Citations

Aortic dilation following single ventricle palliation is increasingly recognized, although its long-term clinical implications remain unclear. We present the case of a 38-year-old male born with a bicuspid aortic valve, d-transposition of the great arteries, ventricular septal defect, right ventricular hypoplasia with a straddling right atrioventricular valve. He was palliated with Fontan circulation and developed severe neo-aortic root and arch dilation with native aortic valve stenosis, requiring surgical intervention. His neo-aortic root measured 81 × 65 mm, necessitating a Bentall procedure with total arch and native aortic valve replacement. This case underscores the variable progression of aortic dilation in patients with palliated single ventricle physiology and the need for strict surveillance and individualized management. Larger cohort studies are needed to further refine the criteria for surgical intervention in this unique population.

Background: Spasticity is common in spinal cord injury (SCI) and multiple sclerosis (MS), and it can manifest as repeated, rhythmic muscle contractions called clonus. The spontaneous nature of clonus can disrupt independent performance of activities of daily living and negatively impact overall health and quality of life. Objectives: To quantify biomarkers of clonus and explore management of clonus in individuals with SCI or progressive MS using epidural spinal cord stimulation (ES) or dorsal root stimulation (DRS). Methods: Four male participants were included in this case series study: 3 with SCI and 1 with MS. All participants underwent temporary percutaneous ES lead placement over the dorsolateral thoracolumbar region of the spinal cord. Participants with SCI were also implanted with DRS leads at the L4 dorsal root. Clonus was elicited mechanically at the ankle while recording electromyography of the soleus muscle synchronized to direct spinal cord field potential recordings from ES and DRS percutaneous leads. Results: Clonus was evident as a prominent band (5-8 Hz) in recordings from ES leads, DRS leads, soleus muscle, and accelerometry. In 4 participants, percutaneous spinal stimulation reduced median clonus duration and cycle count. Clonus was immediately suppressed upon activation of spinal cord stimulation, and the suppression persisted even when clonus was reinitiated after turning off the stimulation. Conclusion: The use of objective biomarkers, including spinal cord potentials, to quantify clonus in real time combined with the immediate and reversible effects of stimulation highlight the potential of neuromodulation as a therapeutic tool for managing clonus. These data demonstrate preliminary efficacy of ES and DRS for clonus monitoring and treatment in 4 participants.

Glioblastoma (GBM) is an aggressive brain tumor with a highly immunosuppressive microenvironment that promotes tumor progression and therapy resistance. Tumor-associated macrophages (TAMs), comprising up to 50% of the tumor mass, are recruited via chemokine axes such as CCL2/CCR2, CX3CL1/CX3CR1, and CXCL12/CXCR4 and adopt an M2-like immunosuppressive phenotype, facilitating immune escape and angiogenesis. Key signaling pathways, including CSF1R, STAT3, NF-κB, PI3K/Akt, and HIF-1α, regulate TAM function, making them promising therapeutic targets. Strategies such as TAM depletion, reprogramming, and immune checkpoint blockade (PD-1/PD-L1, and CD47-SIRPα) have shown potential in preclinical models. Emerging approaches, including CAR-macrophage (CAR-M) therapy, nanotechnology-based drug delivery, and exosome-mediated modulation, offer new avenues for intervention. However, clinical translation remains challenging due to GBM’s heterogeneity and adaptive resistance mechanisms. Future research should integrate multi-omics profiling and AI-driven drug discovery to refine TAM-targeted therapies and improve patient outcomes. This review provides a comprehensive analysis of TAM-mediated immune regulation in GBM and explores evolving therapeutic strategies aimed at overcoming its treatment barriers.

Importance Multiparametric magnetic resonance imaging (MRI), with or without prostate biopsy, has become the standard of care for diagnosing clinically significant prostate cancer. Resource capacity limits widespread adoption. Biparametric MRI, which omits the gadolinium contrast sequence, is a shorter and cheaper alternative offering time-saving capacity gains for health systems globally. Objective To assess whether biparametric MRI is noninferior to multiparametric MRI for diagnosis of clinically significant prostate cancer. Design, Setting, and Participants A prospective, multicenter, within-patient, noninferiority trial of biopsy-naive men from 22 centers (12 countries) with clinical suspicion of prostate cancer (elevated prostate-specific antigen [PSA] level and/or abnormal digital rectal examination findings) from April 2022 to September 2023, with the last follow-up conducted on December 3, 2024. Interventions Participants underwent multiparametric MRI, comprising T2-weighted, diffusion-weighted, and dynamic contrast–enhanced (DCE) sequences. Radiologists reported abbreviated biparametric MRI first (T2-weighted and diffusion-weighted), blinded to the DCE sequence. After unblinding, radiologists reported the full multiparametric MRI. Patients underwent a targeted biopsy with or without systematic biopsy if either biparametric MRI or multiparametric MRI was suggestive of clinically significant prostate cancer. Main outcomes and measures The primary outcome was the proportion of men with clinically significant prostate cancer. Secondary outcomes included the proportion of men with clinically insignificant cancer. The noninferiority margin was 5%. Results Of 555 men recruited, 490 were included for primary outcome analysis. Median age was 65 (IQR, 59-70) years and median PSA level was 5.6 (IQR, 4.4-8.0) ng/mL. The proportion of patients with abnormal digital rectal examination findings was 12.7%. Biparametric MRI was noninferior to multiparametric MRI, detecting clinically significant prostate cancer in 143 of 490 men (29.2%), compared with 145 of 490 men (29.6%) (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points; P = .50). Biparametric MRI detected clinically insignificant cancer in 45 of 490 men (9.2%), compared with 47 of 490 men (9.6%) with the use of multiparametric MRI (difference, −0.4 [95% CI, −1.2 to 0.4] percentage points). Central quality control demonstrated that 99% of scans were of adequate diagnostic quality. Conclusion and relevance In men with suspected prostate cancer, provided image quality is adequate, an abbreviated biparametric MRI scan, with or without targeted biopsy, could become the new standard of care for prostate cancer diagnosis. With approximately 4 million prostate MRIs performed globally annually, adopting biparametric MRI could substantially increase scanner throughput and reduce costs worldwide. Trial registration ClinicalTrials.gov Identifier: NCT04571840

