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Abstract The discrepancy between estimated glycemia from HbA1c values and actual average glucose (AG) levels has significant implications for treatment decisions and patient understanding. Factors contributing to the gap include red blood cell (RBC) lifespan and glucose uptake into the RBC. Personalized models have been proposed to enhance AG prediction accuracy by considering interpersonal variation. This study contributes to our understanding of personalized models for estimating AG from HbA1c. Utilizing data from seven studies (340 participants), including Hispanic/Latino populations with or at risk of non-insulin-treated type 2 diabetes (T2D), we examined kinetic features across cohorts. Additionally, the study simulated scenarios to understand data requirements for improving accuracy. Personalized approaches improved agreement between AG estimations and CGM-AG, particularly with four or more weeks of training CGM data. A multiple linear regression model using kinetic parameters and added clinical features was shown to improve the accuracy of personalized models further. As CGM usage extends beyond type 1 diabetes, there is growing interest in leveraging CGM data for clinical decision-making. Patient-specific models offer a valuable tool for managing glycemic status in patients with discordant HbA1c and AG values.

Summary: Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

BackgroundThe proliferation of digital technology has the potential to transform diabetes management. One of the critical aspects of modern diabetes management remains the achievement of glycemic targets to avoid acute and long-term complications. ObjectiveThis study aims to describe the landscape of evidence pertaining to the relative effectiveness or efficacy and safety of various digital interventions for the self-management of type 2 diabetes mellitus (T2DM), with a primary focus on reducing glycated hemoglobin A1c (HbA1c) levels. MethodsA systematic literature review (SLR) was conducted by searching Embase, MEDLINE, and CENTRAL on April 5, 2022. Study selection, data extraction, and quality assessment were performed by 2 independent reviewers. Eligibility criteria for the SLR included randomized controlled trials (RCTs) and comparative observational studies evaluating interventions containing both human (eg, coaching) and digital components (eg, glucose meter) in adult patients with T2DM. The primary meta-analysis was restricted to studies that reported laboratory-measured HbA1c. In secondary analyses, meta-regression was performed with the intensity of coaching in the digital intervention as a categorical covariate. ResultsIn total, 28 studies were included in this analysis. Most studies (23/28, 82%) used the reduction of HbA1c levels as the primary end point, either directly or as a part of a multicomponent outcome. In total, 21 studies reported statistically significant results with this primary end point. When stratified into 3 intervention categories by the intensity of the intervention supporting the digital health technology (analyzing all 28 studies), the success rate appeared to be proportional to the coaching intensity (ie, higher-intensity studies reported higher success rates). When the analysis was restricted to RCTs using the comparative improvement of HbA1c levels, the effectiveness of the interventions was less clear. Only half (12/23, 52%) of the included RCTs reported statistically significant results. The meta-analyses were broadly aligned with the results of the SLR. The primary analysis estimated a greater reduction in HbA1c associated with digital interventions compared with usual care (–0.31%, 95% CI –0.45% to –0.16%; P

PURPOSEThere is an urgent need to improve access to cancer therapy globally. Several independent initiatives have been undertaken to improve access to cancer medicines, and additional new initiatives are in development. Improved sharing of experiences and increased collaboration are needed to achieve substantial improvements in global access to essential oncology medicines.METHODSThe inaugural Access to Essential Cancer Medicines Stakeholder Meeting was organized by ASCO and convened at the June 2022 ASCO Annual Meeting in Chicago, IL, with two subsequent meetings, Union for International Cancer Control World Cancer Congress held in Geneva, Switzerland, in October 2022 and at the ASCO Annual Meeting in June of 2023. Invited stakeholders included representatives from cancer institutes, physicians, researchers, professional societies, the pharmaceutical industry, patient advocacy organizations, funders, cancer organizations and foundations, policy makers, and regulatory bodies. The session was moderated by ASCO. Past efforts and current and upcoming initiatives were initially discussed (2022), updates on progress were provided (2023), and broad agreement on resulting action steps was achieved with participants.RESULTSSummit participants recognized that while much work was ongoing to enhance access to cancer therapeutics globally, communication and synergy across projects and organizations could be enhanced by providing a platform for collaboration and shared expertise.CONCLUSIONThe summit resulted in new cross-stakeholder insights and planned collaboration addressing barriers to accessing cancer medications. Specific actions and timelines for implementation and reporting were established.

