Facing Our History-Building an Equitable Future.

This report is the product of a major year-long initiative to acknowledge and reckon with past injustice, as well as progress toward justice, within the American Society of Human Genetics (ASHG) and the broader field of human genetics. Approved by the ASHG Board of Directors and launched in 2021, the initiative was sparked by the social and racial reckonings in 2020. The ASHG Bboard of Directors asked ASHG to acknowledge and provide examples of how human genetics theories and knowledge "have been used to feed and justify racism, eugenics, and other systemic forms of injustice, and to focus specifically on examples of ASHG's role in fostering or failing to rebuke harms and on steps the Society could take to address findings." The initiative was undertaken with support and input from an expert panel of human geneticists, historians, clinician-scientists, equity scholars, and social scientists and included a research and environmental scan, four expert panel meetings, and a community dialogue as its main activities.

A Graded Approach to Intravenous Dextrose for Neonatal Hypoglycemia Decreases Blood Glucose Variability, Time in the Neonatal Intensive Care Unit, and Cost of Stay.

OBJECTIVE: To determine associations between a graded approach to intravenous (IV) dextrose treatment for neonatal hypoglycemia and changes in blood glucose (BG), length of stay (LOS), and cost of care. STUDY DESIGN: Retrospective cohort study of 277 infants born at ≥35 weeks of gestation in an urban academic delivery hospital, comparing the change in BG after IV dextrose initiation, neonatal intensive care unit (NICU) LOS, and cost of care in epochs before and after a hospital protocol change. During epoch 1, all infants who needed IV dextrose for hypoglycemia were given a bolus and started on IV dextrose at 60 mL/kg/day. During epoch 2, infants received IV dextrose at 30 or 60 mL/kg/day based on the degree of hypoglycemia. Differences in BG outcomes, LOS, and cost of hospital care between epochs were compared using adjusted median regression. RESULTS: In epoch 2, the median (IQR) rise in BG after initiating IV dextrose (19 [10, 31] mg/dL) was significantly lower than in epoch 1 (24 [14,37] mg/dL; adjusted ß = -6.0 mg/dL, 95% CI -11.2, -0.8). Time to normoglycemia did not differ significantly between epochs. NICU days decreased from a median (IQR) of 4.5 (2.1, 11.0) to 3.0 (1.5, 6.5) (adjusted ß = -1.9, 95% CI -3.0, -0.7). Costs associated with NICU hospitalization decreased from a median (IQR) $14 030 ($5847, $30 753) to $8470 ($5650, $19 019) (adjusted ß = -$4417, 95% CI -$571, -$8263) after guideline implementation. CONCLUSIONS: A graded approach to IV dextrose was associated with decreased BG lability and length and cost of NICU stay for infants with neonatal hypoglycemia.

Finding the Gaps in Retesting for Chlamydia and Gonorrhea: Differences Across High-Volume Testing Departments in an Urban Health Care Setting.

BACKGROUND: The Centers of Disease Control and Prevention guidelines recommend that all patients be retested 3 months after a positive chlamydia (CT) or gonorrhea (GC) result. However, retest rates are generally low, and only a quarter of patients return to clinic for retesting. This analysis explored retesting patterns in a high sexually transmitted infection (STI)/human immunodeficiency virus (HIV)-risk setting to illuminate gaps in adherence to guideline recommendations. METHODS: Retrospective chart data from a large urban safety-net institution were analyzed descriptively. Patients who received a positive CT/GC test from January to February 2017 were followed up for at least 4 months to assess if retesting occurred within approximately 3 months. RESULTS: Our sample of 207 patients was primarily non-Hispanic Black (92.8%), younger than 25 years (63.3%) and women (60.4%). Over half had been initially diagnosed with CT, one-third with GC, and one-tenth with both CT and GC. Eighty-nine (43.0%) patients were retested during the observed period; mean time between tests was 2.7 months. Retesting was most common in infectious diseases/HIV primary care (73.6%) and obstetrics/gynecology (44.9%). Patients who were first diagnosed in emergency medicine were significantly less likely to be retested. Retested patients included a large number of HIV-positive men (31 of 89 total) and pregnant women (23 of 54 women). CONCLUSIONS: Forty-three percent of patients were retested within approximately 3 months of their initial positive CT/GC diagnosis, exceeding previously published rates. Nonetheless, in light of the growing STI epidemic, health care systems should prioritize retesting across high-volume testing specialties, rethink retesting models, and facilitate referrals to ensure that patients receive guideline-recommended, comprehensive STI care.

