United States

Abstract Title: Advancements in Nanomedicine: A Study on Lipid Nanoparticle Reliability and Formulation Optimization

Background: Lipid nanoparticles (LNP) have emerged as vital tools for delivering nucleic acids like messenger RNA (mRNA) and small interfering RNA (siRNA), playing a key role in the development of COVID-19 vaccines and RNA interference (RNAi)-based therapies for diseases including cancer and cardiovascular disorders. Despite their potential, inquiries into the comparative formulation efficiencies of LNPs when encapsulating siRNA versus mRNA payloads remain limited. Noteworthy challenges endure in optimizing LNP formulations, ensuring stability, scalability, and the mitigation of potential side effects. This study explores the encapsulation efficiency of LNPs for siRNA and mRNA, aiming to enhance the formulation of vaccines and gene therapies. We hypothesize that there is a difference in formulation efficiency and stability between siRNA and mRNA. Specific Aims: Aim 1: Compare the difference in formulation efficiency between siRNA and mRNA. Aim 2: Assess the stability of mRNA-LNP at room temperature.

Methods: Using siRNA targeting Firefly Luciferase and mRNA for NanoLuciferase, we prepared lipid formulations with ALC-0315, DSPC, cholesterol, and PEG-DMG. Following dialysis against PBS, we assessed cholesterol content, siRNA/mRNA concentration, and encapsulation efficiency through RiboGreen assays and determined particle size and polydispersity index (PDI) to evaluate stability. 
Results: In our experimental investigations, we have demonstrated the encapsulation formulation efficiencies for various components. Specifically, the encapsulation formulation efficiency for siRNA targeting Luciferase was found to be 85-95% (N=8, P&lt;0.05), while that for mRNA encoding NanoLuciferase yielded a value of 80-90% (N=7, P&lt;0.05). Furthermore, a comparative examination between siRNA and mRNA revealed distinct data regarding encapsulation formulation efficiency. Our findings also encompassed particle size measurements, indicating that siRNA-LNP had longer stability at room temperature compared to mRNA-LNP. mRNA-LNP had a significant increase in particle size compared to siRNA-LNP. The results pertaining to PDI showed that mRNA-LNP had a significant increase in PDI over a 12-hour time period.

Conclusion: These results provide valuable insights into the encapsulation properties and stability profiles of various components within lipid nanoparticles, contributing to the advancement of nanoparticle-based drug delivery systems. To further expand on these findings and advance research and therapeutic applications, future investigations may encompass evaluating encapsulation efficiency with plasmid DNA, exploring novel ionizable cationic lipids, and extending studies to encompass larger animal models.

AMA Research Challenge 2024 

Advancements in Nanomedicine: A Study on Lipid Nanoparticle Reliability and Formulation Optimization

Abstract Title: Advancements in Nanomedicine: A Study on Lipid Nanoparticle Reliability and Formulation Optimization

Background: Lipid nanoparticles (LNP) have emerged as vital tools for delivering nucleic acids like messenger RNA (mRNA) and small interfering RNA (siRNA), playing a key role in the development of COVID-19 vaccines and RNA interference (RNAi)-based therapies for diseases including cancer and cardiovascular disorders. Despite their potential, inquiries into the comparative formulation efficiencies of LNPs when encapsulating siRNA versus mRNA payloads remain limited. Noteworthy challenges endure in optimizing LNP formulations, ensuring stability, scalability, and the mitigation of potential side effects. This study explores the encapsulation efficiency of LNPs for siRNA and mRNA, aiming to enhance the formulation of vaccines and gene therapies. We hypothesize that there is a difference in formulation efficiency and stability between siRNA and mRNA. Specific Aims: Aim 1: Compare the difference in formulation efficiency between siRNA and mRNA. Aim 2: Assess the stability of mRNA-LNP at room temperature.