Abstract In type 2 diabetes (T2D), the dawn phenomenon is an overnight glucose rise recognized to contribute to overall glycemia and is a potential target for therapeutic intervention. Existing CGM-based approaches do not account for sensor error, which can mask the true extent of the dawn phenomenon. To address this challenge, we developed a probabilistic framework that incorporates sensor error to assign a probability to the occurrence of dawn phenomenon. In contrast, the current approaches label glucose fluctuations as dawn phenomena as a binary yes/no. We compared the proposed probabilistic model with a standard binary model on CGM data from 173 participants (71% female, 87% Hispanic/Latino, 54 ± 12 years, with either a diagnosis of T2D for six months or with an elevated risk of T2D) stratified by HbA1c levels into normal but at risk for T2D, with pre-T2D, or with non-insulin-treated T2D. The probabilistic model revealed a higher dawn phenomenon frequency in T2D [49% (95% CI 37–63%)] compared to pre-T2D [36% (95% CI 31–48%), p = 0.01] and at-risk participants [34% (95% CI 27–39%), p

Abstract Digital phenotyping refers to characterizing human bio-behavior through wearables, personal devices, and digital health technologies. Digital phenotyping in populations facing a disproportionate burden of type 2 diabetes (T2D) and health disparities continues to lag compared to other populations. Here, we report our study demonstrating the application of multimodal digital phenotyping, i.e., the simultaneous use of CGM, physical activity monitors, and meal tracking in Hispanic/Latino individuals with or at risk of T2D. For 14 days, 36 Hispanic/Latino adults (28 female, 14 with non-insulin treated T2D) wore a continuous glucose monitor (CGM) and a physical activity monitor (Actigraph) while simultaneously logging meals using the MyFitnessPal app. We model meal events and daily digital biomarkers representing diet, physical activity choices, and corresponding glycemic response. We develop a digital biomarker for meal events that differentiates meal events into normal and elevated categories. We examine the contribution of daily digital biomarkers of elevated meal event count and step count on daily time-in-range 54-140 mg/dL (TIR54–140) and average glucose. After adjusting for step count, a change in elevated meal event count from zero to two decreases TIR54–140 by 4.0% (p = 0.003). An increase in 1000 steps in post-meal step count also reduces the meal event glucose response by 641 min mg/dL (p = 0.0006) and reduces the odds of an elevated meal event by 55% (p

Abstract “Leaving no one behind” is the fundamental objective of the 2030 Agenda for Sustainable Development. Latin America and the Caribbean is marked by social inequalities, whilst its total population is projected to increase to almost 760 million by 2050. In this context, contemporary and spatially detailed datasets that accurately capture the distribution of residential population are critical to appropriately inform and support environmental, health, and developmental applications at subnational levels. Existing datasets are under-utilised by governments due to the non-alignment with their own statistics. Therefore, official statistics at the finest level of administrative units available have been implemented to construct an open-access repository of high-resolution gridded population datasets for 40 countries in Latin American and the Caribbean. These datasets are detailed here, alongside the ‘top-down’ approach and methods to generate and validate them. Population distribution datasets for each country were created at a resolution of 3 arc-seconds (approximately 100 m at the equator), and are all available from the WorldPop Data Repository.

Objective To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.Design Phase 3b multicentre, double-blind, randomised placebo-controlled trial.Setting Twenty-one hospitals in the UK.Participants Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.Intervention Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment.Main outcome measure The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.Secondary outcome measures The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.Results 18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.Conclusions The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.Trial registration number Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

Abstract Understanding the fine scale and subnational spatial distribution of reproductive, maternal, newborn, child, and adolescent health and development indicators is crucial for targeting and increasing the efficiency of resources for public health and development planning. National governments are committed to improve the lives of their people, lift the population out of poverty and to achieve the Sustainable Development Goals. We created an open access collection of high resolution gridded and district level health and development datasets of India using mainly the 2015–16 National Family Health Survey (NFHS-4) data, and provide estimates at higher granularity than what is available in NFHS-4, to support policies with spatially detailed data. Bayesian methods for the construction of 5 km × 5 km high resolution maps were applied for a set of indicators where the data allowed (36 datasets), while for some other indicators, only district level data were produced. All data were summarised using the India district administrative boundaries. In total, 138 high resolution and district level datasets for 28 indicators were produced and made openly available.

