Commercial landscape of noninvasive prenatal testing in the United States

Cell-free fetal DNA-based noninvasive prenatal testing (NIPT) could significantly change the paradigm of prenatal testing and screening. Intellectual property (IP) and commercialization promise to be important components of the emerging debate about clinical implementation of these technologies. We have assembled information about types of testing, prices, turnaround times, and reimbursement of recently launched commercial tests in the United States from the trade press, news articles, and scientific, legal, and business publications. We also describe the patenting and licensing landscape of technologies underlying these tests and ongoing patent litigation in the United States. Finally, we discuss how IP issues may affect clinical translation of NIPT and their potential implications for stakeholders. Fetal medicine professionals (clinicians and researchers), genetic counselors, insurers, regulators, test developers, and patients may be able to use this information to make informed decisions about clinical implementation of current and emerging noninvasive prenatal tests. © 2013 John Wiley & Sons, Ltd.     

The value and limitations of using predetermined criteria in decision making for maternal-fetal interventions

Maternal-fetal interventions—such as prenatal fetal myelomeningocele (MMC) repair—are at the forefront of clinical innovation within maternal-fetal medicine, pediatric surgery, and neonatology. Many centers determine eligibility for innovative procedures using pre-determined inclusion and exclusion criteria based on seminal studies, for example, the “Management of Myelomeningocele Study” for prenatal MMC repair. What if a person's clinical presentation does not conform to predetermined criteria for maternal-fetal intervention? Does changing criteria on a case-by-case basis (i.e., ad hoc) constitute an innovation in practice and flexible personalized care or transgression of commonly held standards with potential negative consequences? We outline principle-based, bioethically justified answers to these questions using fetal MMC repair as an example. We pay special attention to the historical origins of inclusion and exclusion criteria, risks and benefits to the pregnant person and the fetus, and team dynamics. We include recommendations for maternal-fetal centers facing these questions.     

美、日土壤污染防治法律度对中国土壤立法的启示

目前中国土壤污染问题日趋严重。尽管中国现行的法律体系存在一些有关土壤污染防治的规定,但仍存在一定的局限性,中国目前还没有专门的《土污染防治法》,从而不能为中国土壤污染的防治工作提供有力地法律支撑和法律保障。本文在分析美国、日本有关土壤污染防治立法的基础上,就中国土壤污染防治立法提出了几点建议。     

Climate change, aerobiology, and public health in the Northeast United States

The epidemiological implications with respect to climate change and public health (e.g., shifts in disease vectors) are beginning to be acknowledged. Less recognized however, are the potential links between climate, plant biology and public health. In addition to being affected by climate (e.g., temperature determines plant range), carbon dioxide (CO₂) represents the raw material needed for photosynthesis and its rapid increase in the atmosphere is expected to stimulate plant growth. While there are a number of means by which plant biology intersects with human health (e.g., plant nutrition), one of the most widely recognized is aerobiology; specifically, the ability of plants to both produce pollen and to serve as a substrate for molds/fungi (e.g., sporulation). The current review represents an initial attempt to coalesce what is known regarding the likely impacts of climate/CO₂ on plant pollen/fungal spores and associated allergic disease that are, or could be, specific to the Northeast United States. Although the current results indicate a number of potentially unfavorable effects, we wish to stress that the current data are based on a small number of experiments. Additional data are crucial to both reduce epidemiological uncertainty and to derive a robust set of mitigation / adaptation strategies.     

Negotiated environmental and occupational health and safety agreements in the United States: lessons for policy

