SARM1 knockout does not rescue neuromuscular phenotypes in a Charcot-Marie-Tooth disease Type 1A mouse model.

Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice. CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1-/- mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were evaluated histologically. Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, genetic deletion of SARM1 conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout. Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in C3-PMP CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.

Adding Nocturnal Advanced Practice Providers to an Academic Inpatient Neurology Service Improves Residents' Educational Experience.

Background and Objectives: In the inpatient academic medical center, increased demand for clinical services often equates to an increased workload for trainees, which could have a positive or negative impact on their educational experience. In 2020, our academic medical center hired Advanced Practice Providers (APPs) to provide continuous additional overnight coverage for our neurology ward teaching service. We hypothesized that adding APPs and reducing overnight clinical workload for residents would have a positive impact on resident education. Methods: We performed a mixed-methods, prospective study that included needs-assessments by residents, semi-structured interviews with both residents and APPs, and surveys to residents and nursing staff. In addition, we collected quantitative data such as hours of sleep, number of admissions, and number of pages to capture the impact of APPs on resident overnight shifts. Results: The addition of APPs overnight increased the median hours of sleep overnight from 1 hour to 3 hours (P < .001) and decreased the median number of pages overnight from 31.5 to 17 (P < .001). The median number of patients the resident was responsible for cross-covering overnight decreased from 24 patients to 14 patients (P < .001). The majority of resident responses (94%) agreed that the addition of APPs benefited their education by reducing workload and increasing time allotted to reading and formulating plans for overnight admissions. 88% of residents agreed that the addition of APPs improved quality of life and reduced risk of burnout. Conclusion: Advanced Practice Providers significantly reduced resident workload, leading residents to report improvements in the educational experience overnight and reduced perceived risk of burnout.

Chemoprophylaxis for venous thromboembolism in pelvic and/or acetabular fractures: A systematic review.

BACKGROUND: It is unclear which pharmacological agents, and at what dosage and timing, are most effective for venous thromboembolism (VTE) prophylaxis in patients with pelvic/acetabular fractures. METHODS: We searched the Cochrane Database of Systematic Reviews, Embase, Web of Science, EBSCO, and PubMed on October 3, 2020, for English-language studies of VTE prophylaxis in patients with pelvic/acetabular fractures. We applied no date limits. We included studies that compared efficacy of pharmacological agents for VTE prophylaxis, timing of administration of such agents, and/or dosage of such agents. We recorded interventions, sample sizes, and VTE incidence, including deep vein thrombosis (DVT) and pulmonary embolism. RESULTS: Two studies (3604 patients) compared pharmacological agents, reporting that patients who received direct oral anticoagulants (DOACs) were less likely to develop DVT than those who received low molecular weight heparin (LMWH) (p < 0.01). Compared with unfractionated heparin (UH), LMWH was associated with lower odds of VTE (odds ratio [OR] = 0.37, 95% confidence interval [CI]: 0.22-0.63) and death (OR = 0.27, 95% CI: 0.10-0.72). Three studies (3107 patients) compared timing of VTE prophylaxis, reporting that late prophylaxis was associated with higher odds of VTE (OR = 1.9, 95% CI: 1.2-3.2) and death (OR = 4.0, 95% CI: 1.5-11) and higher rates of symptomatic DVT (9.2% vs. 2.5%, p = 0.03; and 22% vs. 3.1%, p = 0.01). One study (31 patients) investigated dosage of VTE prophylaxis, reporting that a higher proportion of patients with acetabular fractures were underdosed (23% of patients below range of anti-Factor Xa [aFXa] had acetabular fractures vs. 4.8% of patients within adequate range of aFXa, p<0.01). CONCLUSIONS: Early VTE chemoprophylaxis (within 24 or 48 h after injury) was better than late administration in terms of VTE and death. Many patients with acetabular fractures are underdosed with LMWH, with inadequate aFXa levels. Compared with UH, LMWH was associated with lower odds of VTE and death. DOACs were associated with lower risk of DVT compared with LMWH. LEVEL OF EVIDENCE: III, systematic review of retrospective cohort studies.

Is there an increased risk for subtrochanteric stress fracture with the Femoral Neck System versus multiple cannulated screws fixation?