Methods: Using siRNA targeting Firefly Luciferase and mRNA for NanoLuciferase, we prepared lipid formulations with ALC-0315, DSPC, cholesterol, and PEG-DMG. Following dialysis against PBS, we assessed cholesterol content, siRNA/mRNA concentration, and encapsulation efficiency through RiboGreen assays and determined particle size and polydispersity index (PDI) to evaluate stability. 
Results: In our experimental investigations, we have demonstrated the encapsulation formulation efficiencies for various components. Specifically, the encapsulation formulation efficiency for siRNA targeting Luciferase was found to be 85-95% (N=8, P<0.05), while that for mRNA encoding NanoLuciferase yielded a value of 80-90% (N=7, P<0.05). Furthermore, a comparative examination between siRNA and mRNA revealed distinct data regarding encapsulation formulation efficiency. Our findings also encompassed particle size measurements, indicating that siRNA-LNP had longer stability at room temperature compared to mRNA-LNP. mRNA-LNP had a significant increase in particle size compared to siRNA-LNP. The results pertaining to PDI showed that mRNA-LNP had a significant increase in PDI over a 12-hour time period.

Conclusion: These results provide valuable insights into the encapsulation properties and stability profiles of various components within lipid nanoparticles, contributing to the advancement of nanoparticle-based drug delivery systems. To further expand on these findings and advance research and therapeutic applications, future investigations may encompass evaluating encapsulation efficiency with plasmid DNA, exploring novel ionizable cationic lipids, and extending studies to encompass larger animal models.

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Purpose
Excess visceral fat and altered lipid metabolism are both associated with prostate cancer progression. Our aim was to determine if a weight loss lifestyle intervention using diet and exercise changed the intake of dietary fat and nutrients, the fatty acid composition and signaling pathways of periprostatic adipose tissue (PPAT), and the sphingolipid signature in the blood in men with prostate cancer. 

Materials and Methods
Forty men scheduled for radical prostatectomy (RP) were randomized into intervention (n=20) or active control (n=20) arms in a phase II trial. Participants in the intervention adhered to a lifestyle intervention using diet and exercise for 4-16 weeks before and 6-months after RP. Participants in the active control arm were given standard of care and standardized educational materials. Blood samples, dietary information, and health metrics of participants were collected at three time points: baseline (4-16 weeks prior to RP), 1 week prior to RP, 6 months after RP. PPAT biopsies were collected at the time of RP. Fatty acid analysis of PPAT was performed using flame-ionization gas chromatography. RNA from third passage adipose stromal cells (ASCs) were isolated using a RNeasy kit (Qiagen). RNA samples were analyzed using nCounter® PanCancer Immune Panel (NanoString). Sphingolipids were analyzed in plasma via Xevo GS-X2 quadrupole time-of-flight mass spectrometers using a 2D column configuration.

Results
The weight management program produced clinically significant weight loss in the intervention group compared to the control arm, with 5.5% weight loss from baseline to surgery. Dietary intake of myristic acid, palmitic acid, margaric acid, stearic acid, linoleic acid, arachidic acid, and linolelaidic acid significantly decreased in the intervention group from baseline to pre-surgery; between arm changes were significant. Oleic acid consumption significantly increased in the intervention group; between arm changes were significant. ASC transcriptomic analysis revealed lower gene expression of COLEC12 and higher expression of IL-17F, and biological mapping of transcriptome data using Ingenuity Pathway Analysis predicted inhibition of leptin and IL-6 signaling in the intervention group. The plasma sphingolipid signature significantly decreased in the intervention group and did not change in the control group. 

Conclusions
Our study demonstrated significant changes in the intake of dietary fatty acids which did not correlate with effects on the composition of the PPAT. Clinically significant weight loss produced transcriptomic changes in the PPAT, with downregulation of pathways associated with PCa progression. The improved plasma sphingolipid signature in the intervention suggests favorable changes in lipid metabolism protective against prostate cancer progression.

