Citations

OBJECTIVE The goal of this study was to compare different recognized definitions of osteoporosis in patients with degenerative lumbar spine pathology undergoing elective spinal fusion surgery to determine which patient population should be considered for preoperative optimization. METHODS A retrospective review of patients in whom lumbar spine surgery was planned at 2 academic medical centers was performed, and the rate of osteoporosis was compared based on different recognized definitions. Assessments were made based on dual-energy x-ray absorptiometry (DXA), CT Hounsfield units (HU), trabecular bone score (TBS), and fracture risk assessment tool (FRAX). The rate of osteoporosis was compared based on different definitions: 1) the WHO definition (T-score ≤ −2.5) at total hip or spine; 2) CT HU of < 110; 3) National Bone Health Alliance (NBHA) guidelines; and 4) “expanded spine” criteria, which includes patients meeting NBHA criteria and/or HU < 110, and/or “degraded” TBS in the setting of an osteopenic T-score. Inclusion criteria were adult patients with a DXA scan of the total hip and/or spine performed within 1 year and a lumbar spine CT scan within 6 months of the physician visit. RESULTS Two hundred forty-four patients were included. The mean age was 68.3 years, with 70.5% female, 96.7% Caucasian, and the mean BMI was 28.8. Fracture history was reported in 53.8% of patients. The proportion of patients identified with osteoporosis on DXA, HUs, NBHA guidelines, and the authors’ proposed “expanded spine” criteria was 25.4%, 36.5%, 75%, and 81.9%, respectively. Of the patients not identified with osteoporosis on DXA, 31.3% had osteoporosis based on HU, 55.1% had osteoporosis with NBHA, and 70.4% had osteoporosis with expanded spine criteria (p < 0.05), with poor correlations among the different assessment tools. CONCLUSIONS Limitations in the use of DXA T-scores alone to diagnose osteoporosis in patients with lumbar spondylosis has prompted interest in additional methods of evaluating bone health in the spine, such as CT HU, TBS, and FRAX, to inform guidelines that aim to reduce fracture risk. However, no current osteoporosis assessment was developed with a focus on improving outcomes in spinal surgery. Therefore, the authors propose an expanded spine definition for osteoporosis to identify a more comprehensive cohort of patients with potential poor bone health who could be considered for preoperative optimization, although further study is needed to validate these results in terms of clinical outcomes.

Abstract Macropinocytosis supports the metabolic requirement of RAS‐transformed pancreatic ductal adenocarcinoma cells (PDACs). However, regulators of RAS‐transformation (activation) that lead to macropinocytosis have not been identified. Herein, we report that UBAP2 (ubiquitin‐binding associated protein 2), regulates the activation of KRAS and macropinocytosis in pancreatic cancer. We demonstrate that UBAP2 is highly expressed in both pancreatic cancer cell lines and tumor tissues of PDAC patients. The expression of UBAP2 is associated with poor overall survival in several cancers, including PDAC. Silencing UBAP2 decreases the levels of activated KRAS, and inhibits macropinocytosis, and tumor growth in vivo. Using a UBAP2‐deletion construct, we demonstrate that the UBA‐domain of UBAP2 is critical for the regulation of macropinocytosis and maintaining the levels of activated KRAS. In addition, UBAP2 regulates RAS downstream signaling and helps maintain RAS in the GTP‐bound form. However, the exact mechanism by which UBAP2 regulates KRAS activation is unknown and needs further investigation. Thus, UBAP2 may be exploited as a potential therapeutic target to inhibit macropinocytosis and tumor growth in activated KRAS‐driven cancers.

Abstract Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer’s disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer’s disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset −9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer’s disease, which is alike sporadic Alzheimer’s disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer’s disease.

Study Design: Retrospective cohort study. Objectives: Studies in the lumbar spine suggest a correlation between sarcopenia and worse patient outcomes. The purpose of this study was to determine whether paraspinal Goutalier grade of fat degeneration is associated with patient-reported outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF). Methods: We performed a retrospective review of a prospective cohort of patients undergoing 1- to 3-level ACDF at a single institution between the years 2011-2014. We utilized preoperative magnetic resonance images to classify patients into Goutalier grades. Patient-reported outcomes, including Neck Disability Index (NDI), RAND score, and EQ-5D score were collected and analyzed according to patients’ Goutalier grade. Results: We identified 69 patients for inclusion. A total of 29 patients were classified as Goutalier 0-1 (group 1), 29 were Goutalier 1.5-2 (group 2), and 11 were Goutalier 2.5-4.0 (group 3). All Goutalier groups experienced significant improvement in all 3 outcome scores. Average postoperative NDI scores were 25.3 in group 1, 13.9 in group 2, and 25.1 in group 3 ( P = .02). The percentage of patients in each group reporting worse disability after surgery was 17.2%, 3.3%, and 9.1%, respectively ( P = .05). No statistically significant difference was seen between groups in postoperative EQ-5D ( P = .07) or RAND scores ( P > .05). Conclusions: The present study is the first to assess the association between cervical paraspinal muscle Goutalier grade and patient-reported outcomes following ACDF. Based on our study, patients with worse cervical paraspinal degeneration may benefit from improved symptom relief in comparison to patients with a lesser degree of degeneration undergoing ACDF.

