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Individualized therapy trials: navigating patient care, research goals and ethics
‘Individualized therapy’ trials (sometimes called
n
-of-1 trials) use patients as their own controls to evaluate treatments. Here we divide such trials into three categories: multi-crossover trials aimed at individual patient management, multi-crossover trial series and pre–post trials. These trials all customize interventions for patients; however, the latter two categories also aim to inform medical practice and thus embody tensions between the goals of care and research that are typical of other types of clinical trials. In this Perspective, we discuss four domains where such tensions play out—clinical equipoise, informed consent, reporting and funding, and we provide recommendations for addressing each.
In this Perspective, the authors discuss the ethical challenges of individualized therapy (also called
n
-of-1) trials and argue that, although customized for the patient, these constitute ‘research’ nonetheless.
Journal Article
Batman and Robin. Volume 1, Born to kill
A shadowy figure emerges from Bruce Wayne's past. His name is NoBody, and he's not happy that Batman Incorporated is shining a light on his own shadowy war against evil.
Book
Is preclinical research in cancer biology reproducible enough?
The Reproducibility Project: Cancer Biology (RPCB) was established to provide evidence about reproducibility in basic and preclinical cancer research, and to identify the factors that influence reproducibility more generally. In this commentary we address some of the scientific, ethical and policy implications of the project. We liken the basic and preclinical cancer research enterprise to a vast 'diagnostic machine' that is used to determine which clinical hypotheses should be advanced for further development, including clinical trials. The results of the RPCB suggest that this diagnostic machine currently recommends advancing many findings that are not reproducible. While concerning, we believe that more work needs to be done to evaluate the performance of the diagnostic machine. Specifically, we believe three questions remain unanswered: how often does the diagnostic machine correctly recommend against advancing real effects to clinical testing?; what are the relative costs to society of false positive and false negatives?; and how well do scientists and others interpret the outputs of the machine?
Journal Article
The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model
Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.
Exposure at birth to maternal microbiota has significant effects on offspring health and development. Here, the authors validate a model where inoculation of mice at birth with human vaginal microbiota produces significant effects on offspring health that are further amplified by an unhealthy prenatal environment.
Journal Article
Cubital Tunnel Syndrome: Current Concepts
Purpose of ReviewCompressive neuropathy of the ulnar nerve across the elbow is a common diagnosis encountered frequently within a hand and upper extremity clinical practice. Appropriate and timely evaluation, diagnosis, objective testing, and evidence-based decisions regarding treatment options are paramount in the optimal care of the patient with this pathology. An understanding of current literature is critical in determining and understanding best practices.Recent FindingsA thorough review of the recent literature regarding physical examination, diagnostic testing, and nonoperative versus operative results was performed. Regarding physical examination, the glenohumeral internal rotation test and scratch collapse test are more effective and sensitive than traditional maneuvers such as Tinel’s testing and the elbow flexion test. Electrodiagnostic testing, magnetic resonance imaging, and ultrasound evaluation have all been shown to be effective in diagnosing cubital tunnel syndrome. However, no single test has proven itself to be superior. Nonoperative treatment can be successful for mild cases of cubital tunnel syndrome. Surgical release techniques comparing open with endoscopic release are equivocal, and in situ release versus transposition techniques show that transposition should not be performed routinely.SummaryThe diagnosis and treatment of cubital tunnel syndrome do not have a well-defined algorithm based on current literature. The treating physician must therefore utilize the available information to determine a diagnostic and treatment plan individualized to the patient. More rigorous scientific studies are needed to determine the most effective surgical approaches for cubital tunnel syndrome.
Journal Article
Maternal preconception stress produces sex-specific effects at the maternal:fetal interface to impact offspring development and phenotypic outcomes
Entering pregnancy with a history of adversity, including adverse childhood experiences and racial discrimination stress, is a predictor of negative maternal and fetal health outcomes. Little is known about the biological mechanisms by which preconception adverse experiences are stored and impact future offspring health outcomes. In our maternal preconception stress (MPS) model, female mice underwent chronic stress from postnatal days 28–70 and were mated 2 weeks post-stress. Maternal preconception stress dams blunted the pregnancy-induced shift in the circulating extracellular vesicle proteome and reduced glucose tolerance at mid-gestation, suggesting a shift in pregnancy adaptation. To investigate MPS effects at the maternal:fetal interface, we probed the mid-gestation placental, uterine, and fetal brain tissue transcriptome. Male and female placentas differentially regulated expression of genes involved in growth and metabolic signaling in response to gestation in an MPS dam. We also report novel offspring sex- and MPS-specific responses in the uterine tissue apposing these placentas. In the fetal compartment, MPS female offspring reduced expression of neurodevelopmental genes. Using a ribosome-tagging transgenic approach we detected a dramatic increase in genes involved in chromatin regulation in a PVN-enriched neuronal population in females at PN21. While MPS had an additive effect on high-fat-diet (HFD)-induced weight gain in male offspring, both MPS and HFD were necessary to induce significant weight gain in female offspring. These data highlight the preconception period as a determinant of maternal health in pregnancy and provides novel insights into mechanisms by which maternal stress history impacts offspring developmental programming. Summary Sentence Stress experienced prior to conception blunted maternal metabolic adaptation to pregnancy and altered the transcriptome at the maternal:fetal interface in a sex-specific manner, resulting in lasting changes in offspring brain development and growth. Graphical Abstract
Journal Article