Augusta University
  • Augusta, GA, United States
Recent publications
Background Many documented secondary neurologic manifestations are associated with COVID-19, including mild peripheral and central nervous system disorders (such as hypo/anosmia, hypo/ageusia, and cranial nerve VII palsy) and severe problems (such as ischemic stroke, Guillain-Barré syndrome, and encephalitis). The list is growing. A new addition is non-alcohol Wernicke’s encephalopathy. Case presentation We present the case of a 24-year-old male with no past medical history who developed stroke-like symptoms two days after testing positive for COVID-19. MRI of his brain showed T2 FLAIR hyperintensity in the splenium of the corpus collosum, mamillary bodies, periaqueductal gray matter, tectum, and ventral and dorsal medulla, an MRI signal concerning for non-alcohol Wernicke’s encephalopathy. Our patient had no risk factors for Wernicke’s encephalopathy. He was admitted and started on thiamine for Wernicke’s encephalopathy and steroids for his cranial VII nerve palsy. Both his symptoms and imaging improved. He was discharged on oral thiamine. Follow-up in the Neurology Clinic has confirmed his continued stable state. Conclusions This case is one of three documented cases of Wernicke’s encephalopathy believed to be caused by COVID-19 in patients without risk factors or chronic alcohol use. Ours is also the first case in which Wernicke’s encephalopathy presents with a concomitant cranial nerve VII palsy. While Emergency Medicine doctors must maintain a high index of suspicion for stroke in younger patients with COVID-19, our patient’s case augments the correlation between COVID-19 and Wernicke’s encephalopathy in patients without other risk factors for developing the syndrome.
Background Targeting mitochondrial oncoproteins presents a new concept in the development of effective cancer therapeutics. ATAD3A is a nuclear-encoded mitochondrial enzyme contributing to mitochondrial dynamics, cholesterol metabolism, and signal transduction. However, its impact and underlying regulatory mechanisms in cancers remain ill-defined. Methods We used head and neck squamous cell carcinoma (HNSCC) as a research platform and achieved gene depletion by lentiviral shRNA and CRISPR/Cas9. Molecular alterations were examined by RNA-sequencing, phospho-kinase profiling, Western blotting, RT-qPCR, immunohistochemistry, and immunoprecipitation. Cancer cell growth was assessed by MTT, colony formation, soft agar, and 3D cultures. The therapeutic efficacy in tumor development was evaluated in orthotopic tongue tumor NSG mice. Results ATAD3A is highly expressed in HNSCC tissues and cell lines. Loss of ATAD3A expression suppresses HNSCC cell growth and elicits tumor regression in orthotopic tumor-bearing mice, whereas gain of ATAD3A expression produces the opposite effects. From a mechanistic perspective, the tumor suppression induced by the overexpression of the Walker A dead mutant of ATAD3A (K358) produces a potent dominant-negative effect due to defective ATP-binding. Moreover, ATAD3A binds to ERK1/2 in the mitochondria of HNSCC cells in the presence of VDAC1, and this interaction is essential for the activation of mitochondrial ERK1/2 signaling. Most importantly, the ATAD3A-ERK1/2 signaling axis drives HNSCC development in a RAS-independent fashion and, thus, tumor suppression is more effectively achieved when ATAD3A knockout is combined with RAS inhibitor treatment. Conclusions These findings highlight the novel function of ATAD3A in regulating mitochondrial ERK1/2 activation that favors HNSCC development. Combined targeting of ATAD3A and RAS signaling may potentiate anticancer activity for HNSCC therapeutics.