Exploring the Role of a Lifestyle Intervention on Periprostatic Adipose Tissue and Fat Metabolism in Men with Prostate Cancer

Background 
Despite advancements in treatment, laryngeal cancer survival rates remain largely unchanged due to late-stage detection. Screening and monitoring patients with laryngeal leukoplakia, a precursor to malignancy, is invasive, costly, and requires repeated visits to otolaryngology clinics, which impede timely laryngeal cancer detection. Field cancerization theory suggests that when cancer develops, subcellular changes occur proximal and distal to the site of malignancy. Elastic scattering spectroscopy (ESS), a real-time, non-invasive tool capable of differentiating tissue microarchitecture, may therefore be able to detect (and screen for) laryngeal cancer by easily measuring tissue changes in the oral cavity. This preliminary study tested whether ESS measurements obtained in the oral cavity could accurately differentiate between patients who have laryngeal cancer versus laryngeal leukoplakia. 
Methods
Under an Institutional Review Board approved protocol, 20 patients were enrolled; 10 patients with laryngeal cancer and 10 patients with laryngeal leukoplakia. All patients were clinically assessed and categorized per standard clinical practice. Patient demographics were collected, including age, race, sex, and smoking history. ESS spectral measurements were taken in several sub-anatomical sites within patients’ oral cavities. A machine-learning algorithm was developed to classify patients based on ESS spectra obtained from patients with benign laryngeal leukoplakia and from patients with laryngeal cancer. Specificity, sensitivity, negative predictive value (NPV), hit-to-climb ratio (HCR), and area under the curve (AUC) were calculated. Additional algorithms stratified spectral data by sub-anatomic site and patients’ smoking status to further refine diagnostic capability. 
Results 
The overall algorithm had a sensitivity=77%, specificity=56%, NPV=62.5%, HCR=1.73, and AUC=0.63. Stratifying by former and active smokers, algorithm sensitivities were 82% and 80%, respectively. Analysis by sub-anatomical location showed that an algorithm based exclusively on lateral tongue spectra had an AUC of 0.76, with further stratification by former and active smokers demonstrating AUCs of 0.95 and 0.81, sensitivities of 97% and 81%, and specificities of 80% and 71%, respectively. Additionally, a mucosal lip-based algorithm showed a sensitivity of 90%, specificity of 80% and NPV of 80% in former smokers. 
Conclusion 
ESS algorithms demonstrated high sensitivity in differentiating patients with leukoplakia versus squamous cell carcinoma when subclassified by smoking status and sub-anatomical site within the oral cavity. Utilization of ESS as a real-time, non-invasive screening tool may provide prompt detection of malignancy in non-specialized settings, potentially leading to timely diagnosis, treatment, and increased survivability. A follow-up study with a larger sample size.

Differentiating Laryngeal Cancer from Laryngeal Leukoplakia using Elastic Scattering Spectroscopy of the Oral Cavity: A Pilot Study

Purpose/Objective(s): In the era of rituximab, large B-cell lymphoma (LBCL) with secondary skeletal involvement has been associated with worse overall survival (OS) and higher relapse rates. Prospective data suggest an improvement in progression-free survival (PFS), and OS in patients with skeletal involvement treated with consolidative radiation (RT). Despite these positive results, real-world adoption of skeletal radiation and associated oncologic outcomes, need to be better characterized. We hypothesized that RT for patients with skeletal involvement from LBCL remains underutilized, leading to the detriment of OS.

Materials/Methods:
We conducted a retrospective analysis using the National Cancer Database for patients with LBCL with bone involvement with chemotherapy +/- RT from 2016-2020. Due to limitations on how skeletal involvement was coded prior to 2016, we excluded data from previous years. Patients who did not receive rituximab+chemotherapy, had prior malignancy, unknown RT treatment, or unknown follow-up were excluded. Patients who received palliative doses of RT (<30 Gy) were also excluded. Receipt of radiation treatment was defined as skeletal (SRT), non-skeletal (NSRT), or none. Trends in the utilization of RT were assessed using linear and logistic regressions. Survival analysis was performed using Cox regression and Kaplan-Meier methods.

