Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis ...transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
After newborn screening has been completed, many states retain residual newborn screening dried blood samples for various purposes, including program evaluation, quality assurance, and biomedical ...research. The extent to which states possess legal authority to retain residual dried blood samples (DBS) and use them for purposes unrelated to newborn screening is unclear.
The purpose of this study was to evaluate state laws regarding the retention and use of DBS.
State statutes and regulations related to newborn screening of all 50 states plus the District of Columbia were accessed online between November 2008 and December 2009 and reviewed by 2 independent reviewers to determine the extent to which the retention and use of DBS were addressed.
The retention or use of DBS has not been addressed in 18 states. In 4 states, DBS becomes state property. Eight states require that parents be provided information regarding the retention of DBS. Parents in 5 states may request the destruction of their child's residual sample. Parental consent is required under certain circumstances to release DBS for research in 6 states. One state prohibits DBS from being used for research purposes.
States have wide variability in their policies regarding the retention and use of DBS. Many states have not addressed key issues, and some states that retain DBS may be acting outside the scope of their legal authority. The lack of transparency on the part of states in retaining DBS may undermine public trust in state newborn screening programs and the research enterprise.
The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis ...transmembrane conductance regulator (CFTR) function.
To derive CFTR function of a variety of
genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators.
CFTR function assigned to 226 unique
genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Cross-sectional FEV
% predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies.
CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV
% predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype.
Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.
National guidelines recommend that maternity systems provide patient-centered access to immediate postpartum long-acting reversible contraception (ie, insertion of an intrauterine device or implant ...during the delivery hospitalization). Hospitals face significant barriers to offering these services, and efforts to improve peripartum contraception care quality have met with mixed success. Implementation toolkits—packages of resources and strategies to facilitate the implementation of new services—are a promising approach for guiding clinical practice change.
This study aimed to develop a theory-informed toolkit, evaluate the feasibility of toolkit-based implementation of immediate postpartum long-acting reversible contraception care in a single site, and refine the toolkit and implementation process for future effectiveness testing.
We conducted a single-site feasibility study of the toolkit-based implementation of immediate postpartum contraception services at a large academic medical center in 2017 to 2020. Based on previous qualitative work, we developed a theory-informed implementation toolkit. A stakeholder panel selected toolkit resources to use in a multicomponent implementation intervention at the study site. These resources included tools and strategies designed to optimize implementation conditions (ie, implementation leadership, planning, and evaluation; the financial environment; engagement of key stakeholders; patient needs; compatibility with workflow; and clinician and staff knowledge, skills, and attitudes). The implementation intervention was executed from January 2018 to April 2019. Study outcomes included implementation outcomes (ie, provider perceptions of the implementation process and implementation tools assessed via online provider survey) and healthcare quality outcomes (ie, trends in prenatal contraceptive counseling, trends in immediate postpartum long-acting reversible contraceptive utilization both ascertained by institutional administrative data, and the patient experience of contraceptive care assessed via serial, cross-sectional, online patient survey items adapted from the National Quality Forum-endorsed, validated Person-Centered Contraceptive Counseling measure).
In the implementation process, among 172 of 401 eligible clinicians (43%) participating in surveys, 70% were “extremely” or “somewhat” satisfied with the implementation process overall. In the prenatal contraceptive counseling, among 4960 individuals undergoing childbirth at the study site in 2019, 1789 (36.1%) had documented prenatal counseling about postpartum contraception. Documented counseling rates increased overall throughout 2019 (Q1, 12.5%; Q4, 51.0%) but varied significantly by clinic site (Q4, range 30%–79%). Immediate postpartum long-acting reversible contraception utilization increased throughout the study period (before implementation, 5.46% of deliveries; during implementation, 8.95%; after implementation, 8.58%). In the patient experience of contraceptive care, patient survey respondents (response rate, 15%–29%) were largely White (344/425 81%) and highly educated (309/425 73% with at least a 4-year college degree), reflecting the study site population. Scores were poor across settings, with modest improvements in the hospital setting from 2018 to 2020 (prenatal visits, 67%–63%; hospitalization, 45%–58%; outpatient after delivery, 69%–65%). Based on these findings, toolkit refinements included additional resources designed to routinize prenatal contraceptive counseling and support a more patient-centered experience of contraceptive care.
A toolkit-based process to implement immediate postpartum long-acting reversible contraceptive services at a single academic center was associated with high acceptability but mixed healthcare quality outcomes. Toolkit resources were added to optimize counseling rates and the patient experience of contraceptive care. Future research should formally test the effectiveness of the refined toolkit in a multisite, prospective trial.
•Per the Guide for Authors (https://www.elsevier.com/journals/journal-of-cystic-fibrosis/1569-1993/guide-for-authors), highlights are for full research articles only. Please let us know if this is ...incorrect and if we should submit them with this Short Communication.
In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants.