Purkinje cells derived from TSC patients display hypoexcitability and synaptic deficits associated with reduced FMRP levels and reversed by rapamycin.

Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC. Our results show that hiPSC-derived PCs from patients with pathogenic TSC2 mutations displayed mTORC1 pathway hyperactivation, defects in neuronal differentiation and RNA regulation, hypoexcitability and reduced synaptic activity when compared with those derived from controls. Our gene expression analyses revealed downregulation of several components of fragile X mental retardation protein (FMRP) targets in TSC2-deficient hiPSC-PCs. We detected decreased expression of FMRP, glutamate receptor δ2 (GRID2), and pre- and post-synaptic markers such as synaptophysin and PSD95 in the TSC2-deficient hiPSC-PCs. The mTOR inhibitor rapamycin rescued the deficits in differentiation, synaptic dysfunction, and hypoexcitability of TSC2 mutant hiPSC-PCs in vitro. Our findings suggest that these gene expression changes and cellular abnormalities contribute to aberrant PC function during development in TSC affected individuals.

Probing Mechanical Properties of Brain in a Tuberous Sclerosis Model of Autism.

Causes of autism spectrum disorders (ASD) are understood poorly, making diagnosis and treatment challenging. While many studies have investigated the biochemical and genetic aspects of ASD, whether and how mechanical characteristics of the autistic brain can modulate neuronal connectivity and cognition in ASD are unknown. Previously, it has been shown that ASD brains are characterized by abnormal white matter and disorganized neuronal connectivity; we hypothesized that these significant cellular-level structural changes may translate to changes in the mechanical properties of the autistic brain or regions therein. Here, we focused on tuberous sclerosis complex (TSC), a genetic disorder with a high penetrance of ASD. We investigated mechanical differences between murine brains obtained from control and TSC cohorts at various deformation length- and time-scales. At the microscale, we conducted creep-compliance and stress relaxation experiments using atomic force microscope(AFM)-enabled indentation. At the mesoscale, we conducted impact indentation using a pendulum-based instrumented indenter to extract mechanical energy dissipation metrics. At the macroscale, we used oscillatory shear rheology to quantify the frequency-dependent shear moduli. Despite significant changes in the cellular organization of TSC brain tissue, we found no corresponding changes in the quantified mechanical properties at every length- and time-scale explored. This investigation of the mechanical characteristics of the brain has broadened our understanding of causes and markers of TSC/ASD, while raising questions about whether any mechanical differences can be detected in other animal models of ASD or other disease models that also feature abnormal brain structure.

"I can be pro-abortion and pro-birth": Opportunities and challenges for full spectrum care among doulas in Georgia.