The NCCN Guidelines for Biliary Tract Cancers (BTCs) provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts is convened at least once annually to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. This manuscript focuses on the adjuvant chemotherapy and chemoradiation treatment options for BTCs as well as the systemic treatment recommendations for patients with advanced BTCs.

Objectives: To describe changes in the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam in sublesional motor and sensory domains following short-term epidural electrical stimulation of lumbosacral spinal segments in individuals with spinal cord injury (SCI). Methods: Twenty individuals with SCI underwent implantation of percutaneous epidural spinal cord stimulation followed by stimulation parameter optimization and 10-12 sessions of stimulation-enabled motor training. Pre-/postintervention ISNCSCI exams were compared to determine changes in motor/sensory scores for regions within 3 levels of the neurological level of injury (NLI) and caudal to this, with subanalyses per motor/sensory complete versus incomplete baseline status. Results: Individuals with motor complete SCI gained 6% ± 3% of available motor points within 3 levels of NLI and 1% ± 0% of motor points caudal to this ( P = .08). Motor incomplete individuals gained 9% ± 22% of available motor points within 3 levels of NLI and lost 4% ± 7% of motor points caudal to this ( P = .63). Following stimulation, changes in motor scores with potential high functional impact occurred in 3 individuals (5 total muscle groups with conversion from baseline <3/5 strength to ≥3/5 at completion). Individuals with sensory complete SCI had fewer sensory gains within 3 levels of NLI (6%) compared to those with sensory incomplete SCI (30%, P = .02). Discussion: Spinal cord stimulation after SCI rapidly induces changes in both motor and sensory domains that are retained after stimulation is removed. These changes primarily occur within 3 levels of the NLI and occur to a greater degree in those with incomplete SCI.

Abstract Germline and osteoblast-directed deletion of G protein-gated inwardly rectifying K+ channel 3 (Girk3) was recently shown to increase bone mass after 18 wk of age in male mice. Here, we show that germline Girk3 deletion also increases trabecular and cortical bone mass and increases the mechanical strength of the femur in female mice after 18 wk of age. Unlike male mice, however, osteoblast-directed Girk3 deletion using 2.3 kb-Col1a1-Cre does not increase bone mass in adult female mice. To discover mechanisms underlying high bone mass in female Girk3−/− mice, bulk RNA-sequencing was performed on 2-d-old calvarial bone, revealing lower expression of proinflammatory cytokines such as IL-1β and IL-6 in Girk3−/− mice. Accordingly, cytokines and chemokines are largely suppressed in the circulation of adult Girk3−/− mice compared to WT littermates. The cytokines GM-CSF, IL-1β, IL-2, and IL-9 are reduced in the serum of both male and female Girk3−/− mice, while eotaxin, IFNγ, MIP-1α, and others are sexually dimorphic. Histomorphometry reveals that osteoclast activity is modestly reduced in Girk3−/− bone, which is supported by in vitro osteoclast resorption assays. However, deletion of Girk3 in myeloid-lineage cells with LysM-Cre is not sufficient to recapitulate high bone mass in either male or female mice. Moreover, female Girk3−/− mice are not protected from ovariectomy-induced bone loss. Finally, single-cell screening using cytometry by time-of-flight in the BM revealed no differences in immune cell abundances due to global Girk3 deletion. Taken together, while Girk3 regulates inflammatory cytokine expression in the bone and serum, deletion of Girk3 in myeloid-lineage cells does not affect bone mass.

Clonus is a disabling symptom of upper motor neuron dysfunction in patients with multiple sclerosis (MS). We report immediate termination of mechanically evoked clonus by epidural lumbosacral spinal cord stimulation (ES) in a 58-year-old man with secondary progressive MS. This observation was captured during training using video and skin surface electromyography of soleus muscle activity. ES immediately reduced mechanically evoked clonus duration and cycle count compared to trials without stimulation, as determined by a Kruskal–Wallis test ( p < 0.05, n = 2–3 trials), and reverted to baseline status when stimulation was off.