Citations

Abstract Temporal lobe epilepsy is a common neurological disease characterized by recurrent seizures that often originate within limbic networks involving amygdala and hippocampus. The limbic network is involved in crucial physiologic functions involving memory, emotion and sleep. Temporal lobe epilepsy is frequently drug-resistant, and people often experience comorbidities related to memory, mood and sleep. Deep brain stimulation targeting the anterior nucleus of the thalamus (ANT-DBS) is an established therapy for temporal lobe epilepsy. However, the optimal stimulation parameters and their impact on memory, mood and sleep comorbidities remain unclear. We used an investigational brain sensing-stimulation implanted device to accurately track seizures, interictal epileptiform spikes (IES), and memory, mood and sleep comorbidities in five ambulatory subjects. Wireless streaming of limbic network local field potentials (LFPs) and subject behaviour were captured on a mobile device integrated with a cloud environment. Automated algorithms applied to the continuous LFPs were used to accurately cataloged seizures, IES and sleep-wake brain state. Memory and mood assessments were remotely administered to densely sample cognitive and behavioural response during ANT-DBS in ambulatory subjects living in their natural home environment. We evaluated the effect of continuous low-frequency and duty cycle high-frequency ANT-DBS on epileptiform activity and memory, mood and sleep comorbidities. Both low-frequency and high-frequency ANT-DBS paradigms reduced seizures. However, continuous low-frequency ANT-DBS showed greater reductions in IES, electrographic seizures and better sleep and memory outcomes. These results highlight the potential of synchronized brain sensing and dense behavioural tracking during ANT-DBS for optimizing neuromodulation therapy. While studies with larger patient numbers are needed to validate the benefits of low-frequency ANT-DBS, these findings are potentially translatable to individuals currently implanted with ANT-DBS systems.

Abstract Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Patients and Methods: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL −1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response >12 months and ongoing even after stopping treatment (5.4–69.0 months). Patients with PD-L1–positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1–negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

The trial-to-implant ratio for spinal cord stimulation (SCS) has long served as a cornerstone metric for optimizing patient selection and cost containment. Historically, screening trials played a pivotal role in identifying non-responders, thereby minimizing unnecessary permanent implantations. The utility of the trial paradigm is supported by Medicare data from 2009, which reported a trial-to-implant ratio of 42.5%. However, advancements in SCS technology have significantly transformed the neuromodulation landscape and have been associated with higher rates of trial success. By 2018, the Medicare data showed trial-to-implant ratios exceeding 63%, with randomized clinical trials from 2020 to 2021 reporting ratios exceeding 80%–90%. These significant increases in trial-to-implant ratios suggest that only a minority of SCS candidates do not undergo a subsequent permanent device implantation. As such, re-evaluation of the trial-to-implant paradigm, from the perspective of practicing pain physicians in the USA, in light of evolving clinical practices and economic pressures, is warranted. This discourse explores the benefits and limitations of the trial-to-implant ratio, emphasizing its role as a safeguard against overutilization and a tool for standardizing clinical practices but weighed against its shortcomings including a lack of alignment with long-term outcomes, underscore the need for alternative metrics that include per capita trial utilization and explant-to-implant ratios. European responses to similar questions have resulted in utilizing validated symptom screening tools and direct-to-implant pathways in lieu of a screening trial altogether as potential strategies to optimize SCS utilization while maintaining cost-effectiveness. As healthcare systems adapt to advancements in neuromodulation, a balanced perspective on trial-to-implant ratios and complementary metrics is essential to ensure equitable access, sustainable outcomes and evidence-based care for the future of SCS therapy.

BACKGROUND: Within the US, there has been an overall increase in cost of malpractice insurance for surgeons and decrease in federal reimbursement for surgical work. This study aimed to analyze state-to-state variability to understand differences in costs relative to reimbursement for surgeons and temporal trends. STUDY DESIGN: This study uses publicly available data to conduct a cross-sectional evaluation of surgeon medical malpractice premium rates and surgical reimbursement between 2013 and 2023. Surgeon reimbursement was represented in terms of the unit reimbursement rate for laparoscopic cholecystectomy (LC). The ratio of surgeon reimbursement to malpractice cost was calculated and considered as the number of LCs required in each state to cover the cost of malpractice insurance. RESULTS: Inflation-adjusted reimbursement for LC decreased in all states with a mean decrease of 24%. Although there was an overall decrease in inflation-adjusted medical malpractice premium cost, some states experienced an increase of up to 22% (Rhode Island), whereas other states experienced a decrease in cost of 62% (Oregon). For the year 2023, there was significant variability in the number of LCs needed to afford malpractice insurance premiums across states, ranging from 21 (Minnesota) to 163 (Illinois). Rhode Island experienced the greatest increase in change from 2013 to 2023 (63%), whereas Oregon experienced the greatest decrease (50%). CONCLUSIONS: This study finds significant variation in Medicare-based surgeon compensation relative to malpractice insurance costs across the US. This discrepancy highlights the challenges faced by surgical practices due to inconsistent insurance cost and decreases in reimbursement rates.

