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BACKGROUND Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS We observed widespread intratumor heterogeneity for both somatic copy-number alterations and mutations. Driver mutations in EGFR, MET, BRAF, and TP53 were almost always clonal. However, heterogeneous driver alterations that occurred later in evolution were found in more than 75% of the tumors and were common in PIK3CA and NF1 and in genes that are involved in chromatin modification and DNA damage response and repair. Genome doubling and ongoing dynamic chromosomal instability were associated with intratumor heterogeneity and resulted in parallel evolution of driver somatic copy-number alterations, including amplifications in CDK4, FOXA1, and BCL11A. Elevated copy-number heterogeneity was associated with an increased risk of recurrence or death (hazard ratio, 4.9; P = 4.4×10-4), which remained significant in multivariate analysis. CONCLUSIONS Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. [ABSTRACT FROM AUTHOR]

Neoantigen immunogenicity prediction is a highly challenging problem in the development of personalised medicines. Low reactivity rates in called neoantigens result in a difficult prediction scenario with limited training datasets. Here we describe ImmugenX, a modular protein language modelling approach to immunogenicity prediction for CD8+ reactive epitopes. ImmugenX comprises of a pMHC encoding module trained on three pMHC prediction tasks, an optional TCR encoding module and a set of context specific immunogenicity prediction head modules. Compared with state-of-the-art models for each task, ImmugenX's encoding module performs comparably or better on pMHC binding affinity, eluted ligand prediction and stability tasks. ImmugenX outperforms all compared models on pMHC immunogenicity prediction (Area under the receiver operating characteristic curve = 0.619, average precision: 0.514), with a 7% increase in average precision compared to the next best model. ImmugenX shows further improved performance on immunogenicity prediction with the integration of TCR context information. ImmugenX performance is further analysed for interpretability, which locates areas of weakness found across existing immunogenicity models and highlight possible biases in public datasets., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.A.Q. is co-founder and chief scientific officer and own shares in Achilles Therapeutics. C.S. acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc., a collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical and Personalis. He is chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the steering committee chair. He is also co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s scientific advisory board (SAB). He receives consultant fees from Achilles Therapeutics (also an SAB member); Bicycle Therapeutics (also an SAB member); Genentech; Medicxi; the China Innovation Centre of Roche (CICoR), formerly Roche Innovation Centre Shanghai; Metabomed (until July 2022); Relay Therapeutics; and the Sarah Cannon Research Institute. C.S has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche-Ventana; previously held stock options in Apogen Biotechnologies and GRAIL; currently has stock options in Epic Bioscience and Bicycle Therapeutics; and has stock options and is co-founder of Achilles Therapeutics. S.R.H. is the cofounder of PokeAcell and is co-inventor of licensed patents related to T cell detection. H.O’B., M.S., L.M. and F.O’F. are employees of Achilles Therapeutics. H.O’B. and M.S. are both named inventors on patents for ImmugenX., (Copyright: © 2024 O’Brien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The growing awareness of colonialism's role in global health partnerships between HICs and LMICs and the associated calls for decolonization in global health has led to discussion for a paradigm shift that would lead to new ways of engagement and partnerships, as well as an acknowledgement that colonialism, racism, sexism, and capitalism contribute to inequity. While there is general agreement among those involved in global health partnerships that the current system needs to be made more equitable, suggestions for how to address the issue of decolonization vary greatly, and moving from rhetoric to reform is complicated. Based on a comprehensive (but not exhaustive) review of the literature, there are several recurring themes that should be addressed in order for the inequities in the current system to be changed. The degree to which decolonization of global health will be successful depends on how the global health community in both the HICs and LMICs move forward to discuss these issues. Specifically, as part of a paradigm shift, attention needs to be paid to creating a more equal and equitable representation of researchers in LMICs in decision-making, leadership roles, authorship, and funding allocations. There needs to be agreement in defining basic principles of best practices for global partnership, including a universal definition of 'decolonization of global health'; the extent to which current policies allow the perpetuation of power imbalance between HICs and LMICs; a set of principles, best practices, and models for equitable sharing of funds and institutional costs among partners; a mechanism to monitor progress prospectively the equitable sharing of credits (e.g., leadership, authorship), including a set of principles, best practices, and models; and, a mechanism to monitor progress prospectively the extent to which decolonialization will contribute to strengthening institutional capacity in the LMIC institutions., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Understanding how health care utilization responds to cost-sharing is of central importance for providing high quality care and limiting the growth of costs. We study whether the framing of cost-sharing incentives has an effect on health care utilization. For this we make use of a policy change in the Netherlands. Until 2007, patients received a refund if they consumed little or no health care; the refund was the lower the more care they had consumed. From 2008 onward, there was a deductible. This means that very similar economic incentives were first framed in terms of smaller gains and later as losses. We find that patients react to incentives much more strongly when they are framed in terms of losses. The effect on yearly spending is 8.6 percent. This suggests that discussions on the optimal design of cost-sharing incentives should also revolve around the question how these are presented to patients., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Debate around a common definition of global health has seen extensive scholarly interest within the last two decades; however, consensus around a precise definition remains elusive. The objective of this study was to systematically review definitions of global health in the literature and offer grounded theoretical insights into what might be seen as relevant for establishing a common definition of global health., Method: A systematic review was conducted with qualitative synthesis of findings using peer-reviewed literature from key databases. Publications were identified by the keywords of 'global health' and 'define' or 'definition' or 'defining'. Coding methods were used for qualitative analysis to identify recurring themes in definitions of global health published between 2009 and 2019., Results: The search resulted in 1363 publications, of which 78 were included. Qualitative analysis of the data generated four theoretical categories and associated subthemes delineating key aspects of global health. These included: (1) global health is a multiplex approach to worldwide health improvement taught and pursued at research institutions; (2) global health is an ethically oriented initiative that is guided by justice principles; (3) global health is a mode of governance that yields influence through problem identification, political decision-making, as well as the allocation and exchange of resources across borders and (4) global health is a vague yet versatile concept with multiple meanings, historical antecedents and an emergent future., Conclusion: Extant definitions of global health can be categorised thematically to designate areas of importance for stakeholders and to organise future debates on its definition. Future contributions to this debate may consider shifting from questioning the abstract 'what' of global health towards more pragmatic and reflexive questions about 'who' defines global health and towards what ends., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Regulated prices are common in markets for medical care. We estimate the effect of changes in regulated reimbursement prices on volume of hospital care based on a reform of hospital financing in Germany. Uniquely, this reform changed the overall level of reimbursement-with increasing prices for some hospitals and decreasing prices for others-without directly affecting the relative prices for different groups of patients or types of treatment. Based on administrative data, we find that hospitals react to increasing prices by decreasing the service supply and to decreasing prices by increasing the service supply. Moreover, we find some evidence that volume changes for hospitals with different price changes are nonlinear. We interpret our findings as evidence for a negative income effect of prices on volume of care., (© 2019 The Authors. Health Economics published by John Wiley & Sons Ltd.)

