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Biomechanical Markers of Lower Extremity Fatigue: A Literature Review
No full textPurpose: Lower-extremity (LE) muscular fatigue plays a pivotal role in injury occurrence across various domains, including sports, occupational settings, and daily activities. This is partly because fatigued muscles can absorb less energy before reaching the degree of stretch that causes injury. This review explores the significance of employing measurable biomechanical markers to assess lower extremity fatigue. Some studies have shown significant changes in post-fatigue functional tasks (vertical jump height), acceleration/velocity, postural stability (center of pressure), spatio-temporal gait metrics, and pressure distribution, but few reviews have compared these factors to identify the best predictors of fatigue. With the prevalence of musculoskeletal injuries, understanding the biomechanical changes associated with fatigue becomes imperative for predicting and preventing injury.
Methods: PubMed, Google Scholar, and Scopus were searched using 20 distinct queries, which yielded 3,068 articles. The inclusion criteria used were: An experimental pre/post-test design, fatiguing protocol targeting lower extremities, recent studies after 2010, greater than 10 participants, data recorded via force plates or IMU, and a healthy adult population. In total, 44 articles met the inclusion criteria.
Results: Of the included studies, CoP changes were dependent on the protocol used. High-intensity fatigue protocols were associated with significant increases in postural instability, measured by CoP displacement, velocity, and variability in both sagittal and coronal planes, but CoP measures were inconclusive in low-moderate intensity fatiguing protocols. When observing Spatio-Temporal gait metrics, the literature showed a strong positive correlation between increased ground contact time and fatigue. Stride length was negatively correlated with fatigue. Step width variability and single stance time were increased following fatigue. In terms of pressure distributions, increasing muscle fatigue was correlated with increases in plantar pressure. Peak pressure and force of metatarsals I - V were inconclusive, attributable to varying rear versus forefoot strike patterns, however, medial and lateral heel peak pressures consistently increased with muscle fatigue. In line with these findings, various studies demonstrated that increasing fatigue correlated with kinetic parameters such as increased stride cadence and, consequently, increased tibial acceleration. Prolonged or repetitive exposure to elevated tibial acceleration levels may be associated with greater impact forces and loading on the lower extremities, potentially contributing to muscle fatigue and elevating the risk of overuse injuries. Functional tests, such as jump height, showed a significant negative relationship with fatigue regardless of protocol intensity. A study comparing different jump height modalities and fatigue showed the highest repeatability and immediate/prolonged fatigue produced changes with CMJ, supported by its widespread use as an indicator for fatigue.
Conclusions: We consistently found significant increases in sagittal plane CoP velocity, ground contact time, heel loading, and tibial acceleration with a significant decrease in CMJ height following LE fatigue. Limitations included variability in the fatigue protocols used and limited research that met inclusion criteria. In the future, these results can have implications for the development of wearables to track fatigue in athletes to decrease the incidence of injury
Identification of Estrogen-Responsive Proteins in Mouse Seminal Vesicles Through Mass Spectrometry-Based Proteomics
Get PDFBackground: Although estrogenic compounds promise therapeutic potential in treating various conditions, concerns regarding their endocrine-disrupting effects have been raised. Current methodologies for screening estrogenicity in rodent models are limited to the female-specific uterotrophic bioassay. Studies have reported enlargement of the seminal vesicles in orchiectomized males treated with estrogens. However, identifying estrogenicity strictly through changes in wet weights is uninformative regarding the molecular mechanisms of these agents. Therefore, protein-based biomarkers can complement and improve the sensitivity of weight-based assessments. To this end, we present a discovery-driven proteomic analysis of 17beta-estradiol's