Treatment for Mild Chronic Hypertension during Pregnancy.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, <160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks' gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P<0.001). The percentage of small-for-gestational-age birth weights below the 10th percentile was 11.2% in the active-treatment group and 10.4% in the control group (adjusted risk ratio, 1.04; 95% CI, 0.82 to 1.31; P = 0.76). The incidence of serious maternal complications was 2.1% and 2.8%, respectively (risk ratio, 0.75; 95% CI, 0.45 to 1.26), and the incidence of severe neonatal complications was 2.0% and 2.6% (risk ratio, 0.77; 95% CI, 0.45 to 1.30). The incidence of any preeclampsia in the two groups was 24.4% and 31.1%, respectively (risk ratio, 0.79; 95% CI, 0.69 to 0.89), and the incidence of preterm birth was 27.5% and 31.4% (risk ratio, 0.87; 95% CI, 0.77 to 0.99). CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.).

Stretching is not essential for managing MS spasticity: A randomized controlled trial.

BACKGROUND: Clinical practice, expert opinion, and evidence-based guidelines recommend daily stretching as first-line treatment for multiple sclerosis (MS) spasticity, but this has not been evaluated by fully powered clinical trials. OBJECTIVE: To determine whether MS Spasticity: Take Control (STC), a guideline-based program of spasticity education and stretching exercises has different effects on the impact of spasticity than a control program of different spasticity education and range of motion (ROM) exercises. METHODS: Ambulatory people with self-reported MS spasticity were randomly assigned to STC or ROM, delivered in same duration, facilitator-led, group classes, face-to-face (F2F) initially and later virtually, due to coronavirus disease 2019 (COVID-19). Multiple Sclerosis Spasticity Scale (MSSS) scores were compared between groups at 1 (primary outcome) and 6 months after interventions. RESULTS: A total of 231 people enrolled. There was no significant difference in MSSS scores between STC and ROM at 1 month (mean difference = 0.28, 95% (confidence interval (CI)) = [-9.45 to 10.01], p = 0.955). There were significant group mean improvements in MSSS scores and most other outcomes at 1 and 6 months. CONCLUSION: Education with stretching exercises, the first-line recommended treatment for MS spasticity, and education with ROM exercises may both improve MS spasticity to a similar degree. This study debunks the belief that stretching is essential to managing MS spasticity.

Randomized Controlled Trial of the Behavioral Intervention for Physical Activity in Multiple Sclerosis Project: Response Heterogeneity and Predictors of Change.

BACKGROUND: We reported that a social cognitive theory-based (SCT), Internet-delivered behavioral intervention increased device-measured minutes/day of moderate-to-vigorous physical activity (MVPA) over a 6-month period among persons with multiple sclerosis (MS). This paper examined the pattern and predictors of heterogeneity in change for MVPA. Based on previous research, we hypothesized that mild MS disability, fewer MS symptoms, lower baseline MVPA, and positive SCT characteristics (e.g., high exercise self-efficacy) would be associated with greater change in MVPA. METHOD: Persons with MS (N = 318) were randomized into behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions that were administered via Internet websites and supported with behavioral coaching. Demographic, clinical, symptom, behavioral, and SCT data were from before the 6-month period of delivering the conditions, and MVPA data were from before and after the 6-month period. We examined heterogeneity based on waterfall plots, box plots, and the Levene statistic. We identified predictors of MVPA change using bivariate correlation and multiple, linear regression analyses per condition. RESULTS: The Levene statistic indicated statistically significant heterogeneity of variances for MVPA change between conditions (p = .003), and the waterfall plots and box plots indicated greater heterogeneity in MVPA change for the behavioral intervention. MVPA change score was correlated with baseline MVPA (r = - .33 and r = - .34, p = .0004 and p = .0001) in both conditions and walking impairment (r = - .188, p = .047) and race (r = .233, p = .014) in the behavioral intervention condition. The regression analysis indicated that baseline MVPA (Standardized B = - .449, p = .000002), self-reported walking impairment (Standardized B = - .310, p = .0008), and race (Standardized B = .215, p = .012) explained 25.6% of variance in MVPA change for the behavioral intervention condition. CONCLUSION: We provide evidence for walking impairment, baseline MVPA, and race as predictors of the heterogeneity in the pattern of MVPA change with a behavioral intervention.

