A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides.

BACKGROUND: Vupanorsen is a GalNAc3-conjugated antisense oligonucleotide targeting angiopoietin-like 3 (ANGPTL3) mRNA shown to reduce atherogenic lipoproteins in individuals with dyslipidemia. OBJECTIVES: The aim of this study was to satisfy Chinese regulatory requirements and support ethnic sensitivity assessment by evaluating pharmacokinetics (PK), pharmacodynamics (PD), and safety of vupanorsen in healthy Chinese adults with elevated triglycerides (TG). METHODS: In this phase I, parallel-cohort, open-label study, 18 Chinese adults with elevated fasting TG (≥ 90 mg/dL) were randomized 1:1 to receive a single subcutaneous dose of vupanorsen 80 mg or 160 mg. PK parameters, PD markers (including ANGPTL3, TG, non-high-density lipoprotein cholesterol [non-HDL-C]), and safety were assessed. RESULTS: Absorption of vupanorsen was rapid (median time to maximum concentration [Tmax]: 2.0 h for both doses), followed by a multiphasic decline (mean terminal half-life 475.9 [80 mg] and 465.2 h [160 mg]). Exposure (area under curve [AUC] and maximum plasma concentration [Cmax]) generally increased in a greater than dose-proportional manner from 80 mg to 160 mg. Time-dependent reductions in ANGPTL3 and lipid parameters were observed. Mean percentage change from baseline for the 80-mg and 160-mg doses, respectively, were - 59.7% and - 69.5% for ANGPTL3, - 41.9% and - 52.5% for TG, and - 23.2% and - 25.4% for non-HDL-C. No serious or severe adverse events (AEs), deaths, or discontinuations due to AEs were reported. Three participants experienced treatment-related AEs; all were mild and resolved by end of study. CONCLUSIONS: This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04916795.

Rate of Reoperation Following Decompression-Only Procedure for Lumbar Degenerative Spondylolisthesis: A Systematic Review of Literature.

Background: Management of lumbar degenerative spondylolisthesis with decompression-only procedure has been performed for its added benefit of a shorter duration of surgery, lower blood loss, and shorter hospital stay. However, reported failure rates for decompression-only procedures vary depending on the methods utilized for decompression. Hence, we aim to identify the failure rates of individual methods of decompression-only procedures performed for degenerative lumbar spondylolisthesis. Methods: An independent systematic review of 4 scientific databases (PubMed, Scopus, clinicaltrials.gov, Web of Science) was performed to identify relevant articles as per the preferred reporting in systematic reviews and meta-analysis guidelines. Studies reporting on failure rates defined by reoperation at the index level following decompression-only procedure for degenerative lumbar spondylolisthesis were included for analysis. Studies were appraised using ROBINS tool of Cochrane, and analysis was performed using the Open Meta[Analyst] software. Results: The overall failure rate of decompression-only procedure was 9.1% (95% confidence interval [CI] [6.5-11.7]). Furthermore, open decompression had failure rate of 10.9% (95% CI [6.0-15.8]), while microendoscopic decompression had failure rate of 6.7% (95% CI [2.9-10.6]). The failure rate gradually increased from 6.9% (95% CI [2.0-11.7]) at 1 year to 7% (95% CI [3.6-10.3]), 11.7% (95% CI [4.5-18.9]), and 11.7% (95% CI [6.6-16.7]) at 2, 3, and 5 years, respectively. Single level decompression had a failure rate of 9.6% (95% CI [6.3-12.9]), while multilevel decompression recorded a failure rate of 8.7% (95% CI [5.6-11.7]). Conclusion: High-quality evidence on the decompression-only procedure for degenerative spondylolisthesis is limited. The decompression-only procedure had an overall failure rate of 9.1% without significant differences between the decompression techniques. Level of Evidence: Level IV. See Instructions for Authors for a complete description of levels of evidence.

Clinicopathologic Features and Outcomes of Acute Leukemia Harboring PICALM::MLLT10 Fusion.

The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutions and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutions' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients.

Triglyceride-rich lipoprotein, remnant cholesterol, and apolipoproteins CII, CIII and E in patients with schizophrenia.

