Characterization of Fine Motor and Visual Motor Skills in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome is a genetic inflammatory disorder resulting in dispersed neurologic dysfunction. Despite a recognition of overall motor impairment, fine and visual motor skills are undercharacterized. We hypothesize that there is a spectrum of fine and visual motor skills in the Aicardi-Goutières syndrome population as captured by a standard outcome measure, the Peabody Developmental Motor Scales (PDMS-2), which will be proportional to overall disease severity.In a cohort of 74 subjects, the Peabody Developmental Motor Scales-2 grasping and visual-motor integration subtests were administered concurrently with the Aicardi-Goutières syndrome Severity Scale (severe [range 0-3], moderate [range 4-8], and attenuated [range 9-11]). The cohort was also compared by genotype and performance as defined by raw scores. The distribution of Peabody Developmental Motor Scales-2 scores within a genotype was assessed by interquartile ranges (IQRs).Peabody Developmental Motor Scales-2 grasping and visual-motor integration performance was the least variable in the TREX1-cohort (IQR: 10.00-12.00) versus the SAMHD1 and IFIH1 cohorts (IQR: 51.00-132.00 and 48.50-134.00, respectively). Neurologic severity highly correlated with both fine and visual motor skills (Spearman correlation: r = 0.87, 0.91, respectively). A floor effect (lowest 10% of possible scores) was observed within the severe cohort (n = 32/35), whereas a ceiling effect (top 10%) was observed in the attenuated cohort (n = 13/17).This study characterized the spectrum of fine and visual motor function in the Aicardi-Goutières syndrome population, which correlated with overall neurologic dysfunction. The Peabody Developmental Motor Scales-2 grasping and visual-motor integration showed promise as potential assessment tools in moderate and attenuated Aicardi-Goutières syndrome cohorts. A better understanding of fine and visual motor function in this population will benefit clinical care and clinical trial design.

Preterm Birth Risk and Maternal Nativity, Ethnicity, and Race.

Importance: Immigrant birthing people have lower rates of preterm birth compared with their US-born counterparts. This advantage and associated racial and ethnic disparities across the gestational age spectrum have not been examined nationally. Objective: To examine associations of maternal nativity, ethnicity, and race with preterm birth. Design, Setting, and Participants: This cohort study used birth certificates from the National Vital Statistics System to analyze in-hospital liveborn singleton births in the US between January 1, 2009, and December 31, 2018. Data were analyzed from January to June 2023. Exposure: Mutually exclusive nativity, ethnicity, and race subgroups were constructed using nativity (defined as US-born or non-US-born), ethnicity (defined as Hispanic or non-Hispanic), and race (defined as American Indian or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific Islander, White, or other [individuals who selected other race or more than 1 race]). Main Outcomes and Measures: The primary outcome of interest was preterm birth. Modified Poisson and multinomial logistic regression models quantified relative risk (RR) of preterm birth overall (<37 weeks' gestation) and by gestational category (late preterm: 34-36 weeks' gestation; moderately preterm: 29-33 weeks' gestation; and extremely preterm: <29 weeks' gestation) for each maternal nativity, ethnicity, and race subgroup compared with the largest group, US-born non-Hispanic White (hereafter, White) birthing people. The RR of preterm birth overall and by category was also measured within each racial and ethnic group by nativity. Models were adjusted for maternal demographic and medical covariates, birth year, and birth state. Results: A total of 34 468 901 singleton live births of birthing people were analyzed, with a mean (SD) age at delivery of 28 (6) years. All nativity, ethnicity, and race subgroups had an increased adjusted risk of preterm birth compared with US-born White birthing people except for non-US-born White (adjusted RR, 0.85; 95% CI, 0.84-0.86) and Hispanic (adjusted RR, 0.98; 95% CI, 0.97-0.98) birthing people. All racially and ethnically minoritized groups had increased adjusted risks of extremely preterm birth compared with US-born White birthing people. Non-US-born individuals had a decreased risk of preterm birth within each subgroup except non-Hispanic Native Hawaiian or Other Pacific Islander individuals, in which immigrants had significantly increased risk of overall (adjusted RR, 1.07; 95% CI, 1.01-1.14), moderately (adjusted RR, 1.10; 95% CI, 0.92-1.30), and late (adjusted RR, 1.11; 95% CI, 1.02-1.22) preterm birth than their US-born counterparts. Conclusions and Relevance: Results of this cohort study suggest heterogeneity of preterm birth across maternal nativity, ethnicity, and race and gestational age categories. Understanding these patterns could aid the design of targeted preterm birth interventions and policies, especially for birthing people typically underrepresented in research.

