The medical device development ecosystem: Current regulatory state and challenges for future development: A review.

BACKGROUND/PURPOSE: There has been increasing emphasis on the development of new technology to mitigate unmet clinical needs in cardiovascular disease. This emphasis results in part from recognition that many devices, although being initially developed in the United States, were studied, and then eventually approved abroad before being returned to the U.S. for clinical application. The FDA (Food and Drug Administration) guidance document on Early Feasibility Studies (EFS) and then the 21st Century Cures Act from 2013 to 2016 focused on these issues. MATERIALS/METHODS: There are multiple components of medical device translational pathways to be considered in continuing to reach the goal of providing early access to safe and effective products to the U.S. POPULATION: This review article documents the various stages from early idea innovation to device design and iteration to clinical testing and then potential approval and application in the wide clinical practice of cardiovascular health care. RESULTS: The CDRH (Centers for Devices and Radiological Health) has focused on key components including EFS, Breakthrough Devices Program, Total Product Life Cycle, the Unique Device Identification Program, the establishment of a Digital Health Center of Excellence, and leveraging Collaborative Communities. Each of these initiatives focuses on improving the Medical Device Development Ecosystem. CONCLUSIONS: Major changes in device translational research have improved the device research climate in the United States. Goals remain including increased training and education for constituencies aspiring to work in the field of device development and regulation as part of a continuous health care learning system.

Substantial light woodland and open vegetation characterized the temperate forest biome before Homo sapiens.

The extent of vegetation openness in past European landscapes is widely debated. In particular, the temperate forest biome has traditionally been defined as dense, closed-canopy forest; however, some argue that large herbivores maintained greater openness or even wood-pasture conditions. Here, we address this question for the Last Interglacial period (129,000-116,000 years ago), before Homo sapiens-linked megafauna declines and anthropogenic landscape transformation. We applied the vegetation reconstruction method REVEALS to 96 Last Interglacial pollen records. We found that light woodland and open vegetation represented, on average, more than 50% cover during this period. The degree of openness was highly variable and only partially linked to climatic factors, indicating the importance of natural disturbance regimes. Our results show that the temperate forest biome was historically heterogeneous rather than uniformly dense, which is consistent with the dependency of much of contemporary European biodiversity on open vegetation and light woodland.

Proceedings of the NHLBI Workshop on Artificial Intelligence in Cardiovascular Imaging: Translation to Patient Care.

Artificial intelligence (AI) promises to revolutionize many fields, but its clinical implementation in cardiovascular imaging is still rare despite increasing research. We sought to facilitate discussion across several fields and across the lifecycle of research, development, validation, and implementation to identify challenges and opportunities to further translation of AI in cardiovascular imaging. Furthermore, it seemed apparent that a multidisciplinary effort across institutions would be essential to overcome these challenges. This paper summarizes the proceedings of the National Heart, Lung, and Blood Institute-led workshop, creating consensus around needs and opportunities for institutions at several levels to support and advance research in this field and support future translation.

Generating and evaluating evidence of the clinical utility of molecular diagnostic tests in oncology.

PURPOSE: Enthusiasm for molecular diagnostic (MDx) testing in oncology is constrained by the gaps in required evidence regarding its impact on patient outcomes (clinical utility (CU)). This effectiveness guidance document proposes recommendations for the design and evaluation of studies intended to reflect the evidence expectations of payers, while also reflecting information needs of patients and clinicians. METHODS: Our process included literature reviews and key informant interviews followed by iterative virtual and in-person consultation with an expert technical working group and an advisory group comprising life-sciences industry experts, public and private payers, patients, clinicians, regulators, researchers, and other stakeholders. RESULTS: Treatment decisions in oncology represent high-risk clinical decision making, and therefore the recommendations give preference to randomized controlled trials (RCTs) for demonstrating CU. The guidance also describes circumstances under which alternatives to RCTs could be considered, specifying conditions under which test developers could use prospective-retrospective studies with banked biospecimens, single-arm studies, prospective observational studies, or decision-analytic modeling techniques that make a reasonable case for CU. CONCLUSION: Using a process driven by multiple stakeholders, we developed a common framework for designing and evaluating studies of the clinical validity and CU of MDx tests, achieving a balance between internal validity of the studies and the relevance, feasibility, and timeliness of generating the desired evidence.Genet Med 18 8, 780-787.

Adapting through glacial cycles: insights from a long-lived tree (Taxus baccata).

