Cytomegalovirus infection in recipients of related and unrelated donor bone marrow transplants: no evidence of increased incidence in patients receiving unrelated donor grafts

Recent reports suggest an increased incidence of cytomegalovirus (CMV) infection in recipients of unrelated donor (UD) bone marrow transplantation (BMT).
In this study we have collated the incidence of CMV infection and disease in sequential UD ( n  = 119) and related donor (RD; n  = 79) BMT performed in a single institution over a 7-year period. Low-risk patients (CMV seronegative recipient and donor) accounted for 51% of UD BMT ( n  = 61) and 62% of RD BMT ( n  = 49), with CMV excretion documented in one RD BMT only. The remaining high-risk patients received identical prophylaxis regimens with aciclovir and intravenous immunoglobulin (IVIG). Two groups consisting of 58 UD BMT (median age 9.0 years, range 0.7–45.3 years) and 30 RD BMT (median age 13.6 years, range 1.6–47.6 years) were analysed. CMV reactivation/re-infection was documented in 15 UD BMT (26%) and 10 RD BMT (33%) ( P  = 0.72), and CMV disease in four UD BMT (8%) and four RD BMT (13%) ( P  = 0.533). In this series the risk of CMV excretion and disease following UD BMT was similar to that following RD BMT.     

Head Impact Exposure in Youth Football: High School Ages 14 to 18 Years and Cumulative Impact Analysis

Sports-related concussion is the most common athletic head injury with football having the highest rate among high school athletes. Traditionally, research on the biomechanics of football-related head impact has been focused at the collegiate level. Less research has been performed at the high school level, despite the incidence of concussion among high school football players. The objective of this study is to twofold: to quantify the head impact exposure in high school football, and to develop a cumulative impact analysis method. Head impact exposure was measured by instrumenting the helmets of 40 high school football players with helmet mounted accelerometer arrays to measure linear and rotational acceleration. A total of 16,502 head impacts were collected over the course of the season. Biomechanical data were analyzed by team and by player. The median impact for each player ranged from 15.2 to 27.0 g with an average value of 21.7 (±2.4) g. The 95th percentile impact for each player ranged from 38.8 to 72.9 g with an average value of 56.4 (±10.5) g. Next, an impact exposure metric utilizing concussion injury risk curves was created to quantify cumulative exposure for each participating player over the course of the season. Impacts were weighted according to the associated risk due to linear acceleration and rotational acceleration alone, as well as the combined probability (CP) of injury associated with both. These risks were summed over the course of a season to generate risk weighted cumulative exposure. The impact frequency was found to be greater during games compared to practices with an average number of impacts per session of 15.5 and 9.4, respectively. However, the median cumulative risk weighted exposure based on combined probability was found to be greater for practices vs. games. These data will provide a metric that may be used to better understand the cumulative effects of repetitive head impacts, injury mechanisms, and head impact exposure of athletes in football.     

Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, “subconcussive” RHIs represent a more frequent and asymptomatic form of exposure. The neural network‐level signatures characterizing subconcussive RHIs in youth collision‐sport cohorts such as American Football are not known. Here, we used resting‐state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8–14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non‐collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in‐ and off‐season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network‐level FC abnormalities following repetitive, non‐concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.     

Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS

The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine–glycine–glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS.     

Integrating micro CT indices,CT imaging and computational modelling to assess the mechanical performance of fluoride treated bone

In this study we evaluate the influence of low-dose fluoride treatment on 23 patient biopsies. Computational finite element (FE) models of each biopsy were subjected to a range of loads including compression, shear and torsion. The modelling framework was validated against three 3D printed models with known material properties subjected to compression till failure using an Instron machine. The primary outcomes from this study were that mechanical strength was not significantly correlated to low-dose (<10 mg/day) of fluoride levels (one-way ANOVA, P-values of 0.78, 0.69 and 0.62 for compression, shear and torsion, respectively). However, when bulk bone material properties were derived from DXA bone mineral density (BMD) from each patient's proximal femur a non-significant linear decline in mechanical strength with increase in fluoride was predicted. When the same material property was used for all bones (to evaluate bone architecture influence) then mechanical strength showed a characteristic concave upwards trend, consistent with the variation of micro CT derived percentage bone volume (BV/TV). The secondary outcomes from this study were that in compression, BV/TV was observed to be a strong surrogate measure for mechanical strength (R² = 0.83), while bone surface density (R² = 0.6), trabecular thickness (R² = 0.5) and intersection surface (R² = 0.6) also explained the variation of mechanical strength well. However, trabecular separation and trabecular number were mildly correlated with mechanical strength (R² of 0.31 and 0.35, respectively). Compression was the loading mode most strongly correlated to micro CT indices. Material properties adapted from the proximal femur reduced the CT index correlations by up to 58% indicating that bulk density from a near proximity is a poor representation of specific localised density. Substituting the 3D micro CT indices with 2D histomorphometric data decreased correlations by at least 33% indicating that structural identification on a plane is not representative of the full 3D architecture necessary for a complete bone strength analysis. The presented computational framework may be used to assess the roles that bone architecture and loading modes play in bone quality, and which micro CT indices are good surrogate measures for mechanical strength.     

Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons

Acidic extracellular solution activates transient H(+)-gated currents in dorsal root ganglion (DRG) neurons. The biophysical properties of three degenerin/epithelial sodium (DEG/ENaC) channel subunits (BNC1, ASIC, and DRASIC), and their expression in DRG, suggest that they might underlie these H(+)-gated currents and function as sensory transducers. However, it is uncertain which of these DEG/ENaC subunits generate the currents, and whether they function as homomultimers or heteromultimers. We found that the biophysical properties of transient H(+)-gated currents from medium to large mouse DRG neurons differed from BNC1, ASIC, or DRASIC expressed individually, but were reproduced by coexpression of the subunits together. To test the contribution of each subunit, we studied DRG from three strains of mice, each bearing a targeted disruption of BNC1, ASIC, or DRASIC. Deletion of any one subunit did not abolish H(+)-gated currents, but altered currents in a manner consistent with heteromultimerization of the two remaining subunits. These data indicate that combinations of two or more DEG/ENaC subunits coassemble as heteromultimers to generate transient H(+)-gated currents in mouse DRG neurons.