effects on the seminal vesicles. Methods: We treated orchidectomized mice with the hormone for five days and used the vehicle-treated group as a control. Seminal vesicles were analyzed by shotgun approach using data-dependent nanoflow liquid chromatography-tandem mass spectrometry and label-free quantification. Proteins found to be differentially expressed between the two groups were processed through a bioinformatics pipeline focusing on pathway analyses and assembly of protein interaction networks. Results: Out of 668 identified proteins that passed rigorous validation criteria, 133 were regulated significantly by 17beta-estradiol. Ingenuity Pathway Analysis((R)) linked them to several hormone-affected pathways, including those associated with immune function such as neutrophil degranulation. The altered protein interaction networks were also related to functions including endocrine disruption, abnormal metabolism, and therapeutic effects. Conclusions: We identified several potential biomarkers for estrogenicity in mouse seminal vesicles, many of them not previously linked with exogenous 17beta-estradiol exposure.Funding provided by the National Institutes of Health (NIH) in Bethesda, MD, USA (grant numbers CA215550 (L.P.) and EY027005 (K.P.T.)) and the Robert A. Welch Foundation (endowment BK-0031 to L.P.). A.K. was also supported by a Neurobiology of Aging and Alzheimer's Disease Training Grant (NIH T32 AG020494)
Prodrug nanotherapy demonstrates in vivo anticryptosporidial efficacy in a mouse model of chronic Cryptosporidium infection
Get PDFThe gastrointestinal disease cryptosporidiosis, caused by the genus Cryptosporidium, is a common cause of diarrheal diseases in children, particularly in developing countries and frequently fatal in immunocompromised individuals. Cryptosporidium hominis (Ch)-specific bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) has been a molecular target for inhibitor design. (Note that this bifunctional enzyme has also been referred to as TS-DHFR in previous literature since the functional biochemical reaction first involves the conversion of methylene tetrahydrofolate to dihydrofolate at the TS site.) While nanomolar inhibitors of Ch DHFR-TS have been identified at the biochemical level, effective delivery of these compounds to achieve anticryptosporidial activity in cell culture and in vivo models of parasite infection remains a major challenge in developing new therapies. Previous studies, using a nanotherapy approach, have shown a promising Ch DHFR-TS inhibitor, 906, that can successfully target Cryptosporidium parasites in cell culture with nanomolar anticryptosporidial activity. This formulation utilized poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with 906 (NP-906) and conjugated with a Cryptosporidium monoclonal antibody (MAb) on the nanoparticle surface to specifically target the glycoprotein GP25-200 in excysting oocysts. However, a limitation for in vivo use is antibody susceptibility to gastric acidity. To address this gap, a prodrug diethyl ester form of 906 (MAb-NP-Prodrug) was synthesized that allowed higher compound loading in the MAb-coated PLGA nanoparticles. An oral formulation was prepared by loading lyophilized MAb-NP-Prodrug into gelatin capsules with an enteric coating for gastric stability. Proof-of-concept studies with this oral formulation demonstrated antiparasitic activity in a chronic mouse model of Cryptosporidium infection. Efficacy was observed after a low daily dose of 2 x 8 mg kg(-1) for 5 days, when examined 6 and 20 days postinfection, offering a new avenue of drug delivery to be further explored.We also wish to thank Dr Firouz Asgarzadeh at Evonik for providing a sample of the Eudragit L100-55 polymer. This work is supported by the National Institutes of Health under Award Numbers (AI083146) to K. S. A., Training Grant (5T32AI007404-23) to D. J. C., and (R21CA194295), (S21MD012472) and (U54MD006882) to J. K. V
Patients Present With Recurrent Takotsubo Cardiomyopathy