Results:
A total of 641 patients met the inclusion criteria, with 8.7% receiving SRT, 7.2% receiving NSRT, and 84.1% without RT. In 2016, 80.6% and 13.9% of patients received no RT and SRT, respectively. In 2020, 84.9% and 7.9% of patients received no RT (slope: 1.1%/yr; p=0.141) and SRT (slope: -1.6%/yr; p=0.186), respectively. No patient or clinical factors were associated with receipt of either SRT or RT in general. Median follow-up was 2.6 years (IQR: 1.1-4.2 years). The 3-yr OS rates in the SRT, NSRT, and no RT cohorts were 87.0% (95% CI 74.7–93.6%), 83.4% (95% CI 68.1–91.8%), and 72.6% (95% CI 68.5–76.3%), respectively. Relative to no RT, receipt of SRT was associated with improved OS on univariable Cox regression (HR: 0.41; p=0.020) and multivariable (MVA) Cox regression (HR: 0.44; p=0.032). In comparison, relative to no RT, receipt of NSRT was not associated with improved OS on univariable Cox regression (HR: 0.54; p=0.087) or multivariable (MVA) Cox regression (HR: 0.55; p=0.098). Factors associated with OS on MVA included age and Charlson Deyo score. Other factors including race, ethnicity, insurance type, hospital type, and IPI score were not significant.

Conclusion:
Consistent with prospective data, SRT conferred a statistically significant improvement in OS, with a numerical improvement similar to prior prospective analyses. Despite this benefit, rates of consolidative RT to skeletal sites are low and potentially decreasing. Future studies should further elucidate the benefit of consolidative RT for patients with LBCL with skeletal involvement and barriers to such treatment.

Radiation to Sites of Skeletal Involvement in Large B-Cell Lymphoma: Trends and Impact on Survival

Abstract Title
Comparative Evaluation of the Efficacy of Intramuscular versus Transdermal Diclofenac in Post-Operative Pain Management in Modified Radical Mastectomy Patients 

Background 
Postoperative pain management is crucial for patient recovery following surgery, and adequate analgesia can mitigate various physiological and psychological complications. Breast cancer, being a common carcinoma, often requires modified radical mastectomy (MRM), which is associated with significant postoperative pain. Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), is widely used for pain management but poses challenges with oral and intramuscular administration due to systemic side effects and local irritation. A newly introduced diclofenac transdermal patch offers an alternative, potentially improving analgesic efficacy and patient compliance. 

Methods 
This study was conducted on 60 patients aged 25-65, classified as ASA grade I and II, scheduled for elective MRM under general anesthesia. Patients were randomly allocated into two groups: Group M (30 patients) received intramuscular diclofenac (75 mg) half an hour before the end of surgery, and Group P (30 patients) received a transdermal diclofenac patch (100 mg) at the beginning of surgery. Preoperative assessments included clinical history, physical examination, and routine laboratory investigations. Postoperative pain was evaluated using the Visual Analog Scale (VAS) at various intervals, and rescue analgesia was administered when VAS scores reached five or more. Additional observations included heart rate, blood pressure, and side effects. Statistical analysis was performed.

Results 
Both groups were comparable in demographic parameters (age, height, weight, duration of surgery). Postoperative heart rate and blood pressure variations showed no significant differences between the groups. VAS scores revealed statistically significant lower pain levels in Group P at 8 and 12 hours postoperatively (p<0.05). The mean duration of analgesia was significantly longer in Group P (14.28±4.49 hours) compared to Group M (7.91±2.81 hours) (p<0.05). The total dose of rescue analgesia was higher in Group M (1.13±0.34) compared to Group P (1±0) (p<0.05). Side effects were more frequent in Group M, with three patients (10%) reporting adverse events like pain on the injection site and nausea and vomiting, compared to 1 patient (3.3%) in Group P who complained of erythema on the patch site. 

Conclusion 
The diclofenac transdermal patch provides superior postoperative analgesia compared to intramuscular diclofenac, with significantly prolonged pain relief and reduced need for rescue analgesia. Additionally, the patch demonstrated a lower incidence of side effects, making it a more effective and patient-friendly option for managing postoperative pain in patients undergoing MRM. This study supports the adoption of the diclofenac transdermal patch as a viable alternative for postoperative pain management in breast cancer surgeries.

Comparative Evaluation of the Efficacy of Intramuscular versus Transdermal Diclofenac in Postoperative Pain Management in Modified Radical Mastectomy Patients

Objective: This study aims to compare the risk of intracranial hemorrhage (ICH) progression in traumatic brain injury (TBI) patients treated with unfractionated heparin (UFH) versus low molecular weight heparin (LMWH) for venous thromboembolism (VTE) prophylaxis.