Background: The work of full spectrum doulas (i.e., non-medically trained care workers offering support before, during, and after pregnancy including abortion)-is increasingly important as abortion access decreases across the U.S. Few studies have examined the work of community-based doulas in restrictive abortion settings or how they might further incorporate full spectrum care. As part of the community-engaged mixed methods Georgia Doula Study, this analysis examines the scope of work of community-based doulas regarding full spectrum and abortion services, doula opinions on full spectrum and abortion work, and potential barriers and facilitators for full spectrum doula care in metro-Atlanta, Georgia. Methods: From October 2020 to February 2022, the team recruited 20 community-based doulas with 8 who provide full spectrum services including abortion. Surveys covered demographics, doula scope of work, family planning attitudes, and abortion stigma. Survey data were analyzed using descriptive and bivariate statistics. In-depth interviews further explored those topics. They were de-identified and thematically analyzed using a semi-deductive approach. Results: The findings are organized around five themes: (1) doulas of all kinds center reproductive autonomy; (2) abortion doulas play important roles in reproductive autonomy; (3) doulas have mixed feelings about contraceptive counseling; (4) abortion doulas provide diverse services carrying numerous benefits in a stigmatized environment; and (5) abortion doulas experience challenges including stigma but they offer solutions. All but two doulas in this study were interested in learning how to incorporate contraception and abortion services in their current scope of work, and most participants supported the role of full spectrum doulas. Conclusion: This analysis highlights the experiences of abortion and full spectrum doulas, reactions of the larger doula community to those services, and facilitators and barriers to full spectrum doula care in a restrictive abortion setting. There are urgent needs and opportunities for full spectrum doulas to offer life-protecting services to pregnant people across the U.S. and globally. Coordination efforts for U.S. abortion care post-Roe v. Wade must include community-based doulas, who are largely open to aiding abortion clients through education, connection to care, and emotional support.

"I want to serve those communities [but] my price tag is not what they can afford": The community-engaged Georgia doula study.

INTRODUCTION: In Georgia, maternal mortality is relatively high, and Black women are three times as likely to die from pregnancy-related causes as white women. Doulas can improve perinatal health and reduce disparities, but doula accessibility in Georgia is unclear. METHODS: This community-engaged mixed methods study surveyed and interviewed 17 doulas in Georgia. Surveys included structured questions on demographics, businesses, clientele, training, and challenges; we analyzed them using descriptive statistics. In-depth interviews included open-ended questions on doula care benefits, building their businesses, and improving access to doula care. We analyzed the content of transcripts using coding and memoing. RESULTS: Our diverse doula participants described providing life-saving services including education, referral to care, and patient advocacy. Yet they described numerous challenges to providing care and building their businesses. Almost all participants reported having fewer than their ideal number of clients and all reported being insufficiently paid for their services. Although training, mentoring, and networking help build their businesses, many doulas want to serve Black women, transgender men, gender non-binary individuals, and families living on lower incomes. Participants suggested Medicaid reimbursement and community health worker models as potential interventions for increasing equitable doula care access. DISCUSSION: Doulas can improve perinatal health outcomes and are urgently needed. Yet they face challenges in building businesses and finding clientele, especially from communities and groups at highest risk of negative outcomes during pregnancy, childbirth, and the postpartum period. Identifying avenues for supporting publicly-funded reimbursement, expanding equity-focused doula training, and fostering stronger doula networks with mentorship appears warranted.

"We really are seeing racism in the hospitals": Racial identity, racism, and doula care for diverse populations in Georgia.

INTRODUCTION: Poor birth outcomes are more prevalent for Black communities, but strong evidence shows that doula care can improve those outcomes. More evidence is needed to understand racial differences, discrimination, and equity in doula care. METHODS: The current study's objective was to describe the experiences of Black doulas as well as the challenges and facilitators of providing doula care to communities of color in Georgia. From Fall 2020-Fall 2021, 20 surveys and in-depth interviews were conducted with doulas as part of a community-based participatory study co-led by Healthy Mothers, Healthy Babies Coalition of Georgia and academic researchers. RESULTS: Doula participants were diverse in age (5% under 25, 40% 25-35, 35% 36-45, and 20% 46+) and race/ethnicity (45% white, 50% Black, 5% Latinx). Most (70%) Black doulas reported that more than 75% of their clientele is Black, while most (78%) white doulas reported that less than 25% of their clientele is Black. Doulas noted the alarming Black maternal mortality rate and how mistreatment causes Black clients to lose trust in medical staff, leaving them in need of advocates. Black doulas were passionate about serving and advocating with Black clients. Participants also described how language and cultural barriers, particularly for Asian and Latinx people, reduce clients' ability to self-advocate, increasing the need for doulas. Doulas also discussed the ways that race influences their connections with clients and their dissatisfaction with the lack of cultural humility or sensitivity training in standard doula training. CONCLUSION: Our findings indicate that Black doulas provide essential and supportive services to Black birthing people, and those services are more urgently needed than ever following the overturn of Roe v. Wade. Doula training must be improved to address the cultural needs of diverse clients. Increasing access to doula care for Asian and Latinx communities could also address language and cultural barriers that can negatively impact their maternal and child health outcomes.