The interest in so-called voluntary approaches to supplement or replace formal environmental, or occupational health and safety regulation has taken on new importance in both Europe and the United States. These approaches fall into two sharp divisions: (1) industry-initiated codes of good practice focusing on environmental management systems or performance goals, and (2) negotiated agreements between government and individual firms or industry sector trade associations focusing on regulation or compliance. This paper addresses the latter.In the United States, the motivations behind negotiated agreements are manifold and sometimes contradictory including desires (1) to facilitate the achievement of legislated or mandatory environmental goals by introducing flexibility and cost-effective compliance measures, (2) to negotiate levels of compliance (standards) fulfilling legislative mandates, (3) to negotiate legal definitions of Best Available Technology and other technology-based requirements, and (4) to weaken environmental initiatives. Efforts in furtherance of negotiated agreements have thus been greeted with mixed results by the various stakeholders. In the context of an anti-regulatory climate in the United States, the Administrative Procedures Act has been amended to allow “negotiated rulemaking” in achieving regulatory agency mandates. However, even before this legal innovation, regulatory agencies have been negotiating regulations. Independent of this legal avenue, negotiated compliance with industry associations is being fostered through the Environmental Protection Agency's (EPA's) “Commonsense Initiative” and with individual firms through “EPA's Project XL”, again with mixed reception.The proposed paper describes and analyses negotiated agreements in the United States in the context of (1) EPA efforts to ensure environmental protection and (2) the Occupational Safety and Health Administration efforts to ensure worker health and safety. These agreements can be described according to the following taxonomy: (a) Negotiated regulation (either preceding formal regulation or as a substitute for formal regulation); (b) Negotiated compliance (implementing regulation or informal agreements) (i) the means and timetable for coming into compliance with emission, effluent, or concentration requirements (ii) negotiation in the context of an enforcement action in which the firm is out of legal compliance (for example, encouraging cleaner production through the leveraging of penalty reductions).The criteria for evaluation include: environmental or health and safety outcomes, effects on stimulating technological change, time for development (time to completion)/implementation (likelihood of court challenge), stakeholder influence (ability of large firms to dominate outcome, environmentalists–industry, or labour–management balance of power),and administrative features.     

美国控制空气污染物的对策

城市大气污染是世界各国面临的最大挑战之一,如今已被各国政府高度重视。如何更好的防止大气污染,减轻其危害的影响,是当今重大而紧迫的课题。自20世纪70年代以来,中国政府加强了对环保工作的力度,颁布并采取了一些大气污染政策和措施,收到一定的效果,但从总体上看,环境污染和破坏还没有完全被控制。美国历史上也曾经历过严重的大气污染。但通过一系列防治法规体系的控制,美国的空气质量已得到明显的改善。文章详细介绍了美国控制空气污染的立法及对策,并对其特点进行分析,重点介绍了美国控制有毒空气污染物的对策,比较了美国控制有毒空气污染物的法规与我国法规的差异,以期为有关部门制定我国的空气污染控制对策提供支持。     

对美军装备采购合同管理的分析与借鉴

装备采购合同管理是装备采购管理的重要组成部分,是军方依法执行合同、实现合同权利的主要手段。对美军装备合同管理进行分析,进而提出若干有益于我军装备采购合同管理的借鉴意见。     

Fetal therapy: practical ethical considerations

Progress in prenatal diagnosis can lead to the diagnosis of severe fetal abnormalities for which natural history anticipates a fatal outcome or the development of severe disability despite optimal postnatal care. Intrauterine therapy can be offered in these selected cases. Prenatal diagnosis is the only field of medicine in which termination is an option in the management of severe diseases. Fetal therapy has therefore developed as an alternative to fatalist expectant prenatal management as well as to termination of pregnancy (TOP). There are few standards of fetal care that have gone beyond the stage of equipoise and even fewer have been established based on appropriate studies comparing pre- and postnatal care. Several ethical questions are being raised as fetal surgery develops, including basic Hippocratic principles of patients' autonomy and doctors' duty of competence moving the boundaries between experimental surgery, therapeutic innovation and standard care. In addition, the technical success of a fetal intervention can only rarely fully predict the postnatal outcome. Managing uncertainty regarding long-term morbidity and the possibility for fetal therapy to change the risk of perinatal death into that of severe handicap remains a critical factor affecting women's choice for TOP as an alternative to fetal therapy. Copyright © 2011 John Wiley & Sons, Ltd.     

Changing trends in carrier screening for genetic disease in the United States

Genetic disease is the leading cause of infant death in the United States, accounting for approximately 20% of annual infant mortality. Advances in genomic medicine and technological platforms have made possible low cost, pan-ethnic expanded genetic screening that enables obstetric care providers to offer screening for over 100 recessive genetic diseases. However, the rapid integration of genomic medicine into routine obstetric practice has raised some concerns about the practical implementation of such testing. These changing trends in carrier screening, along with concerns and potential solutions, will be addressed. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.     