We examine sources of regional variation in ambulatory care utilization in Germany. We exploit patient migration to examine which share of regional variation in ambulatory care utilization can be attributed to demand factors and to supply factors, respectively. Based on administrative claim-level data we find that regional variation can be overwhelmingly explained by patient characteristics. Our results contrast with previous results for other countries, and they suggest that institutional rules in Germany successfully constrain supply-side variation in ambulatory care use between German regions for most patients. Furthermore, we find that both demographics and other patient characteristics substantially contribute to regional variation and that causes of regional variation vary when comparing different regions within Germany., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Starting from December 2012, insurers in the European Union were prohibited from charging gender-discriminatory prices. We examine the effect of this unisex mandate on risk segmentation in the German health insurance market. Although gender used to be a pricing factor in Germany's private health insurance (PHI) sector, it was never used as a pricing factor in the social health insurance (SHI) sector. The unisex mandate makes PHI relatively more attractive for women and less attractive for men. Based on data from the German socio-economic panel, we analyze how the unisex mandate affects the difference between women and men in switching rates between SHI and PHI. We find that the unisex mandate increases the probability of switching from SHI to PHI for women relative to men. On the other hand, the unisex mandate has no effect on the gender difference in switching rates from PHI to SHI. Because women have on average higher health care expenditures than men, our results imply a worsening of the PHI risk pool and an improvement of the SHI risk pool. Our results demonstrate that regulatory measures such as the unisex mandate can affect risk selection between public and private health insurance sectors., (© 2019 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Immune checkpoint blockade has significantly improved clinical outcomes for patients with non-small cell lung cancer (NSCLC) and other solid tumours, but many patients do not respond and acquired resistance is common. Aspects of the tumour microenvironment linked to clinical outcomes include the proportion of tumour-infiltrating lymphocytes (TIL), tumour programmed death ligand 1 ( PD-L1) score and tumour mutation burden. Adoptive cell therapy (ACT), a technique that works by infusing ex vivo expanded T lymphocytes to increase the effector cell pool in tumours, is anticipated to become a viable therapeutic option for patients with solid tumours, akin to chimeric antigen receptor T cell (CAR-T) therapy in haematological malignancies. TIL therapy has shown durable clinical responses in heavily pre-treated patients with melanoma and other solid tumours. We review the experience of ACT with TILs and the recent evidence that clonal neoantigens might be the most relevant immunotherapeutic targets in heterogeneous solid tumours such as NSCLC. Clonal (or truncal) neoantigens arise from the earliest mutagenic events in tumour evolution, and are retained over time in all tumour cells within a patient, making them the ideal target for T cell therapy. NSCLC has one of the highest clonal mutation burdens of all cancers through exposure to carcinogens in tobacco smoke, providing a strong rationale to develop clonal neoantigen reactive T cells (cNeT) for this indication. The first treatment modality to test this concept clinically is ATL001, a cNeT product that is derived from autologous TILs and enriched for T cells specifically recognizing clonal neoantigenic epitopes by selective expansion. Clinical studies of ATL001 will commence in 2019., (© 2019 Achilles Therapeutics Limited.)

