Diabetic retinopathy (DR) is a significant cause of vision loss and a research subject that is constantly being explored for new mechanisms of damage and potential therapeutic options. There are many mechanisms and pathways that provide numerous options for therapeutic interventions to halt disease progression. The purpose of the present literature review is to explore both basic science research and clinical research for proposed mechanisms of damage in diabetic retinopathy to understand the role of triglyceride and cholesterol dysmetabolism in DR progression. This review delineates mechanisms of damage secondary to triglyceride and cholesterol dysmetabolism vs. mechanisms secondary to diabetes to add clarity to the pathogenesis behind each proposed mechanism. We then analyze mechanisms utilized by both triglyceride and cholesterol dysmetabolism and diabetes to elucidate the synergistic, additive, and common mechanisms of damage in diabetic retinopathy. Gathering this research adds clarity to the role dyslipidemia has in DR and an evaluation of the current peer-reviewed basic science and clinical evidence provides a basis to discern new potential therapeutic targets. Diabetic retinopathy (DR) is a significant complication of diabetes mellitus (DM) characterized by ischemic microvascular disease of the retina and retinal neurodegeneration, ultimately leading to vision loss . Damage In order to determine how lipids impact retinal health in the context of DM, shared and distinct mechanisms underlying dyslipidemia and diabetes need to be considered Figure 1Systemic therapy for glycemic control reduces the risk for developing DR and attenuates the disease progression. However, the utility of therapeutic control of abnormal lipid metabolism in DR therapy has yet to be determined . DyslipiThe pathways/mechanisms selected for discussion in this section are the best studied mechanisms for dyslipidemic retinal damage. Studies were selected for their evaluation of retinal damage from dyslipidemia/hypercholesterolemia with exclusion of confounding variables such as hyperglycemia. Specific pathways/mechanisms are emphasized if they are directly involved in the pathogenesis of DR and demonstrate potential as targets for pharmaceutical advancement Figure 1In rabbit models of dyslipidemia and metabolic syndrome, a high cholesterol diet increases amyloid-beta (Aβ) levels in retinal photoreceptors, inner and outer neural layers, and ganglion cell layers . The proIn vitro models using RPE cell lines demonstrated cholesterol dysmetabolism-induced Aβ peptide accumulation , a product formed from the oxidation of cholesterol. 7-KCh blood levels are elevated in diabetic patients . HoweverIn rabbit models, hypercholesteremia impairs retinal function by diminishing retinal ganglion cell density and decreasing thickness of the photoreceptor layer and inner nuclear layer . DestrucTo further expound on the participation of lipids, we will discuss nitric oxide (NO), and the three distinct isoforms of NO synthase responsible for its synthesis: iNOS, neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS). These enzymes play a critical role in endothelial dysfunction in the context of DR development and progression. It is well-established that elevated lipid levels cause endothelial dysfunction due to a marked reduction in the bioavailability of NO. Microvascular complications in DR can be detected histologically as microvascular basement membrane thickening, closures and rarefaction of capillaries, and diagnosed clinically by impaired endothelial function and eNOS uncoupling . EndotheTo date, the results from epidemiological studies focused on lipid profiles and DR are inconsistent. While some studies have determined a relationship between elevated levels of total cholesterol and LDL-cholesterol and the development and progression of DR, other studies were unable confirm these findings . Thus, tA study from Montgomery et al. examined the retinal function of mice following the chemical induction of sustained dyslipidemia . IsolateIn vivo studies using mice retinal tissue suggest TRPV4 is a sensor of both physical and chemical stimuli and helps regulate the permeability of the inner retinal endothelial barrier  oxidase (NOX). For this reason, one might hypothesize that decreased levels of NOX should decrease the burden of oxidative stress in any cell in the body. A study tested this hypothesis on retinal neurons in mice with deletion of the NOX2 gene, which encodes a catalytic subunit of the active enzyme . The knoin vivo and in vitro  migration into nuclear layers of the retina. This decreased influx of inflammatory cells suggests a potential pharmaceutical target for preventing ocular inflammation in DR  and ox-LDL immune complexes into human diabetic retinas post-mortem, using immunohistochemical staining for IgG in order to correlate its presence to proportional cytotoxic effects on retinal pericytes . Retinalytokines . The stuytokines .To effectively evaluate the role that the intertwining pathophysiologies diabetes and dyslipidemia/hypertriglyceridemia have in DR, it is paramount to examine the clinical studies that evaluate patients with both pathologies. The