Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Fast Feed Advancement for Preterm and Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES: Fast feed advancement may reduce hospital stay and infection but may increase adverse outcomes in preterm and low birth weight infants. The objective of this study was to assess effects of fast feed advancement (≥30 ml/kg per day) compared with slow feed advancement (\u3c30 ml/kg per day) in preterm and low birth weight infants. METHODS: Data sources include Medline, Scopus, Web of Science, CINAHL, and Index Medicus through June 30, 2021. Randomized trials were selected. Primary outcomes were mortality, morbidity, growth, and neurodevelopment. Data were extracted and pooled using random-effects models. The Cochrane Risk of Bias 2 tool was used. RESULTS: A total of 12 RCTs with 4291 participants were included. At discharge, there was moderate certainty evidence that fast advancement likely slightly reduces the risk of: mortality (relative risk [RR] 0.93, 95% confidence interval [95% CI] 0.73 to 1.18, I2 = 18%, 11 trials, 4132 participants); necrotizing enterocolitis (RR 0.89, 95% CI 0.68 to 1.15, I2 = 0%, 12 trials, 4291 participants); sepsis (RR 0.92, 95% CI 0.83 to 1.03, I2 = 0%, 9 trials, 3648 participants); and feed intolerance (RR 0.92, 95% CI 0.77 to 1.10, I2 = 0%, 8 trials, 1114 participants). Fast feed advancement may also reduce the risk of apnea (RR 0.72, 95% CI 0.47 to 1.12, I2 = 0%, low certainty, 2 trials, 153 participants). Fast feed advancement decreases time to regain birth weight (mean difference [MD] -3.69 days, 95% CI -4.44 to -2.95, I2 = 70%, high certainty, 6 trials, 993 participants,) and likely reduces the duration of hospitalization (MD -3.08 days, 95% CI -4.34 to -1.81, I2 = 77%, moderate certainty, 7 trials, 3864 participants). Limitations include heterogeneity between studies and small sample sizes. CONCLUSIONS: Fast feed advancement reduces time to regain birth weight and likely reduces the length of hospital stay; it also likely reduces the risk of neonatal morbidity and mortality slightly. However, it may increase the risk of neurodevelopmental disability slightly. More studies are needed to understand the long-term effects of fast feed advancement

Duration of Exclusive Breastfeeding for Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES: Cessation of exclusive breastfeeding (EBF) with early introduction of complementary food provides additional calories for catch-up growth but may also increase the risk of adverse outcomes. The objective of this study was to assess effects of exclusive breastfeeding for less than 6 months compared with 6 months in preterm and low birth weight infants. METHODS: Data sources include Medline, Scopus, Web of Science, CINAHL, and Index Medicus through June 30, 2021. Study selection includes randomized trials and observational studies. Primary outcomes were mortality, morbidity, growth, and neurodevelopment. Data were extracted and pooled using random-effects models. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias of included studies. RESULTS: A total of 2 studies of 307 preterm or low birth weight infants were included. None of the study results could be pooled. Both studies compared EBF for 4 months to 6 months. Growth was similar between the 4-month and 6-month EBF groups for the following outcomes: weight-for-age z-score at corrected age 12 months (mean [standard deviation], 4-month group: -1.7 [1.1], 6-month group: -1.8 [1.2], 1 study, 188 participants, low certainty evidence), absolute weight gain (gram) from 16 to 26 weeks of age (4-month group: 1004 [366], 6-month group: 1017 [350], 1 study, 119 participants, very low certainty evidence), and linear growth gain (cm) from 16 to 26 weeks of age (4-month group: 4.3 [0.9], 6-month group: 4.5 [1.2], 1 study, 119 participants, very low certainty evidence). There were no apparent differences in reported morbidity symptoms. No difference in the timing to achieve motor development milestones between the 2 groups was found (1 study; 119 participants, very low certainty evidence). A limited number of studies prevented data pooling. CONCLUSIONS: The evidence is very uncertain about the effect of exclusive breastfeeding for less than 6 months for preterm and low birth weight infants. Further studies are warranted to better answer this question

Responsive Feeding for Preterm or Low Birth Weight Infants: A Systematic Review and Meta-analysis

BACKGROUND AND OBJECTIVES: Responsive feeding may improve health outcomes in preterm and low birth weight (LBW) infants. Our objective was to assess effects of responsive compared with scheduled feeding in preterm and LBW infants. METHODS: Data sources include PubMed, Scopus, Web of Science, CINAHL, LILACS, and MEDICUS. Randomized trials were screened. Primary outcomes were mortality, morbidity, growth, neurodevelopment. Secondary outcomes were feed intolerance and duration of hospitalization. Data were extracted and pooled with random-effects models. RESULTS: Eleven eligible studies were identified, and data from 8 randomized control trials with 455 participants were pooled in the meta-analyses. At discharge, the mean difference in body weight between the intervention (responsive feeding) and comparison (scheduled feeding) was -2.80 g per day (95% CI -3.39 to -2.22, I2 = 0%, low certainty evidence, 4 trials, 213 participants); -0.99 g/kg per day (95% CI -2.45 to 0.46, I2 = 74%, very low certainty evidence, 5 trials, 372 participants); -22.21 g (95% CI -130.63 to 86.21, I2 = 41%, low certainty evidence, 3 trials, 183 participants). The mean difference in duration of hospitalization was -1.42 days (95% CI -5.43 to 2.59, I2 = 88%, very low certainty evidence, 5 trials, 342 participants). There were no trials assessing other growth outcomes (eg, length and head circumference) mortality, morbidity or neurodevelopment. Limitations include a high risk of bias, heterogeneity, and small sample size in included studies. CONCLUSIONS: Overall, responsive feeding may decrease in-hospital weight gain. Although the evidence is very uncertain, responsive feeding may slightly decrease the duration of hospitalization. Evidence was insufficient to understand the effects of responsive compared with scheduled feeding on mortality, morbidity, linear growth, and neurodevelopmental outcomes in preterm and LBW infants