Fostering a healthier generation of children with sickle cell disease through advancements in care.

Sickle cell disease (SCD) is an inherited disorder of hemoglobin that affects tens of millions of individuals worldwide. Without preventive and disease-modifying therapy, SCD results in many acute and chronic complications impacting both quality and length of life. We are currently in a new generation of SCD care in high resource settings due to recent advancements in care. Universal newborn screening (NBS) for SCD with associated parental education and preventive care significantly improved mortality rates. Beginning in the 1990s, hydroxyurea emerged as a promising pharmacologic treatment for SCD due to its ability to increase the amount of fetal hemoglobin. It is now the mainstay of treatment, with strong recommendations to begin as early as the first year of life with the goal of reducing most short- and long-term complications and allowing for a normalized quality of life. More recently, gene therapy has come to the forefront in SCD and brings the hope of a cure for many patients. In 2023, the FDA approved two cell-based gene therapies for patients with SCD. The future is bright for patients with SCD, and the current generation of affected children will expectantly be able to grow up free of suffering and severe, frequent pain.

Hourglass-like constrictions on MRI are common in electromyography-confirmed cases of neuralgic amyotrophy (Parsonage-Turner syndrome): A tertiary referral center experience.

INTRODUCTION/AIMS: Hourglass-like constrictions (HGCs) of involved nerves in neuralgic amyotrophy (NA) (Parsonage-Turner syndrome) have been increasingly recognized with magnetic resonance neurography (MRN). This study sought to determine the sensitivity of HGCs, detected by MRN, among electromyography (EMG)-confirmed NA cases. METHODS: This study retrospectively reviewed records of patients with the clinical diagnosis of NA, and with EMG confirmation, who underwent 3-Tesla MRN within 90 days of EMG at a single tertiary referral center between 2011 and 2021. "Severe NA" positive cases were defined by a clinical diagnosis and specific EMG criteria: fibrillation potentials or positive sharp waves, along with motor unit recruitment (MUR) grades of "discrete" or "none." On MRN, one or more HGCs, defined as focally decreased nerve caliber or diffusely beaded appearance, was considered "imaging-positive." Post hoc inter-rater reliability for HGCs was measured by comparing the original MRN report against subsequent blinded interpretation by a second radiologist. RESULTS: A total of 123 NA patients with 3-Tesla MRN performed within 90 days of EMG were identified. HGCs were observed in 90.2% of all NA patients. In "severe NA" cases, based on the above EMG criteria, HGC detection resulted in a sensitivity of 91.9%. Nerve-by-nerve analysis (183 nerve-muscle pairs, nerves assessed by MRN, muscles assessed by EMG) showed a sensitivity of 91.0%. The second radiologist largely agreed with the original HGC evaluation, (94.3% by subjects, 91.8% by nerves), with no significant difference between evaluations (subjects: χ2 = 2.27, P = .132, nerves: χ2 = 0.98, P = .323). DISCUSSION: MRN detection of HGCs is common in NA.

Parsonage-Turner syndrome following monkeypox infection and vaccination.

Beginning in May 2022, monkeypox infection and vaccination rates dramatically increased due to a worldwide outbreak. This case highlights magnetic resonance (MR) neurography findings in an individual who developed Parsonage-Turner syndrome (PTS) 5 days after monkeypox symptom onset and 12 days after receiving the JYNNEOS vaccination. MR neurography of the patient's left suprascapular nerve demonstrated intrinsic hourglass-like constrictions, a characteristic finding of peripheral nerves involved in PTS. Other viral infections and vaccinations are well-documented triggers of PTS, an underrecognized peripheral neuropathy that is thought to be immune-mediated and results in severe upper extremity pain and weakness. The close temporal relationship between monkeypox infection and vaccination, and PTS onset, in this case, suggests a causal relationship and marks the first known report of peripheral neuropathy associated with monkeypox.

Magnetic resonance imaging of femoral nerve injury in the setting of anterior approach total hip arthroplasty.

PURPOSE: To illustrate MRI findings in patients with femoral neuropathy following anterior approach total hip arthroplasty (THA). METHODS: This was a retrospective review of patients who underwent MRI for femoral neuropathy following anterior approach THA between January 1, 2010, and July 1, 2022. Included patients had no preexisting neurologic condition. Clinical and diagnostic data were collected. MRIs were reviewed in consensus by 2 musculoskeletal radiologists. RESULTS: A total of 115 patient records were reviewed, 17 of which were included in the final analysis (mean age 64 years; 11 females). Study subjects presented with weakness with hip flexion and knee extension and pain and numbness in the femoral nerve distribution. In 7 subjects, the femoral nerve appeared normal. In 5 subjects, the femoral nerve was hyperintense on fluid-sensitive fat-suppressed imaging. In 4 patients, mass effect on the femoral nerve by either ill-defined soft tissue edema (n = 2), seroma (n = 1), or heterotopic ossification (n = 1) was detected. Only 1 patient had a nerve transection. Patients were imaged at a median time of 8 months (range: 1 day to 11 years) following arthroplasty placement. Clinical follow-up was available in 8 patients, of whom half had complete symptomatic resolution and half had partial improvement at a mean follow-up time of 39.3 months (SD 51.1). Of these 8, 1 underwent revision arthroplasty, 1 had removal of hardware, and another had excision of heterotopic ossification. CONCLUSION: MRI provides a means to directly evaluate the femoral nerve following anterior approach THA in both the immediate and chronic postoperative periods.

Visualization of Median Nerve Entrapment After Reduction of an Elbow Fracture Dislocation Using 3-Dimensional Magnetic Resonance Imaging: A Case Report.

CASE: A 10-year-old girl presented after closed reduction of an elbow fracture dislocation. She demonstrated intact vascularity but a dense median nerve palsy. Preoperative magnetic resonance neurography (MRN) precisely mapped the median nerve entrapped within the medial epicondylar fracture. Intraoperatively, the median nerve was freed preceding reduction and fracture fixation. Postoperatively, neurological symptoms completely resolved, and she regained full elbow function. CONCLUSION: Median nerve injury can present without associated vascular injury. In this case, MRN was helpful in preoperatively illustrating the spatial relationship between the median nerve and the medial epicondyle.

A programmable encapsulation system improves delivery of therapeutic bacteria in mice.

Living bacteria therapies have been proposed as an alternative approach to treating a broad array of cancers. In this study, we developed a genetically encoded microbial encapsulation system with tunable and dynamic expression of surface capsular polysaccharides that enhances systemic delivery. Based on a small RNA screen of capsular biosynthesis pathways, we constructed inducible synthetic gene circuits that regulate bacterial encapsulation in Escherichia coli Nissle 1917. These bacteria are capable of temporarily evading immune attack, whereas subsequent loss of encapsulation results in effective clearance in vivo. This dynamic delivery strategy enabled a ten-fold increase in maximum tolerated dose of bacteria and improved anti-tumor efficacy in murine models of cancer. Furthermore, in situ encapsulation increased the fraction of microbial translocation among mouse tumors, leading to efficacy in distal tumors. The programmable encapsulation system promises to enhance the therapeutic utility of living engineered bacteria for cancer.

Leveraging Systematic Functional Analysis to Benchmark an In Silico Framework Distinguishes Driver from Passenger MEK Mutants in Cancer.

Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation.See related commentary by Whitehead and Sebolt-Leopold, p. 4042.