Background There is growing potential for nanocarrier-based drug delivery in cancer. However, an incomplete understanding of nano–bio interactions and the challenges regarding processing and fabrication in scale-up engineering techniques, controls over drug release, efficacy, and cytotoxicity to the human cell are the major challenges for its clinical success. The purpose of the study was to develop an electrospraying processing of injectable nanonized encapsulated chemotherapeutics to target primary and metastatic breast cancer tumor microenvironment for precise and controlled delivery. Results A novel coaxial electrospraying of multiple cancer drugs (paclitaxel and GW2580) as core and polycaprolactam (PCL) as the shell has been developed to produce multi-cancer drug nanocapsules. Using electrospraying process, we have successfully made nanocapsules containing paclitaxel to target breast cancer cells and GW2580, a colony-stimulating factor 1 receptor (CSF1R) inhibitor to target CSF1R+ myeloid cells in the tumor microenvironments (TME). The UV–vis drug release test for 14 days shows a prolonged and sustained release pattern of both the drugs. In vitro and in vivo results showed the effects of nanocapsules containing multiple drugs in controlling the growth of tumor cells and increased survival of the animal bearing breast cancers. Conclusion Nanonized multi-cancer drugs were encapsulated in a PCL shell. The drug doses ratio and the polymer-to-drug ratio were controlled by engineered process parameters. The studies showed the importance of making nanocapsules containing nanocrystals of multiple drugs, which will pave the way of making multiple drug combinations in a controlled manner and capsules can be designed for sustained release of the drugs after accumulation into the TME. TME-directed therapy can be a norm in future cancer treatment strategies. These injectable nanocapsules will allow cancer site-specific precision and controlled delivery to cure primary and metastatic breast cancer and to overcome the chemotherapy resistance.
Hypertension remains the leading risk factor for cardiovascular disease. Young females tend to be protected from hypertension compared with age-matched males. Although it has become increasingly clear that the immune system plays a key role in the development of hypertension in both sexes, few studies have examined how cytokines mediate hypertension in males versus females. We previously published that there are sex differences in the levels of the cytokine tumor necrosis factor (TNF)-α in spontaneously hypertensive rats (SHR). The goal of this study was to test the hypothesis that TNF-α inhibition with etanercept will lower BP in male and female SHR. However, as male SHR have a more pro-inflammatory status than female SHR, we further hypothesize that males will have a greater decrease in BP with TNF-α inhibition than females. Young adult male and female SHR were administered increasing doses of the TNF-α inhibitor etanercept or vehicle twice weekly for 31 days and BP was continuously measured via telemetry. Following treatment, kidneys and urine were collected and analyzed for markers of inflammation and injury. Despite significantly decreasing renal TNF-α levels, renal phospho-NFκB and urinary MCP-1 excretion, etanercept did not alter BP in either male or female SHR. Interestingly, treatment with etanercept increased urinary excretion of protein, creatinine and KIM-1 in both sexes. These results indicate that TNF-α does not contribute to sex differences in BP in SHR but may be vital in the maintenance of renal health.
Many studies have shown that using a computer-aided detection (CAD) system does not significantly improve diagnostic accuracy in radiology, possibly because radiologists fail to interpret the CAD results properly. We tested this possibility using screening mammography as an illustrative example. We carried out two experiments, one using 28 practicing radiologists, and a second one using 25 non-professional subjects. During each trial, subjects were shown the following four pieces of information necessary for evaluating the actual probability of cancer in a given unseen mammogram: the binary decision of the CAD system as to whether the mammogram was positive for cancer, the true-positive and false-positive rates of the system, and the prevalence of breast cancer in the relevant patient population. Based only on this information, the subjects had to estimate the probability that the unseen mammogram in question was positive for cancer. Additionally, the non-professional subjects also had to decide, based on the same information, whether to recall the patients for additional testing. Both groups of subjects similarly (and significantly) overestimated the cancer probability regardless of the categorical CAD decision, suggesting that this effect is not peculiar to either group. The misestimations were not fully attributable to causes well-known in other contexts, such as base rate neglect or inverse fallacy. Non-professional subjects tended to recall the patients at high rates, even when the actual probably of cancer was at or near zero. Moreover, the recall rates closely reflected the subjects’ estimations of cancer probability. Together, our results show that subjects interpret CAD system output poorly when only the probabilistic information about the underlying decision parameters is available to them. Our results also highlight the need for making the output of CAD systems more readily interpretable, and for providing training and assistance to radiologists in evaluating the output.
Background Thyroid storm is a life-threatening manifestation of thyrotoxicosis and presents with fever, diaphoresis, tachycardia, hypertension, and widened pulse pressure. Case presentation We present a case of intraoperative thyroid storm in a 12-year-old female undergoing posterior spinal fusion. Despite adequate depth of anesthesia and analgesia, the patient was persistently tachycardic and hypertensive. The surgical procedure was uneventful. A thyroid panel drawn immediately after surgery showed undetectable thyroid stimulating hormone (TSH) and high free thyroxine (T4) consistent with thyroid storm. Conclusions Intraoperative thyroid storm in a pediatric patient is extremely rare with nonspecific clinical symptoms. Low to undetectable TSH and elevated free T4 is diagnostic.
