Real-time biofeedback integrated into neuromuscular training reduces high-risk knee biomechanics and increases functional brain connectivity: A preliminary longitudinal investigation

Prospective evidence indicates that functional biomechanics and brain connectivity may predispose an athlete to an anterior cruciate ligament injury, revealing novel neural linkages for targeted neuromuscular training interventions. The purpose of this study was to determine the efficacy of a real-time biofeedback system for altering knee biomechanics and brain functional connectivity. Seventeen healthy, young, physically active female athletes completed 6 weeks of augmented neuromuscular training (aNMT) utilizing real-time, interactive visual biofeedback and 13 served as untrained controls. A drop vertical jump and resting state functional magnetic resonance imaging were separately completed at pre- and posttest time points to assess sensorimotor adaptation. The aNMT group had a significant reduction in peak knee abduction moment (pKAM) compared to controls (p = .03, d = 0.71). The aNMT group also exhibited a significant increase in functional connectivity between the right supplementary motor area and the left thalamus (p = .0473 after false discovery rate correction). Greater percent change in pKAM was also related to increased connectivity between the right cerebellum and right thalamus for the aNMT group (p = .0292 after false discovery rate correction, r² = .62). No significant changes were observed for the controls (ps > .05). Our data provide preliminary evidence of potential neural mechanisms for aNMT-induced motor adaptations that reduce injury risk. Future research is warranted to understand the role of neuromuscular training alone and how each component of aNMT influences biomechanics and functional connectivity.     

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Circulating tumor cell (CTC) and cell‐free (cf) DNA‐based genomic alterations are increasingly being used for clinical decision‐making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low‐pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium‐223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR‐V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC‐specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA‐discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR‐V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.     

Analysis of structure and gene expression in developing kidneys of male and female rats exposed to low protein diets in utero

A maternal low protein (LP) diet in rodents often results in low nephron endowment and renal pathophysiology in adult life, with outcomes often differing between male and female offspring. Precisely how a maternal LP diet results in low nephron endowment is unknown. We conducted morphological and molecular studies of branching morphogenesis and nephrogenesis to identify mechanisms and timepoints that might give rise to low nephron endowment. Sprague–Dawley rats were fed a normal protein (19.4% protein, NP) or LP (9% protein) diet for 3 weeks prior to mating and throughout gestation. Embryonic day 14.25 (E14.25) kidneys from males and females were either cultured for 2 days after which branching morphogenesis was quantified, or frozen for gene expression analysis. Real-time PCR was used to quantify expression of key nephrogenesis and branching morphogenesis genes at E14.25 and 17.25. At E17.25, nephron number was determined in fixed tissue. There was no effect of either maternal diet or sex on branching morphogenesis. Nephron number at E17.25 was 14% lower in male and female LP offspring than in NP controls. At E14.25 expression levels of genes involved in branching morphogenesis (Gfrα1, Bmp4, Gdnf) and nephrogenesis (Hnf4a, Pax2, Wnt4) were similar in the dietary groups, but significant differences between sexes were identified. At E17.25, expression of Gfrα1, Gdnf, Bmp4, Pax2 and Six2 was lower in LP offspring than NP offspring, in both male and female offspring. These findings provide new insights into how a LP diet leads to low nephron endowment and renal sexual dimorphism.     

Molecular Characterization of a Catalase-Negative Methicillin-Susceptible Staphylococcus aureus subsp. aureus Strain Collected from a Patient with Cutaneous Abscess

We describe a cutaneous abscess caused by catalase-negative methicillin-susceptible Staphylococcus aureus subsp. aureus in a patient who was concomitantly colonized with virulent USA300 methicillin-resistant S. aureus (MRSA). Sequencing of the katA gene demonstrated a thymine insertion leading to a frameshift mutation and premature truncation of catalase to 21 amino acids.     

Reduction in False-Positive Aspergillus Serum Galactomannan Enzyme Immunoassay Results Associated with Use of Piperacillin-Tazobactam in the United States

Piperacillin-tazobactam (PTZ) is known to cause false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA), due to contamination with galactomannan (GM). We tested 32 lots of PTZ and 27 serum specimens from patients receiving PTZ. GM was not detected in the lots of PTZ; one serum specimen (3.7%) was positive. PTZ formulations commonly used in the United States today appear to be a rare cause for false-positive GM results.     

Whole-Genome Analysis of Exserohilum rostratum from an Outbreak of Fungal Meningitis and Other Infections

Exserohilum rostratum was the cause of most cases of fungal meningitis and other infections associated with the injection of contaminated methylprednisolone acetate produced by the New England Compounding Center (NECC). Until this outbreak, very few human cases of Exserohilum infection had been reported, and very little was known about this dematiaceous fungus, which usually infects plants. Here, we report using whole-genome sequencing (WGS) for the detection of single nucleotide polymorphisms (SNPs) and phylogenetic analysis to investigate the molecular origin of the outbreak using 22 isolates of E. rostratum retrieved from 19 case patients with meningitis or epidural/spinal abscesses, 6 isolates from contaminated NECC vials, and 7 isolates unrelated to the outbreak. Our analysis indicates that all 28 isolates associated with the outbreak had nearly identical genomes of 33.8 Mb. A total of 8 SNPs were detected among the outbreak genomes, with no more than 2 SNPs separating any 2 of the 28 genomes. The outbreak genomes were separated from the next most closely related control strain by ∼136,000 SNPs. We also observed significant genomic variability among strains unrelated to the outbreak, which may suggest the possibility of cryptic speciation in E. rostratum.     

Reduced respiratory sinus arrhythmia in adults born at extremely low birth weight: Evidence of premature parasympathetic decline?

Individuals born at extremely low birth weight (ELBW; < 1000 g) are exposed to early adversity in multiple forms. Given that substantial development of the autonomic nervous system (ANS) occurs during the third trimester of gestation, ANS functioning may be altered in adults who were born before reaching 28 weeks of gestational age. The aims of the study were to: 1) determine whether two indices of ANS functioning [resting heart period (HP) and respiratory sinus arrhythmia (RSA)], differed between adult ELBW survivors and normal birth weight (NBW) controls, and 2) ascertain whether ANS functioning was differentially vulnerable to age-related decline in the ELBW participants. Resting HP and RSA (reflecting cardiac efficiency and responsive cardiac control, respectively) were assessed in 30 non-impaired ELBW survivors and 47 NBW controls at ages 22–26 and again at 30–35 years. At each assessment, resting RSA was significantly lower in the ELBW group than in the NBW comparison group. In addition, individual differences in RSA within the ELBW group were poorly preserved over time. These findings are suggestive of a premature decline in parasympathetic functioning in some adult ELBW survivors.