Abstract The TopBP1-ATR axis is critical for maintaining genomic stability during DNA replication stress, yet the precise regulation of TopBP1 in replication stress responses remains poorly understood. In this study, we identified PHD and Ring Finger Domains 1 (PHRF1) as an important ATR activator through its interaction with TopBP1. Our analysis revealed a correlation between PHRF1 and genomic stability in cancer patients. Mechanistically, PHRF1 is recruited to DNA lesions in a manner dependent on its PHD domain and histone methylation. Subsequently, PHRF1 mono-ubiquitinates TopBP1 at lysine 73, which enhances the TopBP1-ATR interaction and activates ATR. Depletion of PHRF1 disrupts ATR activation and sensitizes cells to replication stress-inducing agents. Furthermore, conditional knockout of Phrf1 in mice leads to early lethality and impaired ATR-Chk1 axis signaling. Collectively, our findings establish PHRF1 as a novel E3 ligase for TopBP1, coordinating the replication stress response by enhancing TopBP1-ATR signaling.

BACKGROUND AND OBJECTIVES: The lateral transorbital approach (LTOA) has gained increased recognition, but there is still a paucity of data on its effectiveness and advantages compared with the LTOA with lateral orbitotomy, herein denoted as the lateral orbital wall approach (LOWA). The aim of this study was to provide an anatomical reappraisal and the authors' clinical experience to compare the 2 approaches to the orbit and middle cranial fossa (MCF). METHODS: Eight latex-injected cadaveric specimens were used to perform LTOA and LOWA. The operative depth of each approach to key anatomical landmarks was measured. Fifty high-resolution computed tomography studies were reviewed to calculate the operative angles. We reviewed 40 consecutive cases treated with LTOA and LOWA at our institution. RESULTS: Compared with the LTOA, the LOWA provided shorter operative depths to the optic foramen ( P < .05), foramen ovale ( P < .05), and to the junction eyeball-cranial nerve II ( P = .13). It also offered better access to the anterior aspect of the orbit with less orbital content retraction. The LTOA and LOWA provided different operative angles to key anatomical landmarks in the orbit and MCF ( P < .05). In our chart review, 31 patients underwent the LTOA, whereas 9 underwent the LOWA to treat orbital and MCF lesions. Patients undergoing LOWA experienced postoperative complications related to periorbital nerves, such as frontalis palsy (n = 1) and supraorbital neuralgia (n = 1). Patients undergoing LTOA were more prone to complications associated with intraorbital manipulation (n = 4), including diplopia and ptosis. CONCLUSION: Our data suggest that the LTOA can be an effective surgical strategy for addressing orbital apex and MCF lesions. Although the LOWA provides access to the aforementioned areas, it may be more suitable for anterior orbital lesions that require direct access with wider entry exposure and extensive orbital content manipulation.

Traumatic brain injury (TBI) is a leading cause of disability and death globally, presenting significant challenges for diagnosis, prognosis, and treatment. As healthcare technology advances, artificial intelligence (AI) has emerged as a promising tool in enhancing TBI rehabilitation outcomes. This literature review explores the current and potential applications of AI in TBI management, focusing on AI’s role in diagnostic tools, neuroimaging, prognostic modeling, and rehabilitation programs. AI-driven algorithms have demonstrated high accuracy in predicting mortality, functional outcomes, and personalized rehabilitation strategies based on patient data. AI models have been developed to predict in-hospital mortality of TBI patients up to an accuracy of 95.6%. Furthermore, AI enhances neuroimaging by detecting subtle abnormalities that may be missed by human radiologists, expediting diagnosis and treatment decisions. Despite these advances, ethical considerations, including biases in AI algorithms and data generalizability, pose challenges that must be addressed to optimize AI’s implementation in clinical settings. This review highlights key clinical trials and future research directions, emphasizing AI’s transformative potential in improving patient care, rehabilitation, and long-term outcomes for TBI patients.