clinical studies help delineate dyslipidemia as an effect modifier vs potential confounder the in patients DR and highlight an accelerated progression of disease in these patients. These clinical studies also provide a rationale for therapies targeting dyslipidemia can provide a clinical significant impact Table 1.Examining a national health database of Taiwan, diabetic patients with dyslipidemia had a statistically significant increase in the incidence of retinopathy when compared to diabetic patients without dyslipidemia . Adjustei.e., a conventional serum lipid profile) and DR.In patients without DR, studies have also found concurrent dyslipidemia to be a predictive factor for the eventual development of retinopathy. Diabetic patients with no clinical evidence of DR, have significantly lower VD (vascular density) size and FAZ (foveolar avascular zone) size than healthy patients. A study evaluating these early subclinical retinal changes in diabetics found dyslipidemia and high LDL-c to be the most significant risk factors for early retino-vascular damage . A recenThe apo-B/apo-A ratio’s utility in predicting retinal damage is not only based on the damage secondary to elevated LDL but also the lack of protective HDL. A population-based study of 11,265 patients from U.S communities found elevated HDL to be protective against early microvascular changes and damage . InteresWith regard to the role of apolipoproteins and DR discussed above, different apolipoproteins appear to have different contributions to the overall pathogenesis of DR. One study by Kawai et al. demonstrated increased levels of apo-A1 in the tear fluid of DR patients when compared to patients with DM but without DR. Importantly, it was determined that no apo-A1 was present in the tears of healthy control subjects . In a stThe signaling pathways/mechanisms of disease discussed in this section are common to both dyslipidemia and diabetes. A deeper understanding of the specific signaling pathways that result in damage to the retina and aid in pharmaceutical development and therapies Figure 1In vitro models or rat retinal cells, AMPK-activating compounds decrease apoptosis in rat retinal Müller cells -activated protein kinase (AMPK). This molecule is activated within hepatocytes by metformin, a drug used to treat diabetes, resulting in both increased glucose utilization and favorable lipid profiles by lowering triglycerides and VLDL . In vitrer cells .In mouse models, AMPK has been associated with improving insulin sensitivity , 78 and in vivo administration of simvastatin reduced ROS-mediated apoptosis of both pericytes and vascular endothelial cells in rats and attenuated apoptosis of bovine retinal endothelial cells in vitro by decreasing p38 mitogen-activated protein kinase (MAPK) activity, modulating PARP signaling, along with decreasing vascular endothelial growth factor (VEGF) expression and vascular permeability  release resulting in vascular repair through induction of Akt signaling and activation of eNOS . In addisitivity ; this fuWithin the peroxisome-proliferator-activated receptor (PPAR) protein family of transcription factors that regulate lipid metabolism, PPARα is activated by fibrates, a class of lipid-lowering drugs . PPARβ/δIn addition, PPARβ/δ plays a unique role in each disease state independent of AMPK activation. In mouse models of diabetes, PPARβ/δ increases insulin sensitivity through increased glucose catabolism, shunting glucose into lipogenesis pathways and increasing fatty acid oxidation in skeletal muscle .Protective properties of PPARs were tested in an ex vivo model of ototoxicity using gentamicin to induce ROS production, lipid peroxidation, and apoptosis in cultured explants of the mouse organ of Corti . AdminisLipid peroxidation has been identified as a hallmark of disease development and progression in both dyslipidemia and hyperglycemia, resulting in oxidative stress in retinas of diabetic rats, which contain double the amount of lipid peroxides than retinas of control rats . FurtherA critical signaling molecule at the intersection of the two pathologies is fibroblast growth factor (FGF) 21. When administered to mice, it reduces plasma glucose and triglycerides, while also lowering LDL, raising HDL, and increasing insulin sensitivity , 101. In2, leukotriene B4, and leukotriene C4) were found independent of age  medication . FurtherFibrates and other PPARα agonists that alleviate complications of diabetes elicit a range of pleiotropic effects . Notablyn-3 PUFAs are typically decreased in DR, especially in the later stages of DR  and docosahexaenoic acid (DHA), attenuated oxidative stress and inflammation in these diabetic and dyslipidemic rats , positioes of DR , togethees of DR .The therapeutic strategies mentioned above that primarily focus on fatty acids for treating DR are based on the unique physiological properties of the human retina. For example, polyunsaturated fatty acids, which are extremely susceptible to oxidation, are present in the membranes of photoreceptor outer segments in high concentrations . As the As previously discussed, both diabetes and dyslipidemia cause retinal damage as a result of exposure to oxidative