Pregnancy-related pharmacokinetics and antimicrobial prophylaxis during fetal surgery,cefazolin and clindamycin as examples

Antimicrobial prophylaxis during surgery aims to prevent post-operative site infections. For fetal surgery, this includes the fetal and amniotic compartments. Both are deep compartments as drug equilibrium with maternal blood is achieved relatively late. Despite prophylaxis, chorio-amnionitis or endometritis following ex utero intrapartum treatment or fetoscopy occur in 4.13% and 1.45% respectively of the interventions. This review summarizes the observations on two commonly administered antimicrobials (cefazolin, clindamycin) for surgical prophylaxis during pregnancy, with emphasis on the deep compartments. For both compounds, antimicrobial exposure is on target when we consider the maternal and fetal plasma compartment. In contrast, amniotic fluid concentrations-time profiles display a delayed and much more blunted pattern, behaving as deep compartment. For cefazolin, there are data that document further dilution in the setting of polyhydramnios. Along this deep compartment concept, there is some accumulation during repeated administration, modeled for cefazolin and observed for clindamycin. The relative underexposure to antimicrobials in amniotic fluid may be reflected in the pattern of maternal-fetal complications after fetal surgery, and suggest that antimicrobial prophylaxis practices for fetal surgery should be reconsidered. Further studies should be designed by a multidisciplinary team (fetal surgeons, clinical pharmacologists and microbiologists) to facilitate efficient evaluation of antimicrobial prophylaxis.     

China, the United States and technology cooperation on climate control

The U.S. and China are the world's largest and second largest CO₂ emitters, respectively, and to what extent the U.S. and China get involved in combating global climate change is extremely important both for lowering compliance costs of climate mitigation and adaptation and for moving international climate negotiations forward. While it is unavoidable that China will take on commitments at some specific point of time in the future, this paper has argued that the proposal for joint accession by the U.S. and China is not a way forward. For various reasons, such a proposal is in the U.S. interest, but is not in the interest of China. Given the U.S. political reality and institutional settings on the one hand and China's over-riding concern about economic growth and poverty reduction on the other, the two countries are unlikely to take on emissions caps under an international regime, at least for the time being. Therefore, we need to explore the area where cooperation between the two countries to address climate change seems best. The research, development and deployment of clean technology is the area that is in the best interests of the two countries. The U.S. has adopted a technology-oriented approach to climate issues, and has launched the four multilateral initiatives on technology cooperation and the Asia Pacific Partnership for Clean Development and Climate (APP). China has participated in all these U.S.-led initiatives, and is a partner to the APP. Strengthened technology cooperation between the two countries through these initiatives and the APP has led some tangible benefits. However, it should be pointed out that while technology is a critical ingredient in a climate policy package, efforts such as the APP can only be part of the solution. They alone cannot ensure that best available technologies are always deployed in the marketplace, and that new technologies will roll out at the pace and on the scale that we need. In order to have such technology-oriented approach to play a full role, we do need a coordinated policy framework agreed via the Kyoto Protocol or a follow-up regime or the parent United Nations Framework Convention.     

Inclusion of sex chromosomes in noninvasive prenatal testing in Asia,Australia, Europe and the USA: A survey study

Objective

To examine the extent to which sex chromosomes are included in current noninvasive prenatal testing (NIPT) and the reporting practices with respect to fetal chromosomal sex and sex chromosome aberrations (SCAs), in addition to an update on the general implementation of NIPT.

Method

A questionnaire addressing the research objectives was distributed by email to fetal medicine and clinical genetics experts in Asia, Australia, Europe and the USA.

Results

Guidelines on NIPT are available in the majority of the included countries. Not all existing guidelines address reporting of fetal chromosomal sex and SCAs. In most settings, NIPT frequently includes sex chromosomes (five Australian states, China, Hong Kong, Israel, Singapore, Thailand, USA and 23 of 31 European countries). This occurs most often by default or when parents wish to know fetal sex. In most settings, a potential SCA is reported by stating the risk hereof as “low” or “high” and/or by naming the SCA. Less than 50% of all pregnant women receive NIPT according to respondents from three Australian states, China, Israel, Singapore, Thailand and 24 of 31 European countries. However, this percentage, the genomic coverage of NIPT and its application as primary or secondary screening vary by setting.

Conclusion

In most of the studied countries/states, NIPT commonly includes sex chromosomes. The reporting practices concerning fetal chromosomal sex and SCAs are diverse and most commonly not addressed by guidelines. In general, NIPT is variably implemented across countries/states.     