Despite the large body of research devoted to understanding the role of Quaternary glacial cycles in the genetic divergence of European trees, the differential contribution of geographic isolation and/or environmental adaptation in creating population genetic divergence remains unexplored. In this study, we used a long-lived tree (Taxus baccata) as a model species to investigate the impact of Quaternary climatic changes on genetic diversity via neutral (isolation-by-distance) and selective (isolation-by-adaptation) processes. We applied approximate Bayesian computation to genetic data to infer its demographic history, and combined this information with past and present climatic data to assess the role of environment and geography in the observed patterns of genetic structure. We found evidence that yew colonized Europe from the East, and that European samples diverged into two groups (Western, Eastern) at the beginning of the Quaternary glaciations, c. 2.2 Myr before present. Apart from the expected effects of geographical isolation during glacials, we discovered a significant role of environmental adaptation during interglacials at the origin of genetic divergence between both groups. This process may be common in other organisms, providing new research lines to explore the effect of Quaternary climatic factors on present-day patterns of genetic diversity.

Insights from the early experience of the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry.

The current system for postmarket surveillance of medical devices in the United States is limited. To help change this paradigm for transcatheter valve therapies (TVTs), starting with transcatheter aortic valve replacement, the Society of Thoracic Surgeons and the American College of Cardiology partnered to form the TVT Registry program in close collaboration with the U.S. Food and Drug Administration and the Center for Medicare and Medicaid Services. The goal of the TVT Registry is to measure and improve quality of care and patient outcomes in clinical practice and to have a pivotal role in the scientific evidence and surveillance for medical devices. Challenges were faced in the early experience of the registry included developing multistakeholder partnerships, data collection requirements, and the use of the registry for pre- and post-market device evaluations. In addressing these challenges, the TVT Registry demonstrates that it is feasible for professional societies to assume a pivotal role in pre- and/or post-market studies, leveraging a clinical registry infrastructure. Sharing the TVT Registry experience may help other professional societies and stakeholders better anticipate and plan for these challenges.

Mental health effects from urban bed bug infestation (Cimex lectularius L.): a cross-sectional study.

OBJECTIVE: To assess whether bed bug infestation was linked to sleep disturbances and symptoms of anxiety and depression. DESIGN: Exploratory cross-sectional study. SETTING: Convenience sample of tenants recruited in apartment complexes from Montreal, Canada. PARTICIPANTS: 39 bed bug-exposed tenants were compared with 52 unexposed tenants. MAIN OUTCOME MEASURES: The effect of bed bug-exposed tenants on sleep disturbances, anxiety and depression symptoms measured using the Pittsburgh Sleep Quality Index, 5th subscale, Generalised Anxiety Disorder 7-item scale and Patient Health Questionnaire, 9-item, respectively. RESULTS: In adjusted models, bed bug infestation was strongly associated with measured anxiety symptoms (OR (95% CI)=4.8 (1.5 to 14.7)) and sleep disturbance (OR (95% CI)=5.0 (1.3-18.8)). There was a trend to report more symptoms of depression in the bed bug-infested group, although this finding was not statistically significant ((OR (95% CI)=2.5(0.8 to 7.3)). CONCLUSIONS: These results suggest that individuals exposed to bed bug infestations are at risk of experiencing sleep disturbance and of developing symptoms of anxiety and possibly depression. Greater clinical awareness of this problem is needed in order for patients to receive appropriate mental healthcare. These findings highlight the need for undertaking of deeper inquiry, as well as greater collaboration between medical professionals, public health and community stakeholders.

Active and uncontrolled asthma among children exposed to air stack emissions of sulphur dioxide from petroleum refineries in Montreal, Quebec: a cross-sectional study.

BACKGROUND: Little attention has been devoted to the effects on children's respiratory health of exposure to sulphur dioxide (SO2) in ambient air from local industrial emissions. Most studies on the effects of SO(2) have assessed its impact as part of the regional ambient air pollutant mix. OBJECTIVE: To examine the association between exposure to stack emissions of SO(2) from petroleum refineries located in Montreal's (Quebec) east-end industrial complex and the prevalence of active asthma and poor asthma control among children living nearby. METHODS: The present cross-sectional study used data from a respiratory health survey of Montreal children six months to 12 years of age conducted in 2006. Of 7964 eligible households that completed the survey, 842 children between six months and 12 years of age lived in an area impacted by refinery emissions. Ambient SO(2) exposure levels were estimated using dispersion modelling. Log-binomial regression models were used to estimate crude and adjusted prevalence ratios (PRs) and 95% CIs for the association between yearly school and residential SO(2) exposure estimates and asthma outcomes. Adjustments were made for child's age, sex, parental history of atopy and tobacco smoke exposure at home. RESULTS: The adjusted PR for the association between active asthma and SO(2) levels was 1.14 (95% CI 0.94 to 1.39) per interquartile range increase in modelled annual SO(2). The effect on poor asthma control was greater (PR=1.39 per interquartile range increase in modelled SO(2) [95% CI 1.00 to 1.94]). CONCLUSIONS: Results of the present study suggest a relationship between exposure to refinery stack emissions of SO(2) and the prevalence of active and poor asthma control in children who live and attend school in proximity to refineries.

