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Mendelian randomization (MR) is an application of instrumental variable (IV) methods to observational data in which the IV is a genetic variant. MR methods applicable to the general exponential family of distributions are currently not well characterized. We adapt a general linear model framework to the IV setting and propose a general MR method applicable to any full-rank distribution from the exponential family. Empirical bias and coverage are estimated via simulations. The proposed method is compared to several existing MR methods. Real data analyses are performed using data from the REGARDS study to estimate the potential causal effect of smoking frequency on stroke risk in African Americans. In simulations with binary variates and very weak instruments the proposed method had the lowest median [Q1 , Q3 ] bias (0.10 [-3.68 to 3.62]); compared with 2SPS (0.27 [-3.74 to 4.26]) and the Wald method (-0.69 [-1.72 to 0.35]). Low bias was observed throughout other simulation scenarios; as well as more than 90% coverage for the proposed method. In simulations with count variates, the proposed method performed comparably to 2SPS; the Wald method maintained the most consistent low bias; and 2SRI was biased towards the null. Real data analyses find no evidence for a causal effect of smoking frequency on stroke risk. The proposed MR method has low bias and acceptable coverage across a wide range of distributional scenarios and instrument strengths; and provides a more parsimonious framework for asymptotic hypothesis testing compared to existing two-stage procedures.

Objective The aim of the study is to describe the rates of neonatal death and severe neonatal morbidity in a contemporary cohort, as well as to evaluate the predictive value of birth gestational age (GA) and birth weight, independently and combined, for neonatal mortality and morbidity in the same contemporary cohort. Study Design We performed a secondary analysis of an international, multicenter randomized controlled trial of delayed umbilical cord clamping versus umbilical cord milking in preterm infants born at 230/7 to 316/7 weeks of gestation. The current analysis was restricted to infants delivered Results Of 474 neonates in the original trial, 180 (38%) were included in this analysis. Overall, death occurred in 27 (15%) and severe morbidity in 139 (77%) neonates. Rates of mortality and morbidity declined with increasing GA (mortality 54% at 23 vs. 9% at 27 weeks). SGA infants (n = 25) had significantly higher mortality compared with non-SGA infants across all GAs (p Conclusion Death and severe neonatal morbidity declined with advancing GA, with higher rates of death in SGA infants. Birth GA and birth weight were both good predictors of outcomes; however, combining the two was not more predictive, even in SGA infants. Key Points

OBJECTIVE This study aimed to determine whether outcomes differed between infants enrolled in the PREMOD2 trial and those otherwise eligible but not enrolled, and whether the use of waiver effected these differences. STUDY DESIGN The multicenter PREMOD2 (PREmature infants receiving Milking Or Delayed cord clamping) trial was approved for waiver of antenatal consent by six of the nine sites institutional review boards, while three sites exclusively used antenatal consent. Every randomized subject delivered at a site with a waiver of consent was approached for postnatal consent to allow for data collection. Four of those six sites' IRBs required the study team to attempt antenatal consent when possible. Three sites exclusively used antenatal consent. RESULTS Enrolled subjects had higher Apgar scores, less use of positive pressure ventilation, a lower rate of bronchopulmonary dysplasia, and a less frequent occurrence of the combined outcome of severe intraventricular hemorrhage or death. A significantly greater number of infants were enrolled at sites with an option of waiver of consent (66 vs. 26%, risk ratio = 2.54, p

Objective: To compare temporal trends in clinical and health care resource utilization (HRU) outcomes in people with refractory and nonrefractory generalized myasthenia gravis (gMG). Methods: A retrospective analysis of data from adults with gMG in the Myasthenia Gravis Foundation of America Patient Registry. gMG status (ever-refractory or always nonrefractory) and clinical (Myasthenia Gravis—Activities of Daily Living [MG-ADL] scores, exacerbations) and HRU outcomes were determined from questionnaires self-completed 6-monthly for up to 4 years. The probability of each outcome was compared for the 2 groups over time. Results: The mean MG-ADL score and the probability of experiencing each outcome were significantly greater in the ever-refractory versus nonrefractory groups during each year of follow-up. Between-group differences in time trends were statistically significant for intensive care and feeding-tube use. Conclusions: People who have ever had refractory gMG may have worse functional status, more exacerbations, and higher HRU than people with consistently nonrefractory disease.

