Obstetric Racial Disparities in the Era of the ARRIVE (A Randomized Trial of Induction Versus Expectant Management) Trial and the Coronavirus Disease 2019 (COVID-19) Pandemic.

OBJECTIVE: To evaluate the influence of the ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial and the coronavirus disease 2019 (COVID-19) pandemic on racial and ethnic differences in labor induction, pregnancy-associated hypertension, and cesarean delivery among non-Hispanic Black and non-Hispanic White low-risk, first-time pregnancies. METHODS: We conducted an interrupted time series analysis of U.S. birth certificate data from maternal non-Hispanic Black and non-Hispanic White race and ethnicity, first pregnancy, 39 or more weeks of gestation, with no documented contraindication to vaginal delivery or expectant management beyond 39 weeks. We compared the rate of labor induction (primary outcome), pregnancy-associated hypertension, and cesarean delivery during three time periods: pre-ARRIVE (January 1, 2015-July 31, 2018), post-ARRIVE (November 1, 2018-February 29, 2020), and post-COVID-19 (March 1, 2020-December 31, 2021). RESULTS: In the post-ARRIVE period, the rate of labor induction increased in both non-Hispanic White and non-Hispanic Black patients, with no statistically significant difference in the magnitude of increase between the two groups (rate ratio for race [RR race ] 0.98, 95% CI, 0.95-1.02, P =.289). Post-COVID-19, the rate of labor induction increased in non-Hispanic White but not non-Hispanic Black patients. The magnitude of the rate change between non-Hispanic White and non-Hispanic Black patients was significant (RR race 0.95, 95% CI, 0.92-0.99, P =.009). Non-Hispanic Black pregnant people were more likely to have pregnancy-associated hypertension and more often delivered by cesarean at all time periods. CONCLUSION: Changes in obstetric practice after both the ARRIVE trial and the COVID-19 pandemic were not associated with changes in Black-White racial differences in labor induction, cesarean delivery, and pregnancy-associated hypertension.

Depression following small vessel stroke is common and more prevalent in women.

OBJECTIVES: We sought to examine the frequency of depression after small vessel-type stroke (SVS) and associated risk factors. MATERIALS AND METHODS: We conducted a retrospective analysis of a prospective cohort of patients enrolled in the American Stroke Association-Bugher SVS Study, which included 200 participants within 2-years of SVS and 79 controls without a history of stroke from 2007 to 2012 at four sites. The primary outcome was PHQ-8, with scores ≥10 consistent with post-stroke depression (PSD). A logistic regression adjusted for age, race, sex, history of diabetes and Short-Form Montreal Cognitive Assessment score (SF-MoCA) was used to compare the risk of having depression after SVS compared to controls. Another logistic regression, adjusted for age, sex, race, level of education, SF-MoCA, white matter disease (WMD) burden, stroke severity (NIHSS), time between stroke and depression screen, history of diabetes, and history of hypertension was used to identify factors independently associated with depression in participants with SVS. RESULTS: The cohort included 161 participants with SVS (39 excluded due to missing data) and 79 controls. The mean interval between stroke and depression screening was 74 days. Among participants with SVS, 31.7% (n = 51) had PSD compared to 6.3% (n = 5) of controls (RR = 5.44, 95% CI = 2.21-13.38, p = 0.0002). The only two variables independently associated with PSD in participants with SVS were female sex (RR = 1.84, 95% CI = 1.09-3.09, p = 0.020) and diabetes (RR 1.69, 95% CI 1.03-2.79). CONCLUSIONS: After adjusting for several demographic and clinical variables, having a SVS was associated with an approximate 5-fold increased risk of depression and was more frequent in women and in those with diabetes. The extent of WMD was not independently associated with PSD, suggesting that small vessel disease in the setting of an overt SVS may not account for the increased prevalence of depression.

Conjugation of HIV-1 envelope to hepatitis B surface antigen alters vaccine responses in rhesus macaques.