"Doulas shouldn't be considered visitors, we should be considered a part of [the] team": doula care in Georgia, USA during the COVID-19 pandemic.

Doula support improves maternal-child health outcomes. However, during the COVID-19 pandemic, hospitals restricted the number of support people allowed during childbirth. An academic-community research team conducted 17 in-depth interviews and structured surveys with doulas in metro-Atlanta, Georgia, USA from November 2020 to January 2021. Surveys were analysed for descriptive statistics in Stata v. 14, and interviews were analysed in Dedoose using a codebook and memo-ing for thematic analysis. All 17 doulas reported COVID-19 changed their practices: most were unable to accompany clients to delivery (14), started using personal protective equipment (13), used virtual services (12), and had to limit the number of in-person prenatal/postpartum visits (11). Several attended more home births (6) because birthing people were afraid to have their babies in the hospital. Some stopped seeing clients altogether due to safety concerns (2). Many lost clientele who could no longer afford doula services, and some offered pro bono services. Most doulas pointed to restrictive hospital policies that excluded doulas and disallowed virtual support as they felt doulas should be considered a part of the team and clients should not be forced to decide between having their doula or their partner in the room. COVID-19 has severely impacted access to and provision of doula care, mostly due to economic hardship for clients and restrictive hospital policies. At the same time, doulas and their clients have been resourceful - using virtual technology, innovative payment models, and home births.

A randomized controlled trial investigating the impact of maternal dietary supplementation with pomegranate juice on brain injury in infants with IUGR.

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24-34 weeks' gestation. Ninety-nine mothers and their eligible fetuses (n = 103) were recruited from Brigham and Women's Hospital and randomly assigned to 8 oz pomegranate (n = 56) or placebo (n = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants (n = 26 pomegranate, n = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation.Clinical trial registration: NCT04394910, https://clinicaltrials.gov/ct2/show/NCT04394910 , Registered May 20, 2020, initial participant enrollment January 16, 2016.

Type of feeding provided with dextrose gel impacts hypoglycemia outcomes: comparing donor milk, formula, and breastfeeding.

OBJECTIVE: Examine neonatal hypoglycemia (NH) outcomes based on type of feeding provided with first dextrose gel. STUDY DESIGN: Retrospective matched cohort study of 99 infants ≥35 weeks gestational age who received dextrose gel in combination with breastfeeding, formula feeding, or donor milk feeding for NH. The exposure was feeding type. The outcomes were: (1) median change in blood glucose (Δ BG) concentration after first gel, (2) odds of second gel, and (3) odds of recurrent NH. RESULTS: Median Δ BG was greater in formula (17.0 mg/dL) and donor milk (19.0 mg/dL) fed vs. breastfed infants (7.0 mg/dL). Donor milk and formula feeding were both associated with lower odds of second gel and recurrent NH. Associations remained significant in late-preterm infants, but only formula feeding remained significant in full-term infants. CONCLUSIONS: Formula and donor milk feedings both raised blood sugar concentrations, but the impact differed by gestational age.

Incorporating dextrose gel and feeding in the treatment of neonatal hypoglycaemia.