The making of fetal surgery

Fetal diagnosis prompts the question for fetal therapy in highly selected cases. Some conditions are suitable for in utero surgical intervention. This paper reviews historically important steps in the development of fetal surgery. The first invasive fetal intervention in 1963 was an intra-uterine blood transfusion. It took another 20 years to understand the pathophysiology of other candidate fetal conditions and to develop safe anaesthetic and surgical techniques before the team at the University of California at San Francisco performed its first urinary diversion through hysterotomy. This procedure would be abandoned as renal and pulmonary function could be just as effectively salvaged by ultrasound-guided insertion of a bladder shunt. Fetoscopy is another method for direct access to the feto-placental unit. It was historically used for fetal visualisation to guide biopsies or for vascular access but was also abandoned following the introduction of high-resolution ultrasound. Miniaturisation revived fetoscopy in the 1990s, since when it has been successfully used to operate on the placenta and umbilical cord. Today, it is also used in fetuses with congenital diaphragmatic hernia (CDH), in whom lung growth is triggered by percutaneous tracheal occlusion. It can also be used to diagnose and treat urinary obstruction. Many fetal interventions remain investigational but for a number of conditions randomised trials have established the role of in utero surgery, making fetal surgery a clinical reality in a number of fetal therapy programmes. The safety of fetal surgery is such that even non-lethal conditions, such as myelomeningocoele repair, are at this moment considered a potential indication. This, as well as fetal intervention for CDH, is currently being investigated in randomised trials. Copyright © 2010 John Wiley & Sons, Ltd.     

In utero therapy for lower urinary tract obstruction

Lower urinary tract obstruction has a significant impact on neonatal and child health. Pulmonary hyperplasia and renal impairment could be direct or indirect consequences of this condition leading to significant morbidity and mortality. Evaluation of fetuses with suspected lower urinary tract obstruction is performed not only to confirm the diagnosis but also to assess renal prognosis. Ultrasound examination and urinary analysis aid in the evaluation of these fetuses. The decision to perform fetal intervention in these cases is a difficult one. Vesico‒amniotic fetal shunting, open fetal surgery and more recently endoscopic fetal surgery for this condition are available as possible modalities of fetal intervention. Case selection for fetal intervention is extremely important in order to both avoid unnecessary intervention in those unlikely to survive, and also to avoid procedure related complications in fetuses likely to do well without intervention. Vesico‒amniotic shunting has the advantage of bypassing the obstruction, however it is often associated with complications. Open fetal surgery is not usually recommended because of the complications and high fetal loss rate. Endoscopic surgery to visualise and treat the cause of lower urinary tract obstruction has been tried. Fetal endoscopic surgery is in its infancy and endoscopic procedures are limited to a few groups. This current review addresses evaluation, case selection and therapeutic options for lower urinary tract obstruction in utero. It also discusses the limited data against which the efficacy of the various options can be assessed. The current state of fetal intervention is detailed in the present review. Copyright © 2001 John Wiley & Sons, Ltd.     

International Society for Prenatal Diagnosis 2022 DEBATE: There should be formal accreditation and ongoing quality assurance/review for units offering fetal therapy that includes public reporting of outcomes

The field of fetal therapy has so far escaped from formal accreditation and quality control. Despite that, current published evidence shows that outcomes of interventions in younger fetal therapy centers are similar to what is achieved in more experienced centers and outcomes of interventions have improved over time. The question however remains what is not being published and what should be the standard of care, given the lack of level 1 evidence from randomized controlled trials for many interventions. Formal collaborative networks such as NAFTnet and others allow for anonymized benchmarking of center outcomes, without publicly shaming (and financially punishing) underperforming centers. Large registries also allow for tracking of rare complications and may result in improved patient outcomes over time. Core outcome sets, which could serve as a basis for outcome reporting, are available for some conditions, but certainly not for all, resulting in communication difficulties between centers. Formal accreditation, quality control, and outcome reporting are hard to implement, expensive, and may result in decreasing access to care by pushing smaller centers out of the market. Despite the existing difficulties, international societies have committed to quality improvement, and fetal therapy programs are strongly recommended to participate in voluntary outcome tracking.     

Dysplastic and polycystic kidneys: diagnosis,associations and management

Cystic and bright kidneys can pose a significant diagnostic dilemma when discovered as an incidental finding at the time of a routine fetal ultrasound scan. There are diverse aetiologies with equally variable implications for the prognosis in the affected fetus, and for future pregnancies. Accurate antenatal diagnosis in the absence of any positive family history is often not possible and a team approach to management (to include the fetal medicine specialist, paediatric nephrologist or urologist, geneticists and in some cases, pathologist) is essential. In this review we will attempt to describe the embryology and aetiology of these conditions and suggest an approach to management. Copyright © 2001 John Wiley & Sons, Ltd.     