An effective HIV-1 vaccine remains a critical unmet need for ending the AIDS epidemic. Vaccine trials conducted to date have suggested the need to increase the durability and functionality of vaccine-elicited antibodies to improve efficacy. We hypothesized that a conjugate vaccine based on the learned response to immunization with hepatitis B virus could be utilized to expand T cell help and improve antibody production against HIV-1. To test this, we developed an innovative conjugate vaccine regimen that used a modified vaccinia virus Ankara (MVA) co-expressing HIV-1 envelope (Env) and the hepatitis B virus surface antigen (HBsAg) as a prime, followed by two Env-HBsAg conjugate protein boosts. We compared the immunogenicity of this conjugate regimen to matched HIV-1 Env-only vaccines in two groups of 5 juvenile rhesus macaques previously immunized with hepatitis B vaccines in infancy. We found expansion of both HIV-1 and HBsAg-specific circulating T follicular helper cells and elevated serum levels of CXCL13, a marker for germinal center activity, after boosting with HBsAg-Env conjugate antigens in comparison to Env alone. The conjugate vaccine elicited higher levels of antibodies binding to select HIV Env antigens, but we did not observe significant improvement in antibody functionality, durability, maturation, or B cell clonal expansion. These data suggests that conjugate vaccination can engage both HIV-1 Env and HBsAg specific T cell help and modify antibody responses at early time points, but more research is needed to understand how to leverage this strategy to improve the durability and efficacy of next-generation HIV vaccines.

Cryocompression to Reduce Peripheral Neuropathy in Gynecologic Cancer: A Randomized Controlled Trial.

OBJECTIVE: To investigate the efficacy of cryocompression therapy to prevent chemotherapy-induced peripheral neuropathy. METHODS: This single-institution, randomized, self-controlled trial of cryocompression enrolled gynecologic cancer patients planned for five to six cycles neurotoxic chemotherapy. Exclusion criteria were prior neurotoxic chemotherapy or baseline peripheral neuropathy. Participants were randomized to cryocompression on dominant versus non-dominant hand and foot (treatment), with no intervention on the opposite side (control). Compression socks and gloves and ice bags were applied 15 minutes before, during, and 15 minutes after infusion. Primary outcome measures included the PNQ (Patient Neurotoxicity Questionnaire) and the Semmes-Weinstein monofilament test; secondary outcomes included the FACT/GOG-NTX (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity) and patient acceptability and tolerability. Sixty patients completing the study were necessary to detect a 70% reduction in the odds of PNQ grade C or higher peripheral sensory neuropathy with 80% power. RESULTS: Ninety-one patients were enrolled from January 2021 to October 2022; 69 were eligible for final analysis. Of the 91 patients, 64.8% were White, 30.8% were Black, and 1.1% were Hispanic or Latina. With successive cycles, more patients had sensory PNQ grade C or higher neuropathy on the control side compared with the cryocompression side. Cryocompression decreased the odds of sensory neuropathy (PNQ grade C or higher) by 46% at final visit (odds ratio 0.54, 95% CI 0.31-0.94; P =.03). There was no difference in tactile sensitivity based on the monofilament test between sides at the final visit. At the final visit, average FACT/GOG-NTX-11 (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity 11 Item Version) scores were significantly lower on the cryocompression than the control side (estimate -0.97, 95% CI -1.89 to -0.06; P =.04), as were FACT/GOG-NTX-4 (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity 4 Item Version) scores (estimate -0.35, 95% CI -0.64 to -0.05; P =.02). More than 85% of patients assessed the intervention as acceptable and tolerable. CONCLUSIONS: Cryocompression therapy reduces subjective chemotherapy-induced peripheral sensory neuropathy in patients who are receiving paclitaxel or cisplatin for gynecologic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04563130.

Validation of a sonographic checklist for the detection of histologic placenta accreta spectrum.

