adjacent-below levels, and four at remote levels. The remote fractures occurred at significantly greater time intervals after the index procedure (P < 0.001). Conclusion. This study demonstrated a higher rate of subsequent fracture after kyphoplasty compared with natural history data for untreated fractures. Most of these occurred at an adjacent level within 2 months of the index procedure. After this 2-month period, there were only occasional subsequent fracture which occurred at remote levels. This confirms biomechanical studies show ing that cement augmentation places additional stress on adjacent levels. Patients with an increase in back plain after kyphoplasty should be evaluated carefully for subsequent adjacent fractures. especially during the first 2 months after the index procedure.

Background Although media reporting on health risks has a tendency to stir up worry, this worry is often misplaced when reports involve the misrepresentation of unsubstantiated scientific evidence. The presence of endocrine-disrupting compounds and pharmaceuticals and personal care products in the water supply has attracted substantial media attention, particularly in the USA, followed by intense policy discussions, despite the fact there is no concrete evidence to suggest a risk to public health. Working with a wide range of stakeholders including water utilities, public health officials, and consumer associations, we set out to explore the public's perspective on the health risks posed by contaminants, their science, and regulation to support the water industry in the development of fresh and effective communication. Methods To better assess public conceptualisations and measure public knowledge about contaminants in the UK and USA, we combined structured focus groups (11 groups of 12 participants), analysed by grounded theory, and a perceptions questionnaire (533 participants), analysed by regression analysis of a-priori hypotheses, with a range of tasks informed by cognitive semantics. These tasks include a quantitative and qualitative linguistic analysis of media and outreach texts (500 texts), several media text or report scenarios (embedded in focus groups and surveys), plus a free word association test incorporated into a language survey (two samples of 50 participants). The cognitive components were designed to investigate how members of the public reacted to and assessed these messages and the language and rhetorical techniques used to represent them. Ethics approval was granted by King's College London research ethics committee. Only adults were included in the study; all demographic data were compared with UK and US census data (appendix). Findings Reading media reports was more likely to predict worry about contaminants, with females compared with males (p=0·007) and those with long-term illness or disability compared with those without (p=0·018) more likely to worry. Despite a greater tendency to worry, neither group was more likely to search for information about contaminants (for both groups p>0·05). Additionally, some members of the public believed that tap water containing contaminants is still safe to drink, yet worry about it and filter it or avoid drinking it altogether. The cognitive instruments embedded in the methodology enabled the identification of words and notions that were used to communicate the risks, science, and regulation of contaminants that were responsible for causing worry. Although uncertainty and contamination as notions and the language associated with contaminants have very strong negative associations, regulations drew very strong positive associations, and thus the notion of unregulated contaminants proved the most worrisome of all. Interpretation Unnecessary worry about uncertain health risks on the basis of unsubstantiated evidence can lead to behaviour changes and can have wider implications for regulators and public health organisations. The language used in communication aimed at attenuation and reassurance needs to be tailored to consumer conceptualisations because some terms can evoke strong negative associations even if the message is positive. The project findings and recommendations are being directly fed into water industry communication policy and are being used to tailor communication to a wide range of consumer groups. Funding The Water Research Foundation fully funded the study and appointed a project advisory committee.

Periods of extremely hot and cold weather can cause significant mortality and morbidity in both temperate and more extreme climates. In the UK, their occurrence prompts the issuing of number and colour coded warnings providing an assessment of the level of risk. These are designed to minimize health impact by prompting timely and appropriate mitigating actions by the public. Drawing upon the interdisciplinary notion of framing, I report on a study that identified a central role for language in mediating how these warnings are interpreted and evaluated. I use an innovative approach that combines the quantitative tools of corpus linguistics to identify the language used to represent warnings and the risks of extreme temperature in the mass media, with qualitative analysis of focus group discussions of typical texts. A comparison of both datasets indicates a multi-layered interactivity between the myriad ways in which language can give salience to aspects of a risk scenario and an interpreter’s knowledge and perception of a threat, and that underlying such interactions, is the conceptualization of risk as scalar property.