Neurological and Neuroradiological Manifestations in Neonates Born to Mothers With Coronavirus Disease 2019.

BACKGROUND: To investigate the complications that occurred in neonates born to mothers with coronavirus disease 2019 (COVID-19), focusing on neurological and neuroradiological findings, and to compare differences associated with the presence of maternal symptoms. METHODS: Ninety neonates from 88 mothers diagnosed with coronavirus disease 2019 (COVID-19) during pregnancy were retrospectively reviewed. Neonates were divided into two groups: symptomatic (Sym-M-N, n = 34) and asymptomatic mothers (Asym-M-N, n = 56). The results of neurological physical examinations were compared between the groups. Data on electroencephalography, brain ultrasound, and magnetic resonance imaging abnormalities were collected for neonates with neurological abnormalities. RESULTS: Neurological abnormalities at birth were found in nine neonates (Sym-M-N, seven of 34, 20.6%). Decreased tone was the most common physical abnormality (n = 7). Preterm and very preterm birth (P < 0.01), very low birth weight (P < 0.01), or at least one neurological abnormality on physical examination (P = 0.049) was more frequent in Sym-M-N neonates. All infants with abnormalities on physical examination showed neuroradiological abnormalities. The most common neuroradiological abnormalities were intracranial hemorrhage (n = 5; germinal matrix, n = 2; parenchymal, n = 2; intraventricular, n = 1) and hypoxic brain injury (n = 3). CONCLUSIONS: Neonates born to mothers with symptomatic COVID-19 showed an increased incidence of neurological abnormalities. Most of the mothers (96.4%) were unvaccinated before the COVID-19 diagnosis. Our results highlight the importance of neurological and neuroradiological management in infants born to mothers with COVID-19 and the prevention of maternal COVID-19 infection.

Optimizing hand-function patient outcome measures for inclusion body myositis.

Inclusion body myositis is the most commonly acquired myopathy after the age of 45. The slowly progressive and heterogeneous disorder is a challenge for measuring clinical trial efficacy. One current method for measuring progression utilizes the Inclusion Body Myositis-Functional Rating Scale. We have found that the upper extremity domain scores in the Inclusion Body Myositis-Functional Rating Scale do not consistently change until there is extreme loss of grip and finger flexor strength. Therefore, we performed a cross-sectional observational study of 83 inclusion body myositis patients and 38 controls recruited at the 2019 Annual Patient Conference of The Myositis Association. We evaluated new Inclusion Body Myositis Patient-Reported Outcome measures for upper extremity function modified from the NIH Patient-Reported Outcomes Measurement Information System as well as pinch and grip strength. We found that Patient-Reported Outcome measures hand-function have a higher correlation with pinch and grip strength than the Inclusion Body Myositis-Functional Rating Scale.

A cross-sectional study of hand function in inclusion body myositis: Implications for functional rating scale.

Inclusion body myositis (IBM) is a slowly progressive and heterogeneous disorder that is a challenge for measuring clinical trial efficacy. The current methods of measuring progression of the disease utilizes the Inclusion Body Myositis Functional Rating Scale, grip strength by dynamometer, and finger flexor strength. One of the hallmarks of the disease is selective deep finger flexor weakness. To date, no adequate data has been available to determine how well the Functional Rating Scale relates to this hallmark physical exam deficit. Our study is the first to investigate the degree of correlation between items pertaining to hand function in the Functional Rating Scale with measured grip and finger flexor strength in IBM patients. We have found a lower than expected correlation with finger flexor strength and even lower with grip strength. The current Functional Rating Scale will benefit from optimization to measure clinical progression more accurately.

The carboxy-terminal third of dystrophin enhances actin binding activity.

Dystrophin is an actin binding protein that is thought to stabilize the cardiac and skeletal muscle cell membranes during contraction. Here, we investigated the contributions of each dystrophin domain to actin binding function. Cosedimentation assays and pyrene-actin fluorescence experiments confirmed that a fragment spanning two-thirds of the dystrophin molecule [from N-terminal actin binding domain (ABD) 1 through ABD2] bound actin filaments with high affinity and protected filaments from forced depolymerization, but was less effective in both assays than full-length dystrophin. While a construct encoding the C-terminal third of dystrophin displayed no specific actin binding activity or competition with full-length dystrophin, our data show that it confers an unexpected regulation of actin binding by the N-terminal two-thirds of dystrophin when present in cis. Time-resolved phosphorescence anisotropy experiments demonstrated that the presence of the C-terminal third of dystrophin in cis also influences actin interaction by restricting actin rotational amplitude. We propose that the C-terminal region of dystrophin allosterically stabilizes an optimal actin binding conformation of dystrophin.

Impacts of dystrophin and utrophin domains on actin structural dynamics: implications for therapeutic design.

We have used time-resolved phosphorescence anisotropy (TPA) of actin to evaluate domains of dystrophin and utrophin, with implications for gene therapy in muscular dystrophy. Dystrophin and its homolog utrophin bind to cytoskeletal actin to form mechanical linkages that prevent muscular damage. Because these proteins are too large for most gene therapy vectors, much effort is currently devoted to smaller constructs. We previously used TPA to show that both dystrophin and utrophin have a paradoxical effect on actin rotational dynamics-restricting amplitude while increasing rate, thus increasing resilience, with utrophin more effective than dystrophin. Here, we have evaluated individual domains of these proteins. We found that a "mini-dystrophin," lacking one of the two actin-binding domains, is less effective than dystrophin in regulating actin dynamics, correlating with its moderate effectiveness in rescuing the dystrophic phenotype in mice. In contrast, we found that a "micro-utrophin," with more extensive internal deletions, is as effective as full-length dystrophin in the regulation of actin dynamics. Each of utrophin's actin-binding domains promotes resilience in actin, while dystrophin constructs require the presence of both actin-binding domains and the C-terminal domain for full function. This work supports the use of a utrophin template for gene or protein therapy designs. Resilience of the actin-protein complex, measured by TPA, correlates remarkably well with previous reports of functional rescue by dystrophin and utrophin constructs in mdx mice. We propose the use of TPA as an in vitro method to aid in the design and testing of emerging gene therapy constructs.