Comparability of Internet and telephone data in a survey on the respiratory health of children.

BACKGROUND: Mixing survey administration modes has generated concern about the comparability of responses between modes. OBJECTIVE: To explore the differences in respondent profiles, and responses between Internet and telephone questionnaires in a survey on respiratory diseases. METHODS: The data were generated from a mixed Internet and telephone survey of respiratory diseases among children in Montreal (Quebec), in 2006. Comparison of 12 selected questions was performed after standardization for respondent education and income. Stratification of analysis on education and income categories was also performed for the questions with significantly divergent responses. RESULTS: Six questions showed significant differences in responses between modes after standardization. The largest differences among the closed-ended questions were observed for highly prevalent symptoms, dry cough during the night (difference of 9% for positive answer [P<0.01]) and symptoms of allergic rhinitis (difference of 7% for positive answer [P<0.01]). A large discrepancy was also found in the multiple choice question and with an open-ended response (ie, free answer). For the three potentially sensitive questions, a desirability bias was probably present in one question on smoking habits (difference of 2.6 % for positive answer [P<0.05]). CONCLUSION: The differences observed between Internet and telephone responses to selected questions were not completely explained by socioeconomic disparities among the respondents. In a mixed-mode survey (Internet and telephone), caution should be used when formulating sensitive, complex, open-ended and long-ended questions, and those related to highly prevalent and nonspecific symptoms.

Medicare coverage: engaging on evidence.

Experience tells us that many developers of innovative technologies fail to anticipate the evidentiary needs of insurers, particularly of Medicare. Some assume that Medicare payment begins pro forma upon approval or clearance by the US FDA with little regard to the distinct role of the Centers for Medicare & Medicaid Services (CMS). We offer our own suggestions, hoping they will lead to mutually satisfying discussions as we consider coverage of regenerative medicine technology. Medicare is governed by Title XVIII of the Social Security Act, which among other provisions describes the scope of the insurance benefit, methods of payment for items and services that may be covered and the process timelines for national coverage determinations. CMS implements these provisions with regulations, instructions in manuals and other guidance that are available to the public. We will focus our comments on the 'reasonable and necessary' requirement for coverage under Part A and Part B of items and services in Section 1862(a)(1)(A) of the Social Security Act.

[Pollen analysis from two littoral marshes (Bourdim and Garaat El-Ouez) in the El-Kala wet complex (North-East Algeria). Lateglacial and Holocene history of Algerian vegetation]. / Nouvelles contributions à l'histoire tardiglaciaire et holocène de la végétation en Algérie: analyses polliniques de deux profils sédimentaires du complexe humide d'El-Kala.

The study of two pollen sequences from El-Kala marshes allowed the reconstruction of the regional vegetation history supported by eight radiocarbon dates. Pollen assemblages from Bourdim site were dominated by local input of Alnus and Salix, while regional vegetation was characterized by scattered Quercus suber forests with a well-developed Erica arborea matorral. While the vegetation dynamics recorded at Bourdim is recent (Late Holocene), the majority of the pollen diagram from Garaat El-Ouez is contemporaneous to the Late Pleniglacial and is characterized by open woodlands with Pinus, Poaceae and several heliophilous herbs. The significant values of Cedrus pollen identified in this period indicate that the region of El-Kala most probably played the role of a refugium for this tree.

Home environmental factors associated with poor asthma control in Montreal children: a population-based study.

BACKGROUND: Home environmental exposures may aggravate asthma. Few population-based studies have investigated the relationship between asthma control in children and home environmental exposures. OBJECTIVE: Identify home environmental exposures associated with poor control of asthma among asthmatic children less than 12 years of age in Montreal (Quebec, Canada). METHODS: This cross-sectional population-based study used data from a respiratory health survey of Montreal children aged 6 months to 12 years conducted in 2006 (n = 7980). Asthma control was assessed (n = 980) using an adaptation of the Canadian asthma consensus report clinical parameters. Using log-binomial regression models, prevalence ratios (PRs) with 95% confidence intervals (95% CIs) were estimated to explore the relationship between inadequate control of asthma and environmental home exposures, including allergens, irritants, mold, and dampness indicators. Subjects with acceptable asthma control were compared with those with inadequate disease control. RESULTS: Of 980 children with active asthma in the year prior to the survey, 36% met at least one of the five criteria as to poor control of their disease. The population's characteristics found to be related with a lack of asthma control were younger age, history of parental atopy, low maternal education level, foreign-born mothers, and tenant occupancy. After adjustments, children living along high-traffic density streets (PR, 1.35; 95% CI, 1.00-1.81) and those with their bedroom or residence at the basement level (PR, 1.30; 95% CI, 1.01-1.66) were found to be at increased risk of poor asthma control. CONCLUSIONS: Suboptimal asthma control appears to be mostly associated with traffic, along with mold and moisture conditions, the latter being a more frequent exposure and therefore having a greater public health impact.