In the United States (U.S.), consumption of fresh vegetables and fruits is below recommended levels. Enhancing access to nutritious food through food prescriptions has been recognized as a promising approach to combat diet-related illnesses. However, the effectiveness of this strategy at a large scale remains untested, particularly in marginalized communities where food insecurity rates and the prevalence of health conditions such as type 2 diabetes (T2D) are higher compared to the background population. This study evaluated the impact of a produce prescription program for predominantly Hispanic/Latino adults living with or at risk of T2D. A total of 303 participants enrolled in a 3-month observational cohort received 21 medically prescribed portions/week of fresh produce. A subgroup of 189 participants used continuous glucose monitoring (CGM) to assess the relationship between CGM profile changes and HbA1c level changes.For 247 participants completing the study (76% female, 84% Hispanic/Latino, 32% with T2D, age 56·6 ± 11·9 years), there was a reduction in weight (−1·1 [-1·6 to −0·6] lbs., p 120 mmHg (−4·2 [-6·8 to −1·8] mmHg, p = 0·001). For participants with an HbA1c ≥ 7·0% at baseline, HbA1c fell significantly (−0·5 [-0·9 to −0·1] %, p = 0·01). There were also improvements in food security (p

Aberrant protein acetylation is strongly linked to tumorigenesis, and modulating acetylation through targeting histone deacetylase (HDAC) with small‐molecule inhibitors has been the focus of clinical trials. However, clinical success on solid tumours, such as colorectal cancer (CRC), has been limited, in part because the cancer‐relevant mechanisms through which HDAC inhibitors act remain largely unknown. Here, we have explored, at the genome‐wide expression level, the effects of a novel HDAC inhibitor CXD101. In human CRC cell lines, a diverse set of differentially expressed genes were up‐ and downregulated upon CXD101 treatment. Functional profiling of the expression data highlighted immune‐relevant concepts related to antigen processing and natural killer cell‐mediated cytotoxicity. Similar profiles were apparent when gene expression was investigated in murine colon26 CRC cells treated with CXD101. Significantly, these changes were also apparent in syngeneic colon26 tumours growing in vivo. The ability of CXD101 to affect immune‐relevant gene expression coincided with changes in the tumour microenvironment (TME), especially in the subgroups of CD4 and CD8 tumour‐infiltrating T lymphocytes. The altered TME reflected enhanced antitumour activity when CXD101 was combined with immune checkpoint inhibitors (ICIs), such as anti‐PD‐1 and anti‐CTLA4. The ability of CXD101 to reinstate immune‐relevant gene expression in the TME and act together with ICIs provides a powerful rationale for exploring the combination therapy in human cancers.

PURPOSEThe COVID-19 pandemic significantly disrupted cancer care in Africa, further exposing major health disparities. This paper compares and contrasts the experiences of 15 clinicians in six different African cancer centers to highlight the positive aspects (silver linings) in an otherwise negative situation.METHODSData are from personal experience of the clinicians working at the six cancer centers blended with what is available in the literature.RESULTSThe impact of COVID-19 on cancer care appeared to vary not only across the continent but also over cancer centers. Different factors such as clinic location, services offered, available resources, and level of restrictions imposed because of COVID-19 were associated with these variations. Collectively, delays in treatment and limited access to cancer care were commonly reported in the different regions.CONCLUSIONThere is a lack of data on cancer patients with COVID-19 and online COVID-19 and cancer registries for Africa. Analysis of the available data, however, suggests a higher mortality rate for cancer patients with COVID-19 compared with those without cancer. Positive or silver linings coming out of the pandemic include the adoption of hypofractionated radiation therapy and teleoncology to enhance access to care while protecting patients and staff members. Increasing collaborations using online technology with oncology health professionals across the world are also being seen as a silver lining, with valuable sharing of experiences and expertise to improve care, enhance learning, and reduce disparities. Advanced information and communication technologies are seen as vital for such collaborations and could avail efforts in dealing with the ongoing pandemic and potential future crises.

Abstract Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

Review of the book: Arlene Goldbard. (2006). New Creative Community: The Art of Cultural Development. Oakland, CA: New Village Press. 268 pp., $19.95 (paper). ISBN: 978-0-9766054-5-4.