Effects of a More Selective Arteriovenous Fistula Strategy on Vascular Access Outcomes.

SIGNIFICANCE STATEMENT: The optimal choice of vascular access for patients undergoing hemodialysis-arteriovenous fistula (AVF) or arteriovenous graft (AVG)-remains controversial. In a pragmatic observational study of 692 patients, the authors found that among patients who initiated hemodialysis with a central vein catheter (CVC), a strategy that maximized AVF placement resulted in a higher frequency of access procedures and greater access management costs for patients who initially received an AVF than an AVG. A more selective policy that avoided AVF placement if an AVF was predicted to be at high risk of failure resulted in a lower frequency of access procedures and access costs in patients receiving an AVF versus an AVG. These findings suggest that clinicians should be more selective in placing AVFs because this approach improves vascular access outcomes. BACKGROUND: The optimal choice of initial vascular access-arteriovenous fistula (AVF) or graft (AVG)-remains controversial, particularly in patients initiating hemodialysis with a central venous catheter (CVC). METHODS: In a pragmatic observational study of patients who initiated hemodialysis with a CVC and subsequently received an AVF or AVG, we compared a less selective vascular access strategy of maximizing AVF creation (period 1; 408 patients in 2004 through 2012) with a more selective policy of avoiding AVF creation if failure was likely (period 2; 284 patients in 2013 through 2019). Prespecified end points included frequency of vascular access procedures, access management costs, and duration of catheter dependence. We also compared access outcomes in all patients with an initial AVF or AVG in the two periods. RESULTS: An initial AVG placement was significantly more common in period 2 (41%) versus period 1 (28%). Frequency of all access procedures per 100 patient-years was significantly higher in patients with an initial AVF than an AVG in period 1 and lower in period 2. Median annual access management costs were significantly higher among patients with AVF ($10,642) versus patients with AVG ($6810) in period 1 but significantly lower in period 2 ($5481 versus $8253, respectively). Years of catheter dependence per 100 patient-years was three-fold higher in patients with AVF versus patients with AVG in period 1 (23.3 versus 8.1, respectively), but only 30% higher in period 2 (20.8 versus 16.0, respectively). When all patients were aggregated, the median annual access management cost was significantly lower in period 2 ($6757) than in period 1 ($9781). CONCLUSIONS: A more selective approach to AVF placement reduces frequency of vascular access procedures and cost of access management.

Primary results of a phase-III, randomized controlled trial of the Behavioral Intervention for increasing Physical Activity in Multiple Sclerosis project.

BACKGROUND: We undertook a phase-III, randomized controlled trial (RCT) that examined the effectiveness of a behavioral intervention based on social cognitive theory (SCT) and delivered through the Internet using e-learning approaches for immediate and sustained increases in physical activity among persons with multiple sclerosis (MS). METHOD: The study followed a parallel group RCT design. Persons with MS (N = 318) were randomized into either behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions. The conditions were administered over a 6-month period by persons who were uninvolved in screening, recruitment, random assignment, and outcome assessment. There was a 6-month follow-up period without access of conditions. We collected outcome data every 6 months over the 12-month period. The primary outcome was device-measured minutes/day of moderate-to-vigorous physical activity (MVPA). The data analysis involved a modified intent-to-treat approach (i.e. those who received the allocated conditions) using a linear mixed model. RESULTS: There was a significant group by time interaction on the primary outcome of device-measured minutes/day of MVPA (p < 0.005). MVPA was increased immediately after the 6-month period in the behavioral intervention compared with control, and this difference was sustained over the 6-month follow-up. CONCLUSION: This study provides evidence for the effectiveness of a widely scalable approach for increasing MVPA in persons with MS.

Improving the efficiency of clinical trials in multiple sclerosis.

BACKGROUND: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. OBJECTIVE: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. METHODS: We held an international workshop with experts in clinical trial design. RESULTS: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. CONCLUSION: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.

Hydroxychloroquine for Primary Progressive Multiple Sclerosis.

