Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer’s disease. Recently, we showed that inducing gamma oscillations with ...visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia.
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•40-Hz visual stimulation entrains gamma oscillations in V1, CA1, and PFC•GENUS reduces neuronal and synaptic loss in mouse models of neurodegeneration•GENUS modifies synaptic signaling and synaptic-plasticity-related proteins•GENUS improves spatial learning and memory in Tau P301S and CK-p25 mice
Chronic application of patterned visual stimulation in neurodegeneration mouse models to entrain gamma oscillations results in preservation of neuronal and synaptic density across multiple brain regions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We previously reported that inducing gamma oscillations with a non-invasive light flicker (gamma entrainment using sensory stimulus or GENUS) impacted pathology in the visual cortex of Alzheimer’s ...disease mouse models. Here, we designed auditory tone stimulation that drove gamma frequency neural activity in auditory cortex (AC) and hippocampal CA1. Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice. Changes in activation responses were evident in microglia, astrocytes, and vasculature. Auditory GENUS also reduced phosphorylated tau in the P301S tauopathy model. Furthermore, combined auditory and visual GENUS, but not either alone, produced microglial-clustering responses, and decreased amyloid in medial prefrontal cortex. Whole brain analysis using SHIELD revealed widespread reduction of amyloid plaques throughout neocortex after multi-sensory GENUS. Thus, GENUS can be achieved through multiple sensory modalities with wide-ranging effects across multiple brain areas to improve cognitive function.
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•Auditory gamma entrainment using sensory stimuli (GENUS) boosts hippocampal function•GENUS affects microglia, astrocytes, and vasculature in auditory cortex and hippocampus•Auditory plus visual GENUS induces microglia clustering around plaques•Auditory plus visual GENUS reduces amyloid pathology throughout neocortex
Auditory stimulation combined with light-induced gamma oscillations in the hippocampus CA1 and auditory cortex regions of the brain reduces amyloid levels and improves memory in animal models of Alzheimer’s disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Reconstruction of nasal defects secondary to Mohs micrographic surgery (MMS) presents particular challenges related to the complex topography, skin quality, tissue laxity, and functional and ...aesthetic concerns of the region. Factors affecting outcomes resulting from second intent healing (SIH) on the nose have not been well described. The purpose of the study was to identify factors impacting outcomes of SIH for nasal tumors following MMS. Retrospective analysis was performed of all nasal lesions treated with MMS followed by SIH from a single surgical center over a 1.5-year period. Ninety-six cases were included. Chart review was performed, and data were collected including age, gender, nasal site, tumor type, defect size, depth, and number of MMS stages. Pre- and post-operative follow-up photographs were available for all cases. All five authors evaluated the photographs using the modified Manchester scar scale. Analysis was then conducted to identify features associated with good outcomes. Of the 96 tumors, 39 lesions (40.6%) were located on the nasal tip (including supratip), 32 (33.3%) on the ala/alar groove, 17 (17.7%) on the sidewall, and 8 (8.3%) on the dorsum. The average defect size was 0.83 cm
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(diameter of 1.06 cm ± 0.4). Defect diameter and defect depth were the factors that significantly impacted scar outcome (
p
< 0.001) in multivariate analysis. No significant functional deficits were reported. This retrospective study suggests that nasal defects with area less than 0.83 cm
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(or 1.06 cm diameter) and depth of defect not extending beyond the superficial fat healed well by SIH regardless of location on the nose.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To evaluate the effect of duration of preoperative hip pain symptoms on outcomes in patients undergoing primary hip arthroscopy for the treatment of femoroacetabular impingement syndrome.
A ...systematic review of the literature was conducted with the following key words: “hip arthroscopy,” “outcomes,” “femoroacetabular impingement,” “duration,” “symptoms,” “time,” “delay,” “earlier,” and “timing” was performed in PubMed and Cochrane in May 2022. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for this review. When available, article information including the author, study type, study period, and follow-up, demographics, preoperative duration of symptoms, surgical outcome tools, and secondary surgeries were recorded.
Six studies including 3,298 hips were included in this systematic review. Five studies had a minimum of 2 years’ follow-up, and 1 study had a minimum of 5 years’ follow-up. Femoroacetabular impingement (including subtypes cam and pincer impingement) was a surgical indication in all 6 studies and the most common indication for surgery. All 6 studies reported patient-reported outcome scores. All studies conducted statistical analyses comparing the duration of symptoms’ effect on outcomes and found superior outcomes in patients with shorter duration of symptoms before hip arthroscopy. In 3 studies, modified Harris Hip Score, Hip Outcome Score – Activities of Daily Living, Hip Outcome Score – Sports-Specific Subscale, and visual analog scale for satisfaction ranged from 79.1-82.6, 86.3-88.4, 75-75.5. and 75.3-82.5, respectively, in cohorts with <2-year duration of symptoms, compared with 72-77.7, 79.6-84, 65.0-66.7, and 69.7-75.3 in >2-year cohort. Similarly, in one study, the <2-year duration group was reported to have a conversion to total hip arthroplasty rate of 0.6% and an overall secondary surgery rate of 0.9%, whereas the >2-year duration group had a conversion to total hip arthroplasty rate of 6.4% and an overall secondary surgery rate of 10.1%.