stress, including free radical damage that ultimately leads to deleterious accumulation of ALEs. Interestingly, administering the antioxidant tempol, which acts by neutralizing the superoxide anion, into mouse retinas with DR results in a reduction in retinal cell death as well as a reduction in intraretinal oxidized LDL and glycated LDL levels . This prIdentifying clinical studies that demonstrate viability of dyslipidemia, hypertriglyceridemia and hypercholesterolemia as targets for therapies provides the foundation for continued development in this area of research. These studies suggest that targeting these pathologies result in clinically significant change that provides an additional level of therapeutic options to treat DR patients with these coexisting pathologies. The burden of DR on visual morbidity and the high prevalence of concurrent dyslipidemia results in a necessity to explore the clinical interventions currently possible in this domain.As previously discussed, dyslipidemia and hypercholesterolemia disrupt retinal vasculature through a wide variety of mechanisms; the clinical findings that suggest a role of targeting these factors are discussed here. First, simvastatin can significantly reduce total cholesterol and LDL-C levels. In multiple clinical studies, patients treated with simvastatin had a significant reduction in hard deposits compared to non-treated patients . The benIn a study on statin therapy and retinal blood flow, it was concluded that mean peak systolic flow of the ophthalmic artery significantly decreased in patients with both proliferative and non-proliferative diabetic retinopathy . After aFenofibrate when used as monotherapy has demonstrated beneficial effects on the progression of DR . The FIEThis includes one randomized controlled trial that assessed the effect of fenofibrate on patients’ need for laser phototherapy for DR. The results indicated that treatment with laser therapy was greater in the placebo group then the fenofibrate group and that in patients with pre-existing retinopathy, 2-step progression on the ETDRS (Early Treatment Diabetic Retinopathy Study) scale, determined by funduscopic imaging, was slowed drastically  . What isA prospective, randomized, blinded trial published in the NEJM that also tested statin therapy in the context of multi-drug intervention: in this study, patients received statins as a part of their lipid-lowering therapy, while also receiving treatment for hypertension, hyperglycemia, and cardiac morbidity in the form of renin-angiotensin system blockers, aspirin, and tight glucose regulation. Such intensive therapy reduced progression of diabetic retinopathy, and the need for laser treatment for macular edema, and blindness (n = 160) . FurtherSection 5.1, omega 3 fatty acids have demonstrated benefit in preserving retinal function in rats with concurrent diabetes and dyslipidemia. Along this same vein, Roig-Revert et al. investigated the effect of a dietary supplement containing antioxidants and omega 3 PUFAs such as glutathione and DHA in a Mediterranean cohort in order to ascertain its effect on oxidative stress biomarkers in the retina  to conventional treatment to assess its utility in preventing progression of DR . There aLipid lowering therapy is an area of treatment that continues to be explored in clinical trials. There is currently a multi-arm trial examined the potential benefits on lipid lowering in preventing progression of DR as well as reduction of CV risk in diabetic patients . The thrConceptualization and design, PK. Literature review, data analyzation and writing, HR, JJ, TJ, and PK. All authors have read and agreed to the published version of the manuscript. All authors contributed to the article and approved the submitted version.The study presented in the present publication was supported in part by Sarah Morrison Student Research Awards (HR and JJ), the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research, the Vision Research Foundation of Kansas City (PK) and a departmental challenge grant by Research to Prevent Blindness (PK and TJ) and is gratefully acknowledged.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Strongyloides stercoralis positive, positive for other parasitic infections and negative controls. To test the immobilization of probes onto a screen-printed gold electrode and the serum IgG detection, electrochemical analyses were carried out through differential pulse voltammetry (DPV) and the electrode surface analyses were recorded using atomic force microscopy. (3) Results: The electrochemical response in screen-printed gold electrodes of peptides D3 and C10 when using positive serum was significantly higher than that when using the DP. Our sensor improved sensitivity to detect strongyloidiasis. (4) Conclusions: Probes’ sequences are critical factors for differential electrochemical responses, and the D3 peptide presented the best electrochemical performance for strongyloidiasis detection, and may efficiently substitute whole antigen extracts from parasites for strongyloidiasis diagnosis in electrochemical immunosensors.