The impact of volume and neonatal level of care on outcomes of moderate and late preterm infants.

OBJECTIVE: Evaluate the relationship of neonatal unit level of care (LOC) and volume with mortality or morbidity in moderate-late preterm (MLP) (32-36 weeks' gestation) infants. DESIGN: Retrospective cohort study of 650,865 inborn MLP infants in 4976 hospitals-years using 2003-2015 linked administrative data from 4 states. Exposure was combined neonatal LOC and MLP annual volume. The primary outcome was death or morbidity (respiratory distress syndrome, severe intraventricular hemorrhage, necrotizing enterocolitis, sepsis, infection, pneumothorax, extreme length of stay) with components as secondary outcomes. Poisson regression models adjusted for patient characteristics with a random effect for unit were used. RESULTS: In adjusted models, high-volume level 2 units had a lower risk of the primary outcome compared to low-volume level 3 units (aIRR 0.90 [95% CI 0.83-0.98] vs. aIRR 1.13 [95% CI 1.03-1.24], p < 0.001) CONCLUSION: MLP infants had improved outcomes in high-volume level 2 units compared to low-volume level 3 units in adjusted analysis.

The association of maternal country/region of origin and nativity with infant mortality rate among Hispanic preterm infants.

OBJECTIVES: Among US-born preterm infants of Hispanic mothers, we analyzed the unadjusted and adjusted infant mortality rate (IMR) by country/region of origin and maternal nativity status. STUDY DESIGN: Using linked national US birth and death certificate data (2005-2014), we examined preterm infants of Hispanic mothers by subgroup and nativity. Clinical and sociodemographic covariates were included and the main outcome was death in the first year of life. RESULTS: In our cohort of 891,216 preterm Hispanic infants, we demonstrated different rates of infant mortality by country and region of origin, but no difference between infants of Hispanic mothers who were US vs. foreign-born. CONCLUSION: These findings highlight the need to disaggregate the heterogenous Hispanic birthing population into regional and national origin groups to better understand unique factors associated with adverse perinatal outcomes in order to develop more targeted interventions for these subgroups.

Perinatal Care Measures Are Incomplete If They Do Not Assess The Birth Parent-Infant Dyad As A Whole.

Measures of perinatal care quality and outcomes often focus on either the birth parent or the infant. We used linked vital statistics and hospital discharge data to describe a dyadic measure (including both the birth parent and the infant) for perinatal care during the birth hospitalization. In this five-state cohort of 2010-18 births, 21.6 percent of birth parent-infant dyads experienced at least one complication, and 9.6 percent experienced a severe complication. Severe infant complications were eight times more prevalent than severe birth parent complications. Among birth parents with a severe complication, the co-occurrence of a severe infant complication ranged from 2 percent to 51 percent, whereas among infants with a severe complication, the co-occurrence of a severe birth parent complication was rare, ranging from 0.04 percent to 5 percent. These data suggest that measures, clinical interventions, public reporting, and policies focused on either the birth parent or the infant are incomplete in their assessment of a healthy dyad. Thus, clinicians, administrators, and policy makers should evaluate dyadic measures, incentivize positive outcomes for both patients (parent and infant), and create policies that support the health of the dyad.

Chronic Hypertension in Pregnancy and Racial-Ethnic Disparities in Complications.

OBJECTIVE: To evaluate whether there are individual- and population-level associations between chronic hypertension and pregnancy complications, and to assess differences across seven racial-ethnic groups. METHODS: This population-based study used linked vital statistics and hospitalization discharge data from all live and stillbirths in California (2008-2018), Michigan (2008-2020), Oregon (2008-2020), Pennsylvania (2008-2014), and South Carolina (2008-2020). We used multivariable log-binomial regression models to estimate risk ratios (RRs) and population attributable risk (PAR) percentages with 95% CIs for associations between chronic hypertension and several obstetric and neonatal outcomes, selected based on prior evidence and pathologic pathways. We adjusted models for demographic factors (race and ethnicity, payment method, educational attainment), age, body mass index, obstetric history, delivery year, and state, and conducted analyses stratified across seven racial-ethnic groups. RESULTS: The study included 7,955,713 pregnancies, of which 168,972 (2.1%) were complicated by chronic hypertension. Chronic hypertension was associated with several adverse obstetric and neonatal outcomes, with the largest adjusted PAR percentages observed for preeclampsia with severe features or eclampsia (22.4; 95% CI 22.2-22.6), acute renal failure (13.6; 95% CI 12.6-14.6), and pulmonary edema (10.7; 95% CI 8.9-12.6). Estimated RRs overall were similar across racial-ethnic groups, but PAR percentages varied. The adjusted PAR percentages (95% CI) for severe maternal morbidity-a widely used composite of acute severe events-for people who were American Indian or Alaska Native, Asian, Black, Latino, Native Hawaiian or Other Pacific Islander, White, and Multiracial or Other were 5.0 (1.1-8.8), 3.7 (3.0-4.3), 9.0 (8.2-9.8), 3.9 (3.6-4.3), 11.6 (6.4-16.5), 3.2 (2.9-3.5), and 5.5 (4.2-6.9), respectively. CONCLUSION: Chronic hypertension accounts for a substantial fraction of obstetric and neonatal morbidity and contributes to higher complication rates, particularly for people who are Black or Native Hawaiian or Other Pacific Islander.

