Monitoring and responding to signals of suicidal ideation in pragmatic clinical trials: Lessons from the GRACE trial for Chronic Sickle Cell Disease Pain.

Sickle cell disease (SCD) is a hemoglobin disorder and the most common genetic disorder that affects 100,000 Americans and millions worldwide. Adults living with SCD have pain so severe that it often requires opioids to keep it in control. Depression is a major global public health concern associated with an increased risk in chronic medical disorders, including in adults living with sickle cell disease (SCD). A strong relationship exists between suicidal ideation, suicide attempts, and depression. Researchers enrolling adults living with SCD in pragmatic clinical trials are obligated to design their methods to deliberately monitor and respond to symptoms related to depression and suicidal ideation. This will offer increased protection for their participants and help clinical investigators meet their fiduciary duties. This article presents a review of this sociotechnical milieu that highlights, analyzes, and offers recommendations to address ethical considerations in the development of protocols, procedures, and monitoring activities related to suicidality in depressed patients in a pragmatic clinical trial.

Developing an Implementation Blueprint for the NIH HEAL Initiative GRACE Trial: Perspectives on Acupuncture and Guided Relaxation for Chronic Sickle Cell Disease Pain.

Objective: This study aimed to explore perspectives of people living with sickle cell disease (SCD) and SCD clinic providers and staff about the use of acupuncture and guided relaxation for treating chronic SCD pain. Data obtained were to inform an implementation blueprint for an effectiveness implementation clinical trial (GRACE Trial) testing whether acupuncture or guided relaxation reduces chronic pain when compared with usual care. Design: Qualitative research design. Methods: We conducted 33 semistructured interviews with people with SCD and SCD clinic providers and staff. Interviews were transcribed and coded. A deductive content analysis process was used to identify themes. Results: Four themes were identified: Receptivity to Acupuncture and Guided Relaxation, Limited Awareness, Complementary and Integrative Health (CIH) Therapy Preference, and Access Barriers. Both patients and clinic providers and staff were open to the use of acupuncture and guided relaxation for chronic pain treatment. After learning about these CIH therapies, some patients expressed a preference for one therapy over the other. They also discussed their ability to successfully engage with each therapy. There is a need to dispel misconceptions about the therapies by increasing understanding of how each therapy is implemented and functions to reduce pain. We identified several potential barriers that might affect the success of the trial and future health system integration, including time, transportation, and technology. Conclusion: This study is one of the first to present perspectives of both patients with SCD and clinic providers and staff on the use of acupuncture and guided relaxation for chronic SCD pain. Stakeholders' early input and perspectives highlighted that they welcome nonpharmacological CIH therapies. Implementation of a clinical trial and future health system integration will require the addressing misinformation and identifying strategies to overcome access barriers. Clinical trial registration number: NCT04906447.

Hybrid effectiveness-implementation trial of guided relaxation and acupuncture for chronic sickle cell disease pain (GRACE): A protocol.

Background: People with sickle cell disease frequently use complementary and integrative therapies to cope with their pain, yet few studies have evaluated their effectiveness. The 3-arm, 3-site pragmatic Hybrid Effectiveness-implementation Trial of Guided Relaxation and Acupuncture for Chronic Sickle Cell Disease Pain (GRACE) has 3 priorities: (1) evaluate guided relaxation and acupuncture to improve pain control; (2) determine the most appropriate and effective treatment sequence for any given patient based on their unique characteristics; and (3) describe the processes and structures required to implement guided relaxation and acupuncture within health care systems. Methods: Participants (N = 366) are being recruited and randomized 1:1:1 to one of 2 intervention groups or usual care. The acupuncture intervention group receives 10 sessions over approximately 5 weeks. The guided relaxation intervention group receives access to video sessions ranging from 2 to 20 min each viewed daily over 5 weeks. The usual care group receives the standard of clinical care for sickle cell disease. Participants are re-randomized at 6 weeks depending on their pain impact score. Assessments occur at 6 weeks, 12 weeks, and 24 weeks. The primary outcome is the change in pain impact score and secondary measures include opioid use, anxiety, depression, sleep, pain catastrophizing, substance use, global impression of change, constipation, and hospitalizations. The GRACE study uses the Consolidated Framework for Implementation Research to plan, execute, and evaluate the associated implementation processes. Conclusion: The results from GRACE will represent a critical step toward improving management of pain affecting patients with sickle cell disease.ClinicalTrials.gov Identifier: NCT04906447.

Womb to womb: Maternal litter size and birth weight but not adult characteristics predict early neonatal death of offspring in the common marmoset monkey.

