AbstractObjectiveTo derive a US-based value set for the EQ-5D-5L questionnaire using an international, standardized protocol developed by the EuroQol Group. MethodsRespondents from the US adult ...population were quota-sampled on the basis of age, sex, ethnicity, and race. Trained interviewers guided participants in completing composite time trade-off (cTTO) and discrete choice experiment (DCE) tasks using the EuroQol Valuation Technology software and routine quality control measures. Data were modeled using a Tobit model for cTTO data, a mixed logit model for DCE data, and a hybrid model that combined cTTO and DCE data. Model performance was compared on the basis of logical ordering of coefficients, statistical significance, parsimony, and theoretical considerations. ResultsOf 1134 respondents, 1062, 1099, and 1102 respondents provided useable cTTO, DCE, and cTTO or DCE responses, respectively, on the basis of quality control criteria and interviewer judgment. Respondent demographic characteristics and health status were similar to the 2015 US Census. The Tobit model was selected as the preferred model to generate the value set. Values ranged from −0.573 (55 555) to 1 (11 111), with 20% of all predicted health states scores less than 0 (ie, worse than dead). ConclusionsA societal value set for the EQ-5D-5L was developed that can be used for economic evaluations and decision making in US health systems. The internationally established, standardized protocol used to develop this US-based value set was recommended by the EuroQol Group and can facilitate cross-country comparisons.
During each heartbeat, intercellular electrical coupling via connexin43 (Cx43) gap junctions enables synchronous cardiac contraction. In failing hearts, impaired Cx43 trafficking reduces gap junction ...coupling, resulting in arrhythmias. Here we report that internal translation within Cx43 (GJA1) mRNA occurs, resulting in truncated isoforms that autoregulate Cx43 trafficking. We find that at least four truncated Cx43 isoforms occur in the human heart, with a 20 kDa isoform predominating. In-frame AUG codons within GJA1 mRNA are the translation initiation sites and their ablation arrests trafficking of full-length Cx43. The 20 kDa isoform is sufficient to rescue this trafficking defect in trans, suggesting it as a trafficking chaperone for Cx43. Limiting cap-dependent translation through inhibition of mTOR enhances truncated isoform expression, increasing Cx43 gap junction size. The results suggest that internal translation is a mechanism of membrane protein autoregulation and a potent target for therapies aimed at restoring normal electrical coupling in diseased hearts.
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•Multiple N-terminally truncated isoforms of connexin43 occur in human heart•Internal translation at in-frame AUG codons generates smaller connexin43 isoforms•Trafficking of full-length connexin43 is regulated by smaller truncated isoforms•mTOR pathway regulates truncated isoform translation and connexin43 gap junction size
The connexin43 gene GJA1 contains a single coding exon, implying a single protein product. Here, Smyth and Shaw report that in the human heart, the GJA1 gene can produce up to six previously unidentified smaller proteins originating from internal start sites on GJA1 mRNA. The authors find that a 20 kDa isoform whose translation is inhibited by mTOR is requisite for connexin43 forward trafficking. There may be other functions of GJA1 protein products that are independent of intercellular communication.
Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking 'how can we effectively treat cancer?', we do ...not capture the complexity of a disease encompassing >200 different cancer types - many consisting of multiple subtypes - with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer.
Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging.
We performed an unsupervised analysis of ...microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence.
Here we report that the most dominant pattern of intrinsic gene expression in colon cancer (PC1) was tightly correlated (Pearson R = 0.92, P < 10(-135)) with the EMT signature-- both in gene identity and directionality. In a global micro-RNA screen, we further identified the most anti-correlated microRNA with PC1 as MiR200, known to regulate EMT.
These data demonstrate that the biology underpinning the native, molecular classification of human colon cancer--previously thought to be highly heterogeneous-- was clarified through the lens of comprehensive transcriptome analysis.
In 2017–2019, the March of Dimes convened a workgroup with biomedical, clinical, and epidemiologic expertise to review knowledge of the causes of the persistent Black-White disparity in preterm birth ...(PTB). Multiple databases were searched to identify hypothesized causes examined in peer-reviewed literature, 33 hypothesized causes were reviewed for whether they plausibly affect PTB and either occur more/less frequently and/or have a larger/smaller effect size among Black women vs. White women. While definitive proof is lacking for most potential causes, most are biologically plausible. No single downstream or midstream factor explains the disparity or its social patterning, however, many likely play limited roles, e.g., while genetic factors likely contribute to PTB, they explain at most a small fraction of the disparity. Research links most hypothesized midstream causes, including socioeconomic factors and stress, with the disparity through their influence on the hypothesized downstream factors. Socioeconomic factors alone cannot explain the disparity's social patterning. Chronic stress could affect PTB through neuroendocrine and immune mechanisms leading to inflammation and immune dysfunction, stress could alter a woman's microbiota, immune response to infection, chronic disease risks, and behaviors, and trigger epigenetic changes influencing PTB risk. As an upstream factor, racism in multiple forms has repeatedly been linked with the plausible midstream/downstream factors, including socioeconomic disadvantage, stress, and toxic exposures. Racism is the only factor identified that directly or indirectly could explain the racial disparities in the plausible midstream/downstream causes and the observed social patterning. Historical and contemporary systemic racism can explain the racial disparities in socioeconomic opportunities that differentially expose African Americans to lifelong financial stress and associated health-harming conditions. Segregation places Black women in stressful surroundings and exposes them to environmental hazards. Race-based discriminatory treatment is a pervasive stressor for Black women of all socioeconomic levels, considering both incidents and the constant vigilance needed to prepare oneself for potential incidents. Racism is a highly plausible, major upstream contributor to the Black-White disparity in PTB through multiple pathways and biological mechanisms. While much is unknown, existing knowledge and core values (equity, justice) support addressing racism in efforts to eliminate the racial disparity in PTB.