Methods: A retrospective review was conducted on TBI patients with ICH who were treated at a level one trauma center between January 2018 and July 2020. Patients included had two or more CT head scans and received either UFH or LMWH within 24 hours after stable imaging. The primary outcome was ICH progression on follow-up CT. Secondary outcomes included hospital and intensive care unit (ICU) length of stay (LOS).

Results: Among 335 patients (28% female, 72% male), 160 received UFH, and 175 received LMWH. ICH progression was higher in the UFH group (44% vs. 27%, p=0.002). Hospital LOS and ICU LOS were longer in the UFH group (21.3 vs. 14.9 days, p=0.027; 11.1 vs. 6.5 days, p<0.001, respectively), and remained longer after adjusting for risk level and injury mechanism. Multivariate analysis showed that LMWH was associated with a lower risk of ICH progression (OR: 0.46, 95%CI: 0.27-0.77). Patients with multifocal lesions and those undergoing neurosurgical intervention had higher odds of ICH progression.

Conclusion: UFH administration was associated with a higher risk of intracranial hemorrhage progression, increased hospital LOS, and ICU LOS when compared to LMWH. These results suggest that VTE prophylaxis with LMWH may result in a decreased risk of ICH progression compared to UFH in TBI patients with the added benefit of decreasing LOS.

Progression of Intracranial Hemorrhage in TBI: Comparing Chemoprophylaxis with UFH Versus LMWH

Background
Meropenem (a carbapenem antibiotic) has broad indications for use, including complicated skin and soft tissue infections, complicated abdominal infections, and bacterial meningitis.1,2,4,5 
This study is a retrospective chart review of inpatient cases where this medication was prescribed. The main purpose was to determine the clinical reasoning (therapeutic/prophylactic) for which the medication was prescribed and to determine if treatment was generally successful and the incidence of significant side effects. 

Specific Aims:
1) Determine whether the medication was used mainly for therapy vs preventative uses
2) For those patients for whom it was used to treat a specific microbial agent, to determine the outcome of its use 
(Efficacious = released from hospital (with clinical improvement
and/or lab data demonstrating decreased infectivity ) vs 
Non-efficacious = side effect requiring discontinuation).

Methods
Data was collected via a retrospective chart review of patients prescribed Meropenem between August and October of 2023. Data was analyzed for indications of medication prescription and outcomes were determined based on whether patient was discharged with clinical improvement or the medication was discontinued due to adverse side effects. 
Data collected included the condition for which the patient presented to the hospital, length of stay, treatment type (Meropenem) and dates, patient response, reason for discontinuing medication if applicable, any adverse effects of treatment, and microbiology findings.

Results
87 patients were prescribed meropenem during the period of the study. In 10.5% of patients (n=9), it was prescribed for prophylaxis for to urologic/gastrointestinal surgery and in one patient for empiric treatment of aspiration pneumonia. The remaining 89.5% of patients (n=78) received therapeutic treatment; the majority of these patients (71 patients) had urine, wound and/or blood cultures and labs completed to confirm the appropriate antibiotic usage.
Over 60% of patients (n=48) indicated efficacious treatment (course completed, clinical and/or lab improvement and continued course without side effects); 34.6% of patients (n=27) had meropenem discontinued due to narrowing of therapy and only 5% (n=4) experienced severe side effects, requiring premature cessation of Meropenem.

Conclusion
Overall, Meropenem was well tolerated and generally was prescribed for culture confirmed infections requiring broad antibiotic coverage. Only 5% of the patients experienced disruptive side effects. Several patients had their antibiotic regimen narrowed, indicating good antibiotic stewardship. Patients who required Meropenem for complex infections were able to tolerate the full course and most cleared their infections without complication while under inpatient stay, or continued with treatment at discharge. Meropenem was generally used within acceptable guidelines of usage from an individual patient safety perspective and from a more universal perspective of antibiotic stewardship.