We assess the relative importance of demand and supply factors as determinants of regional variation in healthcare expenditures in the Netherlands. Our empirical approach follows individuals who migrate between regions. We use individual data on annual healthcare expenditures for the entire Dutch population between the years 2006 and 2013. Regional variation in healthcare expenditures is mostly driven by demand factors, with an estimated share of around 70%. The relative importance of different causes varies with the groups of regions being compared., (© 2019 The Authors Health Economics Published by John Wiley & Sons Ltd.)

We examine the effect of retirement on healthcare utilization in China using longitudinal data. We use a nonparametric fuzzy regression discontinuity design, exploiting the statutory retirement age in urban China as a source of exogenous variation in retirement. In contrast to previous results for developed countries, we find that in China retirement increases healthcare utilization. This increase can be attributed to deteriorating health and in particular to the reduced opportunity cost of time after retirement. For the sample as a whole, income is not a dominating mechanism. People with low education, however, are more likely to forego recommended inpatient care after retirement., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Patients undergoing chemotherapy are highly burdened by side effects. These may be caused by the pharmacodynamics of the drug or be driven by psychological factors such as negative expectations or pre-conditioning, which reflect nocebo effects. As such, negative pre-treatment expectations or prior experiences might exacerbate the burden of chemotherapy side effects. Educating patients about this nocebo effect has been put forward as a potential strategy to optimize patients' pre-treatment expectations. In this study, we evaluate whether a briefing about the nocebo effect is efficacious in reducing side effects., Methods: In this exploratory study, a total number of n = 100 outpatients with newly diagnosed gastrointestinal cancers are randomized 1:1 to an information session about the nocebo effect (nocebo-education) or an attention control group (ACG) with matching interaction time. Assessments take place before the intervention (T1 pre), post-intervention (T1 post), and 10 days (T2) and 12 weeks (T3) after the initial chemotherapy. The primary outcomes are the patient-rated number and intensity of side effects at 10-days and at 12-weeks follow-up. Secondary outcomes include coping with side effects, tendency to misattribute symptoms, compliance intention, attitude towards the chemotherapy, co-medication to treat side effects and the clinician-rated severity of toxicity. Further analyses are conducted to investigate whether a potential beneficial effect is mediated by a change of expectations before and after the intervention., Discussion: Informing patients about the nocebo effect might be an innovative and feasible intervention to reduce the burden of side effects and strengthen patients' perceived control over adverse symptoms., Trial Registration: The trial is registered at the German Clinical Trials Register (ID: DRKS00009501 ; retrospectively registered on March 27, 2018). The first patient was enrolled on September 29, 2015.

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus® significantly improved the dissolution rate of IND at pH 6.8 (79.9 ± 0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus® in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance., (Copyright © 2018 Francis Crick Institute. Published by Elsevier Inc. All rights reserved.)

Background: Anyplex™ II HPV HR Detection (Seegene, Seoul, Korea) is a multiplex real-time PCR using tagging oligonucleotide cleavage and extension (TOCE) technology for simultaneous detection and genotyping of 14 high-risk (HR) HPV types, including HPV16 and HPV18., Objectives: To evaluate whether the clinical performance and reproducibility of Anyplex™ II HPV HR Detection meet the international consensus guidelines for HPV test requirements for cervical cancer screening [1]., Study Design: The clinical performance of Anyplex™ II HPV HR Detection for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was determined relative to that of the reference assay, i.e., HR HPV GP5+/6+-PCR-EIA, by analysis of a total of 879 cervical liquid based cytology (LBC) specimens from a screening population, of which 60 were from women with CIN2+. The intra-laboratory reproducibility and inter-laboratory agreement were determined on 509 LBC samples, of which 172 were positive by the reference assay., Results: Anyplex™ II HPV HR Detection showed a clinical sensitivity for CIN2+ of 98.3% (59/60; 95% CI: 89.1-99.8) and a clinical specificity for CIN2+ of 93.6% (764/816; 95% CI: 89.8-96.1). The clinical sensitivity and specificity were non-inferior to those of HR HPV GP5+/6+-PCR-EIA (non-inferiority score test: P=0.005 and P=0.023, respectively). Both intra-laboratory reproducibility (96.8%; 95% CI: 95.3-98.1; kappa value of 0.93) and inter-laboratory agreement (96.0%; 95% CI: 94.3-97.4; kappa value of 0.91) were high., Conclusions: Anyplex™ II HPV HR Detection performs clinically non-inferior to HR HPV GP5+/6+-PCR-EIA. Anyplex™ II HPV HR Detection complies with international consensus validation metrics for HPV DNA tests for cervical cancer screening [1]., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a significant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches., Significance: This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identification of amplifications encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention., (©2015 American Association for Cancer Research.)

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.