GPR15 expression is promoted by Ahr in an evolutionarily conserved manner via cooperation with Foxp3 but inhibited by RORγt.

Abstract Background: Fibromyalgia (FM) is a common chronic pain condition that seriously affects the quality of patient lives. Its etiology, pathogenesis, and treatment still remain uncertain. Dietary supplements have been widely trialed for symptom relief for FM. The review aims to synthesize the previous literature publications to assess the impact of herbs and dietary supplements on FM patients. Methods: We will conduct a literature search in the following databases PubMed, MEDLINE, EMBASE, Cochrane Library, Scopus, and Global Health from database inception to December 2019. Clinical studies published in the English language that used human participants and address the efficacy, safety, and acceptability of herbs and dietary supplements on individuals with FM will be included. The risk of bias and quality assessment of each trial will be evaluated. If trials are enough, a meta-analysis will be conducted using software RevMan5.3, Cochrane Collaboration. Result: Our review will be the first attempt to facilitate evidence-based management using herbs and dietary supplements to treat patients with FM. Conclusion: The findings may provide a framework for future research and clinic practice in FM management. PROSPERO registration number: CRD42020149941

Objective: Laser acupuncture has become increasingly attractive in clinical practice, especially for patients with needle phobias well as elderly people and children. However, literature concerning the safety of laser acupuncture has been limited. This systematic review synthesizes the current available literature on the safety of laser acupuncture. Methods: Ovid MEDLINE, ® Epub Ahead of Print, In-Process & Other Non-Indexed Citations Daily, Ovid Embase, Scopus, and EBM Reviews—Cochrane Central Register of Controlled Trials databases were searched for available randomized controlled trials (RCTs) on laser acupuncture. Safety data were extracted from the included studies. Adverse events (AEs) data were extracted and assessed in terms of severity and causality. Results: Of 737 articles, 21 RCTs were included. The majority of these RCTs reported that laser acupuncture was safe, without AEs; 6 trials reported AEs (including tingling, pain flare-ups, and transient fatigue). All AEs were mild and resolved spontaneously within 24 hours. The causal relationship between AEs and laser acupuncture was felt to be “certain” in 4 studies, “probable” in 1 study, and “possible” in 1 study. AEs were collected and monitored by evaluation methods in 7 trials: 5 with AE questionnaires, 1 with a checklist, and 1 with oral reports. Conclusions: Laser acupuncture appears to be a safe therapy associated with few mild and transient AEs. However, given the heterogeneity of current studies, large, well-designed placebo-controlled RCTs with rigorous evaluation methods are needed to assess the safety of laser acupuncture more completely.

4577 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Though biannual ultrasound surveillance with or without alpha-fetoprotein (AFP) testing is recommended for at-risk patients, its sensitivity for early-stage HCC detection is suboptimal. We therefore evaluated performance of a biomarker panel incorporating methylated DNA markers (MDMs) and proteins for early HCC detection in at-risk patients with chronic liver disease. Methods: In an international, multicenter, case-control study, blood specimens were collected from patients with HCC per AASLD criteria and controls matched for age and liver disease etiology. All patients had underlying cirrhosis or chronic HBV infection. Whole blood was collected in cell-free DNA stabilizing and serum-separation tubes and shipped to a central laboratory for processing. The levels of 5 MDMs, AFP, and AFP-L3 were assessed along with age and sex. We used 537 samples in a 5-fold validation for developing a LASSO regression algorithm to classify samples as HCC positive or negative. Model robustness was tested by perturbing the data in silico and analyzing results with the predictive algorithm. Algorithm performance was compared to AFP alone and the GALAD score (Gender, Age, AFP-L3, AFP, and DCP). Results: The study included 136 HCC cases (81 early-stage—BCLC stage 0/A) and 401 controls. With specificity set at 89%, we developed a model using sex, AFP, and 3 MDMs (HOXA1, TSPYL5, B3GALT6) with higher sensitivity (70%) for early-stage HCC compared to GALAD (54%) or AFP (31% at 20 ng/mL or 52% at ≥7.7 ng/mL) (Table). The AUC for the HCC marker panel was 0.91 (95% CI 0.89 – 0.94) compared to GALAD (0.88; 95% CI 0.85 – 0.91) or AFP (0.84; 95% CI 0.81 – 0.87). The panel performed similarly in viral (AUC = 0.94) and non-viral (AUC = 0.89) etiologies. Conclusions: The robust algorithm based on novel blood-based biomarkers presented here provides higher sensitivity for early-stage HCC compared to other available blood-based biomarkers and, therefore, could significantly impact HCC clinical management and patient outcomes. Further clinical studies to validate the algorithm are ongoing. Clinical trial information: NCT03628651 . [Table: see text]

AbstractProhormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2‐null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2‐null state may affect the function of the hippocampus. In this study, adult PC2‐null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2‐null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field‐excitatory postsynaptic potentials (EPSP), long‐term potentiation (LTP), and paired‐pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2‐null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2‐null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2‐null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2‐null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2‐null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2‐null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.