Mapping EQ-5D-3L to EQ-5D-5L van Hout, Ben A.; Shaw, James W.
Value in health,
September 2021, 2021-09-00, 20210901, Volume:
24, Issue:
9
Journal Article
Peer reviewed
Open access
The original 3-level EQ-5D (EQ-5D-3L) includes 5 dimensions with 3 levels of problems per dimension. Since 2010, a more sensitive version with 5 levels of problems per dimension (EQ-5D-5L) has become ...available. Population value sets have been developed for both versions of the questionnaire. The objective of this research was to develop a mapping function to link EQ-5D-3L responses to value sets for the EQ-5D-5L.
Various algorithms were developed to link EQ-5D-3L and EQ-5D-5L responses using data from an observational study including members of 10 subgroups (N = 3580) who completed both versions of the questionnaire. Nonparametric and ordinal logistic regression models were fit to the data and compared using Akaike’s information criterion (AIC) as well as the mean absolute error and root mean squared error of predictions. Results were contrasted qualitatively and quantitatively with those of an alternative copula-based approach.
Including indicants of problems for other EQ-5D-3L dimensions as regressors in the modeling yielded the greatest improvement in prediction accuracy. Adding age and gender lowered the AIC without improving predictions, while including a latent factor lowered the AIC further and slightly improved predictive accuracy. Models that conditioned on problems in other EQ-5D-3L dimensions yielded more accurate predictions than the alternative copula-based approach in subgroups defined by age and gender.
We present novel algorithms to map EQ-5D-3L responses to EQ-5D-5L value sets. The recommended approach is based on an ordinal logistic regression that disregards age and gender and accounts for unobserved heterogeneity using a latent factor.
Pest and pathogen losses jeopardise global food security and ever since the 19(th) century Irish famine, potato late blight has exemplified this threat. The causal oomycete pathogen, Phytophthora ...infestans, undergoes major population shifts in agricultural systems via the successive emergence and migration of asexual lineages. The phenotypic and genotypic bases of these selective sweeps are largely unknown but management strategies need to adapt to reflect the changing pathogen population. Here, we used molecular markers to document the emergence of a lineage, termed 13_A2, in the European P. infestans population, and its rapid displacement of other lineages to exceed 75% of the pathogen population across Great Britain in less than three years. We show that isolates of the 13_A2 lineage are among the most aggressive on cultivated potatoes, outcompete other aggressive lineages in the field, and overcome previously effective forms of plant host resistance. Genome analyses of a 13_A2 isolate revealed extensive genetic and expression polymorphisms particularly in effector genes. Copy number variations, gene gains and losses, amino-acid replacements and changes in expression patterns of disease effector genes within the 13_A2 isolate likely contribute to enhanced virulence and aggressiveness to drive this population displacement. Importantly, 13_A2 isolates carry intact and in planta induced Avrblb1, Avrblb2 and Avrvnt1 effector genes that trigger resistance in potato lines carrying the corresponding R immune receptor genes Rpi-blb1, Rpi-blb2, and Rpi-vnt1.1. These findings point towards a strategy for deploying genetic resistance to mitigate the impact of the 13_A2 lineage and illustrate how pathogen population monitoring, combined with genome analysis, informs the management of devastating disease epidemics.
Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this ...patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs).
CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40–60 mg/m2 of body surface area), docetaxel (30–40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life–5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636.
Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from −2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, −24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs −7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires.
In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting.
Bristol-Myers Squibb.
Time trade-off (TTO) and discrete choice experiment (DCE) preference-elicitation techniques can be administered using face-to-face interviews (F2F), unassisted online (UO) surveys, or remote-assisted ...(RA) interviews. The objective of this study was to explore how the mode of administration affects the quality and reliability of preference-elicitation data.
EQ-5D-5L health states were valued using composite TTO (cTTO) and DCE approaches by the UK general population. Participants were allocated to 1 of 2 study groups. Group A completed both F2F and UO surveys (n = 271), and group B completed both RA and UO surveys (n = 223). The feasibility of survey completion and the reliability and face-validity of data collected were compared across all modes of administration.
Fewer participants reported receiving sufficient guidance on the cTTO tasks during the UO survey compared with the 2 assisted modes. Participants across all modes typically reported receiving sufficient guidance on the DCE tasks.
cTTO data were less reliable from the UO survey compared with both assisted modes, but there were no differences in DCE data reliability. cTTO data from all modes demonstrated face-validity; however, the UO survey produced higher utilities for moderate and severe health states than both assisted modes. Both F2F and RA modes provided comparably reliable data.
The reliability of DCE data is not affected by the mode of administration. Interviewer-assisted modes of administration (F2F or RA) yield more reliable cTTO data than unassisted surveys. Both F2F and RA surveys produced similar-quality data.
•Preference-elicitation tasks can be administered using various modes of administration, ie, face-to-face (F2F), online remote assisted (RA), or online unassisted (UO). Existing literature suggests that the mode of administration of preference-elicitation tasks can influence the resulting data.•This study compared discrete choice experiment (DCE) and composite time trade-off (cTTO) data across all 3 modes of administration. This study adds to the literature by examining the quality of latent-scale DCE and cTTO data elicited via UO surveys compared with 2 different interviewer-assisted modes (F2F and RA). The study also strengthens existing findings from recent studies comparing F2F with RA interviews for conducting cTTO studies.•The findings from this study support conducting DCE studies to value health states using any mode of administration. cTTO data quality in this study was, however, affected by mode of administration; higher quality data were obtained from F2F and RA modes compared with UO. Interviewer-assisted modes are recommended for cTTO studies based on these findings, although future research should explore optimizing online cTTO surveys to potentially enable high quality data collection from UO settings.
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