Introduction To determine if treatment and clinical outcomes of adrenocortical carcinoma (ACC) vary by race and insurance status. Methods ACC patients from the National Cancer Database (2004-2017) were reviewed. Race was defined as White versus minority (Black and Hispanic). Insurance types were private (PI) versus other (Medicaid/uninsured/unknown). Metastatic ACC (M-ACC) was defined as distant metastases at the time of diagnosis; nonmetastatic ACC (NM-ACC) patient had no distant disease. Results Of 2351 NM-ACC patients, 83.6% were White and 16.4% minority. There were 1216 M-ACC patients, with 80.3% White and 19.8% minority. Both White NM-ACC and M-ACC patients had more PI (each P < 0.001). PI NM-ACC was associated with a shorter duration from diagnosis to first treatment (14 versus 18 d, P = 0.005). Both NM-ACC and M-ACC with PI were more likely to receive surgery (92.6% versus 86.9%, P = 0.001 and 35.4% versus 27%, P = 0.02) and to receive surgery sooner (13 versus 16 d, P = 0.03). M-ACC with PI were more likely to receive chemotherapy (63.6% versus 54.3%, P = 0.01) and to have lymph nodes examined (14.8% versus 8.6%, P = 0.02). Length of stay postoperatively was shorter for White NM-ACC (6 versus 7 d, P = 0.04) and M-ACC (8 versus 17 d, P = 0.02). For NM-ACC and M-ACC, the 30-d readmission, 90-d mortality, and overall survival were similar by race. A multivariable analysis showed minorities (OR 0.69, 95% confidence interval 0.54-0.88, P = 0.003) and patients without PI (OR 0.75, 95% confidence interval 0.58-0.97, P = 0.03) were less likely to have surgery. However, a multivariable analysis showed survival was similar for White versus minority patients and PI versus other. Conclusions White NM-ACC or M-ACC and PI were more likely to receive surgery and timely multimodality care. These disparities were not associated with differences in 90-d mortality or overall survival.
Vascular contributions to cognitive impairment and dementia (VCID) secondary to chronic mild-moderate cerebral ischemia underlie a significant percentage of cases of dementia. We previously reported that either genetic deficiency of the complement C3a receptor (C3aR) or its pharmacological inhibition protects against cerebral ischemia in rodents, while others have implicated C3aR in the pathogenesis seen in rodent transgenic models of Alzheimer’s disease. In the present study, we evaluated the role of complement C3a-C3aR signaling in the onset and progression of VCID. We utilized the bilateral common carotid artery stenosis (BCAS) model to induce VCID in male C57BL/6 wild-type and C3aR-knockout (C3aR−/−) mice. Cerebral blood flow (CBF) changes, hippocampal atrophy (HA), white matter degeneration (WMD), and ventricular size were assessed at 4 months post-BCAS using laser speckle contrast analysis (LSCI) and magnetic resonance imaging (MRI). Cognitive function was evaluated using the Morris water maze (MWM), and novel object recognition (NOR), immunostaining, and western blot were performed to assess the effect of genetic C3aR deletion on post-VCID outcomes. BCAS resulted in decreased CBF and increased HA, WMD, and neurovascular inflammation in WT (C57BL/6) compared to C3aR−/− (C3aR-KO) mice. Moreover, C3aR−/− mice exhibited improved cognitive function on NOR and MWM relative to WT controls. We conclude that over-activation of the C3a/C3aR axis exacerbates neurovascular inflammation leading to poor VCID outcomes which are mitigated by C3aR deletion. Future studies are warranted to dissect the role of cell-specific C3aR in VCID.