Abstract Background In the United States (U.S.), the prevalence of both diagnosed and undiagnosed type 2 diabetes (T2D) is nearly twice as high among Mexican-origin Hispanic/Latino adults compared to non-Hispanic Whites. Rates of diabetes-related complications, e.g., acute stroke and end-stage renal disease, are also higher among Hispanic/Latino adults compared to their non-Hispanic/Latino White counterparts. Beyond genetic and biological factors, it is now recognized that sociocultural influences are also important factors in determining risk for T2D and the associated complications. These influences include ethnicity, acculturation, residence, education, and economic status. The primary objective of this study is to determine the influence of the 5 major determinants of human health (genetics, biology, behavior, psychology, society/environment) on the burden of T2D for Latino families. To achieve this objective, Mil Familias (www.milfamilias.sansum.org/) is establishing an observational cohort of 1000 Latino families, with at least one family member living with T2D. Methods Specially trained, bilingual Latino/a community health workers (Especialistas) recruit participant families and conduct research activities. Each individual family member will contribute data annually on over 100 different variables relating to their genetics, biology, psychology, behavior, and society/environment, creating a Latino-focused biobank (“Living Information Bank”). This observational cohort study is cross-sectional and longitudinal. Participants are divided into 4 groups: adults age ≥ 18 years with and without T2D, and children age ≥ 7 and

Abstract Introduction In this study (PRECISE), we assess the clinical utility of a germline DNA sequencing‐based test (ToxNav) for mutations in DPYD and ENOSF1 genes to alter clinician‐prescribed fluoropyrimidine doses and the use of a digital application (PROMinet) to record patient‐reported chemotherapy toxicity. Materials and methods Adult patients with a histological diagnosis of colorectal cancer (CRC) who consented to fluoropyrimidine‐based chemotherapy were recruited prospectively and given a digital application to monitor and record associated toxicities. Patient samples were analyzed for 18 germline coding variants in DPYD and 1 ENOSF1 variant. Results Genetic testing was performed for 60 patients and identified one patient at increased risk of fluoropyrimidine‐based toxicities. Uptake of genetic testing was high and results were available on average 17 days from initial clinical encounter. Patient‐reported chemotherapy toxicity identified differences in 5‐fluorouracil vs capecitabine regime profiles and identified profiles associated with subsequent need for chemotherapy dose reduction and hospital admission. Discussion The PRECISE clinical trial demonstrated that a germline DNA sequencing‐based test can provide clinically relevant information to alter clinicians' fluoropyrimidine prescription. The study also obtained high volume, high granularity patient‐reported toxicity data that might allow the improvement and personalization of chemotherapy management.

Multi-temporal, globally consistent, high-resolution human population datasets provide consistent and comparable population distributions in support of mapping sub-national heterogeneities in health, wealth, and resource access, and monitoring change in these over time. The production of more reliable and spatially detailed population datasets is increasingly necessary due to the importance of improving metrics at sub-national and multi-temporal scales. This is in support of measurement and monitoring of UN Sustainable Development Goals and related agendas. In response to these agendas, a method has been developed to assemble and harmonise a unique, open access, archive of geospatial datasets. Datasets are provided as global, annual time series, where pertinent at the timescale of population analyses and where data is available, for use in the construction of population distribution layers. The archive includes sub-national census-based population estimates, matched to a geospatial layer denoting administrative unit boundaries, and a number of co-registered gridded geospatial factors that correlate strongly with population presence and density. Here, we describe these harmonised datasets and their limitations, along with the production workflow. Further, we demonstrate applications of the archive by producing multi-temporal gridded population outputs for Africa and using these to derive health and development metrics. The geospatial archive is available at https://doi.org/10.5258/SOTON/WP00650.

Purpose: To examine the burden and cost of diabetes among fee-for-service Medicare beneficiaries. Methods: Medicare 5% File data for type 1 diabetes (T1D) and type 2 diabetes (T2D) consisting of 1,397,933 enrollees in fee-for-service without Medicare Advantage during the period 2012?2013 were analyzed by race and ethnicity. Results: Although non-Hispanic whites (nHWs) comprised most of this population (86%), prevalence of T1D and T2D was higher for Hispanics than nHWs (3.4% vs. 1.8%, p=0.0006, for T1D and 33.4% vs. 21.9%, p

In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.