Introduction The Myasthenia Gravis Patient Registry (MGR) is a voluntary, patient‐submitted database dedicated to improve understanding of care/burden of myasthenia gravis (MG). Methods In this study we present analyses of baseline records through July 2017 (n = 1140) containing data on the MG—Activities of Daily Living (MG‐ADL) and the MG 15‐item Quality of Life (MG‐QOL15) instruments, two validated scales assessing quality of life in MG patients at sign‐up into the MGR. Results Most registrants reported moderate to severe impairment of health‐related quality of life, with a median MG‐ADL score of 6 and a median MG‐QOL15 score of 21. Seventy‐one percent of the patients had received pyridostigmine. Corticosteroids, mycophenolate mofetil, and azathioprine were the most common immunomodulators/immunosuppressants, with 85% of participants having ever using one of these agents. Forty‐seven registrants reported receiving intravenous immunoglobulin, and 30% received plasma exchange. Twelve percent reported other treatments, and 40% were unsure whether they received less common therapies. Forty percent had undergone thymectomy. Discussion The MGR data correlate well with other MG cohorts. Many MG patients remain negatively impacted despite treatment.

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

Mendelian randomization studies have become increasingly common due to the maturation of genome-wide association studies and its potential to ascertain causal relationships. With the increasing use of this method comes the need for medical practitioners and clinicians to develop an understanding of its rationale, limitations, and interpretation. Mendelian randomization attempts to ascertain a causal relationship between some risk factor of interest and some outcome or disease of interest. It exploits Mendel's law on the random assortment of genetic variants. This random assortment of genetic variants mimics the main principle of randomization used in clinical trials; with the genetic variant replacing the randomly allocated treatment. In this paper we provide a readable introduction to the rationale behind Mendelian randomization and its limitations. We also discuss and interpret several examples of Mendelian randomization analyses which pertain to neurological diseases.

Importance Umbilical cord milking as an alternative to delayed umbilical cord clamping may provide equivalent benefits to preterm infants, but without delaying resuscitation. Objective To determine whether the rates of death or severe intraventricular hemorrhage differ among preterm infants receiving placental transfusion with umbilical cord milking vs delayed umbilical cord clamping. Design, Setting, and Participants Noninferiority randomized clinical trial of preterm infants (born at 23-31 weeks’ gestation) from 9 university and private medical centers in 4 countries were recruited and enrolled between June 2017 and September 2018. Planned enrollment was 750 per group. However, a safety signal comprising an imbalance in the number of severe intraventricular hemorrhage events by study group was observed at the first interim analysis; enrollment was stopped based on recommendations from the data and safety monitoring board. The planned noninferiority analysis could not be conducted and a post hoc comparison was performed instead. Final date of follow-up was December 2018. Interventions Participants were randomized to umbilical cord milking (n = 236) or delayed umbilical cord clamping (n = 238). Main Outcomes and Measures The primary outcome was a composite of death or severe intraventricular hemorrhage to determine noninferiority of umbilical cord milking with a 1% noninferiority margin. Results Among 540 infants randomized, 474 (88%) were enrolled and completed the trial (mean gestational age of 28 weeks; 46% female). Twelve percent (29/236) of the umbilical cord milking group died or developed severe intraventricular hemorrhage compared with 8% (20/238) of the delayed umbilical cord clamping group (risk difference, 4% [95% CI, −2% to 9%];P = .16). Although there was no statistically significant difference in death, severe intraventricular hemorrhage was statistically significantly higher in the umbilical cord milking group than in the delayed umbilical cord clamping group (8% [20/236] vs 3% [8/238], respectively; risk difference, 5% [95% CI, 1% to 9%];P = .02). The test for interaction between gestational age strata and treatment group was significant for severe intraventricular hemorrhage only (P = .003); among infants born at 23 to 27 weeks’ gestation, severe intraventricular hemorrhage was statistically significantly higher with umbilical cord milking than with delayed umbilical cord clamping (22% [20/93] vs 6% [5/89], respectively; risk difference, 16% [95% CI, 6% to 26%];P = .002). Conclusions and Relevance In this post hoc analysis of a prematurely terminated randomized clinical trial of umbilical cord milking vs delayed umbilical cord clamping among preterm infants born at less than 32 weeks’ gestation, there was no statistically significant difference in the rate of a composite outcome of death or severe intraventricular hemorrhage, but there was a statistically significantly higher rate of severe intraventricular hemorrhage in the umbilical cord milking group. The early study termination and resulting post hoc nature of the analyses preclude definitive conclusions. Trial Registration ClinicalTrials.gov Identifier:NCT03019367