1. Pryka RD, Haig GM: Meropenem: a new carbapenem antimicrobial. Ann Pharmacother. 1994 Sep;28(9):1045-54. 
2. Meropenem: Drug Information. In: UpToDate, Wolters Kluver (Accessed on May 12, 2024)
3. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013 May;57(5):2326-32. doi: 10.1128/AAC.02176-12. Epub 2013 Mar 11. PMID: 23478961; PMCID: PMC3632900.
4. Baldwin CM, Lyseng-Williamson KA, Keam SJ. Meropenem: a review of its use in the treatment of serious bacterial infections. Drugs. 2008;68(6):803-38. doi: 10.2165/00003495-200868060-00006. PMID: 18416587.
5. Matthew E. Levison, Larry M. Bush, in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (Eighth Edition), 2015

Evaluation of Clinical Indications and Appropriate Usage of Meropenem in an Inpatient Setting

Abstract Title: Prototypical Machine Learning Model for Predicting Postoperative Blood Transfusion

Background 
Postoperative bleeding is a serious surgical complication that can result in re-exploration, transfusion, and mortality. Currently, there is no standardized, quantitative method to screen patients undergoing major surgery to identify patients who are at increased risk of postoperative bleeding. While it has been shown that certain independent risk factors such as age, smoking, medication use, and bleeding disorders play a large role in perioperative bleeding, no prior literature has explored the application of machine learning (ML) models to assess an individual’s risk quantitatively based on co-morbidities and medications. We aim to create an ML model to screen patients undergoing major procedures and assess their risk for significant postoperative bleeding requiring blood transfusion within 30 days. 

Methods
Using the MIMIC-IV dataset available through PhysioNet, we identified 199,277 records of major procedures as defined by the Agency for Healthcare Research and Quality (AHRQ). For each record, patient medical history, demographics, and procedure information were recorded, along with the outcome of blood product administration within 30 days of surgery. A comprehensive list of features can be found in Table 1 to the right. 80% of the records were used to train a Gradient Boosting Machine model, and 20% were used for validation. Based on the receiver operating characteristic (ROC), an optimal threshold of ~0.15 was calculated to differentiate between negative and positive predictions. Performance metrics were reported from the model’s predictions of validation set outcomes.

Results
The final model predicted blood product administration with a sensitivity of 80.82% and specificity of 86.26%. The positive predictive value is 45.26%, and the negative predictive value is 96.97%. The area under the receiver operating characteristic (AUROC) was 0.91. The top five most predictive features, in order, were surgical procedure type, BMI, age, comorbid coagulative disease, and comorbid kidney or ureter disease. 

Conclusion
Our results suggest that an ML model can be utilized to screen patients undergoing major procedures to determine if they are at risk of postoperative bleeding requiring blood transfusion. The model’s predictions can be used to guide postoperative management and follow-up of high-risk patients. Further iterations will modify model inputs and parameters to improve performance and validate the model using another dataset from other institutions. 


Prototypical Machine Learning Model for Predicting Postoperative Blood Transfusion

Objective:
Resistance training, and other exercise regimens, is an overlooked and understudied effective therapy for patients with Parkinson’s disease. We provide cumulative evidence from multiple studies that support the effect of training on Parkinsonian symptoms, as quantified by the UPDRS III rating scale. We present a supplemental non-invasive and non-pharmacologic treatment that can tremendously improve the quality of life and provide a biochemical explanation as to why muscle building offsets the degenerative symptoms of Parkinson’s to delay the loss of fine motor control and prevent comorbidities associated with a sedentary lifestyle.

Background:
Parkinson’s disease (PD) is a progressive neurological movement disorder, with idiopathic onset, that impairs activities of daily living with nearly 10 million individuals diagnosed worldwide according to the Parkinson’s Foundation. Underlying pathology manifests due to the loss of dopaminergic neurons within the substantia nigra pars compacta with a pathological hallmark of α-synuclein Lewy body inclusions. Classical parkinsonian motor features consist of resting tremors, cogwheel rigidity, bradykinesia/akinesia, and gait instability. Pathological advancement gradually debilitates fine-motor activities such as speech and eating. It is vital to continue developing therapies for neurodegenerative disorders such as PD to improve the quality of life in Parkinson’s patients. Typical treatment methodology encompasses levodopa with carbidopa drug courses, as well as deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi). 