Framing the Long-Term <Emphasis Type="Italic">In Situ</Emphasis> Liability Issue for Geologic Carbon Storage in the United States

This paper examines how legal standards of liability may apply to geologic carbon storage. The liability regime governing geologic carbon storage will shape the technology's cost-effectiveness and overall attractiveness. We classify potential sources of liability into operational, in situ, and climate liability. As a first step, we explore in situ liability in the United States. After summarizing legal standards of liability including negligence, breach of implied warranty, strict liability, and product liability, we discuss how liability may be addressed at the level of the federal government, state government, industry, and the firm. Finally, we address the implications of judicial treatment of liability for carbon storage, including the apportionment of liability and the adequacy of current regulations.     

A comprehensive review of climate adaptation in the United States: more than before, but less than needed

We reviewed existing and planned adaptation activities of federal, tribal, state, and local governments and the private sector in the United States (U.S.) to understand what types of adaptation activities are underway across different sectors and scales throughout the country. Primary sources of review included material officially submitted for consideration in the upcoming 2013 U.S. National Climate Assessment and supplemental peer-reviewed and grey literature. Although substantial adaptation planning is occurring in various sectors, levels of government, and the private sector, few measures have been implemented and even fewer have been evaluated. Most adaptation actions to date appear to be incremental changes, not the transformational changes that may be needed in certain cases to adapt to significant changes in climate. While there appear to be no one-size-fits-all adaptations, there are similarities in approaches across scales and sectors, including mainstreaming climate considerations into existing policies and plans, and pursuing no- and low-regrets strategies. Despite the positive momentum in recent years, barriers to implementation still impede action in all sectors and across scales. The most significant barriers include lack of funding, policy and institutional constraints, and difficulty in anticipating climate change given the current state of information on change. However, the practice of adaptation can advance through learning by doing, stakeholder engagements (including “listening sessions”), and sharing of best practices. Efforts to advance adaptation across the U.S. and globally will necessitate the reduction or elimination of barriers, the enhancement of information and best practice sharing mechanisms, and the creation of comprehensive adaptation evaluation metrics.     

Constructing collaborative communities of researchers in the environmental domain. A case study of interdisciplinary research between legal scholars and policy analysts

The article offers an analysis of the interactions between legal and policy science researchers within a European project on flood risk management using a “Policy Arrangement Approach” (PAA). While interdisciplinary research is increasingly becoming a ‘must’ in environmental governance, under what conditions is cooperation possible and desirable? Our analysis shows that the PAA is not mobilized as an interdisciplinary method, but offers a framework for researchers from different disciplines to learn to work together on a subject such as flooding, requiring interdisciplinary insights. The paper shows the steps that are progressively put in place to reach a common language and reformulate issues by benefitting from each other’s view and approaches. The article concludes by drawing attention to new means of knowledge production relating to so-called “messy” or “wicked” problems, such as environmental issues. Within this framework, interdisciplinary work is not considered to be a pre-condition for the study, but rather the result of the research process itself. The analysis draws attention to the actual (working) conditions established to create an interdisciplinary community of flooding practices by challenging disciplinary borders.     

Artificial intelligence,fetal echocardiography,and congenital heart disease

There has been a recent explosion in the use of artificial intelligence (AI), which is now part of our everyday lives. Uptake in medicine has been more limited, although in several fields there have been encouraging results showing excellent performance when AI is used to assist in a well-defined medical task. Most of this work has been performed using retrospective data, and there have been few clinical trials published using prospective data. This review focuses on the potential uses of AI in the field of fetal cardiology. Ultrasound of the fetal heart is highly specific and sensitive in experienced hands, but despite this there is significant room for improvement in the rates of prenatal diagnosis of congenital heart disease in most countries. AI may be one way of improving this. Other potential applications in fetal cardiology include the provision of more accurate prognoses for individuals, and automatic quantification of various metrics including cardiac function. However, there are also ethical and governance concerns. These will need to be overcome before AI can be widely accepted in mainstream use. It is likely that a familiarity of the uses, and pitfalls, of AI will soon be mandatory for many healthcare professionals working in fetal cardiology.