Purpose – Many studies report on the potential ecological impacts of wild dolphin tourism, risks to people, and economic benefits to local communities. Fewer studies report the social aspects (human dimensions) of dolphin tourism, such as visitor satisfaction and attitudes of participants. This communication postulates that human dimensions are an important consideration in any strategy to keep wild dolphin tourism operations sustainable by balancing the welfare of the dolphins and the desires and expectations of tourists to interact with these charismatic, iconic creatures. Methodology – This communication synthesizes learning gained from a recent quantitative systematic literature review of marine wildlife tourism, a previously unreported review of wild dolphin tourism literature, and a recent study from the Dolphin Discovery Centre in Bunbury, Western Australia. Findings – Human attitudes towards marine mammals ultimately reflect how dolphin tourism is developed and managed. It is therefore important to understand how people experience and perceive dolphin tourism. Wild dolphin tourism is of great value to local economies, tour operators, and visitors who enjoy those experiences. The potential impacts that can arise from dolphin tourism need to be understood and minimised by actions under the control of tour operators and government authorities. This is important to make the satisfaction visitors gain from such experiences worthwhile and to ensure the long-term sustainability of wild dolphin tourism experiences. Originality of the research – Most wild dolphin tourism research has an ecological focus. This communication demonstrates that equally important social research, concerned with understanding visitor awareness, knowledge, expectations, and satisfaction, has a vital role to play in developing best practice management for wild dolphin tourism experiences.

Background: Continuous glucose monitoring (CGM) has demonstrable benefits for people living with diabetes, but the supporting evidence is almost exclusively from White individuals with type 1 diabetes. Here, we have quantified CGM profiles in Hispanic/Latino adults with or at-risk of non-insulin treated type 2 diabetes (T2D). Methods: 100 participants (79 female, 86% Hispanic/Latino [predominantly Mexican], age 54·6 [±12·0] years) stratified into (i) at risk of T2D, (ii) with pre-diabetes (pre-T2D), and (iii) with non-insulin treated T2D, wore blinded CGMs for 2 weeks. Beyond standardized CGM measures (average glucose, glucose variability, time in 70–140 mg/dL and 70–180 mg/dL ranges), we also examined additional CGM measures based on the time of day. Findings: Standardized CGM measures were significantly different for participants with T2D compared to at-risk and pre-T2D participants (p

Top-down population modelling has gained applied prominence in public health, planning, and sustainability applications at the global scale. These top-down population modelling methods often rely on remote-sensing (RS) derived representation of the built-environment and settlements as key predictive covariates. While these RS-derived data, which are global in extent, have become more advanced and more available, gaps in spatial and temporal coverage remain. These gaps have prompted the interpolation of the built-environment and settlements, but the utility of such interpolated data in further population modelling applications has garnered little research. Thus, our objective was to determine the utility of modelled built-settlement extents in a top-down population modelling application. Here we take modelled global built-settlement extents between 2000 and 2012, created using a spatio-temporal disaggregation of observed settlement growth. We then demonstrate the applied utility of such annually modelled settlement data within the application of annually modelling population, using random forest informed dasymetric disaggregations, across 172 countries and a 13-year period. We demonstrate that the modelled built-settlement data are consistently the 2nd most important covariate in predicting population density, behind annual lights at night, across the globe and across the study period. Further, we demonstrate that this modelled built-settlement data often provides more information than current annually available RS-derived data and last observed built-settlement extents.

Purpose – To ascertain if place attachment or experiential norms influence visitor attitudes to the feeding of wild dolphins. Design/Methodology/Approach – A cross section of beach based visitors at a popular Australian marine tourism destination were opportunistically sampled using pen and paper questionnaires. Findings – Visitors expressed strong support for the strictly controlled minimalist reward feeding that accompanies beach based wild dolphin interactions at the Bunbury Dolphin Discovery Centre and visitors believe there are tourism benefits to be gained from the regulated feeding of wild dolphins. Results also suggest that neither place attachment nor experiential norms influence visitor attitudes to feeding of the Koombana Bay dolphin population. Originality of the research – This location specific, snapshot, case study suggests that contrary to published theory, place attachment and experiential norms do not influence tourist attitudes to wildlife feeding, especially for charismatic iconic wildlife such as dolphins.