No full textTakotsubo Cardiomyopathy (TTC) was first characterized by Sato and his research group in Japan 1990. It is characterized by hypokinesis of various sections of the heart wall in the left ventricle and most commonly ballooning of the apical section of the heart. These findings are generally resolved within 21 days of the onset without major intervention. Since its discovery many articles have focused on classifying the effects of TTC and case studies have illustrated interesting cases of TTC; however, few publications exist highlighting recurring cases of TTC. This publication focuses on two patients who presented with a recurring case of TTC. Case Presentation: Patient 1 first presented with a two-day history or worsening pain. Upon admission into the emergency department labs reported elevated troponin and low ejection fraction (EF) of 47%. Heart catheterization showed no signs of coronary artery obstruction but confirmed systolic compression at be decreased to 40%. Three years later the same patient presented with severe chest pain, shortness of breath, elevated troponin, and ST segment depression. Heart catheterization again showed no signs of coronary artery obstruction and reduced EF. Patient 2 first presented with pneumonia and sepsis. There were no indications for coronary issues however labs showed elevated troponin. Catheterization showed no signs coronary artery disease, but cardiac echogram demonstrated an EF of 20%. Seven years later the patient was brought to the hospital by emergency services with nausea, vomiting, diarrhea, loss of consciousness, and seizures. Labs revealed elevated troponin and acute ischemia. Follow up with an echo cardiogram showed severe hypokinesis and reduced EF of 25%. Conclusions: Due to how rare recurring cases of TCC are, there is little research regarding outcomes of patients with recurrent TCC. More case presentations and long-term statistics on these patients is required to build a more accurate picture of this cardiomyopathy and educate patients on their condition
Primary Care Physician Density per Capita and its Effects on Diabetic Complications
No full textIntroduction: The state of Texas has a severe shortage of primary care physicians that has worsened in recent years, with only 4 of 254 counties demonstrating a sufficient number of primary care physicians, based on federal guidelines. This number is more pronounced in rural areas. A striking 82% of Texas counties have less than one primary care physician per 3,500 patients (1). In addition, the state of Texas has a significant population of diabetic patients needing physician management. Over 2 million people in Texas have diagnosed diabetes, with over 500,000 that are undiagnosed (2). Without sufficient treatment and surveillance, diabetes can progress to a host of problems including coronary artery disease, chronic kidney disease, retinopathy, amongst other morbidities. Researchers have elucidated the benefits of preventative care for stroke, heart disease, and cancer, but its correlation to diabetic outcomes has not been well documented. Therefore, we wanted to assess the effects of an increased number of primary care physicians per capita on preventing adverse diabetic outcomes in Texas counties.
Methods: To further evaluate the effect of primary care physicians on preventing worse diabetic outcomes, we collected data from Texas Health Data on the admission rate for uncontrolled diabetic admissions in both adult diabetics and the lower extremity amputations for uncontrolled adult diabetics per county in 2019 (3). We then collected the ratio of patients to primary care physicians in each county in the state of Texas in 2019, using the county health rankings database (4). We compiled data from both sources and performed a statistical analysis to evaluate the correlation between primary care physicians per capita and diabetic admissions and amputations in each Texas county. Descriptive statistics were estimated to describe sample characteristics. We estimated the predicted ratio of admissions and amputation rates using bootstrapped ratio testing generated with 50 samples. All data were analyzed in Stata and the level of significance was set at p <.05.
Results: An average population of 295,998 individuals across the state of Texas were part of the final analytic sample. Results showed the mean risk-adjusted admissions per 100,000 were 52.3 (SD = 25.9). Bootstrapped ratio testing indicated a significant ratio of increased amputees and admissions (Bootstrapped Observed ratio: 0.00042, bootstrapped standard error: 0.00001, 95% CI 0.00040, 0.00043), X2= 99.9, p <.0001, given an increased ratio of patients to physicians.
Conclusion: These data further establish the importance of having a sufficient number of primary care providers in rural and underserved areas. The state of Texas and Texas medical schools should establish further methods to encourage physicians to practice in rural areas to decrease the amount of uncontrolled diabetes and amputations in our populations.