Patients with hip pain symptoms of less than 2 years before arthroscopic treatment of femoroacetabular impingement syndrome have better outcomes than those patients who had a longer duration of symptoms. However, significant improvements can still be expected regardless of time between onset of symptoms and surgery.
Level IV, systematic review of Level III and Level IV studies.
Research experience is believed to be an important component of the neurosurgery residency application process. One measure of research productivity is publication volume. The preresidency ...publication volume of U.S. neurosurgery interns and any potential association between applicant publication volume and the match results of top-ranked residency programs have not been well characterized.
In this study, we sought to characterize the preresidency publication volume of U.S. neurosurgery residents in the 2018–2019 intern class using the Scopus database.
For each intern, we recorded the total number of publications, total number of first or last author publications, total number of neuroscience-related publications, mean number of citations per publication, and mean impact factor of the journal per publication. Preresidency publication volumes of interns at the top-25 programs (based on a composite ranking score according to 4 different ranking metrics) were compared with those at all other programs.
We found that 82% of neurosurgery interns included in the analysis (190 interns from 95 programs) had at least 1 publication. The average number of publications per intern among all programs was 6 ± 0.63 (mean ± standard error of the mean). We also found that interns at top-25 neurosurgery residency programs tended to have a higher number of publications (8.3 ± 1.2 vs. 4.8 ± 0.7, P = 0.0137), number of neuroscience-related publications (6.8 ± 1.1 vs. 4.1 ± 0.7, P = 0.0419), and mean number of citations per publication (9.8 ± 1.7 vs. 5.7 ± 0.8, P = 0.0267) compared with interns at all other programs.
Our results provide a general estimate of the preresidency publication volume of U.S. neurosurgery interns and suggest a potential association between publication volume and matching in the top-25 neurosurgery residency programs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background:
There is a paucity of aggregate data documenting mid- to long-term outcomes of patients after hip arthroscopy with labral reconstruction.
Purpose:
To report mid- to long-term outcomes in ...patients after undergoing either primary or revision hip arthroscopy with labral reconstruction for the treatment of irreparable labral tears.
Study Design:
Systematic review; Level of evidence, 4.
Methods:
A systematic review of the PubMed, Cochrane, and Scopus databases in May 2022 was conducted with the following keywords: “hip arthroscopy,”“labral reconstruction,”“irreparable,”“labrum,”“reconstruction,”“five-year,”“midterm,”“5 year,”“long-term,”“10 year,” ten-year,” and “femoroacetabular impingement” using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Midterm was defined as mean 5-year follow-up, and long-term was defined as mean 10-year or longer follow-up. For each included article, the demographic, radiographic, intraoperative, and surgical variables, as well as patient-reported outcomes (PROs), psychometric thresholds, and secondary surgeries were recorded. Forest plots were created for PROs that were reported in ≥3 studies; heterogeneity was assessed using I2 values.
Results:
Out of 463 initial articles, 5 studies including 178 hips with primary and 41 hips with revision surgeries were included. One study had an average 5-year follow-up, three studies had a minimum 5-year follow-up and one study had a minimum 10-year follow-up. The most common indications for hip arthroscopy with labral reconstruction were irreparable labral tears. The most common PRO was the modified Harris Hip Score (mHHS), which was reported in all 5 studies. The mean preoperative mHHS ranged from 58.9 to 66, and the mean postoperative mHHS at minimum 5-year follow-up ranged from 80.2 to 89. The preoperative and postoperative mHHSs for the single long-term follow-up study were 60 and 82, respectively. All 5 studies demonstrated significant improvements in reported PROs. All 5 studies reported secondary surgery rates, with 1 study reporting rates at both 5- and 10-year follow-up. Conversion to total hip arthroplasty ranged from 0% to 27%, while overall secondary surgery rates ranged from 0% to 36%.
Conclusion:
Findings demonstrated that patients undergoing primary and revision hip arthroscopy with labral reconstruction experienced favorable outcomes and high rates of clinical benefit and survivorship at mid- to long-term follow-up.
(1) To evaluate minimum 10-year PROs (patient-reported outcomes) and survivorship after primary hip arthroscopy and (2) to identify predictors of failure for secondary arthroscopy and conversion to ...total hip arthroplasty (THA).