BACKGROUND: A preservation system, the Organ Care System (OCS; TransMedics) uses normothermic pulsatile perfusion during organ transport for heart transplantation. This system has demonstrated favorable outcomes in hearts recovered from extended-criteria donors after brain death (DBD) and donors after circulatory death (DCD). METHODS: The OCS Heart Perfusion Registry collects data on US heart transplantations using the OCS, static cold storage (SCS), or thoracoabdominal normothermic regional perfusion (NRP) and donor hearts recovered from DBD or DCD donors. We analyzed donor and recipient characteristics and posttransplantation outcomes in patients transplanted with OCS donor hearts (either DBD or DCD) compared with SCS hearts, and with OCS hearts from DCD donors compared with those recovered with NRP followed by SCS. Propensity score matching was used in survival analyses to adjust for differences among recipient characteristics. RESULTS: Between 2021 and 2023, 3225 consecutive heart transplantations enrolled from 56 centers were analyzed in the Heart Perfusion Registry. The OCS was used in 854 of 3225 heart transplantations (26.4%), among which 340 (39.8%) were DBD and 514 (60.2%) were DCD donors, whereas 2174 DBD donors were recovered with SCS and another 197 DCD donors with NRP techniques. The OCS-DBD group experienced a greater number of organ offer refusals before final acceptance (13 versus 6; Wilcoxon rank sum, P <0.001) and a longer transport distance (667 miles versus 232 miles; Wilcoxon rank sum, P <0.001) compared with SCS-DBD. Survival at 12 months was similar between the 2 groups (89.9% for OCS-DBD versus 90.6% for SCS-DBD; marginal Cox model, P =0.54). Among the OCS-DCD and SCS-DBD groups, survival at 12 months was also similar (91.0% versus 92.5%, respectively; marginal Cox model, P =0.32). The OCS-DCD and NRP-DCD groups demonstrated similar survival (91.0% versus 91.7%, respectively; log rank, P =0.63), although the transport distance was longer in OCS-DCD compared with DCD with NRP followed by SCS (400 miles versus 223 miles; Wilcoxon rank sum, P <0.001). By 2023, 90% of all OCS donor management and recovery was performed with dedicated organ recovery teams. CONCLUSIONS: We demonstrate that real-world implementation of the OCS for DBD donors (using predominantly a dedicated recovery team) is associated with expanded donor criteria, longer transport distance, and excellent posttransplantation outcomes. In OCS-DCD donors, outcomes parallel those of donors recovered with NRP-DCD and compare favorably with DBD donor organs.

Autophagy impairments have been implicated in various aging conditions. Previous studies in cervical motor neurons show an age-dependent increase in the key autophagy proteins LC3 and p62, reflecting autophagy impairment and autophagosome accumulation. Chloroquine is commonly used to inhibit autophagy by preventing autophagosome–lysosome fusion and may thus emulate the effects of aging on the neuromuscular system. Indeed, acute chloroquine administration in old mice decreases maximal transdiaphragmatic pressure generation, consistent with aging effects. We hypothesized that chloroquine alters diaphragm muscle neuromuscular junction (NMJ) morphology and increases denervation. Adult male and female C57BL/6 × 129J mice between 5 and 8 months of age were used to examine diaphragm muscle NMJ morphology and denervation following daily intraperitoneal injections of chloroquine (10 mg/kg/d) or vehicle for 7 days. The motor end-plates and pre-synaptic terminals were fluorescently labeled with α-bungarotoxin and anti-synaptophysin, respectively. Confocal microscopy was used to assess pre- and post-synaptic morphology and denervation. At diaphragm NMJs, chloroquine treatment decreased pre-synaptic volume by 12% compared to the vehicle (p < 0.05), with no change in post-synaptic volume. Chloroquine treatment increased the proportion of partially denervated NMJs by 2.7-fold compared to vehicle treatment (p < 0.05). The morphological changes observed were similar to those previously reported in the diaphragm muscles of 18-month-old mice. These findings highlight the importance of autophagy in the maintenance of the structural properties at adult NMJs in vivo.