Given these findings, we hypothesize that there is an association between the number of physicians per capita and diabetic outcomes. We would like to further evaluate which counties specifically have the least access to primary care physicians, higher diabetic rates, and most unfavorable outcomes. As we perform further research, we would also like to evaluate other confounding variables that were not considered
Transcranial Magnetic Stimulation Efficacy Across Age Groups
No full textPurpose: Transcranial magnetic stimulation is a non-invasive brain stimulation technique that targets treatment-resistant depression and other psychological disorders. TMS involves delivering repetitive magnetic pulses to stimulate electrical activity in the brain, sending a depolarizing current to neurons in the targeted region. For treatment-resistant depression, TMS targets the dorsolateral prefrontal cortex, though for other disorders, the region targeted varies. It is possible that TMS utilizes the neuroplasticity of the brain to cause long-term changes in brain activity. Previous studies have also explored age-related changes in GABA receptors, which could also impact the efficacy of TMS . I hypothesize that younger age groups (18-25 years) would respond better because their brains are still in development. Methods: The Neurostar Magnetic Therapy Machine was used to treat each patient involved in the study. It is FDA approved for the treatment of Major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Correspondingly, the machine administered varying treatments for each disorder through altering total pulses, seconds of stimulation, and the time span of the break between stimulation. Within each disorder, these variables were kept constant. Treatment for MDD involved a standard total of 3000 pulses with intervals of 4 seconds of stimulation and 11 seconds of rest. Contrastingly, OCD treatment included a standard 2000 total pulses with 2 seconds of stimulation and a 20 second rest break in between. The final metric used for data analysis was the Standard Motor Threshold (SMT), which is a measure of the strength of the patient’s medication and varied between each patient. The PHQ-9 survey was the metric used to measure whether a patient had undergone remission, with a score of 0-4 indicating success. An initial PHQ-9 was completed prior to treatment, and then completed weekly, followed by a final survey post-treatment, yielding roughly 7-9 surveys exhibiting the changes in their respective disorders. For this study, only patients who fully underwent remission were included in the data set. Records of each patient’s PHQ-9 surveys were obtained digitally through the “Trakstar” EMR program, which held every completed survey of each patient. Results: The data supports that patients within the 41-60 age group were the most responsive to TMS. Following that age group in terms of responsiveness was the 18-25 age group, then the 61+ age group, and finally the 26-40 age group was ranked last. It can be posited that the reason for the highest rates of responsiveness in this age group is due to their lower neural plasticity, resulting in the changes caused by TMS to last longer. Conclusion: The results reflected that the 41-60 age group responded best, though all age groups had similar rates of responsiveness close to the 50% mark. Further study is needed to confirm the reasons as to why the 41-60 age group responded higher than the rest. Exploring TMS efficacy on patients with secondary disorders to MDD or experimenting with the idea of placing TMS treatments ahead of rounds of psychiatric medications can support the notion that TMS is a safe and effective psychiatric treatment of the future
The Reliability of Artificial Intelligence in Prioritizing Management of Diabetic Macular Edema: A Comparative Study with 2 Retina Specialists
No full textPurpose
There are currently no studies evaluating an Artificial Intelligence (AI) Large Language Model’s (LLM) reliability for ordinally prioritizing patients. In this study, we assess the ChatGPT Plus model (GPT-4) for prioritizing Diabetic Macular Edema (DME) patients, comparing its performance to that of two board-certified retina specialists (RS). We also investigate 2 additional questions: key variables for evaluators (GPT-4 and 2 RS) in DME prioritization, and the impact of incomplete clinical profiles on inter-evaluator agreement.
Methods
We used anonymized DME data from Retina Consultants of Texas to create 28 patient profiles. These profiles were divided into 4 sets based on ascending Diabetic Retinopathy (DR) severity (Set 1), Central Subfield Thickness (CST) (Set 2), modified Best Corrected Visual Acuity (BCVA) (Set 3), and a randomly organized control set (Set 4). We intentionally modified BCVA in Set 3, resulting in clinically incomplete patient profiles. 2 RS and GPT-4 prioritized patients in each set (e.g., Set 1) according to least to most treatment needs. We calculated the mean Cohen's Kappa (k) across all 4 sets to measure agreement between the 2 RS and the 2 RS with GPT-4 (k = 0.40–0.59 (weak), 0.60–0.79 (moderate), 0.80–0.90 (strong), >0.90 (almost-perfect)). Median RS evaluations were used to calculate individual set k as well as mean set k with GPT-4.
