Barriers and solutions to developing and maintaining research networks during a pandemic: An example from the iELEVATE perinatal network.

Introduction: To improve maternal health outcomes, increased diversity is needed among pregnant people in research studies and community surveillance. To expand the pool, we sought to develop a network encompassing academic and community obstetrics clinics. Typical challenges in developing a network include site identification, contracting, onboarding sites, staff engagement, participant recruitment, funding, and institutional review board approvals. While not insurmountable, these challenges became magnified as we built a research network during a global pandemic. Our objective is to describe the framework utilized to resolve pandemic-related issues. Methods: We developed a framework for site-specific adaptation of the generalized study protocol. Twice monthly video meetings were held between the lead academic sites to identify local challenges and to generate ideas for solutions. We identified site and participant recruitment challenges and then implemented solutions tailored to the local workflow. These solutions included the use of an electronic consent and videoconferences with local clinic leadership and staff. The processes for network development and maintenance changed to address issues related to the COVID-19 pandemic. However, aspects of the sample processing/storage and data collection elements were held constant between sites. Results: Adapting our consenting approach enabled maintaining study enrollment during the pandemic. The pandemic amplified issues related to contracting, onboarding, and IRB approval. Maintaining continuity in sample management and clinical data collection allowed for pooling of information between sites. Conclusions: Adaptability is key to maintaining network sites. Rapidly changing guidelines for beginning and continuing research during the pandemic required frequent intra- and inter-institutional communication to navigate.

Head Circumference within the Normal Range and Neurodevelopmental Outcomes in Preterm Infants.

OBJECTIVE: We sought to determine if variation in head circumference (HC) within the range of normal (5th-10th and 90th-95th percentile) is associated with poor neurodevelopmental outcomes (NDO), which defined as mild or moderate delay by Bayley II psychometrics (BSID-II). STUDY DESIGN: This is a secondary analysis of a randomized controlled trial assessing the benefits of magnesium for the prevention of cerebral palsy. Fetuses with a normal HC at birth defined as within 5th to 95th percentile were included. NDO were assessed at age 2 with BSID-II. Moderate delay was defined as a score <70 and mild delay as <85. HC was classified as small normal (5th-10th percentile), normal (10th-90th percentile), and large normal (90th-95th percentile). Logistic regression models adjusted for confounding. Linear regression models estimated the impact for every 1 cm of change in HC. RESULTS: Of 1,236 included infants, 111 (8%) had small normal HC; 1,058 (85%) had normal HC; and 67 (5%) had large normal HC. Baseline characteristics were similar between groups. There was no association with changes in HC within the range of normal and developmental indices. When considered as a continuous variable, every 1 cm increase in HC was also not associated with a significant change in developmental indices. CONCLUSION: Within the normal range (5th-95th percentile), changes in HC did not correlate with changes in NDO at 2 years as measured by Bayley II scales. KEY POINTS: · It is unknown if variations in normal HC are associated with poor neurodevelopmental outcomes.. · Alterations in HC within the range of normal (5th-95th percentile) are not associated with adverse NDO.. · When considered as a continuous variable, a 1 cm increase in HC is not associated with adverse NDO.. · Changes in HC within the range of normal do not appear to be a pathologic change altering NDO..

Prenatal Tobacco Exposure and Childhood Neurodevelopment among Infants Born Prematurely.