Patients with schizophrenia show a disproportionally increased risk of cardiovascular disease. Hypertriglyceridemia is prevalent in this population, however how this relates to levels of remnant cholesterol, triglyceride (TG)-rich lipoprotein (TRL) particle size and composition, TG turnover, and apolipoprotein (apo) and angiopoietin-like protein (ANGPTL) concentrations is unknown. Fasting levels of cholesterol (total [TC], LDL-C, HDL-C, non-HDL-C and remnant cholesterol) and TG were determined in 110 patients diagnosed with schizophrenia, and 46 healthy controls. TRL particle size, concentration and composition, and ß-hydroxybutyrate (TG turnover marker) were assessed by NMR. ApoCII, apoCIII, apoE, ANGPTL3, ANGPTL4 and ANGPTL8 levels were measured by ELISA, and apoCII, apoCIII and apoE were further evaluated in HDL and non-HDL fractions. Patients with schizophrenia had significantly elevated TG, TG:apoB ratio, non-HDL-C, remnant cholesterol, non-HDL-apoCII and non-HDL-apoCIII, and HDL-apoE (all p<0.05), lower HDL-C and apoA-I (all p<0.001), and comparable apoB, TC, TC:apoB ratio, LDL-C, ß-hydroxybutyrate, ANGPTL3, ANGPTL4 and ANGPTL8 to healthy controls. Patients had a 12.0- and 2.5-fold increase in the concentration of large and medium TRL particles respectively, but similar cholesterol:TG ratio within each particle. Plasma TG, remnant cholesterol, and large and medium TRL particle concentrations correlated strongly with apoCII, apoCIII, and apoE in the non-HDL fraction, and with apoCIII and apoE in the HDL fraction in patients with schizophrenia. Differences in TG, HDL-C, TRL particle concentrations, apoCIII and apoE between patients and controls persisted after adjustment for conventional risk factors. Patients with schizophrenia have a marked increase in large and medium TRL species associated with elevated remnant cholesterol, apoCII, apoCIII and apoE. These results are consistent with impaired TRL lipolysis and clearance which may be responsive to targeting apoCIII.

What can go wrong when doing right? A pictorial review of iatrogenic genitourinary complications.

A growing number of treatments for genitourinary diseases can result in various iatrogenic complications. Multimodality imaging in the post-procedural setting is essential for early and accurate diagnosis to limit morbidity and mortality. We review common and uncommon treatment-induced pathologies affecting the genitourinary system via a case-based approach. We illustrate notable complications affecting the kidneys, ureters, bladder, and urethra induced by percutaneous procedures, external beam radiation, immunotherapy, laparoscopic/robotic pelvic surgery, and intravesicular BCG. Finally, we provide guidance on optimal imaging techniques for diagnosis and highlight the role of image-guided interventions for mitigation of complications.

Systematic Review and Meta-Analysis of the Effect of Osteoporosis on Reoperation Rates and Complications after Surgical Management of Lumbar Degenerative Disease.

BACKGROUND: There is considerable heterogeneity in findings and a lack of consensus regarding the interplay between osteoporosis and outcomes in patients with lumbar degenerative spine disease. Therefore, the purpose of this systematic review and meta-analysis was to gather and analyze existing data on the effect of osteoporosis on radiographic, surgical, and clinical outcomes following surgery for lumbar degenerative spinal disease. METHODS: A systematic review was performed to determine the effect of osteoporosis on the incidence of adverse outcomes after surgical intervention for lumbar degenerative spinal diseases. The approach focused on the radiographic outcomes, reoperation rates, and other medical and surgical complications. Subsequently, a meta-analysis was performed on the eligible studies. RESULTS: The results of the meta-analysis suggested that osteoporotic patients experienced increased rates of adjacent segment disease (ASD; p=0.015) and cage subsidence (p=0.001) while demonstrating lower reoperation rates than non-osteoporotic patients (7.4% vs. 13.1%; p=0.038). The systematic review also indicated that the length of stay, overall costs, rates of screw loosening, and rates of wound and other medical complications may increase in patients with a lower bone mineral density. Fusion rates, as well as patient-reported and clinical outcomes, did not differ significantly between osteoporotic and non-osteoporotic patients. CONCLUSIONS: Osteoporosis was associated with an increased risk of ASD, cage migration, and possibly postoperative screw loosening, as well as longer hospital stays, incurring higher costs and an increased likelihood of postoperative complications. However, a link was not established between osteoporosis and poor clinical outcomes.

Cardiac Magnetic Resonance Studies in a Large Animal Model that Simulates the Cardiac Abnormalities of Human Septic Shock.