Results
Evaluations by the 2 RS (denoted RS1 and RS2) and GPT-4 show moderate agreement (Set 3 excluded: RS1-GPT-4 mean set k = 0.631; RS2-GPT-4 mean set k = 0.68). When using the median of RS evaluations, GPT-4's agreement with RS increased within the moderate range (Set 3 excluded: Median RS-GPT-4 mean set k = 0.77). Agreement between the 2 RS was weak (Set 3 excluded: RS1-RS2 mean set k = 0.48). The inclusion of Set 3 in mean set k calculations showed no clear impact. GPT-4 responses/explanations did not acknowledge clinical ambiguities in Set 3, noted by both RS in an optional comment box. Individual k values for Sets 1, 2, 3, and 4 were as follows: 0.58, 0.79, 0.72, 0.93.
Conclusions
The results reveal that GPT-4 shows promise in reliably prioritizing DME patients compared to RS. Ultimately, GPT-4 achieved moderate-strong (k ≥ 0.60) agreement with RS in DME prioritization. Interestingly, GPT-4’s increased agreement with median RS evaluations could indicate an ability to predict the RS consensus despite moderate disagreement between the 2 RS themselves. This is interesting considering an LLM’s inherent function — mathematically predict the average human response to a given text. This further supports GPT-4’s potential as a clinical tool, offering a grounded perspective in decision-making to assist more nuanced human judgment. Incomplete clinical profiles did not clearly impact agreement, possibly suggesting GPT-4’s adaptability. However, GPT-4 failed to recognize ambiguities in patient profiles that both RS noted. Therefore, human specialists may be better equipped to prevent erroneous decisions when evaluating incomplete or exceptional patient cases. Regarding key variables for prioritization, almost-perfect agreement in the control set (Set 4) warrants investigation into additional variables beyond what is explored in this study
Implementation of SERPINA1 Next-generation Sequencing and Bretzi in Alpha-1 Antitrypsin Deficiency
No full textBackground:
Alpha-1 Antitrypsin deficiency (AATD) is a common hereditary disease in families that have autosomal codominant patterns composed of two different variants of alleles, and generally are suspected in young patients (age 25-50) with symptoms of pulmonary emphysema or chronic obstructive pulmonary disease (COPD), with treatment consisting of either augementation therapy with IV purified AAT or symptomatic treatment. It is currently recommended to support initial quantitative serum AAT level measurements with some sort of qualitative testing for comprehensive diagnosis and risk assessment.
Case Presentation:
We report the case of a caucasian 51-year-old female with no significant history of smoking, occupational chemical exposure, and exposure to birds, who presented to the clinic with complaint of persistent dry frequent coughs with associated shortness of breath (SOB), headache, and difficulty sleeping. At the time of initial presentation the patient reports taking Azelastine HCI, Benzonatate, Albuterol Sulfate, ProAir HFA, Zafirlukast, and Fluticasone Propionate with no improvement of symptoms. Initial workup found significant hyperinflation on Chest X-ray and Pulmonary Functions Tests (PFT) and AAT deficiency testing was initiated based on clinical guidelines. Advanced testing with SERPINA1 next generation sequencing was ordered in conjunction with serum AAT levels to confirm the diagnosis and the patient was started on a month course of Trelegy with minimal improvement of symptoms. A sample of Bretzi was given and on follow-up, patient endorsed resolution of symptoms with improved quality of life and denied any coughing, wheezing, SOB, chest pain, sinus congestion, runny nose, headache, or dizziness.