However, emerging clinical evidence has demonstrated exercise regimens, specifically resistance training, as an efficacious treatment method in improving motor coordination and mental acuity in Parkinson’s. Muscles working against a force activates muscle fiber hypertrophy, contributing to enlarged contractile myofibrils in skeletal muscle tissue which induces acute effects on functional mobility and thus improved motor outcomes. Increased muscle mass ultimately reduces PD symptoms and contributes to finer motor control. A biochemical perspective provides input onto how exercise leads to endorphins which, in turn, drives dopamine release to offset the dopaminergic deficit found in Parkinson’s patients.

Methods & Data Analysis:
PubMed, Google Scholar, Web of Science, and Cochrane Library databases were utilized to collect manuscripts evaluating resistance training regimens. Relevant information extracted pertained to resistance training, exercise training variables (total sessions, duration, repetitions), therapy length, UPDRS type, and UPDRS III pre-mean and post-mean outcomes. Ten out of 17 potential papers met our search criteria. The seven papers excluded from this review did not specify a UPDRS
III score before or after completing a resistance training regimen. We provide a retrospective systematic review to identify 10 prior research studies that reported UPDRS III scores before and after resistance training in Parkinson disease patients. Then, statistical analysis via a paired t-test was conducted to assess for differences in the mean UPDRS III score before and after resistance training for the 10 articles chosen.

Results:
Upon reviewing 10 randomized control studies investigating the therapeutic effects of various resistance training routines on Parkinsonian symptoms, we found a significant decrease in UPDRS III (Unified Parkinson’s Disease Rating Scale) motor scores following adherence to a longitudinal resistance training program. Parkinson’s patients within each study were subjected to approximately seven to 12 weeks of resistance exercises, primarily targeted to postural and appendicular muscle groups. The mean UPDRS III score across all the trials examined was 31.1 with a standard deviation (SD) of 8.3. The mean post-therapy score was 25.7 with an SD of 8.6. Post-analysis paired t-test showed a statistically significant p-value of 0.00528. The T-score was –3.654, beyond the 95% region of significance of –2.2622 to 2.2622. These results reflect only the 10 papers included in this study and could present analytical bias due to low power.

Discussion: 
We found a significant decrease in UPDRS III scores after a longitudinal resistance training plan. These results suggest that resistance training may be a therapeutic, non-invasive, and non-pharmacological option for the treatment for Parkinson's disease. Repeated resistance training leads to the hypertrophy of muscle fibers, significantly improving muscle motor control Resistance training in the form of exercises such as bench press, rowing, leg curls, leg extensions, and deadlifts significantly decreases motor deficits that lead to tremors, rigidity, and stooped posture.

Conclusion:
UPDRS III results suggest resistance interventions via bench press, leg curls, rowing, leg extensions, and deadlifts significantly reduce motor deficits that lead to Parkinsonian rigidity, postural instability, and resting tremors. Furthermore, we plan to explore if other forms of physical activity including aerobics, Tai Chi, and balance training yield similar or improved symptom relief. Resistance training may be an optimistic, non-invasive and non-pharmacological therapy for Parkinson’s neuropathology as it shows promising measures for the independence and livelihood of PD patients. Future studies should analyze the therapeutic effects of other physical therapies (aerobics, aquatic training etc.) in treating Parkinson disease.

Effect of Resistance Training on Parkinson’s Disease Motor Symptoms:A Systematic Review & Analysis