Gross Motor Function in Pediatric Onset TUBB4A-Related Leukodystrophy: GMFM-88 Performance and Validation of GMFC-MLD in TUBB4A.

TUBB4A pathogenic variants are associated with a spectrum of neurologic impairments including movement disorders and leukodystrophy. With the development of targeted therapies, there is an urgent unmet need for validated tools to measure mobility impairment. Our aim is to explore gross motor function in a pediatric-onset TUBB4A-related leukodystrophy cohort with existing gross motor outcome tools. Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function Classification System (GMFCS-ER), and Gross Motor Function Classification-Metachromatic Leukodystrophy (GMFC-MLD) were selected through face validity. Subjects with a confirmed clinical and molecular diagnosis of TUBB4A-related leukodystrophy were enrolled. Participants' sex, age, genotype, and age at disease onset were collected, together with GMFM-88 and concurrent GMFCS-ER and GMFC-MLD. Performances on each measure were compared. GMFM-88 floor effect was defined as total score below 20%. A total of 35 subjects participated. Median performance by GMFM-88 was 16.24% (range 0-97.31), with 42.9% (n = 15) of individuals performing above the floor. GMFM-88 Dimension A (Lying and Rolling) was the best-performing dimension in the GMFM-88 (n = 29 above the floor). All levels of the Classification Scales were represented, with the exception of the GMFC-MLD level 0. Evaluation by GMFM-88 was strongly correlated with the Classification Scales (Spearman correlations: GMFCS-ER:GMFM-88 r = 0.90; GMFC-MLD:GMFM-88 r = 0.88; GMFCS-ER:GMFC-MLD: r = 0.92). Despite overall observation of a floor effect, the GMFM-88 is able to accurately capture the performance of individuals with attenuated phenotypes. GMFM-88 Dimension A shows no floor effect. GMFC-MLD shows a strong correlation with GMFCS-ER and GMFM-88, supporting its use as an age-independent functional score in TUBB4A-related leukodystrophy.

Exploration of Gross Motor Function in Aicardi-Goutières Syndrome.

Background: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. While the Aicardi-Goutières syndrome severity score favors severely impacted individuals, there is an unmet need to define tools measuring function across the Aicardi-Goutières syndrome spectrum as potential outcome assessments for future clinical trials. Methods: Gross Motor Function Measure-88 (GMFM-88) and AGS Severity Scale were administered in individuals affected by Aicardi-Goutières syndrome (n = 71). We characterized the performance variability by genotype. Derived versions of the GMFM-88, including the GMFM-66, GMFM-66 item set (GMFM-66IS), and GMFM-66 Basal&Ceiling (GMFM-66BC) were calculated. The Aicardi-Goutières syndrome cohort was divided into severe (AGS Severity Scale score <4) or attenuated (≥4). Performance on the AGS Severity Scale highly correlated with total GMFM-88 scores (Spearman Correlation: R = 0.91). To assess variability of the GMFM-88 within genotypic subcohorts, interquartile ranges (IQRs) were compared. Results: GMFM-88 performance in the TREX1 cohort had least variability while the SAMHD1 cohort had the largest IQR (4.23 vs 81.8). Floor effect was prominent, with most evaluations scoring below 20% (n = 46, 64.79%), particularly in TREX1- and RNASEH2-cohorts. Performance by the GMFM-66, GMFM-66IS, and GMFM-66BC highly correlated with the full GMFM-88. The Aicardi-Goutières syndrome population represents a broad range of gross motor skills. Conclusions: This work identified the GMFM-88 as a potential clinical outcome assessment in subsets of the Aicardi-Goutières syndrome population but underscores the need for additional validation of outcome measures reflective of the diverse gross motor function observed in this population, including low motor function. When time is limited by resources or patient endurance, shorter versions of the GMFM-88 may be a reasonable alternative.

Racial and Ethnic Disparities in Sudden Unexpected Infant Death Among US Infants Born Preterm.