A systematic review of the literature was conducted with the following key words: “hip arthroscopy,” “long-term,” “outcomes,” “ten-year,” “survivorship,” “10-year,” “15-year,” “fifteen-year,” 20-year,” “twenty-year,” and “femoroacetabular impingement” in PubMed and Embase in March 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Level I to Level IV evidence was included and reported on minimum 10-year outcomes or greater after primary hip arthroscopy. Long-term studies were defined as minimum 10-year follow-up in accordance with established standards in the literature. Case reports, review articles, technique articles, and opinion articles were excluded. Articles not in English were excluded. Title, author, publication date, study design, demographic, number of hips, follow-up time, study period, indications for hip arthroscopy, PROs, predictors of failure for THA, and rates of secondary surgeries were recorded. Survivorship was defined as a nonconversion to THA. P < .05 was defined as statistical significance.
Twelve studies met the inclusion criteria. In total, 4 studies were Level III, and 8 studies were Level IV. A total of 1,344 hips were included, and follow-up ranged from 10 to 20 years. Femoroacetabular impingement syndrome was the most common indication for hip arthroscopy. Ten of the 12 studies reported on PROs, and 8 studies reported significant improvement after hip arthroscopy at long-term follow-up. The remaining 2 studies reported favorable outcomes that satisfied clinical benefit thresholds at minimum 10-year follow-up. Five studies reported clinical benefit where each patient cohort achieved 80% minimal clinically important difference and 75% patient acceptable symptomatic state for at least one PRO. Rates of secondary arthroscopy ranged from 4.5% to 24%, and rates of conversion to THA varied from 0% to 44.1%. Older age and chondral damage were the most commonly cited predictors for conversion to THA. Conclusions: At long-term follow-up, patients who underwent primary hip arthroscopy demonstrated favorable outcomes and variable rates of secondary surgeries. Patients undergoing hip arthroscopy within the last 20 years with Tönnis grade <1 and labral repair experienced greater than 90% survivorship. Chondral damage and older age were the most cited predictors for conversion to THA.
Level IV, systematic review of Level III and Level IV studies
Clinical routine in hepatology involves the diagnosis and treatment of a wide spectrum of metabolic, infectious, autoimmune and neoplastic diseases. Clinicians integrate qualitative and quantitative ...information from multiple data sources to make a diagnosis, prognosticate the disease course, and recommend a treatment. In the last 5 years, advances in artificial intelligence (AI), particularly in deep learning, have made it possible to extract clinically relevant information from complex and diverse clinical datasets. In particular, histopathology and radiology image data contain diagnostic, prognostic and predictive information which AI can extract. Ultimately, such AI systems could be implemented in clinical routine as decision support tools. However, in the context of hepatology, this requires further large-scale clinical validation and regulatory approval. Herein, we summarise the state of the art in AI in hepatology with a particular focus on histopathology and radiology data. We present a roadmap for the further development of novel biomarkers in hepatology and outline critical obstacles which need to be overcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background: OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting the human TGF-β2 mRNA. OT-101 breaks down immune tolerance and activates immunity against the tumor. The ...Subsequent Chemotherapy (SC) releases tumor antigens and boosts the immunity response along with further epitope expansion. The phase 1/2 clinical data for OT-101/SC is presented here along with supporting preclinical MOA studies.
Methods: Total of 37 pts, 2nd line and beyond received OT-101 with option to go on SC (OT-101/SC) or Best Supportive Care (BSC) (OT-101/BSC). Overall survival (OS) was compared using log-rank statistics. Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. For cytokine analysis, plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of intravenous OT-101 therapy and a subset of 12 patients.
Results: In vitro cell kill assay and in vivo xenograft study were performed with human PBMC and OT-101. OT-101 reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and the Lipofectin control, respectively. Addition of active rh-TGF-β2 protein suppressed the cytotoxic activity of the immune cells in a dose dependent manner. Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft. Median OS (mOS) of the 18 pts receiving OT-101/SC was 9.4mos vs. the 19 pts on OT-101/BSC (2.8mos, p=0.0004). Pts with only liver mets had a mOS of 9.5mos while those with liver mets and others only had a mOS of 4.7mos (p=0.0077). Among the former, one patient had complete response beyond 77.3mos and another had stable disease with OS of 40.3mos. OS was higher for liver mets. only group with OT-101/SC - 12.4mos versus 1.9mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7mos vs. 3.0mos (p<0.0001). OS was higher for DC group with OT-101/SC - 11.8mos vs. 5.0mos, p=0.0021. Patients exhibited spike in IL-8 level which returned to basal level at treatment stop. R2 relating the IL-8 spike and OS were 0.8522 and 0.9895 and p values were 0.0011 and 0.0053 for pts treated subsequently with SC and BSC, respectively. The two lines intersect at the origin with higher response for those with OT-101/SC, suggesting exaggerated response expected for antigen boost during the SC phase.
Conclusions: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization, which is countered by overexpression of TGF-β. Here we report on the use of OT-101/SC to break immune tolerance to pancreatic cancer (PC) for the cure. The MOA for OT-101/SC is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during SC. Contrary to traditional tumor vaccine- this is universally applicable to all patients.
Citation Format: David Nam, Larn Hwang, Vuong Trieu. OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic cancer immunization therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3968.
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