Non-viral gene vectors are commonly used for gene therapy owing to safety concerns with viral vectors. However, non-viral vectors are plagued by low levels of gene transfection and cellular expression. Current efforts to improve the efficiency of non-viral gene delivery are focused on manipulations of the delivery vector, whereas the influence of the cellular environment in DNA uptake is often ignored. The mechanical properties (for example, rigidity) of the substrate to which a cell adheres have been found to mediate many aspects of cell function including proliferation, migration and differentiation, and this suggests that the mechanics of the adhesion substrate may regulate a cell's ability to uptake exogeneous signalling molecules. In this report, we present a critical role for the rigidity of the cell adhesion substrate on the level of gene transfer and expression. The mechanism relates to material control over cell proliferation, and was investigated using a fluorescent resonance energy transfer (FRET) technique. This study provides a new material-based control point for non-viral gene therapy.

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ObjectiveValid, reliable critical appraisal tools advance quality improvement (QI) intervention impacts by helping stakeholders identify higher quality studies. QI approaches are diverse and differ from clinical interventions. Widely used critical appraisal instruments do not take unique QI features into account and existing QI tools (eg, Standards for QI Reporting Excellence) are intended for publication guidance rather than critical appraisal. This study developed and psychometrically tested a critical appraisal instrument, the QI Minimum Quality Criteria Set (QI-MQCS) for assessing QI-specific features of QI publications.MethodsApproaches to developing the tool and ensuring validity included a literature review, in-person and online survey expert panel input, and application to empirical examples. We investigated psychometric properties in a set of diverse QI publications (N=54) by analysing reliability measures and item endorsement rates and explored sources of disagreement between reviewers.ResultsThe QI-MQCS includes 16 content domains to evaluate QI intervention publications: Organisational Motivation, Intervention Rationale, Intervention Description, Organisational Characteristics, Implementation, Study Design, Comparator Description, Data Sources, Timing, Adherence/Fidelity, Health Outcomes, Organisational Readiness, Penetration/Reach, Sustainability, Spread and Limitations. Median inter-rater agreement for QI-MQCS items was κ 0.57 (83% agreement). Item statistics indicated sufficient ability to differentiate between publications (median quality criteria met 67%). Internal consistency measures indicated coherence without excessive conceptual overlap (absolute mean interitem correlation=0.19). The critical appraisal instrument is accompanied by a user manual detailing What to consider, Where to look and How to rate.ConclusionsWe developed a ready-to-use, valid and reliable critical appraisal instrument applicable to healthcare QI intervention publications, but recognise scope for continuing refinement.

The burden of Alzheimer's disease in high-income countries is expected to approximately double between 2015 and 2050. Recent clinical trial results give hope that a diseasemodifying therapy might become available in the near future. The therapy is expected to treat early-stage patients to prevent or delay the progression to dementia. ■ This preventive treatment paradigm implies the need to screen, diagnose, and treat a large population of patients with mild cognitive impairment. There would be many undiagnosed prevalent cases that would need to be addressed initially, and then the longer-term capacity to address incident cases would not need to be as high as the short-term capacity. ■ We use a simulation model to assess the preparedness of the health care system infrastructure in six European countries-France, Germany, Italy, Spain, Sweden, and the United Kingdom-to evaluate, diagnose, and treat the expected number of patients. ■ Projected peak wait times range from five months for treatment in Germany to 19 months for evaluation in France. The first years without wait times would be 2030 in Germany and 2033 in France, and 2042 in the United Kingdom and 2044 in Spain. Specialist capacity is the rate-limiting factor in France, the United Kingdom, and Spain, and treatment delivery capacity is an issue in most of the countries. ■ If a disease-modifying therapy becomes available in 2020, we estimate the projected capacity constraints could result in over 1 million patients with mild cognitive impairment progressing to Alzheimer's dementia while on wait-lists between 2020 and 2044 in these six countries. ■ A combination of reimbursement, regulatory, and workforce planning policies, as well as innovation in diagnosis and treatment delivery, is needed to expand capacity and to ensure that available capacity is leveraged optimally to treat patients with early-stage Alzheimer's disease.

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