Statement of the problem Park-based physical activity (PA) is associated with positive health outcomes (social support, energy, self-esteem, mood, less depression). Integrating park-based PA into peer-led mental health services is an innovative approach that can address health disparities in persons with serious mental illness (SMI). Yet, to date, few PA interventions capitalize on peer counselor (PC) capacity, and none have focused on park-based PA. The purpose of this qualitative study was to ascertain the perspectives of adults with SMI and their counselors about park-based PA to inform the development of a park-based PA intervention lead by PCs. Methods In Spring/Summer 2018, we conducted six 1-h focus groups (FGs) with adults with SMI, and four 1-h FGs with PCs and social workers. Using the person-based approach framework, open-ended questions elicited information regarding peer PA behavior and park use, PA participation motives/barriers, and preference for park-based PA. PCs discussed knowledge and promotion of PA in peer group settings, willingness to lead PA activities, and feedback on intervention strategies. Results Peer FGs averaged 49 ± 8 min. Peer data were coded into three overarching themes: current PA, motivators, and barriers. Peer counselor FGs averaged 60 ± 5 min. Data were coded into five themes: current peer group PA, barriers to peer group PA, motivators for peer group PA, PA intervention recommendations, and implementation barriers. Conclusion Peers and PCs were interested in participating/leading in outdoor PA. Social support, motivation, PA self-efficacy, health concerns, weather, transportation, and PC training are important considerations for intervention development.
The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem to be related with better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude´s TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80 % of patients were able to receive the initial seven-week period of induction / consolidation fully as outpatients and 77 % achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48 %. In adults, the median probability of OS was 24 months, and the 5-year OS was 32 %. Patients with T-cell ALL did significantly worse than those with a B cell phenotype (OS at 5 years 17 versus 40 %, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD. We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.
Front Cover: The cover image is based on the Research Article Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function by Sheng‐Jia Lin et al., https://doi.org/10.1002/humu.24435.
Context: Patients with hematologic malignancies have an increased risk of SARS-CoV-2 infection, severe COVID-19, and higher mortality rates. Objective: We investigated the immunological response to SARS-CoV-2 after infection and/or vaccination and explored the impact of treatment response on antibody levels. Design: We added a cohort of CML patients to the ongoing study SPARTA. We collected saliva and peripheral blood to measure levels of SARS-CoV-2 antigen and antibodies. Results: From 10-1-2021 to 3-31-2022, we prospectively enrolled 69 participants (32 with CML, 37 non-cancer) with similar sociodemographic characteristics. There was a significant difference in the frequency of previous SARS-CoV-2 infections, where the control group had a higher percentage of patients previously diagnosed with COVID-19 (18.8% vs. 84%). Nevertheless, there was no difference in the detection of SARS-CoV-2 at the time of enrollment (0% vs. 5.6%). SARS-CoV-2 antibodies, either IgG or neutralizing (nAB), were detected in most of the participants regardless of cancer status (IgG, 84.4% in the CML cohort and 91.7% in the non-cancer cohort; nAB, 84.4% vs. 88.9%). The two groups had comparable IgG (mean 160.8 vs. 157.5 Ru/mL) and nAB (mean 1,473 vs. 1,509 ng/ml) levels. Overall, IgG and nAB levels were significantly higher in subjects who received the last vaccine dose within 6 months compared to those who received it ≥6 months previously (IgG, CML, mean 177.7 vs. 113.2, control 190.5 vs. 134.4; nAB, CML 1,784 vs. 951.9, control 2,066 vs. 1,335). Both groups had comparable mean antibody levels according to the time since the last dose (IgG, ≤6 months, 177.7 vs. 190.5, ≥6 months, 113.2 vs. 134.4; nAB, ≤6 months, 1,784 vs. 2,066, ≥6 months 951.9 vs. 1,335). There was no difference in the detection and levels of antibodies according to therapy with TKIs (IgG, mean 158.8 vs. 185.2; nAB, 1,515 vs. 1,883) or achieving MMR (IgG, mean 152.4 vs. 177.5; nAB, 1,447 vs. 1,686). Conclusions: The immunological response to SARS-CoV-2 among CML patients is comparable to that in non-CML subjects. TKI therapy and the response to treatment did not impact the development of antibodies. Moreover, antibody levels decreased over time, with the most significant drop after 6 months since the last immunization dose.