Background: Septic shock, in humans and in our well-established animal model, is associated with increases in biventricular end diastolic volume (EDV) and decreases in ejection fraction (EF). These abnormalities occur over 2 days and reverse within 10 days. Septic non-survivors do not develop an increase in EDV. The mechanism for this cardiac dysfunction and EDV differences is unknown. Methods: Purpose-bred beagles randomized to receive intrabronchial Staphylococcus aureus (n=27) or saline (n=6) were provided standard ICU care including sedation, mechanical ventilation, and fluid resuscitation to a pulmonary arterial occlusion pressure of over 10mmHg. No catecholamines were administered. Over 96h, cardiac magnetic resonance imaging, echocardiograms, and invasive hemodynamics were serially performed, and laboratory data was collected. Tissue was obtained at 66h from six septic animals. Results: From 0-96h after bacterial challenge, septic animals vs. controls had significantly increased left ventricular wall edema (6%) and wall thinning with loss of mass (15%) which was more pronounced at 48h in non-survivors than survivors. On histology, edema was located predominantly in myocytes, the interstitium, and endothelial cells. Edema was associated with significantly worse biventricular function (lower EFs), ventricular-arterial coupling, and circumferential strain. In septic animals, from 0-24h, the EDV decreased from baseline and, despite cardiac filling pressures being similar, decreased significantly more in non-survivors. From 24-48h, all septic animals had increases in biventricular chamber sizes. Survivors biventricular EDVs were significantly greater than baseline and in non-survivors, where biventricular EDVs were not different from baseline. Preload, afterload, or HR differences did not explain these differential serial changes in chamber size. Conclusion: Systolic and diastolic cardiac dysfunction during sepsis is associated with ventricular wall edema. Rather than differences in preload, afterload, or heart rate, structural alterations to the ventricular wall best account for the volume changes associated with outcome during sepsis. In non-survivors, from 0-24h, sepsis induces a more severe diastolic dysfunction, further decreasing chamber size. The loss of left ventricular mass with wall thinning in septic survivors may, in part explain, the EDV increases from 24-48h. However, these changes continued and even accelerated into the recovery phase consistent with a reparative process rather than ongoing injury.

TMS provokes target-dependent intracranial rhythms across human cortical and subcortical sites.

BACKGROUND: Transcranial magnetic stimulation (TMS) is believed to alter ongoing neural activity and cause circuit-level changes in brain function. While the electrophysiological effects of TMS have been extensively studied with scalp electroencephalography (EEG), this approach generally evaluates low-frequency neural activity at the cortical surface. However, TMS can be safely used in patients with intracranial electrodes (iEEG), allowing for direct assessment of deeper and more localized oscillatory responses across the frequency spectrum. OBJECTIVE/HYPOTHESIS: Our study used iEEG to understand the effects of TMS on human neural activity in the spectral domain. We asked (1) which brain regions respond to cortically-targeted TMS, and in what frequency bands, (2) whether deeper brain structures exhibit oscillatory responses, and (3) whether the neural responses to TMS reflect evoked versus induced oscillations. METHODS: We recruited 17 neurosurgical patients with indwelling electrodes and recorded neural activity while patients underwent repeated trials of single-pulse TMS at either the dorsolateral prefrontal cortex (DLPFC) or parietal cortex. iEEG signals were analyzed using spectral methods to understand the oscillatory responses to TMS. RESULTS: Stimulation to DLPFC drove widespread low-frequency increases (3-8 Hz) in frontolimbic cortices and high-frequency decreases (30-110 Hz) in frontotemporal areas, including the hippocampus. Stimulation to parietal cortex specifically provoked low-frequency responses in the medial temporal lobe. While most low-frequency activity was consistent with phase-locked evoked responses, anterior frontal regions exhibited induced theta oscillations following DLPFC stimulation. CONCLUSIONS: By combining TMS with intracranial EEG recordings, our results suggest that TMS is an effective means to perturb oscillatory neural activity in brain-wide networks, including deeper structures not directly accessed by stimulation itself.

The impact of enhanced recovery after surgery (ERAS) on opioid consumption and postoperative pain levels in elective spine surgery.

