Week 7: Immersion in Review: A Systematic Approach to Cardiology

Patient problem, diagnosis, treatment. Although I’ve known this general process of medicine, through my immersion experience I sought to gain an in-depth understanding of what this means in cardiology. How are conditions and diseases presented and recognized? Over what range of severities and urgencies do they present? What is the process by which certain conditions are diagnosed, and how are diagnostic tests chosen? This summer has enabled me to obtain a systematic view of cardiology, observing the whole range from clinics to OR’s and seeing all of the diagnostic testing in between.

Seeing the systematic process of medicine not only gave me exposure to (much of) the gamut of cardiovascular diseases, diagnostics, treatments, and technologies, but also gave me great insight into the logical process of medicine. I feel like I now have a grasp on how a clinician might take patient symptoms and stories to an appropriate diagnostic test (such as to one of the many types of stress testing or imaging) in order to best expound patient pathophysiology and decide an appropriate course of treatment, but I have also seen many instances in which clinicians may not have used a systematic and logical approach which can lead to unnecessary testing and sometimes scaring patients.

Above all, I feel that this summer has (1) given me a strong foundation in cardiology for my future PhD research on dilated cardiomyopathy and (2) given me new insight on how biomedical engineering and medicine go hand in hand. Both of these will guide my future career and have given a new context for my research and field, which has only come about due to the nature of this immersion program.

Week 7

This is my final day here and I am really glad for the experience but I am ready to return to Ithaca at this point. I feel like this has been a very productive summer for me and I am sure that this will give me a better perspective going forward with my research. Being able to see the clinical background of the topics that we are researching has been very eye-opening. It has been very helpful for bringing me into the mindset of a doctor rather than from a purely research mindset.

My final week has been a lot of trying to tie up loose ends in terms of the paper that I have been working on. We think we have finalized (hopefully) the data and presentation of tables. There are just a few more things that need to be written and hopefully the submission process will start in the next few weeks or so. 

The overall message of the paper is going to be that mitral regurgitation affects patients' exercise tolerance, independent of factors that are known contributors (age, ejection fraction, stress test results) to decreased tolerance. We have also shown that the etiology of the MR is a determining factor in exercise tolerance as well. Patients with primary valve dysfunction are able to undergo more exercise than patients with ventricle-related MR (functional MR). This makes sense because people with functional MR have other deleterious effects related to their ventricular function. 

Overall, I am very happy with these results and I am glad that I was able to take such a major role in something during my time here. I feel very lucky to have had such a great combination of clinical and research experience, and I hope to be able to continue to collaborate with my clinician and others in the hospital further down the line. 

Week 7

This week I observed several hip and knee revision surgeries in the OR. The most interesting case for me was a patient receiving their second knee revision surgery. The first revision involved implanting a rather large tibial stem, but unfortunately that stem did not osteointegrate as well as the surgeons had hoped. Over time, the combination of the forces applied while walking and poor osteointegration drove the stem deeper and deeper into the tibia, leading to misalignment of the joint. Preforming a second revision is pretty uncommon and can be really tricky because so much of the bone has already been removed. Because this case was so unique, an engineer in the biomechanics group designed a custom implant. He came into the surgery to answer any questions the surgeons had about his implant during the operation, but during the opening incision and preparation he took some time to chat with me about the mechanics of the revision. It’s exciting to see how engineers directly impact patients outcomes. The tibial portion of the implant had cone leading into the tibial shaft. The wider area of the cone should prevent the tibial component from sinking down like the first revision. The tibial component was connected with a hinge joint to the femoral component. The hinge increases stability of the joint, but it does restrict motion. The hinge joint isn’t a true hinge like you might see on a door; it is more like a loose hinge that allows for some extra rotation and extension besides the main flexion and extension. Maintaining these extra degrees of freedom helps make walking more natural. Luckily, the femoral stem component was well fixed in the bone, so they only had to change the surface. This was a good reminder to me about the importance of modular components. Overall this revision was an impressive feat, and I found it so satisfying to seeing the engineering and surgical aspects come together.

On the research side, we did our first trial of crystal violet staining this week. Crystal violet is a way of quantifying bacterial biofilm formation. Eventually the lab would like to use this technique and others to assess the amount and maturity of biofilms on the mouse tibial implants. This week we confirmed that we could grow biofilms in six well plates on the shaking incubator and the biofilms were visible using crystal violet stain. In the future the lab would like to be able to correlate crystal violet absorbance directly to the colony forming unit count.

It’s hard to believe that summer immersion is already over. I appreciate that everyone here welcomed me and gave me this clinical experience. I am excited to take what I have learned back to Ithaca!

Week 7

I cannot believe that the program is already over; it feels like it just started! This week, I had the opportunity to see an MRI-guided breast biopsy. It was very interesting to see how it compared to the stereotactic, tomosynthesis, and ultrasound-guided biopsies. The general procedure was fairly similar with a few differences. Like the stereotactic and tomosynthesis-guided biopsies, an image was obtained in order to locate the area of concern. However, in the MRI-guided biopsy, they took a second image in which they injected the patient with contrast agent in order to locate the area with the highest amount of blood flow. After that, the doctor pinpointed the location on the images, and the computer gave her coordinates to show her where to place the core-needle. The patient was removed from the MRI scanner, and the doctor placed the needle in the correct spot, but then removed it and left behind a plastic guide sheath. This was left behind so that another MRI image could be obtained to confirm the correct placement of the needle, without the needle being in place. After verifying the placement of the needle, the patient was removed from the scanner again, and 12 biopsy cores were removed. The patient was scanned again to verify that the tissue of concern had in fact been removed. The doctor then placed a clip in the area to help with localization in the future. The patient then had a mammogram performed to ensure that the clip was placed in the correct location.

In lab this week, we performed a western blot of multiple cell lines to determine the content of various proteins of interest in these cells. It was the first time that I have done a western blot, and it was very time-consuming! We also started to perform more radiostability studies of our particles in various media. Unfortunately, I will not be here to see how the results turn out in the end, but hopefully they remain stable for several days.

Outside of lab, I am going to see Aladdin tonight! We also did another escape room and got out with 29 minutes left! I am going to miss the city and all of the things it has to offer, but I am looking forward to going back to Ithaca where I can be more relaxed (and everything is less expensive).

Week 6

07-20-2018

The second to last week here in NYC seemed to pass by faster than the previous ones. I continued to practice surgical techniques to prepare for the upcoming live animal practice and devoted a great chunk of my time on getting the paperwork and clearance done for Heidi’s (my advisor, who will be visiting the lab and learning the open ACLT with me) visit next week. In this week’s training, one thing that I found interesting is one suturing method called the mattress stitch. It is commonly used on skin, particularly lose skin. Rodents have much looser skins than humans as a protection from predators, and the skins in their abdomens and legs are especially so. Thus, with a simple stitch, sometime the outer side of the skin will come in contact at the seam, preventing it from healing. The mattress stitch uses the far-far, near-near system. The far-far suture placement passes 4 to 8 mm from the wound edge, deep in the wound below the dermis. The near-near placement occurs at a shallow depth (about 1 mm) and should be in the upper dermis. The near-near placement should be within 1 to 2 mm of the wound edge. [1] This technique permits greater closure strength and better distribution of wound tension.

While shadowing Dr. Rodeo in out-patient clinic, we discussed how different the symptoms manifests despite of similar X-ray and MR imaging readings. Sometimes on the X-ray and MR imaging, the physician would expect the patients to be great pain and could barely move, however, when in reality the patients not only were experiencing tolerable pain but could also participate in moderate exercise/activities or sometime even extreme sports (like the lady I mentioned in last week’s blog, I am still having trouble believing that she actually walked into the clinic by herself). Aside from its clinic implication----that there are some more complicated changes in soft tissue, tendon and nerves in OA independent of the pathological changes in cartilage, these cases made me think how I could design my animal studies to more faithfuly assess the progression of OA in rodents. The current golden standards of assessing OA developments across animal models are X-ray and MR imaging and histological readings. Histological reading are end-point assessments that cannot be used to monitor the progression of OA in the same animal.  X-ray and MR imaging, as mentioned above, may not reflect the true progression of OA. I now believe, in addition to microCT imaging during the study and histological scoring after tissue harvesting, behavioral and functional testing should be included in the rodent student to assess OA development, and eventually as parameters to test the efficacy of our lubricin supplements. So far motion and gait analysis, rotor rod, and pain assessments with heat pad or Von Frey apparatus are on the list to be considered.  

[1] https://www.aafp.org/afp/2002/1215/p2231.html

Figure. Interrupted vertical mattress stitch

Week 6

This week my fellow student intern and I have made good progress on our project for Dr. Kennedy, he has finished compiling the data for this upcoming study on microfracture alone vs microfracture and BioCartilage to treat osteochondral lesions of the talus in humans. I have been compiling a review of the current literature that is related to this topic and been compiling all the sources as well as writing an introduction to this paper. Now that the data has been collected, moving forward we will be able to collaborate together and go through statistical analysis to compare the efficacy of both techniques. This weeks clinical work was very interesting since we had a patient with reflex sympathetic dystrophy come into the clinic, which is a very rare syndrome. Along with that, we also had an undergraduate student shadow at the clinic for the week and she had also been treated by Dr. Kennedy since she developed RSD after an injury. Since this was a biological condition rather than a mechanical one, I found myself to be quite interested in the pathology of the condition, however not much is know about its development. Outside of clinic, the immersion cohort was invited to a dinner hosted by Cornell's radiology department at a restaurant in central park, which was absolutely stunning to attend. The location was absolutely beautiful and I was extremely happy to attend due to the quality of the event and to meet those who attended it. I find myself sad that my time here at HSS is coming to an end and I will be forever grateful for this experience. This has definitely taught me a lot about myself and has certainly helped me shape my goals for the future.

Week 6: Imaging into the brain

Last week, the photoactivation of neurons using optogenetics technique doesn't really work out. We have tried to use light with different frequencies and amplitude. However, there are no observable changes in the electroencephalogram(EEG) recording.

We then plan to check the expression of opsins with fluorescence imaging. The mouse model we are using is designed to express opsins in parvalbumin interneuron, which have a large population in layer 4 of the mouse brain. Thus, a fluorescence endoscope is built using a fiber bundle to image neurons that express fluoresce dye (td-Tomato). The fiber bundle is inserted into the brain to try to image those neurons. However, we suspect that the light source is not bright enough to image the fluorescence signal since we are only using LEDs as the light source. We would try to switch to laser source for a better imaging quality.

Week 6

This week we finally got the chance to meet with Dr. Levine, our surgeon collaborator and one of his surgeon residents. We made a plan about the tissue expander project, consisting on their side recollecting data from each case and determining the cases that had tissue expander in the past and now have implants or flap reconstruction to see if the chest wall compression gets better after the expanders have been removed. They showed great enthusiasm for our new improved imaging parameters, which let us see the chest wall better. Even though our parameters help a lot, they still need to be refined. We got a case on Thursday in which the imaging didn't go so well. I've been also digging through papers about how to quantify the amount of metal artifact in a phantom image. I shout an email to Dr. Sarah Eskreis-Winkler, who works on Yi Wang's lab on this particular subject hoping to get some help from her. Hope I can meet with her on the next weekend.
I also calculated the amount of volume in each tissue expander case and see if it correlates with the amount of chest depression. Until now we do have a correlation, although tiny, in which the most depression occurs when the expander is filled the most. We still need more data if we want our correlation to be stronger.
We also noticed from our images that some patients with implants had inflammation of the chest wall after having implants, and we would like to see if this was due to the expanders or not. So this week I'm planning to go through all the records and see how many patients had the inflammation as a consequence from tissue expanders, which is a very interesting thing to report. 
On Friday we went to a tour of the CITI biomedical imaging center on 72nd st. Dr. Douglas Ballon gave us the tour and it was so amazing! He showed us the MRIs that they use in there (they actually have one 7T but only for animal use), the CT scans, PET, ultrasound and the cyclotron they use to produce the positrons for PET. I was quite amazed by the high technology and resources that are being used in that center, and the high quality research that is being produced in there. He showed us the facilities and taught us the physics behind the machines in such an understandable and easy way! We definitely loved the experience and we would like to go back in the future to see a MRgFUS (MR guided Focused Ultrasound) which is a technology only available at this center to cure essential tremor.

This is me, holding an "imaginary dog"

Week 5: Jerry got seizure

Our lab introduces seizure in a mouse with 2 different chemicals, 4-aminopyridine (4-AP) or FeCl3. 4-Ap is used to acute seizure introduction while FeCl3 is for chronic seizure introduction.

Since different dosage of 4-AP will introduce different amplitude of seizure, we are trying to try different dosage and concentration of the 4-AP to introduce a "good" seizure. Since the experiments in the lab are switching from using mice in anesthesia to awake mouse, we are exploring the best dosage for it.

A good seizure should have an abundant time between Ictal-seizure for better post-processing. If a high dosage of 4-AP is injected, a continuous Ictal-seizure will result and the mouse will die after a few minutes.

FeCl3, on the other hand, requires approximately 9 weeks for seizure to occur. It is used for a longitudinal study of the disease mice model. 

Week 6

This week I focused on diving into the effects of radiation on the microenvironment of the tumor and surrounding healthy tissue. With profound residual effects on the vasculature, stroma, immune cells, and cell signaling of exposed tissue, it seemed logical that irradiation of bone for treatment of metastases would affect true recurrence rates in patients.

Finding epidemiological studies of true metastatic recurrence rates in post-radiotherapy patients is much harder than I anticipated. Doctors in the department told me that it is almost impossible except with records from your own institution – perhaps a project for another student.

It is clear that radiotherapy has the potential to stiffen the extracellular matrix, destroy or thicken blood vessels in a doasge dependent manner, and recruit immune cells (both pro- and anti-cancerous) to the treatment area. Additionally, radiotherapy can drive growth factor and cytokine production in cells, as well as promote release of factors from the ECM. Additionally, the associated inflammatory response has the potential to affect risk of outgrowth or recurrence substantially. In bone, these effects all appear to be muted, thus suggesting that the likelihood of bone metastatic cancer recurrence is not changed in an appreciable way by successful radiotherapy treatment.

Additionally, I watched a fat transfer operation for a patient getting breast reconstruction after a lumpectomy. It was interesting seeing all of the places where a surgeon’s expertise matters in terms of choice of approach, how to handle the tissue, how quickly they move etc. I was also surprised to learn about the extreme fragility of  fat tissue. The surgeons extracted the fat from the abdomen with a vacuum-assisted canula, then washed it several times in Ringer’s lactate solution (sodium lactate solution), partially dried it on pads, then scooped it into 6ml syringes to deliver through a specialized canula.

Week 6: High Five for HiFU!

This week I added the additional patients to get a total of 16 patients and did SUV and texture analysis comparison on them. I did not observe any positive linear correlation between the SUV and MR pixel intensities between the patients. However, there seemed to be a positive correlation between histogram energy, entropy and mean in the PET prostate regions and the MR regions. In the upcoming week, I will add three more patients to the study and find the best fit model that relates texture features between PET and MR, and quantify the goodness of the fit. In addition, with the exception of a outlierm there was also a positive correlation between the Pi-Rads score and the SUV pixel intensity. The Pi-Rads score is like the Gleason score in ranking cancer cells based on their pathology slides, but it is based on looking at the MR images of prostate cancer only. This correlation matches what we predicted since only cancerous lesions are bright in PET scans, and highky invasive cancers will have a high Pi-Rads score, therefore, it makes sense that a higher Pi-Rads score will correspond to a higher SUV intensity.

I also got to have a tour of the Citigroup B

iomedical Imaging Center (CBIC), given by Dr. Doug Ballon. We saw an MRI while it was on, and observed the magnet’s magnetic field lines by bringing our Cornell name tags with a metal end close to the center of the machine. The magnetic forces pulled the metal end of the tag close to the machine, and as we moved the tag, the metal would move also to align itself with the magnetic field lines. We also put a silver dollar coin standing up inside the machine. The coin very slowly fell down, because the magnetic field inside machine combined with the improper induction within the coin caused a changing magnetic field inside the coin which caused a counterclockwise voltage which then causes a magnetic force in the opposite direction to that of the MR magnet. We also saw a $2 million high-intensity focused ultrasound (HIFU) machine for treating essential tremors. This condition causes shaking, mostly in, the hands head, voice or legs. The HIFU is operated by a neurosurgeon and focuses a 0.25-2 MHz ultrasonic beam, with a 1.5 cm diameter, on the patient’s brain. The highly focused beam created a high heat buildup in the region. Although bone is a material that absorbs the ultrasound wave, MR is able to detect the heat maps and guide the beam placement, to prevent overheating. The beam reaches the thalaus, which is located near the center of the brain and is used to noninvasively ablate the erroneous neurons that cause the shaking. The effects are immediate so patients can perform tests to check whether the procedure worked right after. We also saw a cyclotron, that is used to produce the radioactive materials which are bonded to the molecules that will bind to the body during specific PET imaging. Next week, I hope to see more interventional radiology surgeries, finish my research project, win another escape room and see Aladdin on Broadway!

Week 6

As I mentioned during my presentation this morning, my week was devoted to transcribing information from 785 patient files – dictations and CT images. I’ve already described the process for this analysis in previous blog posts, so I don’t think it’s worth while to spend time repeating that methodology. Needless to say, it took a long time. On average, I spent around 4-5 minutes per file.

Instead, I’ll dig into a bit of what Dr. Min mentioned during my presentation: pneumothorax itself is not a kiss of death for a patient’s long-term prognosis. Instead, it is only serious complications that require aspiration or chest tube placement that have a pronounced, negative long-term impact on patient health.

So then, why are we even trying to model partial pneumothorax, if it doesn’t necessarily lead to negative patient health impact? As dumb as the explanation may sound, it’s because to get partial pneumothorax is an intermediate to full pneumothorax (though temporally, you may not be able to detect it). As such, being able to predict partial pneumothorax is an important proxy for predicting the more serious complications.

In an effort to model this three stage classification problem (where 0 is no pneumothorax, 1 is pneumothorax, and 2 is severer pneumothorax), there’s an offshoot of logistic regression that is useful in predicting non-binary but ordered categorical variables – ordinal logistic regression. As I work on processing some of the data, this is an additional algorithm I’ll look to applying if time permits. The reason that this is necessary in the place of multi-class non-ordinal regression harkens back to an initial example I made in previous posts with respect to eye colour. If I were to treat severe complications as a completely separate category, like brown eyes, and then imagined partial pneumothorax as blue eyes, I would be missing out on a key component of the regression, namely, that these results are dependant on another, and would not be accurately modelling the system.

With this week moving by, it’s now time for the last week. We’ll be able to finally pull together some of the regression coefficients and ROC curves, so I’m excited to see the results of our analysis!

Week 6: The Salad Spinner

This week's surgery was fat transfer from the abdomen to the breast to correct an anatomical asymmetry. To prep for the liposuction, the patient's abdomen was injected with a mixture of epinephrine and Lydocaine. This approach is either a wet or super wet liposuction procedure classified by the amount of fluid that is added. The epinephrine induces vasoconstriction to reduce blood flow and minimize bleeding while the Lydocaine is a local anesthetic to numb the tissue. In a fat transfer all the tissue that is removed from the donor site needs to be saved to be implanted. Adipocytes must be kept alive and there are special procedural considerations such as reducing sheer stresses and  reducing exposure to the air that need to be taken. These differ from a standard liposuction because for example, in liposuction you can use laser or ultrasound assisted liposuction which help to remove the fat from the body but these techniques cause cell death in the extracted adipose tissue. During this fat grafting procedure, the fat collected for the transfer was sucked into a "salad spinner" device called the REVOLVER system. With a hand crank motion just like a salad spinner this device was used to rinse the tissue in lactated ringers solution, filter out components, and then to drain and dry the tissue. This process concentrates the fat by removing the injected solution, blood, and water. To further dry the fat after it is rinsed it's rolled out on fluid absorbing telfa pads until it is a thicker consistency. Next the fat is loaded into syringes for transfer to the breast. A special tip is used on the syringe for the injection where the opening for the injection tip is on the side so a vessel can't be punctured which could lead to an embolism. I learned it is  important to distribute the fat in small amounts to increase the surface area to volume ratio. If the injected tissue is not near a blood supply and not re-vascualrized then fat necrosis can occur and lead to calcifications and cysts.

Resident conference

In the OR  Dr. Spector teaches me about what is happening during surgeries which allows me to be able to  follow along during the plastic surgery resident conferences and have a  grasp of the topics at hand. This week the session was on grafts and flaps. Flaps are vascularized while grafts are not. Last week I had seen a flap implantation but at the meeting I learned how they monitor the flap and determine a prognosis after surgery. Things to look for are the color, blanching, thermal output, oxygen saturation, pH, the appearance at the edges, and the doppler signal from the flap. It was interesting to watch the residents do flap design and to see how they would complete a wound closure.

Research

I am happy to report that my cells are alive and well. The first round of Lean (low BMI) cells grew to the appropriate confluence and I was able to freeze them for storage and future use. Learning to do ASC isolations in my short time here has been an great opportunity to optimize the procedure close to the tissue source and this will be a great skill set to have in the future. My decell project is ongoing and awaiting analysis. The preliminary results show evidence of my ability to decell at the tissue level. As part of this project I've learned new lab skills and carried out my first tissue processing, paraffin embedding, sectioning, and H&E stains here. The LBMS has been a such a supportive and fun working environment and it's been a great place to spend my summer. 

Figure 1: Isolated Lean ASCs in culture