OBJECTIVE: Nicotine is an established neuroteratogen, and prenatal tobacco exposure alters the structure of the developing nervous system. An association between prenatal tobacco exposure and impaired neurologic function is less well established. We examine the association between prenatal tobacco exposure and childhood neurodevelopment among infants born preterm. STUDY DESIGN: Secondary analysis of a multicenter randomized controlled trial assessing the benefits of magnesium sulfate for the prevention of cerebral palsy in preterm infants. Women were included if they delivered a singleton and nonanomalous infant before 37 weeks. Exposure was any self-reported prenatal tobacco use. Primary outcome was the original trial composite outcome of moderate or severe cerebral palsy at 2 years of age, or stillbirth, or infant death by 1 year of age. Secondary outcomes included components of the composite and mild cerebral palsy at 2 years, Bayley Scales of Infant Development II motor and mental scores, death before two years, and use of auditory aids or corrective lenses. Multivariable logistic regression models were performed to estimate adjusted odds ratios (aOR) with 95% confidence intervals. RESULTS: Of 1,826 women included, 503 (27.5%) used tobacco. Tobacco users were more likely to be older, unmarried, and white; have a prior preterm birth; have received no prenatal care; and to use illicit drugs or alcohol. Gestational age at delivery, betamethasone exposure, and magnesium exposure were not different between groups. There were no differences in the composite primary outcome or in rates of cerebral palsy by tobacco use. Moderate developmental delay was more common among tobacco exposed in bivariate but not adjusted analysis (20.5 vs. 15.9%, p = 0.035). In adjusted analysis, tobacco exposure was associated with increased use of corrective lenses (5.0 vs. 2.9%, aOR: 2.28, 95% confidence interval: 1.28-4.07). CONCLUSION: Prenatal tobacco exposure is not associated with neurodevelopmental impairment in infants born preterm. However, tobacco exposure may be associated with impaired vision. KEY POINTS: · Tobacco exposure is not associated with impaired neurodevelopment in this preterm population.. · Prenatal tobacco exposure is associated with increased need for corrective lenses.. · Tobacco use in pregnancy may be a risk factor for poorer visual acuity in children..

Characteristics Associated With Consent and Reasons for Declining in a Randomized Trial in Pregnancy.

OBJECTIVE: To evaluate the maternal characteristics associated with consent to a randomized trial of labor induction in pregnancy. METHODS: This is a secondary analysis of low-risk nulliparous women randomized to induction of labor at 39 weeks or expectant management. During the trial, the Data and Safety Monitoring Committee requested additional fields on the screening log, which already included race and ethnicity: maternal age, type of insurance, and the reason for declining consent if declined. RESULTS: From August 2016 (start of additional data collection) to August 2017, 1,965 (28%) of the 7,112 eligible women consented to the trial. Consent was more likely for Black women (41%, adjusted odds ratio [aOR] 1.47, 95% CI 1.24-1.74), and less likely for Asian women (15%, aOR 0.64, 95% CI 0.48-0.84), compared with White women (24%). Women without private insurance were more likely to consent (38%, aOR 1.55, 95% CI 1.34-1.79), compared with those with private insurance (22%). Younger women were also more likely to consent. Among eligible women who declined participation and provided a reason (68%), preference to be expectantly managed (85%) was most common, a response more common in Asian women (aOR 1.75, 95% CI 1.31-2.33) and less common in women without private insurance (aOR 0.60, 95% CI 0.51-0.70). Not wanting to participate in research was more common in Asian women (aOR 2.41, 95% CI 1.44-4.03). Declining consent because family or friends objected was more common in Asian women (aOR 2.51, 95% CI 1.27-4.95) and women without private insurance (aOR 1.68, 95% CI 1.10-2.59). CONCLUSION: Frequency of consent and reasons for declining consent were associated with age, type of insurance, and race and ethnicity. These findings should be considered when developing recruitment strategies that promote diverse participant representation. CLINICAL TRIAL REGISTRATION: ClinialTrials.gov, NCT01990612.

Validation of the SunTech Medical Advantage Model 2 Series Automated Blood Pressure Module in Pregnancy.

OBJECTIVE: We sought to validate the SunTech Medical Advantage Model 2 Series with firmware LX 3.40.8 algorithm noninvasive blood pressure module in a pregnant population, including those with preeclampsia. STUDY DESIGN: Validation study of an oscillometric noninvasive blood pressure module using the ANSI/AAMI ISO 81060-2:2013 standard guidelines. Pregnant women were enrolled into three subgroups: normotensive, hypertensive without proteinuria, and preeclampsia (hypertensive with random protein-to-creatinine ratio ≥ 0.3 or a 24-hour urine protein > 300 mg). Two trained research nurses, blinded to each other's measurements, used a mercury sphygmomanometer to validate the module by following the protocol set forth in the ANSI/AAMI ISO 81060-2:2013 standard guidelines. RESULTS: A total of 45 patients, 15 in each subgroup, were included. The mean systolic and diastolic differences with standard deviations between the module and the mean observers' measurements for all participants were -2.3 ± 7.3 and 0.2 ± 6.5 mm Hg, respectively. The systolic and diastolic standard deviations of the mean of the individual patient's paired module and observers' measurements were 6.27 and 5.98 mm Hg, respectively. The test device, relative to a mercury sphygmomanometer, underestimated the systolic blood pressure in patients with preeclampsia by at least 10 mm Hg in 24% (11/45) of paired measurements. CONCLUSION: The SunTech Medical Advantage Model 2 Series with firmware LX 3.40.8 algorithm noninvasive blood pressure module is validated in pregnancy, including patients with preeclampsia; however, it may underestimate systolic blood pressure measurements in patients with preeclampsia.

The longevity of para-aminopropiophenone (PAPP) wild dog baits and the implications for effective and safe baiting campaigns.

Considerable effort goes into mitigating the impacts caused by invasive animals and prohibiting their establishment or expansion. In Australia, management of wild dogs (Canis lupus dingo and their hybrids) and their devastating impacts is reliant upon poison baiting. The recent release of baits containing the humane toxin para-aminopropiophenone (PAPP) offers potential improvements for control of wild dogs, but little is known about the environmental persistence of PAPP in manufactured baits that could be used to inform best practice guidelines. We investigated the degradation rate of PAPP wild dog baits (DOGABAIT™) under typical field usage and storage conditions in north-eastern Australia and calculated optimal deployment and withholding periods. The PAPP content of buried baits declines faster than surface-laid baits, but both presentations retained lethal doses to wild and domestic dogs for considerable periods (6-16 weeks). Domestic or working dogs should be suitably restrained or excluded from baited areas for extended periods, particularly under dry conditions, to minimise poisoning risk. The period of persistence of PAPP baits may provide opportunities to improve the duration or longer term efficacy of baiting campaigns, but care is needed to protect domestic and working dogs to ensure responsible and safe use.

What we have learned about best practices for recruitment and retention in multicenter pregnancy studies.

For 30 years, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network has had significant impact on clinical practice in obstetrics. The MFMU Network has conducted 50 randomized clinical trials and observational studies designed to improve pregnancy outcomes for mothers and children. Each center has a designated clinical research nurse coordinator who coordinates the day-to-day operations of each trial and leads a research team that is responsible for recruitment and retention of participants. Some of the lessons learned by the nurse coordinators over the past 30 years are described with examples from recent studies. Best practices that we have amassed from our experience are also described.

Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.

Chiropractic management of a patient with migraine headache.

OBJECTIVE: To describe the use of chiropractic care for a patient with migraine headache. CLINICAL FEATURES: A patient suffered from migraine headaches after an automobile accident. Neck disability scores, visual analog score, and algometry scores were used to track patient progress. INTERVENTION AND OUTCOME: The patient's range of motion, flexibility, and strength improved following a regimen of spinal manipulation and active and passive therapeutic care. After 12 weeks of treatment, the duration, frequency, and intensity of her migraines decreased. CONCLUSION: This case offers an example of the potential effects of chiropractic and rehabilitative treatment for migraine headache sufferers.

Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome.

OBJECTIVE: The 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) is associated with attentional problems and executive dysfunction, and is one of the highest known risk factors for schizophrenia. These behavioral manifestations of 22q11.2 deletion syndrome could result from haploinsufficiency of the catechol O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype as a predictor of prefrontal cognitive function in patients with 22q11.2 deletion syndrome. METHOD: Patients with confirmed 22q11.2 deletions (N=44) underwent neurocognitive testing following Val(158)Met genotyping (Met hemizygous: N=16; Val hemizygous: N=28). RESULTS: Analyses of covariance revealed that Met-hemizygous patients performed significantly better on a composite measure of executive function (comprising set-shifting, verbal fluency, attention, and working memory) than did Val-hemizygous patients. CONCLUSIONS: These data are consistent with those of previous studies in normal individuals, suggesting that a functional genetic polymorphism in the 22q11 region may influence prefrontal cognition in individuals with COMT haploinsufficiency.

Independent de novo 22q11.2 deletions in first cousins with DiGeorge/velocardiofacial syndrome.

Deletions of chromosome 22q11.2 are found in the vast majority of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). This most frequent microdeletion syndrome is estimated to occur in 1 in 4,000 live births. The majority of deletions are de novo, with 10% or less inherited from an affected parent. Here, we report two separate families with recurrence of a 22q11.2 deletion in first cousins. In each family, unaffected siblings (brother and sister) had an affected child. Fluorescence in situ hybridization (FISH) studies of the parents of each affected child were normal and hence, relatives were not considered at an increased risk for recurrence in another pregnancy. We used highly polymorphic microsatellite repeat markers from within 22q11.2 to determine the parental origin of each cousin's deletion and to assess whether parental germline mosaicism for the 22q11.2 deletion might be a factor in these cases. This analysis confirmed that in each case, the deletion occurred on a chromosome 22 derived from unrelated parents, consistent with independent de novo deletion events. Thus, we concluded that germline mosaicism as the underlying mechanism for affected cousins in these families was unlikely. Our findings underscore the high frequency with which the 22q11.2 deletion occurs in the general population and demonstrate the important role that PCR-based parental origin determination can have in recurrence risk counselling. Furthermore, relatives of affected individuals may benefit from genetic counselling and consider prenatal testing for the 22q11.2 deletion in future pregnancies, despite a low recurrence risk.

Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion.

Chromosome 22q11.2 deletions are found in almost 90% of patients with DiGeorge/velocardiofacial syndrome (DGS/VCFS). Large, chromosome-specific low copy repeats (LCRs), flanking and within the deletion interval, are presumed to lead to misalignment and aberrant recombination in meiosis resulting in this frequent microdeletion syndrome. We traced the grandparental origin of regions flanking de novo 3 Mb deletions in 20 informative three-generation families. Haplotype reconstruction showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19/20 families. Instead, the normal chromosome 22 in these probands showed interchromosomal exchanges in 2/15 informative meioses, a rate consistent with the genetic distance. Meiotic exchanges, visualized as MLH1 foci, localize to the distal long arm of chromosome 22 in 75% of human spermatocytes tested, also reflecting the genetic map. Additionally, we found no effect of proband gender or parental age on the crossover frequency. Parental origin studies in 65 de novo 3 Mb deletions (including these 20 patients) demonstrated no bias. Unlike Williams syndrome, we found no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11 deleted patients, or in eight non-deleted patients with a DGS/VCFS phenotype using FISH. Our data are consistent with significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 as the likely etiology for the deletion. This type of exchange occurs more often than is described for deletions of chromosomes 7q11, 15q11, 17p11 and 17q11, implying a difference in the meiotic behavior of chromosome 22.

Effects of stimulus rate and gender on the auditory middle latency response.

The effects of stimulus rate and gender on the auditory middle latency response (AMLR) waveforms were examined in 20 young adult male and female subjects. Four different repetition rates were presented to subjects (1.1/sec, 4.1/sec, 7.7/ sec, and 11.3/sec). Stimulus repetition rate had a significant effect on Pa latency, Pa amplitude, and Pb amplitude. Pa and Pb amplitudes decreased with increasing the stimulus rate, and Pa latency significantly increased with increasing the stimulus rate. No significant differences were seen on Pb latency or site of recording. Gender had a significant effect on Pa latency and Pa amplitude. Pa latencies were longer in male subjects, and Pa amplitudes were larger in female subjects. Gender did not have a significant effect on the Pb waveform.