Title: Obesity and Clear Cell Renal Cell Carcinoma: Unraveling the Connection
Objectives: Obesity has been identified as an established risk factor in the development of clear cell renal cell carcinoma (ccRCC). Obesity can lead to chronic cellular insults which may lead to DNA injury and whether these mechanisms are critical to cancer initiation in the kidney is unclear. Understanding how free fatty acids initiate cancer is critical to understanding the role of obesity in cancer initiation and development. We hypothesize that chronic injury and repair due to excess FFA exposure could lead to ccRCC carcinogenesis and aim to define the metabolic phenotype of obesity associated ccRCC. 
Methods: Using publicly available data from The KIRC Cancer Genome Atlas Program (TCGA) and clinicopathologic data, we compared the RNAseq profiles of obese (BMI >= 30) to normal weight (BMI =< 25) sample origins. Of the 337, a total of 333 had BMI available for analysis. We evaluated differences in Hallmark and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Using DESeq, we adjusted for age and sex. We clustered the mRNA, miRNA, and DNA methylation data using the iClusterBayes package. In vitro, HK PCT cells were cultured in DMEM+FBS and treated with bovine serum albumin (BSA)-palmitic acid complex and we measured cell viability at 24 and 48 hours using Alamar Blue. We extracted protein and performed western blots to identify DNA damage (pATM, H2AX) and endoplasmic reticulum stress (ATF4, eFI2alpha). 
Results: We identified several metabolic pathways to be unregulated in the obese group, including adipogenesis, heme metabolism, fatty acid metabolism, and bile acid metabolism. Analysis of methylation levels showed that obese patients appear to present a higher number of hypermethylated genes than normal weight patients. We identified decreased viability of renal proximal tubule and embryonal cells with excess free fatty acid supplementation. We also saw decreased cell viability with supplementation of BSA alone and are exploring the possible implication of BSA in endoplasmic reticulum stress to the cells. To further evaluate fatty acid associated parthenogenesis, we are repeating studies on in vitro HK PCT and treating cells with various concentrations of ceramide extracts. 
Conclusions: Through the investigation of these questions, we hope to improve understanding of obesity associated ccRCC and impact oncological outcomes for patients with this cancer. Understanding changes in lipid metabolism around ccRCC initiation will help identify novel pathways for pharmacologic intervention at earlier stages of the disease.

Obesity and Clear Cell Renal Cell Carcinoma: Unraveling the Connection

Background
The prevalence of obstructive sleep apnea (OSA) in children with Down syndrome is as high as 80% with limited treatment options. While adenotonsillectomy is the first line treatment, less than 33% of children with Down syndrome have resolution of OSA after adenotonsillectomy alone, and subsequent positive airway pressure (PAP) support is often poorly tolerated. Upper airway stimulation, which stimulates the hypoglossal nerve to protrude the tongue and open the airway during sleep, has shown efficacy for adults with OSA, but had not been evaluated in pediatric populations. Our objective was to describe the efficacy of upper airway stimulation for adolescent patients with Down syndrome and severe OSA.

Methods
We conducted a Phase 1, single-arm, multi-center trial of the safety and efficacy of hypoglossal stimulation in adolescent patients with Down syndrome and persistent severe OSA. Patients with Down syndrome were included if they were between 10-21 years old, had persistent severe OSA (AHI >10 after adenotonsillectomy and inability to tolerate CPAP), and had a drug-induced sleep endoscopy that did not show circumferential palatal collapse. Polysomnographic and quality of life outcomes were assessed at 1, 2, 6, and 12 months postoperatively. The prespecified primary outcomes were safety and the change in apnea-hypopnea index (AHI) from baseline to 12 months postoperatively.

Results
Among the 42 patients, 28 patients (66.7%) were male with a mean (SD) age of 15.1 (3.0). The mean decrease in AHI was 12.9 events/h (95% CI, –17.0 to –8.7 events/h). The 12-month response rate was 65.9%, and 73.2% of patients had a 12-month AHI <10 events/h. The most common complication was temporary oral discomfort, which occurred in 5 patients (11.9%). The reoperation rate was 4.8%. The mean improvement for the OSA-18 total score was 34.8 (95% CI, –42.1 to –27.5) and for the Epworth Sleepiness Scale score was 5.1 (95% CI, –7.4 to –2.8). The mean (SD) duration of nightly therapy was 9.0 (1.8) hours, with 40 patients (95.2%) using the device >4 hours nightly.

Conclusion
Upper airway stimulation was safely performed for adolescents who had Down syndrome and persistent severe OSA after adenotonsillectomy with PAP intolerance. Patients had significant improvements in polysomnographic and quality of life outcomes 1 year after surgery. These results describe a novel therapy option for treatment resistant OSA in children with Down syndrome, which led to FDA approval for this indication.

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