BACKGROUND: To standardize research terminology and to reduce unanticipated placenta accreta spectrum, the European Working Group for Abnormally Invasive Placenta developed a consensus checklist for reporting suspected placenta accreta spectrum observed during an antenatal ultrasound. The diagnostic accuracy of the European Working Group for Abnormally Invasive Placenta checklist has not been assessed. OBJECTIVE: This study aimed to test the performance of the European Working Group for Abnormally Invasive Placenta sonographic checklist in predicting histologic placenta accreta spectrum. STUDY DESIGN: This was a multisite, blinded, retrospective review of transabdominal ultrasound studies performed between 26 to 32 weeks' gestation for subjects with histologic placenta accreta spectrum between 2016 and 2020. We matched a control cohort of subjects without histologic placenta accreta spectrum in a 1:1 ratio. To reduce reader bias, we matched the control cohort for known risk factors including previa, number of previous cesarean deliveries, previous dilation and curettage, in vitro fertilization, and clinical factors affecting image quality including multiple gestation, body mass index, and gestational age at the ultrasound. Nine sonologists from 5 referral centers, blinded to the histologic outcomes, interpreted the randomized ultrasound studies using the European Working Group for Abnormally Invasive Placenta checklist. The primary outcome was the sensitivity and specificity of the checklist to predict placenta accreta spectrum. Two separate sensitivity analyses were performed. First, we excluded subjects with mild disease (ie, only assessed subjects with histologic increta and percreta). Second, we excluded interpretations from the 2 most junior sonologists. RESULTS: A total of 78 subjects were included (39 placenta accreta spectrum, 39 matched control). Clinical risk factors and image quality markers were statistically similar between the cohorts. The checklist sensitivity (95% confidence interval) was 76.6% (63.4-90.6) and the specificity (95% confidence interval) was 92.0% (63.4-99.9) with a positive and negative likelihood ratio of 9.6 and 0.3, respectively. When we excluded subjects with mild placenta accreta spectrum disease, the sensitivity (95% confidence interval) increased to 84.7% (73.6-96.4) and the specificity was unchanged at 92.0% (83.2-99.9). Sensitivity and specificity were unchanged when the interpretations from the 2 most junior sonologists were excluded. CONCLUSION: The 2016 European Working Group for Abnormally Invasive Placenta checklist for interpreting placenta accreta spectrum has a reasonable performance in detecting histologic placenta accreta spectrum and excluding cases without placenta accreta spectum.

Association Between Hospital-Documented Atrial Fibrillation and Central Retinal Artery Occlusion.

BACKGROUND: Carotid stenosis is thought to be the primary risk factor for central retinal artery occlusion (CRAO); however, it is not known whether atrial fibrillation (AF)-a cardiac arrhythmia that underlies over 25% of cerebral ischemic strokes-predisposes patients to CRAO. METHODS: A retrospective, observational, cohort study was performed using data from the State Inpatient Databases and State Emergency Department Databases from New York (2006-2015), California (2003-2011), and Florida (2005-2015) to determine the association between AF and CRAO. The primary exposure was hospital-documented AF. The primary end point was hospital-documented CRAO, defined as having an International Classification of Diseases, Ninth Revision, Clinical Modification, code 362.31 in the primary diagnosis position. Cause-specific hazard models were used to model CRAO-free survival among patients according to hospital-documented AF status. RESULTS: Of 39 834 885 patients included in the study, 2 723 842 (median age, 72.7 years; 48.5% women) had AF documented during the exposure window. The median follow-up duration was 6 years and 1 month. Patients with AF were older, more likely to be of non-Hispanic White race/ethnicity, and had a higher burden of cardiovascular comorbidities compared with patients without AF. The cumulative incidence of CRAO determined prospectively after exclusions was 8.69 per 100 000 at risk in those with AF and 2.39 per 100 000 at risk in those without AF over the study period. Before adjustment, AF was associated with higher risk of CRAO (hazard ratio, 2.55 [95% CI, 2.15-3.03]). However, after adjustment for demographics, state, and cardiovascular comorbidities, there was an inverse association between AF and risk of CRAO (adjusted hazard ratio, 0.72 [95% CI, 0.60-0.87]). These findings were robust in our prespecified sensitivity analyses. By contrast, positive control outcomes of embolic and ischemic stroke showed an expected strong relationship between AF and risk of stroke. CONCLUSIONS: We found an inverse association between AF and CRAO in a large, representative study of hospitalized patients; however, this cohort did not ascertain AF or CRAO occurring outside of hospital or emergency department settings.

Direct-to-consumer fertility testing: utilization and perceived utility among fertility patients and reproductive endocrinologists.