A singular focus on maternal health at the time of a pregnancy leaves much about perinatal mortality unexplained, especially when there is growing evidence for maternal early life effects. Further, lumping stillbirth and early neonatal death into a single category of perinatal mortality may obscure different causes and thus different avenues of screening and prevention. The common marmoset monkey (Callithrix jacchus), a litter-bearing nonhuman primate, is an ideal species in which to study the independent effects of a mother's early life and adult phenotypes on pregnancy outcomes. We tested two hypotheses in 59 marmoset pregnancies at the Southwest National Primate Research Center and the Barshop Institute for Longevity and Aging Studies. We explored 1) whether pregnancy outcomes were predicted independently by maternal adult weight versus maternal litter size and birth weight, and 2) whether stillbirth and early neonatal death were differentially predicted by maternal variables. No maternal characteristics predicted stillbirth and no maternal adult characteristics predicted early neonatal death. In univariate Poisson models, triplet-born females had a significantly increased rate of early neonatal death (IRR[se] = 3.00[1.29], p = 0.011), while higher birth weight females had a decreased rate (IRR[se] = 0.89[0.05], p = 0.039). In multivariate Poisson models, maternal litter size remained an independent predictor, explaining 13% of the variance in early neonatal death. We found that the later in the first week those neonates died, the more weight they lost. Together these findings suggest that triplet-born and low birth weight females have distinct developmental trajectories underlying greater rates of infant loss, losses that we suggest may be attributable to developmental disruption of infant feeding and carrying. Our findings of early life contributions to adult pregnancy outcomes in the common marmoset disrupt mother-blaming narratives of pregnancy outcomes in humans. These narratives hold that the pregnant person is solely responsible for pregnancy outcomes and the health of their children, independent of socioecological factors, a moralistic framing that has shaped clinical pregnancy management. It is necessary to differentiate temporal trajectories and causes of perinatal loss and view them as embedded in external processes to develop screening, diagnostic, and treatment tools that consider the full arc of a mother's lived experience, from womb to womb and beyond.

Long-Term Postpartum Cardiac Function and Its Association With Preeclampsia.

Background Preeclampsia is a prominent risk factor for long-term development of cardiovascular disease. Although existing studies report a strong correlation between preeclampsia and heart failure, the underlying mechanisms are poorly understood. One possibility is the glycoprotein growth factor activin A. During pregnancy, elevated activin A levels are associated with impaired cardiac global longitudinal strain at 1 year, but whether these changes persist beyond 1 year is not known. We hypothesized that activin A levels would remain increased more than 1 year after a preeclamptic pregnancy and correlate with impaired cardiac function. Methods and Results To test our hypothesis, we performed echocardiograms and measured activin A levels in women approximately 10 years after an uncomplicated pregnancy (n=25) or a pregnancy complicated by preeclampsia (n=21). Compared with women with a previously normal pregnancy, women with preeclampsia had worse global longitudinal strain (-18.3% versus -21.3%, P=0.001), left ventricular posterior wall thickness (0.91 mm versus 0.80 mm, P=0.003), and interventricular septal thickness (0.96 mm versus 0.81 mm, P=0.0002). Women with preeclampsia also had higher levels of activin A (0.52 versus 0.37 ng/mL, P=0.02) and activin/follistatin-like 3 ratio (0.03 versus 0.02, P=0.04). In a multivariable model, the relationship between activin A levels and worsening global longitudinal strain persisted after adjusting for age at enrollment, mean arterial pressure, race, and body mass index (P=0.003). Conclusions Our findings suggest that both activin A levels and global longitudinal strain are elevated 10 years after a pregnancy complicated by preeclampsia. Future studies are needed to better understand the relationship between preeclampsia, activin A, and long-term cardiac function.

The common marmoset monkey: avenues for exploring the prenatal, placental, and postnatal mechanisms in developmental programming of pediatric obesity.

Animal models have been critical in building evidence that the prenatal experience and intrauterine environment are capable of exerting profound and permanent effects on metabolic health through developmental programming of obesity. However, despite physiological and evolutionary similarities, nonhuman primate models are relatively rare. The common marmoset monkey ( Callithrix jacchus) is a New World monkey that has been used as a biomedical model for well more than 50 years and has recently been framed as an appropriate model for exploring early-life impacts on later health and disease. The spontaneous, multifactorial, and early-life development of obesity in the common marmoset make it a valuable research model for advancing our knowledge about the role of the prenatal and placental mechanisms involved in developmental programming of obesity. This paper provides a brief overview of obesity in the common marmoset, followed by a discussion of marmoset reproduction and placental characteristics. We then discuss the occurrence and utility of variable intrauterine environments in developmental programming in marmosets. Evidence of developmental programming of obesity will be given, and finally, we put forward future directions and innovations for including the placenta in developmental programming of obesity in the common marmoset.

Developmental origins of pregnancy loss in the adult female common marmoset monkey (Callithrix jacchus).

BACKGROUND: The impact of the intrauterine environment on the developmental programming of adult female reproductive success is still poorly understood and potentially underestimated. Litter size variation in a nonhuman primate, the common marmoset monkey (Callithrix jacchus), allows us to model the effects of varying intrauterine environments (e.g. nutrient restriction, exposure to male womb-mates) on the risk of losing fetuses in adulthood. Our previous work has characterized the fetuses of triplet pregnancies as experiencing intrauterine nutritional restriction. METHODOLOGY/PRINCIPAL FINDINGS: We used over a decade of demographic data from the Southwest National Primate Research Center common marmoset colony. We evaluated differences between twin and triplet females in the number of pregnancies they produce and the proportion of those pregnancies that ended in fetal loss. We found that triplet females produced the same number of total offspring as twin females, but lost offspring during pregnancy at a significantly higher rate than did twins (38% vs. 13%, p = 0.02). Regardless of their own birth weight or the sex ratio of the litter the experienced as fetuses, triplet females lost more fetuses than did twins. Females with a male littermate experienced a significant increase in the proportion of stillbirths. CONCLUSIONS/SIGNIFICANCE: These striking findings anchor pregnancy loss in the mother's own fetal environment and development, underscoring a "Womb to Womb" view of the lifecourse and the intergenerational consequences of development. This has important translational implications for understanding the large proportion of human stillbirths that are unexplained. Our findings provide strong evidence that a full understanding of mammalian life history and reproductive biology requires a developmental foundation.