(1) Background: The validation of biological antigens is the study’s utmost goal in biomedical applications. We evaluated three different probes with single and multiple epitopes through electrochemical detection of specific IgG in serum for human strongyloidiasis diagnosis. (2) Methods: Screen-printed gold electrodes were used and probes consisting of two single-epitope synthetic peptides (D3 and C10) with different sequences, and a multi-epitope antigen [detergent phase (DP)—hydrophobic membrane proteins]. Human serum samples from three populations were used:  Strongyloides stercoralis −3/−4 and 0.1 M KCl, pH 7.4, for the interaction investigation between total probe immobilized on working electrode and total soluble IgG recognition. Thus, 80 uL of this solution was pipetted over the three electrodes, closing the working electrode circuit between the other two electrodes (counter electrode and reference) −3/−4 −3/−4 ,24. ThisStrongyloides IgG in these sera.Some amino acids are electroactive compounds, and many have known antioxidant properties in metabolic chains. Masek  describeStrongyloides IgGs in small serum fractions of 2 microliters at the dilutions of 1:80 or 1:160, according to the probe used.Besides, the screen-printed gold electrode is responsible for increasing the Faradaic current due to the larger area of the electrode in contact with the reagents, consequently increasing its sensitivity and limits of detection . Our sysAlthough the evaluated serum contains many interfering substances, such as urea, uric acid, glutamate, and albumin, we can consider that there was no disturbance of the detection process by these substances . The besOur findings also demonstrate that the D3 peptide was superior in electrochemical response probably due to its higher specificity when compared to C10, which is equivalent to saying that the higher the specificity, the higher the antibody affinity. Another possibility is that the D3 probe may bind more strongly to the gold electrode since it has two more sulfur atoms in its sequence . In addiThe AFM surface analysis  showed tThe difference in the roughness coefficient found in our experiments can be explained by the fact that the topography of adsorption and the interaction between biomolecules involved were determined by the composition, amino acid sequence of the peptide, and affinity to the antibodies. These characteristics determine the position of the binding site within the peptide structure and the physicochemical interactions between peptide, the electrode surface and between peptides themselves  with the additional influence of environmental conditions, such as pH and ionic strength ,17,28.Therefore, both AFM images and electrochemical analyses not only confirmed the successful immobilization protocol, but also the greatest specificity and sensitivity of the D3 peptide.Briefly, our results indicate that the direct conversion of a biological event into an electronic signal relies on the specific interaction of nanomaterials’ interfaces with probes. It is important to note that the mimotopes selected by Phage Display and its synthetic version used in this study, represent highly reactive and specific epitopes of proteins, which under proper design and together with gold electrodes, may lead us to build stable electrochemical platforms for disease diagnostics.This work shows the validation of biological antigens through electrochemical detection of specific IgG in serum for human strongyloidiasis diagnosis. We have demonstrated that probes’ sequences are critical factors for differential electrochemical responses. Besides, the D3 peptide presented the best electrochemical performance for strongyloidiasis detection and may efficiently substitute whole antigen extracts from parasites for strongyloidiasis diagnosis in electrochemical immunosensors.


An increasing number of medical trainees across specialties desire and expect Global Health (GH) experiences during training. It is useful for residency programs to know the impact that offering GH opportunities has on resident recruitment. The study objectives were to explore the importance of GH opportunities in residency selection among fourth-year medical students, examine the relationship between interest in GH and career plans, and describe students’ perspectives on prior GH experiences.The authors administered an electronic survey to all fourth-year medical students attending 12 different US institutions in February 2020. Data from the ten schools who were able to comply with the survey distribution methodology and with response rates above 25% were analyzed using descriptive statistics and Pearson’s correlation.A total of 707 fourth-year medical students from the included schools completed the survey out of 1554 possible students (46% response rate). One third of respondents ranked the presence of GH experiences in residency as moderately or very important and 26% felt that the presence of a formal GH curriculum was at least moderately important, with variation noted among specialties. After training, 65% of students envision practicing internationally in some capacity. A desire to care for underserved patients in their careers was significantly correlated with an interest in GH experiences during residency.The opportunity to be involved in GH