Abstract Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome‐guided pre‐clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predicting drug sensitivity for cell lines and patients. Among many novel associations, MERTK was identified as a predictive marker for resistance towards MEK1/2 inhibitors and immunohistochemistry of 1,074 CRC tumours confirmed MERTK as a prognostic survival marker. We provide the proteomic and pharmacological data as a resource to the community to, for example, facilitate the design of innovative prospective clinical trials.

Since the arrival of hip hop in Tanzania in the 1980s, a diverse and vibrant range of musical genres has developed in Tanzania’s commercial capital, Dar es Salaam. Incorporating rapping, these new musical genres and their associated practices have produced new imaginative spaces, social practices, and identities. In this paper, I argue that rappers have appropriated signs and symbols from the transnational image of hip hop to cast themselves as ‘thugs’ or ‘gangsters’, simultaneously imbuing these symbols with distinctly Tanzanian political conceptions of hard work (kazi ya jasho), justice (haki) and self-reliance (kujitegemea). This article examines how the persona of the rapper acts as a nexus for transnational and local moral and ethical conceptions such as self-reliance, strength, and struggle. Exploring the complicated, ambiguous, and contradictory nature of cultural production in contemporary Tanzania, argue that rappers use the practice of rapping to negotiate both the socialist past and neo-liberal present. Drawing on the work of De Certeau and Graeber, I argue that rappers use these circulating signs, symbols, and concepts both tactically and strategically to generate value, shape social reality and inscribe themselves into the social and political fabric of everyday life.

Abstract Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-β superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-β superfamily members activin and TGF-β in advanced colorectal cancer. In two clinical cohorts we observed by immune-based assay that combined serum and tissue activin and TGF-β ligand levels predicts outcome in CRC patients and is superior to single ligand assessment. While TGF-β growth suppression is independent of activin, TGF-β treatment leads to increased activin secretion in colon cancer cells and TGF-β induced cellular migration is dependent on activin, indicating pathway cross-regulation and functional interaction in vitro. mRNA expression of activin and TGF-β pathway members were queried in silico using the TCGA data set. Coordinated ligand and receptor expression is common in solid tumors for activin and TGF-β pathway members. In conclusion, activin and TGF-β are strongly connected signaling pathways that are important in advanced CRC. Assessing activin and TGF-β signaling as a unit yields important insights applicable to future diagnostic and therapeutic interventions.

Purpose: Hyperthermia is a mechanistically plausible partner with chemotherapy, although many of the underlying molecular mechanisms of this combination treatment are not yet properly understood. Preclinical studies suggest that there is potential synergy with gemcitabine and that provides the basis for retrospective analysis of a clinical series combining these treatment modalities for patients with advanced pancreatic cancer. Patients and Methods: Twenty-nine chemotherapy-naive patients with locally advanced or metastatic pancreatic carcinoma with malignant ascites were treated with intraperitoneal cisplatin 30 mg/m2 and gemcitabine 800 to 1,000 mg/m2 intravenously on days 1, 8, and 15 every 28 days until tumor progression. Patients also received regional hyperthermia treatment (41 to 42°C) on the upper abdomen two times per week from days 1 to 21. Results: In all, 83 cycles of chemotherapy were administered and were generally well tolerated. No patients had a complete response, 13 had a partial response, seven had stable disease, and 9 had progressive disease. Mean progression-free survival and overall survival were 119 ± 61days and 195 ± 98 days, respectively. Conclusion: This study provides preliminary evidence that the treatment approach of combined systemic and intraperitoneal chemotherapy plus hyperthermia is well tolerated, is active, and has an acceptable survival profile for patients with stage IV pancreatic cancer and ascites.

Abstract Background Approximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations—the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers. Methods A total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling—including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration. Results Novel, frequent frameshift mutations in four cancer-critical genes were identified by deep exome sequencing, including in CRTC1, BCL9, JAK1, and PTCH1. JAK1 loss-of-function mutations were validated with an overall frequency of 20% in Norwegian and British patients, and mutated tumors had up-regulation of transcriptional signatures associated with resistance to anti-PD-1 treatment. Clonality analyses revealed a high level of intra-tumor heterogeneity; however, this was not associated with disease progression. Among the MSI+ tumors, the total mutation load correlated with the number of predicted neoantigens (P = 4 × 10−5), but not with immune cell infiltration—this was dependent on the CMS class; MSI+ tumors in CMS1 were highly immunogenic compared to MSI+ tumors in CMS2-4. Both JAK1 mutations and CMS1 were favorable prognostic factors (hazard ratios 0.2 [0.05–0.9] and 0.4 [0.2–0.9], respectively, P = 0.03 and 0.02). Conclusions Multilevel genomic analyses of MSI+ colorectal cancer revealed molecular heterogeneity with clinical relevance, including tumor immunogenicity and a favorable patient outcome associated with JAK1 mutations and the transcriptomic subgroup CMS1, emphasizing the potential for prognostic stratification of this clinically important subtype. See related research highlight by Samstein and Chan 10.1186/s13073-017-0438-9