Compendia and anticancer therapy under Medicare.

In 1993, Congress directed the Medicare program to refer to 3 existing published compendia, American Medical Association Drug Evaluations (AMA-DE), United States Pharmacopoeia Drug Information for the Health Professional (USP-DI), and American Hospital Formulary Service Drug Information (AHFS-DI), to identify unlabeled but medically accepted uses of drugs and biologicals in anticancer chemotherapy regimens. Public discussion during the preceding years had centered on whether to designate unlabeled uses of anticancer treatments as experimental and thus outside the scope of Medicare benefits. American Medical Association Drug Evaluations and USP-DI subsequently ceased publication, and the Medicare program faced increasing calls to revise the list of acceptable compendia, as authorized in the statute. In 2007, the Centers for Medicare & Medicaid Services used its regulatory authority to establish a publicly transparent process to revise the list. The Centers for Medicare & Medicaid Services considered 5 requests in 2008 and added National Comprehensive Cancer Network Drugs and Biologics Compendium, DRUGDEX, and Clinical Pharmacology to the list of compendia. DrugPoints was not added, and AMA-DE was removed. Because of the potential for conflicts of interest to lead to biased judgments, the 2008 Medicare Improvements for Patients and Providers Act has a provision that explicitly prohibits inclusion of compendia that do not have a publicly transparent process for evaluating therapies and identifying potential conflicts of interest.

Authenticated DNA from ancient wood remains.

BACKGROUND: The reconstruction of biological processes and human activities during the last glacial cycle relies mainly on data from biological remains. Highly abundant tissues, such as wood, are candidates for a genetic analysis of past populations. While well-authenticated DNA has now been recovered from various fossil remains, the final 'proof' is still missing for wood, despite some promising studies. SCOPE: The goal of this study was to determine if ancient wood can be analysed routinely in studies of archaeology and palaeogenetics. An experiment was designed which included blind testing, independent replicates, extensive contamination controls and rigorous statistical tests. Ten samples of ancient wood from major European forest tree genera were analysed with plastid DNA markers. CONCLUSIONS: Authentic DNA was retrieved from wood samples up to 1,000 years of age. A new tool for real-time vegetation history and archaeology is ready to use.

[Palaeostructures of vegetation at the upper limit of forests in the inner French Alps]. / Paléostructures de végétation à la limite supérieure des forêts dans les Alpes françaises internes.

The comparison of six pollen diagrams from French Alps allows us to reconstruct the past changes of vegetation structure at the upper limit of Subalpine range. Dense populations of Pinus cembra developed between 6500 and 2400 cal. BP, both in the southern Alps and the northern ones. Southern Alps seem however to be characterised by higher altitudinal limits, as shown by the past development of fir forests at 2080 m a.s.l. in the Ubaye valley. This study highlights the importance of taking in account local parameters in regional or continental reviews.

A new scenario for the quaternary history of European beech populations: palaeobotanical evidence and genetic consequences.

Here, palaeobotanical and genetic data for common beech (Fagus sylvatica) in Europe are used to evaluate the genetic consequences of long-term survival in refuge areas and postglacial spread. Four large datasets are presented, including over 400 fossil-pollen sites, 80 plant-macrofossil sites, and 450 and 600 modern beech populations for chloroplast and nuclear markers, respectively. The largely complementary palaeobotanical and genetic data indicate that: (i) beech survived the last glacial period in multiple refuge areas; (ii) the central European refugia were separated from the Mediterranean refugia; (iii) the Mediterranean refuges did not contribute to the colonization of central and northern Europe; (iv) some populations expanded considerably during the postglacial period, while others experienced only a limited expansion; (v) the mountain chains were not geographical barriers for beech but rather facilitated its diffusion; and (vi) the modern genetic diversity was shaped over multiple glacial-interglacial cycles. This scenario differs from many recent treatments of tree phylogeography in Europe that largely focus on the last ice age and the postglacial period to interpret genetic structure and argue that the southern peninsulas (Iberian, Italian and Balkan) were the main source areas for trees in central and northern Europe.