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Expert consensus on the potential benefits of early cancer detection does not exist for most cancer types. We convened 10 practicing oncologists using a RAND/UCLA modified Delphi panel to evaluate which of 20 solid tumors, representing >40 American Joint Committee on Cancer (AJCC)-identified cancer types and 80% of total cancer incidence, would receive potential clinical benefits from early detection. Pre-meeting, experts estimated how long cancers take to progress and rated the current curability and benefit (improvement in curability) of an annual hypothetical multi-cancer screening blood test. Post-meeting, experts rerated all questions. Cancers had varying estimates of the potential benefit of early cancer detection depending on estimates of their curability and progression by stage. Cancers rated as progressing quickly and being curable in earlier stages (stomach, esophagus, lung, urothelial tract, melanoma, ovary, sarcoma, bladder, cervix, breast, colon/rectum, kidney, uterus, anus, head and neck) were estimated to be most likely to benefit from a hypothetical screening blood test. Cancer types rated as progressing quickly but having comparatively lower cure rates in earlier stages (liver/intrahepatic bile duct, gallbladder, pancreas) were estimated to have medium likelihood of benefit from a hypothetical screening blood test. Cancer types rated as progressing more slowly and having higher curability regardless of stage (prostate, thyroid) were estimated to have limited likelihood of benefit from a hypothetical screening blood test. The panel concluded most solid tumors have a likelihood of benefit from early detection. Even among difficult-to-treat cancers (e.g., pancreas, liver/intrahepatic bile duct, gallbladder), early-stage detection was believed to be beneficial. Based on the panel consensus, broad coverage of cancers by screening blood tests would deliver the greatest potential benefits to patients., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: LS, SA, HB, JB, GTB, LC, MC, PC, BJM, DJW reported consulting fees from Partnership for Health Analytic Research (PHAR), LLC and GRAIL, LLC, a subsidiary of Illumina, Inc., currently held separate from Illumina, Inc. under the terms of the Interim Measures Order of the European Commission dated 29 October 2021. ARK and AK are employees of GRAIL, LLC, a subsidiary of Illumina, Inc., currently held separate from Illumina, Inc. under the terms of the Interim Measures Order of the European Commission dated 29 October 2021, who supported this study, and reported stock or stock options in Illumina (parent company of GRAIL, LLC, a subsidiary of Illumina, Inc., currently held separate from Illumina, Inc. under the terms of the Interim Measures Order of the European Commission dated 29 October 2021). MSB, IY, and CC are employees of Partnership for Health Analytic Research (PHAR), LLC which was paid by the following to conduct research related to the work described in the manuscript: Abbvie, Amgen, AstraZeneca, Biomarin Pharmaceuticals, BMS, Celgene, Dompe, Eisai, Exact Sciences Corporation, Genentech, GRAIL, LLC, a subsidiary of Illumina, Inc., currently held separate from Illumina, Inc. under the terms of the Interim Measures Order of the European Commission dated 29 October 2021, Ionis, Jazz, Kite, Novartis, Otsuka, Recordati, Regeneron, Sanofi US Services, Takeda Pharmaceuticals USA. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2022 Schwartzberg 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.)

Background: Ageing populations and rising prevalence of non-communicable diseases (NCDs) increasingly contribute to the growing cost burden facing European healthcare systems. Few studies have attempted to quantify the future magnitude of this burden at the European level, and none of them consider the impact of potential changes in risk factor trajectories on future health expenditures., Methods: The new microsimulation model forecasts the impact of behavioural and metabolic risk factors on NCDs, longevity and direct healthcare costs, and shows how changes in epidemiological trends can modify those impacts. Economic burden of NCDs is modelled under three scenarios based on assumed future risk factors trends: business as usual (BAU); best case and worst case predictions (BCP and WCP)., Findings: The direct costs of NCDs in the EU 27 countries and the UK (in constant 2014 prices) will grow under all scenarios. Between 2014 and 2050, the overall healthcare spending is expected to increase by 0.8% annually under BAU. In the all the countries, 605 billion Euros can be saved by 2050 if BCP is realized compared to the BAU, while excess spending under the WCP is forecast to be around 350 billion. Interpretation: Although the savings realised under the BCP can be substantial, population ageing is a stronger driver of rising total healthcare expenditures in Europe compared to scenario-based changes in risk factor prevalence., Competing Interests: The authors have declared that no competing interests exist.