OBJECTIVE: Primary progressive multiple sclerosis (PPMS) does not respond well to immunomodulatory or immunosuppressive treatment. Chronic activation of microglia has been implicated in the pathophysiology of PPMS. The antimalarial drug hydroxychloroquine (HCQ) reduces the activity of human microglia and has neuroprotective effects in vitro. METHODS: We conducted a single-arm, phase II futility trial of 200 mg oral HCQ twice daily for 18 months. In an effort to investigate disability worsening in the absence of overt focal inflammation, we excluded participants with contrast enhancing lesions on a screening magnetic resonance imaging (MRI). The primary end point was ≥20% worsening on the timed 25-foot walk measured between 6 and 18 months of follow-up. RESULTS: Based on original trial data, 40% of the cohort were expected to worsen. We used a Simon 2-stage design to compare a null hypothesis of 40% of the cohort worsening against the one-sided alternative of 20%. Using a 5% type 1 error rate and 80% power, HCQ treatment would be deemed successful if fewer than 10 of 35 participants experienced clinically significant worsening. The study met its primary end point, as only 8 of 35 participants worsened between 6 and 18 months. HCQ was overall well-tolerated, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were unlikely related to HCQ use. INTERPRETATION: HCQ treatment was associated with reduced disability worsening in people with PPMS. HCQ is a promising treatment candidate in PPMS and should be investigated further in randomized controlled clinical trials. ANN NEUROL 2021;90:940-948.

Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study.

BACKGROUND: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS. OBJECTIVE: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample. METHODS: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS. RESULTS: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT; r = -0.01; r = -0.04), California Verbal Learning Test-II (CVLT-II; r = 0.05; r = 0.05), or Brief Visuospatial Memory Test-Revised (BVMT-R; r = -0.14; r = -0.14) z-scores controlling for age, sex, and education. MVPA and SDMT (r = 0.05), CVLT-II (r = -0.07), and BVMT-R (r = 0.01) z-scores were not significantly correlated. CONCLUSION: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS.

UAB-UCSD O'Brien Center for Acute Kidney Injury Research.

Acute kidney injury (AKI) remains a significant clinical problem through its diverse etiologies, the challenges of robust measurements of injury and recovery, and its progression to chronic kidney disease (CKD). Bridging the gap in our knowledge of this disorder requires bringing together not only the technical resources for research but also the investigators currently endeavoring to expand our knowledge and those who might bring novel ideas and expertise to this important challenge. The University of Alabama at Birmingham-University of California-San Diego O'Brien Center for Acute Kidney Injury Research brings together technical expertise and programmatic and educational efforts to advance our knowledge in these diverse issues and the required infrastructure to develop areas of novel exploration. Since its inception in 2008, this O'Brien Center has grown its impact by providing state-of-the-art resources in clinical and preclinical modeling of AKI, a bioanalytical core that facilitates measurement of critical biomarkers, including serum creatinine via LC-MS/MS among others, and a biostatistical resource that assists from design to analysis. Through these core resources and with additional educational efforts, our center has grown its investigator base to include >200 members from 51 institutions. Importantly, this center has translated its pilot and catalyst funding program with a $37 return per dollar invested. Over 500 publications have resulted from the support provided with a relative citation ratio of 2.18 ± 0.12 (iCite). Through its efforts, this disease-centric O'Brien Center is providing the infrastructure and focus to help the development of the next generation of researchers in the basic and clinical science of AKI. This center creates the promise of the application at the bedside of the advances in AKI made by current and future investigators.

Development of an exosomal gene signature to detect residual disease in dogs with osteosarcoma using a novel xenograft platform and machine learning.

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal messenger RNAs (mRNAs). The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by real-time quantitative reverse transcription PCR (qRT-PCR), while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups ("healthy", "osteosarcoma", "other bone tumor", or "non-neoplastic disease"). Pre-treatment samples from osteosarcoma cases were used as the training set, and a validation set from post-treatment samples was used for testing, classifying as "osteosarcoma detected" or "osteosarcoma-NOT detected". Dogs in a validation set whose post-treatment samples were classified as "osteosarcoma-NOT detected" had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof of concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response.

Comparative responsiveness of the health utilities index and the RAND-12 for multiple sclerosis.