OBJECTIVE: To investigate among US infants born at <37 weeks gestation (a) racial and ethnic disparities in sudden unexpected infant death (SUID) and (b) state variation in SUID rates and non-Hispanic Black (NHB)-non-Hispanic White (NHW) SUID disparity ratio. METHODS: In this retrospective cohort analysis of linked birth and death certificates from 50 states from 2005 to 2014, SUID was defined by the following International Classification of Diseases, 9th or 10th edition, codes listed on death certificates: (7980, R95 or Recode 135; ASSB: E913, W75 or Recode 146; Unknown: 7999 R99 or Recode 134). Multivariable models were used to assess the independent association between maternal race and ethnicity and SUID, adjusting for several maternal and infant characteristics. The NHB-NHW SUID disparity ratios were calculated for each state. RESULTS: Among 4 086 504 preterm infants born during the study period, 8096 infants (0.2% or 2.0 per 1000 live births) experienced SUID. State variation in SUID ranged from the lowest rate of 0.82 per 1000 live births in Vermont to the highest rate of 3.87 per 1000 live births in Mississippi. Unadjusted SUID rates across racial and ethnic groups varied from 0.69 (Asian/Pacific Islander) to 3.51 (NHB) per 1000 live births. In the adjusted analysis, compared with NHW infants, NHB and Alaska Native/American Indian preterm infants had greater odds of SUID (aOR, 1.5;[95% CI, 1.42-1.59] and aOR, 1.44 [95% CI, 1.21-1.72]) with varying magnitude of SUID rates and NHB-NHW disparities across states. CONCLUSIONS: Significant racial and ethnic disparities in SUID among preterm infants exist with variation across US states. Additional research to identify the drivers of these disparities within and across states is needed.

Are COVID-19 mRNA vaccine side effects severe enough to cause missed work? Cross-sectional study of health care-associated workers.

ABSTRACT: The Coronavirus Disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome-coronavirus-2, has claimed 5,587,549 lives worldwide as of January 20, 2022. Fortunately, large-scale vaccination can mitigate the impact of COVID-19 by making the disease milder and less common. Although 75.2% of the United States population has received at least 1 dose of a COVID-19 vaccines thus far, concerns regarding vaccine side effects have contributed to vaccine hesitancy. Furthermore, nearly 50% of adults in the United States are concerned not only about side effects, but about their downstream impact, including missed work.The goal of this cross-sectional study was to investigate the effect of messenger RNA vaccine adverse effects on the propensity to miss work among employees associated with a single, large academic health center.Using Qualtrics, all employees, including faculty, staff, and trainees, of 5 large departments were surveyed to determine whether they received the COVID-19 vaccine and which type, and any symptoms they experienced after receipt of either vaccine dose. We hypothesized that vaccine recipients would be more likely to miss work or feel sick enough to miss work following the second dose.Thirty-seven percent of respondents experienced events severe enough that they needed to miss work from either of the doses, with the majority (27.8%) related to the second dose. These findings are consistent with and expand on the results from the phase 3 trials for Pfizer-BionTech and Moderna, which showed that vaccine side effects were more common after the second dose than after the first dose. Our statistically significant finding was more common among Asians, women, trainees/house staff, and nonphysician clinical employees.With an increasing number of individuals taking the vaccine, employers will need to account for the impact of adverse effects on their employees' ability to work. These findings will further help organizations better plan for staffing as vaccinations increase to mitigate the spread of COVID-19.

Magnesium Citrate Capsules in Colonoscopy Preparation: A Randomized Controlled Trial.

INTRODUCTION: Screening colonoscopies are recommended for the detection and prevention of colon cancer. Liquid colonoscopy preparations may be poorly tolerated. We evaluated the adequacy and tolerability of a novel low-cost colonoscopy preparation consisting of magnesium citrate capsules and bisacodyl (MCCB). METHODS: This is a single-center, assessor-blinded, randomized controlled trial of 51 patients undergoing screening colonoscopies, who received a bowel preparation of either 4 liters of GoLYTELY (Braintree Laboratories, Inc., Braintree, MA) or MCCB. The primary outcome was the rate of adequate colon cleanliness, defined as a total score ≥ 6 on the Boston Bowel Preparation Scale and no colon segment with a score of zero. The secondary outcome was patient satisfaction, assessed by a validated questionnaire. RESULTS: A total of 100% of patients in both arms achieved adequate colon cleanliness, and the magnesium citrate arm had superior patient satisfaction (mean satisfaction score: 54.8 vs. 172.8; p < 0.001). CONCLUSIONS: A pill-based colonoscopy preparation of MCCB may be a low-cost option for patients reluctant to consume a liquid preparation.