Advances in the availability of multi-temporal, remote sensing-derived global built-/human-settlements datasets can now provide globally consistent definitions of “human-settlement” at unprecedented spatial fineness. Yet, these data only provide a time-series of past extents and urban growth/expansion models have not had parallel advances at high-spatial resolution. Here our goal was to present a globally applicable predictive modelling framework, as informed by a short, preceding time-series of built-settlement extents, capable of producing annual, near-future built-settlement extents. To do so, we integrated a random forest, dasymetric redistribution, and autoregressive temporal models with open and globally available subnational data, estimates of built-settlement population, and environmental covariates. Using this approach, we trained the model on a 11 year time-series (2000–2010) of European Space Agency (ESA) Climate Change Initiative (CCI) Land Cover “Urban Areas” class and predicted annual, 100m resolution, binary settlement extents five years beyond the last observations (2011–2015) within varying environmental, urban morphological, and data quality contexts. We found that our model framework performed consistently across all sampled countries and, when compared to time-specific imagery, demonstrated the capacity to capture human-settlement missed by the input time-series and the withheld validation settlement extents. When comparing manually delineated building footprints of small settlements to the modelled extents, we saw that the modelling framework had a 12 percent increase in accuracy compared to withheld validation settlement extents. However, how this framework performs when using different input definitions of “urban” or settlement remains unknown. While this model framework is predictive and not explanatory in nature, it shows that globally available “off-the-shelf” datasets and relative changes in subnational population can be sufficient for accurate prediction of future settlement expansion. Further, this framework shows promise for predicting near-future settlement extents and provides a foundation for forecasts further into the future.

Introduction. Extremity lipomas and well-differentiated liposarcomas (WDLs) are difficult to distinguish on MR imaging. We sought to evaluate the accuracy of MRI interpretation using MDM2 amplification, via fluorescence in-situ hybridization (FISH), as the gold standard for pathologic diagnosis. Furthermore, we aimed to investigate the utility of a diagnostic formula proposed in the literature. Methods. We retrospectively collected 49 patients with lipomas or WDLs utilizing MDM2 for pathologic diagnosis. Four expert readers interpreted each patient’s MRI independently and provided a diagnosis. Additionally, a formula based on imaging characteristics (i.e. tumor depth, diameter, presence of septa, and internal cystic change) was used to predict the pathologic diagnosis. The accuracy and reliability of imaging-based diagnoses were then analyzed in comparison to the MDM2 pathologic diagnoses. Results. The accuracy of MRI readers was 73.5% (95% CI 61–86%) with substantial interobserver agreement (κ=0.7022). The formula had an accuracy of 71%, which was not significantly different from the readers (p=0.71). The formula and expert observers had similar sensitivity (83% versus 83%) and specificity (64.5% versus 67.7%; p=0.659) for detecting WDLs. Conclusion. The accuracy of both our readers and the formula suggests that MRI remains unreliable for distinguishing between lipoma and WDLs.

High-tech augmentative and alternative communication (AAC) methods are on a constant rise; however, the interaction between the user and the assistive technology is still challenged for an optimal user experience centered around the desired activity. This review presents a range of signal sensing and acquisition methods utilized in conjunction with the existing high-tech AAC platforms for individuals with a speech disability, including imaging methods, touch-enabled systems, mechanical and electro-mechanical access, breath-activated methods, and brain–computer interfaces (BCI). The listed AAC sensing modalities are compared in terms of ease of access, affordability, complexity, portability, and typical conversational speeds. A revelation of the associated AAC signal processing, encoding, and retrieval highlights the roles of machine learning (ML) and deep learning (DL) in the development of intelligent AAC solutions. The demands and the affordability of most systems hinder the scale of usage of high-tech AAC. Further research is indeed needed for the development of intelligent AAC applications reducing the associated costs and enhancing the portability of the solutions for a real user’s environment. The consolidation of natural language processing with current solutions also needs to be further explored for the amelioration of the conversational speeds. The recommendations for prospective advances in coming high-tech AAC are addressed in terms of developments to support mobile health communicative applications.