BACKGROUND: Outcome measures need to be valid and have good test-retest reliability and responsiveness. We compared the responsiveness of the RAND-12 and the Health Utilities Index-mark III (HUI3) in persons with multiple sclerosis (MS). METHODS: In Spring 2018 and 2019, North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants completed the HUI3, the RAND-12, and reported disability (Patient Determined Disease Steps (PDDS)) and employment status (full-time, part-time, and no). We used changes in PDDS and employment status as anchors. We assessed responsiveness using effect size, standardized response mean, and the responsiveness index. We used relative efficiency (RE) to compare the responsiveness of the health-related quality of life (HRQOL) scores, adjusting for sociodemographic factors. RESULTS: We included 4769 participants in the analysis. They had a mean (standard deviation (SD)) age of 60.9 (10.1) years, and 3826 participants (80.2%) were women. RE was highest for the HUI3 for changes in in disability status (HUI3: 1.0, Physical Component Score-12 (PCS-12): 0.80, and Mental Component Score-12 (MCS-12): 0.41) and for changes in employment status (HUI3: 1.0, PCS-12: 0.70, and MCS-12: 0.17). CONCLUSION: The HUI3 was more responsive to changes in disability and employment status than the PCS-12 or MCS-12. Given the HUI3's other strong psychometric properties, it may be the preferred generic measure of HRQOL in MS.

Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD.

BACKGROUND: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo. OBJECTIVE: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses. METHODS: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints. RESULTS: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends. CONCLUSION: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Long-term safety and efficacy of highly purified cannabidiol for treatment refractory epilepsy.

OBJECTIVE: To evaluate the safety, efficacy, and tolerability of highly purified cannabidiol (CBD) for the treatment of seizures in children and adults with treatment-resistant epilepsy (TRE) in an open-label, expanded access program (EAP). METHODS: One hundred sixty-nine participants (89 children and 80 adults) with TRE received plant-derived highly purified CBD (Epidiolex® in the U.S.; 100 mg/mL oral solution) with a starting dose of 5 mg/kg/day divided twice per day and titrated to a maximum dose of 50 mg/kg/day over the study period to seizure control and tolerability and followed for up to 2 years. Seizure frequency (calendars) and severity (Chalfont Seizure Severity Score; CSSS) were collected at every study visit. Adverse Events were reported at/between study visits as required, and participants also completed Adverse Events Profile (AEP) which generates a numerical representation of AEs. Response to CBD was defined as ≥50% reduction in seizure frequency. Given non-normal distribution of seizure frequency, a log transformation was applied after which the generalized least squares regression model for longitudinal data was used. RESULTS: Evidence from the adjusted model revealed a significant mean reduction in seizure frequency compared to baseline in children and adults at all time points (1 month and 1 and 2 years). Percentage of children achieving ≥50% seizure frequency reduction was 44% at month 1, and 41% at year 1, and 61% reduction at year 2, while adult responder rates were 34% at month 1, 53% at year 1, and 71% at year 2 (all P < 0.0001). CSSS showed a sustained reduction from baseline to all 3 time points. Children displayed 52% seizure reduction at month 1, a 51% reduction at year 1, and 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85%, respectively (all P < 0.0001). While there were no significant differences between seizure frequency reduction between children and adults at all time points, there was a significant difference in seizure severity reduction at year 1, with adults reporting greater improvement in seizure severity (P < 0.001). The most commonly reported adverse events in the study period were diarrhea, sedation, and decreased appetite. AEP revealed significant improvement from baseline at multiple time points in adults and children, and the mean AEP scores were always lower compared to baseline over the duration of the study. SIGNIFICANCE: Our study provides further evidence of sustained seizure frequency and severity reduction over two years of treatment with highly purified CBD in TRE. In addition, CBD was generally well tolerated with minority of participants experiencing adverse events resulting in stopping CBD.

Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.

BACKGROUND: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. METHODS: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. FINDINGS: Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. INTERPRETATION: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. FUNDING: MedImmune and Viela Bio.

Early Cardiac and Cerebral Hemodynamics with Umbilical Cord Milking Compared with Delayed Cord Clamping in Infants Born Preterm.