Background: The future burden of non-communicable diseases (NCDs) depends on numerous factors such as population ageing, evolution of societal trends, behavioural and physiological risk factors of individuals (e.g. smoking, alcohol use, obesity, physical inactivity, and hypertension). This study aims to assess the burden of NCDs in Europe by 2050 under alternative scenarios., Methods: This study combines qualitative and quantitative forecasting techniques to examine how population health in Europe may evolve from 2015 to 2050, taking into account future societal trends. Four scenarios were developed (one business-as-usual scenario, two response scenarios and one pessimistic scenario) and assessed against 'best' and 'worst'-case scenarios. This study provides quantitative estimates of both diseases and mortality outcomes, using a microsimulation model incorporating international survey data., Findings: Each scenario is associated with a different risk factor prevalence rate across Europe during the period 2015-2050. The prevalence and incidence of NCDs consistently increase during the analysed time period, mainly driven by population ageing. In more optimistic scenarios, diseases will appear in later ages, while in the pessimistic scenarios, NCDs will impair working-age people. Life expectancy is expected to grow in all scenarios, but with differences by up to 4 years across scenarios and population groups. Premature mortality from NCDs will be reduced in more optimistic scenarios but stagnate in the worst-case scenario., Interpretation: Population ageing will have a greater impact on the spread of NCDs by 2050 compared to risk factors. Nevertheless, risk factors, which are influenced by living environments, are an important factor for determining future life expectancy in Europe., Competing Interests: The AIT affiliation of SG does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no competing interests exist.

Introduction: Non-communicable diseases (NCDs) like cancer, cardiovascular disease, and diabetes have spread at a remarkable pace in European countries over the past decades. Overweight/obesity and alcohol use are two leading risk factors contributing to both economic and epidemiological burden associated with NCDs. In OECD countries, the impact of indirect costs of obesity varies between 0.20% and 1.21% of GDP. Indirect costs of alcohol use range from 0.19% (Portugal) to 1.6% (Estonia) of GDP., Aim: To assess the longitudinal impact of alcohol use and high body-mass index (BMI) on labour market outcomes in the European region by modeling the direct effect of high BMI and alcohol use, and the effect via associated diseases., Methods: The impact of BMI, alcohol use, and associated diseases on employment likelihood, intent to retire early, days of absenteeism, and hours of work per week, were modelled via lagged Poisson and Zero-inflated Poisson regressions, adjusting for missingness via inverse probability weighting, as appropriate, using European SHARE data., Results: Controlling for other chronic conditions, being overweight increases employment likelihood among men, but not among women. Obesity decreased female, but not male, employment chances. All chronic conditions linked with high BMI negatively affected employment likelihood, and increased the intention to retire early significantly. Alcohol use positively affects employment likelihood in women at all drinking levels relative to lifetime abstainers, but only in moderate (not heavy) male drinkers. There is super-additionality of impact of NCDs on absenteeism and hours worked, presenting a key economic argument to tackle NCD prevention and compression of morbidity., Implications: NCD prevention is not just important for employment and hours worked, but also for employee morale, especially given increasing retirement age in Europe and globally., Competing Interests: The authors have declared that no competing interests exist.

Background: Whether inpatient services can be successfully substituted by office-based services has been debated for many decades, but the evidence is still inconclusive. This study aims to investigate the effect of office-based care on use and the expenditure for other healthcare services in patients with type II diabetes (T2D)., Methods: A generalized propensity score matching approach was used on pooled Medical Expenditure Panel Survey (MEPS) data for 2000-2012 to explore a dose-response effect. Patients were matched by using a comprehensive set of variables selected following a standard model on access to care., Findings: Office-based care (up to 5 visits/year) acts as a substitute for other healthcare services and is associated with lower use and expenditure for inpatient, outpatient and emergency care. After five visits, office-based care becomes a complement to other services and is associated with increases in expenditure for T2D. Above 20 to 26 visits per year, depending on the healthcare service under consideration, the marginal effect of an additional office-based visit becomes non-statistically significant., Conclusions: Office-based visits appear to be an effective instrument to reduce use of inpatient care and other services, including outpatient and emergency-care, in patients with T2D without any increase in total healthcare expenditure., Competing Interests: The authors have declared that no competing interests exist.

Objective: This paper explores the contribution of body-mass index (BMI) categories in shaping past trends of use of healthcare services and associated expenditure in the US and projects results to 2025., Methods: The study uses Medical Expenditure Panel Survey (MEPS) data for 2000-2012, reweighted on National Health and Nutrition Survey (NHANES) data for 1972-2012 and US Census Bureau data, to carry out projections for up to 2025. A combination of logistic regressions and generalized linear models was used to model use and associated expenditure for the following healthcare services: inpatient care (with/without surgery), office-based care, outpatient-care, drug prescription and home health care. Quantile regressions were used to analyse and project BMI levels., Results: 20.5 million individuals will be severely obese in 2025. Normal-weight and overweight individuals have stable trends in use for many healthcare services. Conversely, use of healthcare services in patients in class II and class III obesity will increase substantially. Total healthcare expenditure increases more quickly in the obese population than in normal-weight individuals., Conclusions: Class III obesity (BMI≥40 kg/m2) significantly affects demand and expenditure for all healthcare services. Careful healthcare service planning and implementing effective policy actions to counteract such trends is crucial to meet future demand., Competing Interests: The author has declared that no competing interests exist.

Nanolithography techniques enable the fabrication of complex nanodevices that can be used for biosensing purposes. However, these devices are normally supported by a substrate and their use is limited to in vitro applications. Following a top-down procedure, we designed and fabricated composite inductance-capacitance (LC) nanoresonators that can be detached from their substrate and dispersed in water. The multimaterial composition of these resonators makes it possible to differentially functionalize different parts of the device to obtain stable aqueous suspensions and multi-sensing capabilities. For the first time, we demonstrate detection of these devices in an aqueous environment, and we show that they can be sensitized to their local environment and to chemical binding of specific molecular moieties. The possibility to optically probe the nanoresonator resonance in liquid dispersions paves the way to a variety of new applications, including injection into living organisms for in vivo sensing and imaging.

Cancer is associated with increased fracture risk, due either to metastasis or associated osteoporosis. After a fracture, blood clots form. Because proteins of the coagulation cascade and activated platelets promote cancer development, a fracture in patients with cancer often raises the question whether it is a pathologic fracture or whether the fracture itself might promote the formation of metastatic lesions. We therefore examined whether blood clot formation results in increased metastasis in a murine model of experimental breast cancer metastasis. For this purpose, a clot was surgically induced in the bone marrow of the left tibia of immundeficient mice. Either one minute prior to or five minutes after clot induction, human cancer cells were introduced in the circulation by intracardiac injection. The number of cancer cells that homed to the intervention site was determined by quantitative real-time PCR and flow cytometry. Metastasis formation and longitudinal growth were evaluated by bioluminescence imaging. The number of cancer cells that homed to the intervention site after 24 hours was similar to the number of cells in the opposite tibia that did not undergo clot induction. This effect was confirmed using two more cancer cell lines. Furthermore, no difference in the number of macroscopic lesions or their growth could be detected. In the control group 72% developed a lesion in the left tibia. In the experimental groups with clot formation 79% and 65% developed lesions in the left tibia (p = ns when comparing each experimental group with the controls). Survival was similar too. In summary, the growth factors accumulating in a clot/hematoma are neither enough to promote cancer cell homing nor support growth in an experimental model of breast cancer bone metastasis. This suggests that blood clot formation, as occurs in traumatic fractures, surgical interventions, and bruises, does not increase the risk of metastasis formation.

Background: Recently, the effects of nanogratings have been investigated on PC12 with respect to cell polarity, neuronal differentiation, migration, maturation of focal adhesions and alignment of neurites., Methodology/principal Findings: A synergistic procedure was used to study the mechanism of alignment of PC12 neurites with respect to the main direction of nanogratings. Finite Element simulations were used to qualitatively assess the distribution of stresses at the interface between non-spread growth cones and filopodia, and to study their dependence on filopodial length and orientation. After modelling all adhesions under non-spread growth cone and filopodial protrusions, the values of local stress maxima resulted from the length of filopodia. Since the stress was assumed to be the main triggering cause leading to the increase and stabilization of filopodia, the position of the local maxima was directly related to the orientation of neurites. An analytic closed form equation was then written to quantitatively assess the average ridge width needed to achieve a given neuritic alignment (R(2) = 0.96), and the alignment course, when the ridge depth varied (R(2) = 0.97). A computational framework was implemented within an improved free Java environment (CX3D) and in silico simulations were carried out to reproduce and predict biological experiments. No significant differences were found between biological experiments and in silico simulations (alignment, p = 0.3571; tortuosity, p = 0.2236) with a standard level of confidence (95%)., Conclusions/significance: A mechanism involved in filopodial sensing of nanogratings is proposed and modelled through a synergistic use of FE models, theoretical equations and in silico simulations. This approach shows the importance of the neuritic terminal geometry, and the key role of the distribution of the adhesion constraints for the cell/substrate coupling process. Finally, the effects of the geometry of nanogratings were explicitly considered in cell/surface interactions thanks to the analytic framework presented in this work.

Gene therapy may represent a promising alternative strategy for cardiac muscle regeneration. In vivo electroporation, a physical method of gene transfer, has recently evolved as an efficient method for gene transfer. In the current study, we investigated the efficiency and safety of a protocol involving in vivo electroporation for gene transfer to the beating heart. Adult male rats were anesthetised and the heart exposed through a left thoracotomy. Naked plasmid DNA was injected retrograde into the transiently occluded coronary sinus before the electric pulses were applied. Animals were sacrificed at specific time points and gene expression was detected. Results were compared to the group of animals where no electric pulses were applied. No post-procedure arrhythmia was observed. Left ventricular function was temporarily altered only in the group were high pulses were applied; CK-MB (Creatine kinase) and TNT (Troponin T) were also altered only in this group. Histology showed no signs of toxicity. Gene expression was highest at day one. Our results provide evidence that in vivo electroporation with an optimized protocol is a safe and effective tool for nonviral gene delivery to the beating heart. This method may be promising for clinical settings especially for perioperative gene delivery.