Conclusion:
This case illustrates a typical clinical presentation of AATD; we conclude that the addition of SERPINA 1 next generation sequencing (FDA determined no need for clearance) as a confirmatory measure and resolution of symptoms with a course of Bretzi, a 3-in-1 maintenance COPD medication cleared by the FDA in 2020, suggest the efficacy of including these relatively new modalities in the treatment of future AATD patients
Intersection Syndrome of the Chiasma Crurale: A Novel Clinical Manifestation on Ankle MRI
No full textBackground: Intersection syndrome describes a painful pathology occurring at the crossing of tendon sheaths, commonly noted in the forearm in the setting of overuse injury. Rarely, intersection syndrome may occur in other areas of similar musculotendinous intersections; one such location, the chiasma crurale, describes the intersection of the flexor digitorum longus tendon and the posterior tibialis tendon located on the posteromedial leg. Magnetic resonance imaging of the chiasma crurale in cadaveric legs has previously been observed; however, no clinical pathology has been reported on MRI. Case Information: A 64-year-old female (BMI: 44.3) with a past medical history of pes planus, bilateral knee replacement, and unspecified discectomy, complains of recurrent shooting pain in her left lower extremity that has been worsening for the past 3 weeks without improvement from an ambulatory boot. She is tender to palpation at the insertion of the PTT, sinus tarsi, and great toe. She was offered surgical and conservative options for treatment and opted for conservative treatment with an ambulatory boot. Conclusions: In this case report, we present a novel clinical finding discovered on ankle MRI, of intersection syndrome of the chiasma crurale
Vascular and metabolic profiles related to white matter hyperintensities in a multiethnic cohort from the HABS-HD study
No full textPurpose: There are more than 6 million people living with Alzheimer’s disease (AD) in the United States. Mexican-Americans (MA) and African-Americans (AA) are disproportionally affected by AD and related dementias, and it is expected that these disparities will increase in the coming years. AD commonly presents with vascular dementia and research has shown the relationship between the two to be complex, with many individuals presenting with mixed dementia. Vascular dementia is commonly related to small vessel disease. Small vessel disease occurs when endothelial damage in cerebrovascular circulation causes ischemia, leading to microinfarcts. The microinfarcts show up as white matter hyperintensities (WMH) in MRI. Most research using WMH to study dementia has been completed with non-Hispanic whites (NHW), though studies have shown a higher incidence of metabolic factors related to AD in MA. It is our goal to use WMH to find further differences in vascular and metabolic factors related to AD among a cohort of NHW, MA, and AA. Method: A cross-sectional analysis of 2363 subjects from the HABS-HD cohort was conducted (967 NHW, 410 AA, and 986 MA). Participants underwent a clinical evaluation and a 3T brain MRI (Siemens Skyra). WMH volume was measured from FLAIR using the Statistical Parametric Mapping (SPM) Lesion Segmentation Tool. WMH were Log transform to achieve normality, and were adjusted for intracranial volume derived from Free3Surfer V6.0 analysis of T1MPRAGE. Fasting blood samples were collected, and clinical measures were conducted using standard procedures. Clinical, vascular, and metabolic risk factors (table 1) were used in linear regression models as predictors of WMH volume adjusted by intracranial volume (ICV). Age, sex, and education were entered as covariates. Results: The total sample was 62.3 percent female with a mean age of 65.4 years and 13.07 years of education. NHW were older, had more years of education, had lower BMI, lower systolic and diastolic blood pressure, and levels of triglycerides, HA1c, and EGFR when compared to AA and MA (p ≤0.005). In NHW, age, sex, education, SBP, DBP, and hypertension significantly predicted WMH volumes (p ≤ 0.005). Age, years of education and BMI were the only significant predictors of WMH volume in AA (p ≤ 0.005), while age, total cholesterol and T4 levels were significant predictors of WMH volume in MA (p ≤ 0.005). Having a diagnosis of diabetes or dyslipidemia, also predicted WMH volume in MA. Conclusion: Results showed that different factors contribute to WMH volume among different ethnicities. Results suggest that in NHW, a vascular profile is most relevant, while in MA and AA, a metabolic profile seems to be driven the association with WMH. Prospective studies are needed to further understand the how the different profiles among different ethnicities affect the presentation of WMH and pathology of SVD.Research reported in this presentation was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG054073 and R01AG058533, P41EB015922 and U19AG078109