OBJECTIVE: To evaluate changes in cerebral oxygenation, peripheral arterial oxygenation, respiratory status, and administered fraction of inspired oxygen during the first 10 minutes of life in premature infants receiving umbilical cord milking compared with delayed cord clamping (DCC). STUDY DESIGN: Premature infants born at 230/7 to 276/7 weeks of gestation were randomized to umbilical cord milking or DCC. A near infrared spectroscopy sensor, pulse oximeter, and electrocardiogram electrodes were placed. Pulse rate, cerebral tissue oxygenation, peripheral oxygen saturation, airway pressure, and fraction of inspired oxygen were collected for 10 minutes in the delivery room. Longitudinal models were used to compare effects of umbilical cord milking and DCC. RESULTS: Fifty-six infants had cerebral oximetry and advanced monitoring at birth. There was an increased incidence of severe intraventricular hemorrhage in infants who received umbilical cord milking compared with DCC (P = .0211). Longitudinal models suggested that peripheral oxygen saturation was higher in the umbilical cord milking group in the first 4 minutes (P = .0221) and that mean airway pressures were lower in the umbilical cord milking group after the first 7 minutes (P = .0072). No statistical differences were observed for fraction of inspired oxygen, cerebral tissue oxygenation, or heart rates. CONCLUSIONS: The data suggest that the rapid transfer of blood during umbilical cord milking may facilitate lung expansion with improved pulmonary blood flow, but may also increase cerebral blood flow, resulting in severe intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03145142.

Developing a crosswalk between the RAND-12 and the health utilities index for multiple sclerosis.

BACKGROUND: Researchers studying health-related quality of life (HRQOL) in multiple sclerosis (MS) can choose from many instruments, but findings from studies which use different instruments cannot be easily combined. We aimed to develop a crosswalk that associates scores from the RAND-12 to scores on the Health Utilities Index-Mark III (HUI3) in persons with MS. METHODS: In 2018, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry completed the RAND-12 and the HUI3 to assess HRQOL. We used item-response theory (IRT) and equipercentile linking approaches to develop a crosswalk between instruments. We compared predicted scores for the HUI3 from each crosswalk to observed scores using Pearson correlations, intraclass correlation coefficients (ICCs), and Bland-Altman plots. RESULTS: Of 11,389 invited participants, 7129 (62.6%) responded. Predicted and observed values of the HUI3 from the IRT-linking method were moderately correlated (Pearson r = 0.76) with good concordance (ICC = 0.72). However, the Bland-Altman plots suggested biased prediction. Predicted and observed values from the equipercentile linking method were also moderately correlated (Pearson r = 0.78, ICC = 0.78). The Bland-Altman plots suggested no bias. CONCLUSION: We developed a crosswalk between the RAND-12 and the HUI3 in the MS population which will facilitate data harmonization efforts.

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.

Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Drug-drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.

OBJECTIVE: We have previously shown that cannabidiol (CBD; Epidiolex®) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12 weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the other antiepileptic drugs (AEDs) had an effect on seizure frequency or severity at 12, 24, or 48 weeks after therapy initiation. METHODS: One hundred and thirty-two adults and children with TRE receiving CBD were studied prospectively. Participants were separated into two groups - either taking (CBD + clobazam) or not taking concomitant clobazam (CBD - clobazam). In the secondary analyses, participants were divided into groups depending on whether they were taking at least 1/4 of the other AEDs shown to interact with CBD (iAED). Seizure counts and Chalfont Seizure Severity Scale (CSSS) were obtained at baseline, 12, 24, and 48 weeks. Groups were compared at each respective time point in the study using generalized estimating equations (GEE) analyses. RESULTS: All groups demonstrated statistically significant reductions in seizure frequency and severity from baseline (all P < 0.05). When participants on CBD + clobazam were compared with CBD - clobazam, there were no significant differences in seizure frequency and severity reduction between the groups at 12 weeks (both P > 0.05). When comparing groups with iAEDs vs. group without iAEDs, independent of coadministration of clobazam, no differences in treatment response were observed (all P > 0.05). Longitudinal analyses up to 48 weeks after therapy initiation did not reveal any differences in treatment response between groups. CONCLUSION: These analyses suggest that concomitant to CBD, AEDs may not have an effect on reducing seizure frequency and severity in patients with TRE.

CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients.

BACKGROUND: Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear. METHODS: We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non-expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post-transplant. RESULTS: The study cohort included 55 (56%) expressers and 43 (44%) non-expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non-expressers (log rank, P = 0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P = 0.16). Early biopsy-proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non-expressers. CONCLUSIONS: Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non-expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes.