Lessons from our Pupils: A Reflection [Podcast Episode 154]

During Episode 154 (LINK), Jay was joined by Drs. Ajay Kuriyan and David Ehmann to discuss phacovitrectomy. One of the tools utilized for assessment prior to this surgery is an A-scan which is also known as an amplitude scan ultrasound biometry. This technique was first used by Mudnt and Hughes in 1956 and is routinely used in ophthalmology today. It is used to measure the anterior chamber depth, axial length, and lens thickness by using ultrasound technology. In an A-scan, sound travels through the eye encountering different kinds of media. A probe that emits a single sound beam is placed on the tear film, which due to its properties can be used for transmission of the beam into the eye. It first travels through the solid cornea, the liquid aqueous, the solid lens, the liquid vitreous, the solid retina, choroid, sclera, and then orbital tissue. The location in which media of different densities meet is called the interface. It is at this junction that an echo is created when the sound beam strikes the interface and bounces back into the probe tip. The echoes that are returned to this probe are converted into a series of spikes that have a height proportional to the strength of the echo, as seen in the figure below.



Image Credit: https://www.cehjournal.org/article/caring-for-a-and-b-scans/



The difference in height of each spike is created by the difference between the two media at each interface. The larger the difference, the taller the spike will appear. A weak spike corresponds to a weak echo due to a lack of difference between two media at the interface. If the two media the sound beam is passing through have identical densities, then no spike will be recorded during the A-scan. The figure shown below represents a normal eye, but if for example, a cataract was present then the central lens area would display spikes of different heights as the sound beam travels though differing densities within the lens nucleus.


Image Credit: https://eyewiki.aao.org/Ophthalmologic_Ultrasound#A-Scan


Lastly, it is important to know that there are several factors that can influence the height of the spikes recorded. The angle at which the sound beam hits the interface will determine how strongly the echo is received. The probe should be held in such a way that the sound beam strikes the structures of the eye at a perpendicular angle. If the transducer is held such that the angle of incidence is higher, some echoes will not return to the transducer, therefore no spike will be recorded. The smoothness and the regularity of the interface the sound is traveling through will also affect the echo. Irregularities can cause reflection and refraction of sound beams, and an increase in density will absorb more energy and cause the signal’s amplitude to decrease in height.

     -Amy Kloosterboer

Jayanth SridharComment
Lessons from our Pupils: A Reflection [Podcast Episode 153]

                For Episode 153 (LINK), Jay was joined by the Physician on FIRE (Financial Independence and Retire Early) to discuss topics important to a physician managing his or her finances. As a fourth-year medical student about to enter my internship and ophthalmology residency, my initial thoughts were that I was still years away from the chance to apply these lessons to myself. However, as my world prepares to shift from tuition payments to monthly income, from loan disbursement to loan repayment, I recently began to realize the importance of my own financial education. With little training outside of one high school course in macroeconomics, I started simple by visiting www.physicianonfire.com, reading the classic White Coat Investor book by James M. Dahle, and discussing lessons learned with friends. To me, the importance of “FIRE” is less of the “Retire Early” and more of the “INDEPENDENCE” – the ability to choose what you want to do, where, how much, and for how long.

                At the beginning of the episode, Jay remarked that there is often a sort of hesitation to discuss finances within medicine. “If you’re doing this for the money,” it is often stated, “then you’re not doing it for the patient and you’re doing it for the wrong reason.” Although there certainly are important lessons behind these adages, that does not mean that we should be unprepared for financial decisions to come. At the end of the day, there will come a time for every physician where his or her financial situation changes – be that anything from graduating residency, to repayment of loans, to starting a family, to health issues, to retirement. We are all at different points in our respective journeys, but it behooves us to try understand more every day. In my reading, the White Coat Investor called out a quote by Dave Ramsey that stuck out to me: “If you will live like no one else, later you can live like no one else.” To me, this quote has implications outside of the financial realm, as well. Medicine is a field of “lifelong learning” with years of training, steep learning curves, and ever-innovating therapies. All of us began our journeys with a desire to help change the lives of our patients, and we are constantly striving to do better and to be better. At this point, it is impossible to know exactly where my career will take me; however, I do know that I would like the opportunity to continue pursuing my passion from beginning to end. And to me, the “independence” aspect of FIRE seems like one way to help make this happen.

- Michael Venincasa

Jayanth SridharComment
Lessons from our Pupils: A Reflection [Podcast Episode 152]

Hello, Listeners! For this week’s blog post, we thought that we would take a closer look at Episode 152 (LINK) and bring you back to your experiences in the biochemistry classroom. In Episode 152 of the podcast, Jay spoke with Dr. Daniel Chao and Dr. Shriji Patel about a few “journal club” topics; one of these discussed a recent article published in JAMA Ophthalmology (LINK) about the possible role of statins in decreasing risk of diabetic retinopathy. With their proven mortality benefits related to cardiovascular disease, it is tough to go through a day in clinic without encountering at least one patient currently taking a statin. That being so, let’s go over how they work!

Statins are a class of lipid-lowering medications that act as competitive HMG-CoA reductase inhibitors. As you recall, this means that the statin binds to the active site of the HMG-CoA reductase enzyme and thereby limits its function. HMG-CoA reductase is utilized in one of the first steps (the rate-limiting step, in fact) of the mevalonate pathway, which converts acetyl-CoA and acetoacetyl-CoA into Cholesterol (see image below). As a result, less cholesterol is synthesized by the liver.

Image Credit: https://en.wikipedia.org/wiki/File:HMG-CoA_reductase_pathway.svg

Image Credit: https://en.wikipedia.org/wiki/File:HMG-CoA_reductase_pathway.svg

However, this is not where the story ends. Statins also work to increase LDL (often referred to as “bad cholesterol”) uptake. The liver extracts cholesterol from the circulation through the use of LDL receptors, which sense and take up circulating LDL. Once statins inhibit the mevalonate pathway, the liver is able to sense the resultant decrease in cholesterol synthesis and up-regulates its LDL receptors. Once in the liver, the uptaken LDL can be processed into bile salts and other products, and there is less LDL floating in circulation.

The mevalonate pathway also includes the synthesis of prenylated proteins (“prenylated” refers to the addition of a hydrophobic lipid group to a molecule). It has been hypothesized that statin-related inhibition of these syntheses is related to some of the important cardiovascular benefits of the medication, including improved endothelial and immune cell function. The evidence for this idea is founded partially in the fact that other classes of drugs that reduce LDL levels—but do not affect prenylated protein synthesis—do not show these additional benefits. However, the effect on these proteins has also been hypothesized as a cause for unwanted side effects of statins, including myopathies and elevated blood glucose.

Back to ophthalmology, it reasonable to wonder whether the benefits found against diabetic retinopathy are related to these “other” cardiovascular effects, like improved endothelial function and modulated inflammatory responses. Although the results are debated, the JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin) study, for example, found that statins can have cardiovascular benefit in patients independent of LDL levels (in patients with already-low levels of cholesterol) through reductions in C-reactive protein levels. Time will tell as to what the role of statins will be in diabetic retinopathy, but it is interesting to consider yet another possible role this class of drugs may play.

  -Michael Venincasa

For more information, check out: https://en.wikipedia.org/wiki/Statin

Jayanth SridharComment
Lessons from our Pupils: A Reflection [Podcast Episode 151]

Dr. Thomas Gardner joined Jay for Episode 151 (LINK) to discuss the mechanisms of visual loss in diabetic retinopathy and the current limitations of the management of diabetic retinopathy. Today we are going to review how diabetes affects the cells of the retina and how these changes present on an exam. 

Diabetic retinopathy is a microvascular disease that occurs as a complication of diabetes mellitus. This is a disease that affects the retinal neurovascular unit, which refers to neurons, glia, and vasculature that work together to regulate normal retinal function. Throughout the course of DR, the different components of this unit can become affected. A critical feature of DR is vascular dysfunction and capillary loss, but evidence has shown that neuropathy can appear first, as some patients present with loss of color vision and contrast sensitivity before microvascular changes can be observed. Furthermore, observational studies are now showing that damage to the neuronal layer can promote microangiopathy. Glial cells are also impacted in diabetes. There is an alteration in the homeostatic function of glial cells, which impacts its ability to regulate retinal blood flow, water balance, and the maintenance of barrier function. Microglial cells are also affected in the progression of diabetes, which causes chronic and subclinical inflammation in the retina. As immune cells become activated in DR, there is enhanced leukocyte-endothelial interaction which causes leukostasis and can lead to damage of the retinal vascular endothelium and surrounding tissue. This can happen due to physical obstruction of the capillaries and through the release of pro-inflammatory cytokines, including VEGF. Lastly, diabetes also impacts the RPE, specifically disrupting photoreceptor and choroidal integrity. However, the importance of the dysfunction of this layer in the overall progression of DR remains unclear and under study.