This paper discusses attitudes and opinions of a diverse group of participants toward the retention and use of residual newborn blood samples for research. Data were drawn from focus groups based in ...six states in the USA, and results provide support for the retention and use of residual newborn blood samples for research when parental permission is asked beforehand. However, there were a number of concerns that also warrant attention for the development of policy and maintaining trust with the public, such as timing of permission, use of samples already stored, level of personal control of sample use and education. The results demonstrate the complexity of the topic and the ethical ambiguities associated with the retention and use of residual newborn blood samples.
► Residual newborn blood samples could serve as a valuable source for biomedical research but public support is essential. ► Results indicate that the US public is supportive of research with residual newborn blood samples when permission is asked. ► A number of concerns were identified that should be addressed for the development of policies for the retention and use of residual newborn samples.
Background Revision ulnar collateral ligament reconstruction remains a challenging problem. The objective of this study was to biomechanically
evaluate an ulnar collateral ligament reconstruction ...technique using a suspension button fixation technique that can be used
even in the case of ulnar cortical bone loss.
Hypothesis An ulnar suspension fixation technique for ulnar collateral ligament reconstruction can restore elbow kinematics and demonstrate
failure strength comparable to that of currently available techniques.
Study Design Controlled laboratory study.
Methods Nine pairs of cadaveric elbows were dissected free of soft tissue and potted. After simulating ulnar cortical bone loss,
ulnar collateral ligament reconstruction was performed in 1 elbow of each pair using palmaris longus autograft and a 30-mm
RetroButton suspended from the far (lateralmost) ulnar cortex. A docking technique was used for humeral fixation of the graft.
Elbow valgus angle was quantified using a Microscribe 3DLX digitizer at multiple elbow flexion angles. Valgus angle was measured
with the ulnar collateral ligament intact, transected, and reconstructed. In addition, load-to-failure testing was performed
in 1 elbow of each pair.
Results Release of the ulnar collateral ligament caused a significant increase in valgus angle at each flexion angle tested ( P < .002). Reconstructed elbows demonstrated no significant differences in valgus angle from the intact elbow at all flexion
angles tested. Load-to-failure tests showed that reconstructed elbows had an ultimate torque (10.3 ± 5.7 N·m) significantly
less than intact elbows (26.4 ± 10.6 N·m) ( P = .001).
Conclusion Ulnar collateral ligament reconstruction using a suspension button fixation technique reliably restored elbow kinematics
to the intact state. Load-to-failure testing demonstrated comparable fixation strength to several historic controls of primary
reconstruction techniques despite the simulated ulnar cortical bone loss.
Clinical Relevance Ulnar collateral ligament reconstruction using a suspension button fixation technique can be considered in the case of ulnar
cortical bone loss in a primary or revision setting.
Advances in genomics are contributing to the development of more effective, personalized approaches to the prevention and treatment of infectious diseases. Genetic sequencing technologies are ...furthering our understanding of how human and pathogen genomic factors - and their interactions - contribute to individual differences in immunologic responses to vaccines, infections and drug therapies. Such understanding will influence future policies and procedures for infectious disease management. With the potential for tailored interventions for particular individuals, populations or subpopulations, ethical, legal and social implications (ELSIs) may arise for public health and clinical practice. Potential considerations include balancing health-related benefits and harms between individuals and the larger community, minimizing threats to individual privacy and autonomy, and ensuring just distribution of scarce resources. In this Opinion, we consider the potential application of pathogen and host genomic information to particular viral infections that have large-scale public health consequences but differ in ELSI-relevant characteristics such as ease of transmission, chronicity, severity, preventability and treatability. We argue for the importance of anticipating these ELSI issues in advance of new scientific discoveries, and call for the development of strategies for identifying and exploring ethical questions that should be considered as clinical, public health and policy decisions are made.
A coalition conference of acute resuscitation researchers was held to discuss the feasibility of applying current federal research regulations regarding informed consent to the emergency setting. ...This article presents consensus recommendations for regulatory changes for consent in emergency research.
Representatives from the Society for Academic Emergency Medicine and the American Heart Association identified several professional organizations as stakeholders in this issue, including research, clinical, bioethics, legal, and patient advocacy groups. The Office for Protection From Research Risks (OPRR), the Food And Drug Administration (FDA), and staff from specific legislative offices were also invited to observe. Forty-three participants attended, including representatives from 12 professional organizations, five medical institutions, and the FDA and OPRR. This was a closed meeting. Participants were self-funded or sponsored by their professional organizations.
Before the meeting, a draft of a position statement was developed by the conference organizers based on the current literature and discussions with experts in the field. This draft, copies of the current federal research regulations, and supporting articles were distributed before the conference.
Participants rotated through moderated discussion sessions to comment on subsections of the draft. Following discussion, a working draft was developed and distributed to each participant and represented organizational board for final review. All comments were considered in the final version of the document.
We believe there are circumstances when it is not feasible to obtain prospective or proxy consent for enrollment into an emergency research protocol. In these circumstances, patients are vulnerable, not only to research risks, but also to being denied potentially beneficial therapy when there is no known effective treatment for their life-threatening condition. We offer recommendations that should be met when the critical nature of the illness or injury or the need to apply an investigational therapy rapidly precludes prospective consent for participation in emergency research.
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