OBJECTIVE: Enhanced Recovery after Surgery (ERAS) protocols were developed to counteract the adverse effects of the surgical stress response, aiming for quicker postoperative recovery. Initially applied in abdominal surgeries, ERAS principles have extended to orthopedic spine surgery, but research in this area is still in its infancy. The current study investigated the impact of ERAS on postoperative pain and opioid consumption in elective spine surgeries. METHODS: A single-center retrospective study of patients undergoing elective spine surgery from May 2019 to July 2020. Patients were categorized into two groups: those enrolled in the ERAS pathway and those adhering to traditional surgical protocols. Data on demographics, comorbidities, length of stay (LOS), surgical procedures, and postoperative outcomes were collected. Postoperative pain was evaluated using the Numerical Rating Scale (NRS), while opioid utilization was quantified in morphine milligram equivalents (MME). NRS and MME were averaged for each patient across all days under observation. Differences in outcomes between groups (ERAS vs. treatment as usual) were tested using the Wilcoxon rank sum test for continuous variables and Pearson's or Fisher's exact tests for categorical variables. RESULTS: The median of patient's mean daily NRS scores for postoperative pain were not statistically significantly different between groups (median = 5.55 (ERAS) and 5.28 (non-ERAS), p=.2). Additionally, the median of patients' mean daily levels of MME were similar between groups (median = 17.24 (ERAS) and 16.44 (non-ERAS), p=.3) ERAS patients experienced notably shorter LOS (median=2 days) than their non-ERAS counterparts (median=3 days, p=.001). The effect of ERAS was moderated by whether the patient had ACDF surgery. ERAS (vs. non-ERAS) patients who had ACDF surgery had 1.64 lower average NRS (p=.006). ERAS (vs. non-ERAS) patients who had a different surgery had 0.72 higher average NRS (p=.02) but had almost half the length of stay, on average (p<.001). CONCLUSIONS: The current study underscores the dynamic nature of ERAS protocols within the realm of spine surgery. While ERAS demonstrates advantages such as reduced LOS and improved patient-reported outcomes, it requires careful implementation and customization to address the specific demands of each surgical discipline. The potential to expedite recovery, optimize resource utilization, and enhance patient satisfaction cannot be overstated. However, the fine balance between achieving these benefits and ensuring comprehensive patient care, especially in the context of postoperative pain management, must be maintained. As ERAS continues to evolve and find its place in diverse surgical domains, it is crucial for healthcare providers to remain attentive to patient needs, adapting ERAS protocols to suit individual patient populations and surgical contexts.

Naturalistic acute pain states decoded from neural and facial dynamics.

Pain is a complex experience that remains largely unexplored in naturalistic contexts, hindering our understanding of its neurobehavioral representation in ecologically valid settings. To address this, we employed a multimodal, data-driven approach integrating intracranial electroencephalography, pain self-reports, and facial expression quantification to characterize the neural and behavioral correlates of naturalistic acute pain in twelve epilepsy patients undergoing continuous monitoring with neural and audiovisual recordings. High self-reported pain states were associated with elevated blood pressure, increased pain medication use, and distinct facial muscle activations. Using machine learning, we successfully decoded individual participants' high versus low self-reported pain states from distributed neural activity patterns (mean AUC = 0.70), involving mesolimbic regions, striatum, and temporoparietal cortex. High self-reported pain states exhibited increased low-frequency activity in temporoparietal areas and decreased high-frequency activity in mesolimbic regions (hippocampus, cingulate, and orbitofrontal cortex) compared to low pain states. This neural pain representation remained stable for hours and was modulated by pain onset and relief. Objective facial expression changes also classified self-reported pain states, with results concordant with electrophysiological predictions. Importantly, we identified transient periods of momentary pain as a distinct naturalistic acute pain measure, which could be reliably differentiated from affect-neutral periods using intracranial and facial features, albeit with neural and facial patterns distinct from self-reported pain. These findings reveal reliable neurobehavioral markers of naturalistic acute pain across contexts and timescales, underscoring the potential for developing personalized pain interventions in real-world settings.

Association of Psychosocial Risk Factors With Quality of Life and Readmissions 1 Year After LVAD Implantation.