OBJECTIVES: To determine the impact of incorporating dextrose gel in the treatment of neonatal hypoglycaemia (NH) and the role of feeding type in NH outcomes. STUDY DESIGN: We conducted a retrospective analysis of 2688 infants >35 weeks' gestation who were screened for NH before and after implementation of a clinical guideline for NH evaluation and treatment. We analysed the proportion of infants who required intravenous dextrose for NH before and after guideline implementation, the change in blood glucose concentrations with gel by feeding type and the odds of successful NH treatment with gel and feeding by feeding type. RESULTS: Following implementation of the guideline, a lower proportion of infants required intravenous dextrose for NH treatment (8.6% (60 infants) before guideline vs. 5.6% (112 infants) after guideline (p=0.007)). The median rise in blood glucose concentration with gel administration in the entire cohort was 0.61 mmol/L (11 mg/dL) (IQR 0.28-1.06 mmol/L (5-19 mg/dL)). Blood glucose concentration of formula-fed infants rose more in response to feeding and gel than breastfed infants (p≤0.0001). Formula feeding was associated with a lower odds of recurrent hypoglycaemia, as defined by requiring a second gel, in a fully adjusted model. Specifically, in infants with a pregel blood glucose of 2.00-2.17 mmol/L (36-39 mg/dL), formula feeding with gel was associated with a lower odds of recurrent hypoglycaemia. CONCLUSIONS: Dextrose gel is an effective tool in the treatment of NH. An infant's pregel blood glucose concentration may be helpful in guiding decisions around type of feeding provided.

Maternal obesity and cesarean section delivery: additional risk factors for neonatal hypoglycemia?

OBJECTIVES: To determine (1) whether higher maternal body mass index (BMI) and Cesarean (C) Section mode of delivery are associated with neonatal hypoglycemia (NH) and (2) whether timing of NH onset differs by risk factors. STUDY DESIGN: Retrospective cohort study (n = 4602) to determine the odds of NH, NH requiring IV dextrose and timing of NH onset among infants with established and plausible (BMI and C-section) risk factors. RESULT: Infants born to class III obese mothers had higher odds of NH (OR 1.3, 95% CI 1.0-1.8) and of requiring IV dextrose (OR 2.2, 95% CI 1.2-3.9). Infants born via C-section had higher odds of requiring IV dextrose (OR 1.4, 95% CI 1.1-1.9). Infants who were delivered to high BMI mothers and by C-section developed NH earlier than the reference group. CONCLUSION: Determining the predictors and timing of NH onset may help develop tailored evaluation and management strategies for at-risk neonates.

Characterizing Multiscale Mechanical Properties of Brain Tissue Using Atomic Force Microscopy, Impact Indentation, and Rheometry.

To design and engineer materials inspired by the properties of the brain, whether for mechanical simulants or for tissue regeneration studies, the brain tissue itself must be well characterized at various length and time scales. Like many biological tissues, brain tissue exhibits a complex, hierarchical structure. However, in contrast to most other tissues, brain is of very low mechanical stiffness, with Young's elastic moduli E on the order of 100s of Pa. This low stiffness can present challenges to experimental characterization of key mechanical properties. Here, we demonstrate several mechanical characterization techniques that have been adapted to measure the elastic and viscoelastic properties of hydrated, compliant biological materials such as brain tissue, at different length scales and loading rates. At the microscale, we conduct creep-compliance and force relaxation experiments using atomic force microscope-enabled indentation. At the mesoscale, we perform impact indentation experiments using a pendulum-based instrumented indenter. At the macroscale, we conduct parallel plate rheometry to quantify the frequency dependent shear elastic moduli. We also discuss the challenges and limitations associated with each method. Together these techniques enable an in-depth mechanical characterization of brain tissue that can be used to better understand the structure of brain and to engineer bio-inspired materials.

Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC. We find that Tsc1/2-deficient neurons accumulate mitochondria in cell bodies, but are depleted of axonal mitochondria, including those supporting presynaptic sites. Axonal and global mitophagy of damaged mitochondria is impaired, suggesting that decreased turnover may act upstream of impaired mitochondrial metabolism. Importantly, blocking mTORC1 or inducing mTOR-independent autophagy restores mitochondrial homeostasis. Our study clarifies the complex relationship between the TSC-mTORC1 pathway, autophagy, and mitophagy, and defines mitochondrial homeostasis as a therapeutic target for TSC and related diseases.