The results of treatment of adolescents and adults with acute lymphoblastic leukemia (ALL) remain unsatisfactory. Pediatric-inspired treatments seem produce better outcomes. 126 adolescent and adult patients with ALL were treated in a 37-year period with a pediatric inspired combined chemotherapy (PICC) schedule, delivered on an outpatient basis and based on the St. Jude's TOTAL XI pediatric protocol employing vincristine, prednisone, asparaginase, daunorubicin, etoposide, cytarabine, methotrexate, mercaptopurine and triple intrathecal therapy. 80% of patients were able to receive the initial seven-week period of induction/consolidation fully as outpatients and 77% achieved a complete remission. In adolescents and young adults (AYAs) the median probability of overall survival (OS) was 44 months, whereas the 5-year OS was 48%. In adults, the median probability of OS was 24 months, and the 5-year OS was 32%. Patients with T-cell ALL did significantly worse than those with a B-cell phenotype (OS at 5 years 17 versus 40%, respectively). These figures are better than those informed in our country employing more aggressive, in-hospital schedules such as the hyper-CVAD (cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone). We found that, in AYAs and adult patients with ALL, the use of an asparaginase-containing PICC delivered on an outpatient basis renders acceptable results, better than those obtained in similar socioeconomic circumstances employing adult-oriented schedules. Additional studies are needed to assess the usefulness of these PICC treatments in adult individuals with ALL treated in underprivileged circumstances, such as those prevailing in LMIC.
Objectives: Quizartinib is an oral, potent, selective, type II FLT3 inhibitor with prolonged OS as a single-agent in relapsed/refractory FLT3-ITD+ AML. We report results from the global, randomized, double-blind, phase 3 QuANTUM-First trial (NCT02668653), evaluating quizartinib plus standard induction and post-remission consolidation (including allogeneic hematopoietic cell transplant [allo-HCT] in first complete remission [CR1]) followed by single-agent continuation (up to 3 years) vs placebo plus chemotherapy in newly diagnosed FLT3-ITD+ AML. Methods: Patients 18-75 years with newly diagnosed FLT3-ITD+ AML received induction with cytarabine 100 or 200 mg/m2/day (days 1-7) and daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day (days 1-3). Patients were randomized to quizartinib (40 mg/day [days 8-21]) or placebo; stratified by region, age, and white blood cell count at diagnosis. Patients with CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus quizartinib (40 mg/day) or placebo and/or allo-HCT followed by continuation with quizartinib (30-60 mg/day) or placebo (up to 3 years). The primary endpoint was OS. Results: Between September 2016 and August 2019, 539 patients were randomized (quizartinib [n=268], placebo [n=271]). Median age was 56 years (range, 20-75 years). As of August 2021 (median follow-up, 39.2 months), 58 patients remained on continuation. Median OS was significantly longer with quizartinib vs placebo (31.9 vs 15.1 months; HR, 0.776; 95% CI, 0.615-0.979; 2-sided P=.0324). CR+CRi rates were 71.6% and 64.9%, respectively. Allo-HCT in CR1 was performed in 157 patients (quizartinib, 31%; placebo, 27%). When censored for allo-HCT, OS trended longer with quizartinib vs placebo (HR, 0.752; 95% CI, 0.562-1.008; 2-sided P=.055). Relapse-free survival was longer with quizartinib vs placebo (HR, 0.733; 95% CI, 0.554-0.969). Grade ≥3 adverse events (AEs) were similar across arms. Discontinuations due to AEs occurred in 20.4% (quizartinib) and 8.6% (placebo). Fifty-six patients died from treatment-emergent AEs (quizartinib, 11.3%; placebo, 9.7%); mostly infections. Grade 3/4 electrocardiographic QT prolongation occurred in 3.0% (quizartinib) and 1.1% (placebo). Conclusions: Quizartinib plus standard therapy, followed by continuation, including after allo-HCT, for up to 3 years was tolerable with statistically significant and clinically meaningful OS improvements in adults ≤75 years with newly diagnosed FLT3-ITD+ AML.
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3,746 members
Kumar Vaibhav
  • Department of Neurosurgery
Alessandro Pozzi
  • Goldstein Center for Esthetic and Implant Dentistry
Nirbhay N. Singh
  • Department of Psychiatry
B.R Achyut
  • Cancer Center
Gabor Csanyi
  • Vascular Biology Center
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30912, Augusta, GA, United States
Head of institution
Dr. Brooks Keel
Website
www.augusta.edu