RESEARCH QUESTION: What is the utilization of direct-to-consumer fertility tests (DTCFT) among fertility patients? How does the perceived utility of DTCFT differ between patients and reproductive endocrinologists (REI)? DESIGN: Infertility patients visiting the Duke Fertility Center between December 2020 and December 2021 were sent an electronic invitation to participate in a patient survey. Members of the Society of Reproductive Endocrinology and Infertility were also sent e-mail invitations to participate in the REI survey. DTCFT were defined as tests not ordered by a physician or performed at a physician's office, including calendar methods of ovulation prediction, urinary ovulation prediction kits, basal body temperature (BBT) monitoring, hormone analysis, ovarian reserve testing and semen analysis. Patients and REI were asked how likely they were to recommend a given DTCFT, on a 0-10 Likert scale. RESULTS: In total, 425 patients (response rate 50.5%) and 178 REI (response rate 21.4%) completed the surveys. Patients reported the utilization of calendar methods of ovulation prediction (83.8%), urinary ovulation prediction (78.8%), BBT monitoring (30.8%), hormone analysis (15.3%), semen analysis (10.1%) and ovarian reserve testing (9.2%). REI rated the utility of all DTCFT significantly lower than patients did (average discordance -4.2, P < 0.001), except for urinary ovulation prediction, which REI gave a significantly higher score (discordance +1.0, P < 0.001). Prior pregnancy was significantly associated with home ovulation prediction utilization among patients (adjusted odds ratio 3.21, 95% confidence interval 1.2-9.83). CONCLUSIONS: Methods of ovulation prediction are commonly used by fertility patients. Significant discordance exists in the perceived utility of DTCFT between patients and REI. Patient education and guidelines are needed to better inform individuals considering DTCFT.

Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp.

BACKGROUND: Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to the clinical syndrome and achieve a realistic sample size to power research studies for a rare disease. Although prior studies have used writing kinematics, their diagnostic performance remains unclear. OBJECTIVE: This study aimed to evaluate the diagnostic performance of automated measures that distinguish subjects with WC from healthy volunteers. METHODS: A total of 21 subjects with WC and 22 healthy volunteers performed a sentence-copying assessment on a digital tablet using kinematic and hand recognition softwares. The sensitivity and specificity of automated measures were calculated using a logistic regression model. Power analysis was performed for two clinical research designs using these measures. The test and retest reliability of select automated measures was compared across repeat sentence-copying assessments. Lastly, a correlational analysis with subject- and clinician-rated outcomes was performed to understand the clinical meaning of automated measures. RESULTS: Of the 23 measures analyzed, the measures of word legibility and peak accelerations distinguished subjects with WC from healthy volunteers with high sensitivity and specificity and demonstrated smaller sample sizes suitable for rare disease studies, and the kinematic measures showed high reliability across repeat visits, while both word legibility and peak accelerations measures showed significant correlations with the subject- and clinician-rated outcomes. CONCLUSIONS: Novel automated measures that capture key aspects of the disease and are suitable for use in clinical research studies of WC dystonia were identified. © 2022 International Parkinson and Movement Disorder Society.

Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease.

BACKGROUND: Pathogenic leucine-rich repeat kinase 2 LRRK2 mutations may increase LRRK2 kinase activity and Rab substrate phosphorylation. Genetic association studies link variation in LRRK2 to idiopathic Parkinson disease (iPD) risk. OBJECTIVES: Through measurements of the LRRK2 kinase substrate pT73-Rab10 in urinary extracellular vesicles, this study seeks to understand how LRRK2 kinase activity might change with iPD progression. METHODS: Using an immunoblotting approach validated in LRRK2 transgenic mice, the ratio of pT73-Rab10 to total Rab10 protein was measured in extracellular vesicles from a cross-section of G2019S LRRK2 mutation carriers (N = 45 participants) as well as 485 urine samples from a novel longitudinal cohort of iPD and controls (N = 85 participants). Generalized estimating equations were used to conduct analyses with commonly used clinical scales. RESULTS: Although the G2019S LRRK2 mutation did not increase pT73-Rab10 levels, the ratio of pT73-Rab10 to total Rab10 nominally increased over baseline in iPD urine vesicle samples with time, but did not increase in age-matched controls (1.34-fold vs. 1.05-fold, 95% confidence interval [CI], 0.004-0.56; P = 0.046; Welch's t test). Effect estimates adjusting for sex, age, disease duration, diagnosis, and baseline clinical scores identified increasing total Movement Disorder Society-Sponsored Revision of the Unified (MDS-UPDRS) scores (ß = 0.77; CI, 0.52-1.01; P = 0.0001) with each fold increase of pT73-Rab10 to total Rab10. Lower Montreal Cognitive Assessment (MoCA) score in iPD is also associated with increased pT73-Rab10. CONCLUSIONS: These results provide initial insights into peripheral LRRK2-dependent Rab phosphorylation, measured in biobanked urine, where higher levels of pT73-Rab10 are associated with worse disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.