The article discusses contemporary trends in the Mission and Ecumenical Studies in the context of World Christianity and Inter-Religious Relations. It engages with late 20th century scholarship, particularly relating to Christianity in Africa and Asia, and interacts with the paradigm-analysis of Mission Studies as advanced by David J. Bosch in his Transforming Mission: Paradigm Shifts in Theology of Mission (Maryknoll: Orbis, 1991).

Abstract This resource is a web-based module that introduces the practice of screening for substance abuse in health care settings and considers the question of when to implement a screening program. It reviews existing standards of screening for substance abuse and asks whether health systems should expand current practices to ask about use of drugs besides alcohol and tobacco. In addition, the module provides in-depth teaching on the key concepts of sensitivity, specificity, and predictive values. The module is multimedia and delivers the above content through the use of video, text, graphics, and voiceover, as well as questions followed by expert and peer feedback. Medical, dental, and nursing students in our research mentorship program were asked to complete the module as part of their summer experience. Evaluation of this pilot revealed that almost all of the students thought the module was easy to navigate; dealt with a subject of interest; covered most of the expected topics; was clear, logical, and orderly; and had the right balance of multimedia. Students felt challenged by the material and stated that it raised questions they had not previously considered about the practice of screening and the interpretation of screening test results. This module is one of six in a series created for the New York University Substance Abuse Research Education and Training Program. The program is a National Institute on Drug Abuse–funded initiative whose aim is to enhance interest in substance abuse research among health professional students, including, but not limited to, students in medicine, nursing, and dentistry.

Citizenship has been included for the first time ever as an explicit part of the school curriculum in England from September 2002. This paper explores how this historic shift has come about through the work of the Advisory Group on Education for Citizenship and the Teaching of Democracy in Schools (commonly known as the Crick Group). The first section sets out the background to why the Crick Group was established and shows how the main lessons from past policy approaches were absorbed by the Group. The second section explains how citizenship education is defined in the school curriculum in England. The third section details some of the current activities designed to encourage the development of effective practice in citizenship. In the final section a number of challenges facing citizenship education are identified. How these challenges are tackled will have a major impact as to the effectiveness of citizenship education practice in schools and elsewhere in England.

Introduction Poor diet is the leading cause of poor health in USA, with fresh vegetable consumption below recommended levels. We aimed to assess the impact of medical prescriptions for fresh (defined as picked within 72 hours) vegetables, at no cost to participants on cardiometabolic outcomes among adults (predominantly Mexican-American women) with or at risk of type 2 diabetes (T2D).Methods Between February 2019 and March 2020, 159 participants (122 female, 75% of Mexican heritage, 31% with non-insulin treated T2D, age 52.5 (13.2) years) were recruited using community outreach materials in English and Spanish, and received prescriptions for 21 servings/week of fresh vegetable for 10 weeks. Pre-post comparisons were made of weight; waist circumference; blood pressure; Hemoglobin A1c (HbA1c, a measure of long-term blood glucose control); self-reported sleep, mood and pain; vegetable, tortilla and soda consumption. After obtaining devices for this study, 66 of 72 participants asked, agreed to wear blinded continuous glucose monitors (CGM).Results Paired data were available for 131 participants. Over 3 months, waist circumference fell (−0.77 (95% CI −1.42 to 0.12) cm, p=0.022), as did systolic blood pressure (SBP) (−2.42 (95% CI −4.56 to 0.28) mm Hg, p=0.037), which was greater among individuals with baseline SBP >130 mm Hg (−7.5 (95% CI −12.4 to 2.6) mm Hg, p=0.005). Weight reduced by −0.4 (−0.7 to –0.04) kg, p=0.029 among women. For participants with baseline HbA1c >7.0%, HbA1c fell by −0.35 (-0.8 to –0.1), p=0.009. For participants with paired CGM data (n=40), time in range 70–180 mg/dL improved (from 97.4% to 98.9%, p