experiences during training can be an important factor for many medical students when considering residency choice, and the availability of these opportunities may be a valuable recruitment tool. Students valuing GH opportunities during residency are more interested in working with underserved populations in their future careers. Global Health (GH) education and experiences are becoming an increasingly popular, and ever more important aspect of medical training . As our GH electives in medical training have many educational benefits, including increased appreciation of cost barriers associated with patient care, increased perceived utility of the history and physical examination, improved resource allocation and decreased utilization of diagnostic tests, more positive attitudes towards public health interventions, increased awareness of the social determinants of health, and enhanced cultural sensitivity , 2. TraiMedical trainees are increasingly seeking out GH experiences . In the In addition to the associated educational and recruitment benefits, GH opportunities during medical training likely also influence career choice. Residents who participate in GH electives are more likely to pursue careers in resource-limited settings locally or abroad, in academics, and in public service . ParticiPrevious studies have focused on data from residents and residency programs, but none have surveyed fourth-year medical students in the process of applying for residency. Given the importance of GH training and potential benefits in recruitment, we sought to explore fourth-year medical students’ perspectives on (1) influence of GH opportunities on residency choice, (2) future career plans related to GH, and (3) prior GH experiences.An electronic Qualtrics survey was developed by members of the Midwest Consortium of Global Child Health Educators, of which many authors are members. Face validity was determined by the authors, which includes interdisciplinary undergraduate and graduate medical educators at five US midwestern colleges of medicine with active GH work. To assess the feasibility of our study and overall interest in GH experiences during residency training, a pilot study was performed at five of the included institutions in March 2019, yielding 212 responses (32% response rate). The initial study confirmed our suspicions that availability of GH opportunities can be a factor in medical students’ choice of residency. Over one-third of respondents found the availability of GH experiences in residency to be moderately or very important. After presenting the results of the pilot study to the Midwest Consortium of Global Child Health Educators in Fall 2019, the study group was expanded to include a total of 12 medical schools across the US. GH educators in the Midwest Consortium of Global Child Health Educators and the Midwest Universities for Global Health were invited to have their institution participate in the study. The initial survey was modified, and the study design was refined; notable changes included broadening the definition of GH elective rotations in medical school to include work with local underserved, refugee, and immigrant communities, and omitting the words “global health” from the invitation email in order to decrease chance of response bias. Institutional review boards from each institution approved or exempted the project. An informational consent letter was provided to each participant at the start of the survey that invited them to participate in a brief research survey regarding their perspective on the presence of certain curricula in medical school and residency. Surveys were administered via an emailed internet link to all fourth-year medical students at 12 US medical schools in February 2020. The survey was administered in the month prior to residency Match Day to help minimize recall bias. The survey consisted of 14 questions utilizing Likert scales, multiple-choice, and multiselect questions  Table .Table 2Thirty-three percent of students rated the availability of GH experiences during residency as “moderately” or “very important” when selecting a residency program. Regarding formal GH training opportunities, 26% of students reported it as “moderately” or “very important” that a residency program has an established GH curriculum . Higher proportions of respondents ranked GH experiences as important in residency selection among those applying to Internal Medicine/Pediatrics , Otolaryngology , Obstetrics and Gynecology 26/53, 49%), Ophthalmology , Dermatology , and Pediatrics    have participated in an elective rotation in a limited-resource setting, either globally or locally. Students participated in a wide array of experiences, including international (76%), local low-resource settings (46%), immigrant health (12%), refugee health (9%), Indian Health Services (4%), and US-Mexico border (2%). The large majority (78%) of students who have completed one of these experiences in medical school state that they are more likely to seek similar GH experiences in residency as a result of this elective experience. For students who did not complete a GH elective, cost was the most common barrier 52%)  core competencies . This st