BACKGROUND: Among patients with advanced heart failure (HF), treatment with a left ventricular assist device (LVAD) improves health-related quality of life (HRQOL). We investigated the association between psychosocial risk factors, HRQOL and outcomes after LVAD implantation. METHODS: A retrospective cohort (n = 9832) of adults aged ≥ 19 years who received durable LVADs between 2008 and 2017 was identified by using the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS). Patients were considered to have psychosocial risk factors if ≥ 1 of the following were present: (1) substance abuse; (2) limited social support; (3) limited cognitive understanding; (4) repeated nonadherence; and (5) major psychiatric disease. Multivariable logistic and linear regression models were used to evaluate the association between psychosocial risk factors and change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 scores from baseline to 1 year, persistently poor HRQOL (KCCQ-12 score < 45 at baseline and 1 year), and 1-year rehospitalization. RESULTS: Among the final analytic cohort, 2024 (20.6%) patients had ≥ 1 psychosocial risk factors. Psychosocial risk factors were associated with a smaller improvement in KCCQ-12 scores from baseline to 1 year (mean ± SD, 29.1 ± 25.9 vs 32.6 ± 26.1; P = 0.015) for a difference of -3.51 (95% confidence interval [CI]: -5.88 to -1.13). Psychosocial risk factors were associated with persistently poor HRQOL (adjusted odds ratio [aOR] 1.35, 95% confidence interval [CI] 1.04-1.74), and 1-year all-cause readmission (adjusted hazard ratio [aHR] 1.11, 95% CI 1.05-1.18). Limited social support, major psychiatric disorder and repeated nonadherence were associated with persistently poor HRQOL, while major psychiatric disorder was associated with 1-year rehospitalization. CONCLUSION: The presence of psychosocial risk factors is associated with lower KCCQ-12 scores and higher risk for readmission at 1 year after LVAD implantation. These associations are statistically significant, but further research is needed to determine whether these differences are clinically meaningful.

The Effect of Osteoporosis on Complications and Reoperation Rates After Surgical Management of Adult Thoracolumbar Spinal Deformity: A Systematic Review and Meta Analysis.

STUDY DESIGN: Systematic Review. OBJECTIVES: While substantial research has explored the impact of osteoporosis on patients undergoing adult spinal deformity (ASD) correction, the literature remains inconclusive. As such, the purpose of this study is to synthesize and analyze existing studies pertaining to osteoporosis as a predictor of postoperative outcomes in ASD surgery. METHODS: We performed a systematic review and meta-analysis to determine the effect that a diagnosis of osteoporosis, based on ICD-10 coding, dual-energy X-ray absorptiometry (DEXA) or computed tomography, has on the incidence of adverse outcomes following surgical correction of ASD. Statistical analysis was performed using Comprehensive Meta-Analysis (Version 2) using a random effects model to account for heterogeneity between studies. RESULTS: After application of inclusion and exclusion criteria, 36 and 28 articles were included in the systematic review and meta-analysis, respectively. The meta-analysis identified greater rates of screw loosening amongst osteoporotic patients (70.5% vs 31.9%, P = .009), and decreased bone mineral density in patients who developed proximal junctional kyphosis (PJK) (.69 vs .79 g/cm2, P = .001). The systematic review demonstrated significantly increased risk of any complication, reoperation, and proximal junctional failure (PJF) associated with reduced bone density. No statistical difference was observed between groups regarding fusion rates, readmission rates, and patient-reported and/or functional outcome scores. CONCLUSION: This study demonstrates a higher incidence of screw loosening, PJK, and revision surgery amongst osteoporotic ASD patients. Future investigations should explore outcomes at various follow-up intervals in order to better characterize how risk changes with time and to tailor preoperative planning based on patient-specific characteristics.

Impact of bariatric surgery on cytochrome P 450 enzyme activity.

Bariatric surgeries are becoming more prevalent as obesity rates continue to rise. Being that it is an effective weight-loss procedure, it can induce significant anatomical, physiological, and metabolic alterations, which affect the pharmacokinetics of various medications. Cytochrome (CYP) P450 is a group of enzymes that are primarily responsible for metabolizing most medications. Bariatric surgery may affect CYP activity and consequently alter metabolism of various medications, and the resulting weight loss may influence the metabolism of various drugs. This study investigates the impact of bariatric surgery on which CYP enzymes are affected and their effects medications. Authors of this study did an extensive literature review and research in databases including PubMed and EMBASE. The evidence was gathered for medication efficacy influenced by enzyme fluctuations to advocate for further studies for patients that undergo bariatric surgery. The search was limited to English-language results and is deemed up to date as of September 2023. There are numerous studies that indicated alterations of the CYP enzyme activity, which affects the pharmacokinetics of medications used to treat acute and chronic conditions after bariatric surgery. There are various mechanisms involved in CYP enzyme activity leading to fluctuations and the clearance of medications and subsequently compromising the efficacy and safety of these agents. It is imperative to conduct more prospective randomized control studies with longer duration to guide clinicians on how to manage medications with various CYP activity for patients' post-bariatric surgery.