Currently, DR is classified based on the microvascular lesions observed. In the earlier stages, there is nonproliferative diabetic retinopathy (NDPR) that then advances to proliferative diabetic retinopathy (PDR). Changes of the retina in NDPR include the appearance of intraretinal hemorrhages, microaneurysms, venous caliber abnormalities, formation of intraretinal microvascular abnormalities, cotton-wool spots from neuronal infarcts, and retinal neovascularization. As the vascular bed experiences a gradual decrease in perfusion, vessel integrity is lost, ultimately leading to occlusion or degeneration of capillaries. This causes decreased oxygenation to the retinal layer, which eventually leads to expression of proangiogenic growth factors and development of PDR. Hypoxia causes formation of new blood vessels that are fragile and can protrude into the preretinal space. Rupture of these vessels can cause vitreous hemorrhage or tractional retinal detachment. Throughout the progression of NPDR and PDR, diabetic macular edema can arise from the breakdown of the blood-retinal barrier. This breakdown causes leakage of proteins and fluid into the retina, which appears as abnormal retinal thickening and even edema of the macula. 

Jayanth SridharComment
Lessons from our Pupils: A Reflection [Podcast Episode 150]

For this week’s blog post related to Podcast Episode 150, we are going to do something different and look at one of the resources patients can use to find clinical trials and how to navigate it. ClinicalTrials.gov is a a database of trials conducted around the world that are privately and publicly funded that can be used to find trials for a condition or disease. Like Dr. Sridhar and Dr. Pennesi, it can be difficult for a patient to look up information due to the technical terminology used. Today we are going to talk about how to navigate through it, and what certain terms mean.

When first opening the website, the following screen is the first thing that you see:


Image Credit: https://clinicaltrials.gov/ct2/home

This is the simple search format they offer. The first thing that must be selected is the status of the study. Here you can select for studies that are recruiting participants or those that have not yet started to recruit participants (“recruiting and not yet recruiting studies”) or all studies, including those that are no longer recruiting, are suspended, terminated, completed or more. The next box to be filled out is that of the disease or condition of interest. For example, if you are looking for studies related to X-linked retinoschisis, this is where it can be specified. The third box allows you to narrow your search and include things like a drug name, the name of the investigator, or the NCT number which is the National Clinical Trial identifier given to each registered clinical trial. Finally, in the last box the search can be narrowed to a desired country. 

For this post, we will be looking at clinical trials related to X-linked retinoschisis. After selecting “All studies” and specifying the condition or disease as “X-linked retinoschisis”, the search returns the following widnow:


Image Credit: https://clinicaltrials.gov/ct2/home

As can be seen, all the clinical trials available for X-linked retinoschisis appear here. Each study shows the status, title, the condition they are studying, the intervention they are using, and the location.  On the left-hand side, there is a filter panel that can help narrow results. Once again, you can filter by the status of the study by selecting the options you are interested in. Next is the eligibility criteria. These are the key requirements that people who want to participate in the study must meet. Each study will have different criteria including age and sex. Following eligibility criteria, you can narrow results by study type. An interventional or clinical trial is a type of study in which the effect of an intervention or treatment is studied by assigning a participant to a group. In an observational study the participants are assessed for certain health outcomes but are not assigned to a specific intervention or treatment. The last type of study is an expanded access study, and these are ways for patients with serious diseases or conditions who can’t participate in a clinical trial to receive medical products that have not yet been approved by the FDA. You can select studies that have or do not have results, and the phase they are on. A phase 1 study is usually conducted with healthy volunteers with the goal of determining a drug’s most serious side effects and how the drug is broken down in the body and excreted. In phase 2 the focus is on whether the drug works in people with a certain condition or disease. Phase 3 aims to find more information regarding the drug’s safety and effectiveness at different dosages. The last phase is phase 4, which happens after the drug has been approved by the FDA for marketing and includes further studying the safety, efficacy, and how to best utilize this drug. Lastly, the funder type and study documents can be selected.

Once you find a trial of interest, you can learn more information by clicking on the study title. The new window will give a background information to the study and talk about what it is trying to accomplish and how, what intervention or drug they are using, and a brief section on what will be expected of the participant. It will also list the study start and end date, any inclusion and exclusion criteria that must be met in order to participate, and contact information for those interested in participating in the trial if it is still recruiting participants.

              -Amy Kloosterboer

Jayanth SridharComment