Citations

Purpose: Planning for robotic-assisted partial nephrectomy requires surgeons to review two-dimensional CT or MRI scans to understand three-dimensional (3D) anatomy. We sought to determine the drivers of improvements in key surgical outcomes when using patient-specific 3D virtual reality (VR) models for operative planning. Materials and Methods: A multicenter, randomized, single-blind clinical trial was conducted from January 2019 to December 2020. Patients undergoing robotic-assisted partial nephrectomy were randomly assigned to a control group undergoing usual preoperative planning with CT and/or MRI only or to an intervention group where imaging was supplemented with a 3D VR model. A survey was administered to surgeons after review of the model and after the operation. The primary outcome measure was operative time, and secondary outcomes included clamp time, estimated blood loss, and hospital stay. Results: Qualitative data analysis of 44 cases in the treatment arm was performed. Surgeons reported seeing anatomic details much better in the 3D model 55% of the time and modified their preoperative plan based on anatomy shown in the 3D model 30% of the time. Cases in which the surgeon reported modifying their preoperative plan after viewing the model (30%) had significantly lower operative time, blood loss, and clamp time (P < .05). In addition, increased surgeon confidence after viewing the model significantly lowered operative time, estimated blood loss, and clamp time (P < .05). Conclusions: We demonstrate that surgeons who use 3D VR models for robotic kidney surgery are able to visualize anatomic structures and select the optimal approach, leading to better surgical outcomes. Trial Registration: ClinicalTrials.gov identifier NCT0333434.

Abstract The field of oncology has been transformed by immune checkpoint inhibitors (ICI) and other immune-based agents; however, many patients do not receive a durable benefit. While biomarker assessments from pivotal ICI trials have uncovered certain mechanisms of resistance, results thus far have only scraped the surface. Mechanisms of resistance are as complex as the tumor microenvironment (TME) itself, and the development of effective therapeutic strategies will only be possible by building accurate models of the tumor-immune interface. With advancement of multi-omic technologies, high-resolution characterization of the TME is now possible. In addition to sequencing of bulk tumor, single-cell transcriptomic, proteomic, and epigenomic data as well as T-cell receptor profiling can now be simultaneously measured and compared between responders and nonresponders to ICI. Spatial sequencing and imaging platforms have further expanded the dimensionality of existing technologies. Rapid advancements in computation and data sharing strategies enable development of biologically interpretable machine learning models to integrate data from high-resolution, multi-omic platforms. These models catalyze the identification of resistance mechanisms and predictors of benefit in ICI-treated patients, providing scientific foundation for novel clinical trials. Moving forward, we propose a framework by which in silico screening, functional validation, and clinical trial biomarker assessment can be used for the advancement of combined immunotherapy strategies.

AbstractIntroductionPersistent pain following breast surgery is common and may be challenging to treat. In patients refractory to conservative treatments, ultrasound‐guided fascial plane blocks of thoracic nerves can be a useful option.ResultsThis type of neuro blockade technique provides advantages in terms of safety and efficacy that are convenient for physicians managing refractory and complex cases of post‐breast surgery syndrome.ConclusionThis technical review aims to present an up‐to‐date summary of the most common ultrasound‐guided fascial plane blocks for chronic pain in post‐breast surgery patients, provide a detailed technical description of each intervention, and propose preferred injections based on the anatomical location of the pain.

AbstractBackgroundMicroglia, the resident brain immune cells, play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA‐155 (miR‐155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer’s disease (AD) pathogenesis remains unclear.MethodsWe used RNAseq and immunohistochemistry (n = 6‐8 per sex per group) to investigate the gene expression profile and AD pathology. We further utilized single‐cell RNAseq (n = 5 per group) to identify microglial clusters. Whole‐tissue proteomics (n = 4) was applied to detect the protein changes in brain milieu. Moreover, we used spontaneous alternation and forced alternation tests to evaluate the cognition (n = 33‐36).ResultWe report that microglial deletion of miR‐155 induces a pre‐MGnD activation state via interferon‐g (IFNg) signaling and blocking IFNg signaling attenuates MGnD induction and microglial phagocytosis. Single‐cell RNAseq analysis of microglia from AD mouse model identifies Stat1 and Clec2d as pre‐MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque‐associated synaptic degradation, and improves cognition.ConclusionOur study demonstrates a novel miR‐155‐mediated regulatory mechanism of MGnD and the beneficial role of IFNg‐responsive pre‐MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR‐155 and IFNg as potential therapeutic targets for AD.

AbstractBackgroundAPOE ε4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD).MethodGeneration of CX3CR1‐CREERT2 mice crossed to APOE‐KI(E3 and E4)fl/fl: APP/PS1 and APOE‐KI(E3 and E4)fl/fl: P301S mice. Microglia and astrocytes were isolated and sequenced using either bulk RNA‐seq (MGnD‐Paradigm) or single‐cell RNA‐seq. Crosstalk between cells was determined using the NichenetR database and validated using 1) recombinant Lgals3 intracranial injection into APP/PS1 mice and 2) adoptive transfer of microglia, from APOE3‐KI, APOE4‐KI, and APOE4‐cKO mice challenged with labeled apoptotic neurons, into WT mice and isolation of astrocytes. Validation in the brain of AD donors carrying the APOE e3/3 and e3/4 alleles.ResultHere we show, in mice and in humans, a negative role of microglial APOE4 in the induction of MGnD response to neurodegeneration. Deletion of microglial APOE4 restores MGnD phenotype, associated with neuroprotection in P301S tau transgenic mice, and decreases pathology in APP/PS1 mice. MGnD‐astrocyte crosstalk associated with b‐amyloid (Ab) plaque encapsulation and clearance is mediated via Lgals3 signaling following microglial APOE4 deletion. In the brain of AD donors carrying the APOE ε4 allele, we found a sex‐dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, as compared to APOE ε3/3 carriers. Mechanistically, APOE4‐mediated induction of ITGB8‐TGFb signaling impairs MGnD response via upregulation of TGFb‐mediated microglial homeostatic checkpoints, including INPP5D. Microglial deletion of Inpp5d restores MGnD‐astrocyte crosstalk and facilitates plaque clearance in APP/PS1 mice. Genetic and pharmacological blocking of ITGB8‐TGFb signaling enhanced MGnD response associated with increased plaque clearance in AD mice.ConclusionWe identify the microglial APOE4‐ITGB8‐TGFb pathway as a negative regulator of microglia‐astrocyte response to AD pathology, and restoring MGnD phenotype via blocking ITGB8‐TGFb signaling may provide new molecular targets to modulate and restore functional microglia in AD.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving the upper and lower motor neurons. Perioperative management of patients with ALS can be challenging due to the risk of hemodynamic instability, aspiration, and ventilatory failure. We discuss a 58-year-old male patient with ALS who underwent open abdominal surgery under regional anesthesia utilizing a remimazolam infusion for sedation. While various sedation agents have been used successfully in patients with ALS, remimazolam, a new short-acting benzodiazepine with unique pharmacologic properties and reversible anxiolysis, provides amnesia while avoiding ventilatory depression.