Purpose: This study sought to compare the risk of subtrochanteric stress-riser fractures and biomechanical stability of the Femoral Neck System (FNS) versus multiple screw fixation (MSF). Methods: Eight paired cadaveric femurs were randomly assigned to FNS or MSF. Physiologic load mimicking single leg stance at the subtrochanteric region was applied to the constructs. Results: No constructs failed in the subtrochanteric region during loading. There was no significant difference in force (P = 0.364) or loading cycles (P = 0.348) between groups. Conclusion: FNS constructs were not associated with an increased incidence of iatrogenic subtrochanteric fractures or biomechanical stability versus MSF.

Tranexamic acid use in pelvic and/or acetabular fracture surgery: A systematic review and meta-analysis.

PURPOSE: The purpose of this study is to determine whether tranexamic acid (TXA) use was associated with lower rates of blood transfusion in patients undergoing pelvic and/or acetabular fracture surgery. METHODS: Four studies were included, 3 of which were included in the pooled data analysis for a total of 308 patients. RESULTS: The transfusion rate was significantly lower in the TXA group (44%) compared with the non-TXA group (57%) (P = 0.02). CONCLUSION: TXA use was associated with a significantly lower transfusion rate in patients who underwent pelvic and/or acetabular fracture surgery. LEVEL OF EVIDENCE: Level 3. Systematic review of retrospective cohort studies and prospective randomized controlled trials.

Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity.

Given the immense antigenic load present in the microbiome, we hypothesized that microbiota mimotopes can be a persistent trigger in human autoimmunity via cross-reactivity. Using antiphospholipid syndrome (APS) as a model, we demonstrate cross-reactivity between non-orthologous mimotopes expressed by a common human gut commensal, Roseburia intestinalis (R. int), and T and B cell autoepitopes in the APS autoantigen ß2-glycoprotein I (ß2GPI). Autoantigen-reactive CD4+ memory T cell clones and an APS-derived, pathogenic monoclonal antibody cross-reacted with R. int mimotopes. Core-sequence-dependent anti-R. int mimotope IgG titers were significantly elevated in APS patients and correlated with anti-ß2GPI IgG autoantibodies. R. int immunization of mice induced ß2GPI-specific lymphocytes and autoantibodies. Oral gavage of susceptible mice with R. int induced anti-human ß2GPI autoantibodies and autoimmune pathologies. Together, these data support a role for non-orthologous commensal-host cross-reactivity in the development and persistence of autoimmunity in APS, which may apply more broadly to human autoimmune disease.

Pseudouridines in spliceosomal snRNAs.

Spliceosomal RNAs are a family of small nuclear RNAs (snRNAs) that are essential for pre-mRNA splicing. All vertebrate spliceosomal snRNAs are extensively pseudouridylated after transcription. Pseudouridines in spliceosomal snRNAs are generally clustered in regions that are functionally important during splicing. Many of these modified nucleotides are conserved across species lines. Recent studies have demonstrated that spliceosomal snRNA pseudouridylation is catalyzed by two different mechanisms: an RNA-dependent mechanism and an RNA-independent mechanism. The functions of the pseudouridines in spliceosomal snRNAs (U2 snRNA in particular) have also been extensively studied. Experimental data indicate that virtually all pseudouridines in U2 snRNA are functionally important. Besides the currently known pseudouridines (constitutive modifications), recent work has also indicated that pseudouridylation can be induced at novel positions under stress conditions, thus strongly suggesting that pseudouridylation is also a regulatory modification.

Functions and mechanisms of spliceosomal small nuclear RNA pseudouridylation.

Pseudouridines are the most abundant and highly conserved modified nucleotides identified in spliceosomal small nuclear RNAs (snRNAs). Most pseudouridines are also clustered in functionally important regions of spliceosomal snRNAs. Experiments carried out in several independent experimental systems show that the pseudouridines in spliceosomal snRNAs are functionally important for pre-messenger RNA (mRNA) splicing. Experimental data also indicate that spliceosomal snRNA pseudouridylation can be catalyzed by both RNA-dependent (box H/ACA Ribonucleoproteins) and RNA-independent (protein-only enzymes) mechanisms.