What follows are highlights from these studies:

HSS Study Uses Machine Learning to Predict Risk of Long-Term Pain After Knee Replacement Surgery

A new study led by researchers at HSS used a type of AI known as machine learning (ML) to identify key clinical and biological factors that raise a person’s risk of having persistent pain after total knee arthroplasty (TKA). Risk factors included elevated levels of certain inflammatory cytokines (proteins) in the blood, severe preoperative pain, and a longer period of tourniquet use in the operating room.

“These findings highlight the importance of incorporating biological markers like cytokine levels with patient-specific pain profiles and what the surgeon does during the operation to more accurately predict the risk of long-term pain after surgery,” says Meghan Kirksey, MD, PhD, an anesthesiologist at HSS and senior author of the study.

ML is a specialized approach that uses algorithms and statistical models to analyze patterns in large amounts of data to learn, predict, and make recommendations.

“Machine learning is allowing us to look at patient and clinician information in new ways,” says Alexandra Sideris, PhD, Director of the HSS Pain Prevention Research Center and a coauthor of the study. “It gives us a multidimensional approach to understanding patients’ pain experience that we didn’t have in our arsenal even five or 10 years ago.”

One in five people has significant knee pain months after having TKA, also known as total knee replacement surgery. “The lingering pain greatly affects their daily activities and quality of life, so that’s why it’s an important focus for us,” explains Dr. Sideris.

Persistent postoperative pain (PPP) is typically flagged when a patient has lasting pain at the site of the operation that is above a four on a scale of zero to 10 and severely impacts their activities of daily living three to six months after surgery.

The researchers used four different ML models to analyze data from a previously published study that collected comprehensive clinical information and blood samples from 160 patients before and after TKA at HSS. The new study identified key predictors associated with PPP beyond risk factors that were already known such as sex (women tend to have a higher risk), preexisting pain, and mental health issues like anxiety and depression.

The findings showed that having high blood levels of an inflammatory marker called TARC immediately after surgery raises the risk of PPP. “This molecule hasn’t been extensively studied in pain, but the evidence shows that it was consistently associated with persistent pain six months after surgery across all four ML models we tested,” notes Dr. Kirksey.

Other top predictors of PPP that emerged from the analysis included a higher preoperative pain score at rest, longer tourniquet time (a tourniquet is a device that squeezes the leg to help clear the area of blood flow during surgery), and higher blood levels of other inflammatory cytokines right after surgery.

In this study, researchers entered 318 clinical and biological characteristics collected from patients in the older study and asked each of the ML models to figure out the most important features associated with pain after TKA. The researchers also evaluated the accuracy of the ML models they used and found that XGBoost was the most informative.

“To my knowledge, this is the first study that looked at all of this information and tried to make sense of the best ML approach to use,” says Dr. Sideris. “What is exciting to us is that there was one feature – TARC – that consistently popped up across all four models and it wasn’t on anybody’s radar beforehand…this gives us hope that ML can help us identify with high integrity targets that haven’t been studied before.”

The researchers note that more research is needed to know if their findings can be used to impact clinical care. “Our goal is to be able to use these tools and data to tailor pain management strategies, prevent long-term complications, and personalize treatment decisions,” says Dr. Kirksey.

HSS AI Analysis Reveals What Patients Are Googling About Local Anesthesia

A new study by researchers at HSS used AI to systematically evaluate the types of questions that patients are Googling related to regional (local) anesthesia, identify websites that are frequently presented in search results, and assess the quality of the information provided.

“We knew that patients frequently search for information about anesthesia online, but we wanted to know exactly what they were looking for so that we could proactively address these topics and concerns in our conversations in the clinic and our patient education materials,” says Jashvant Poeran, MD, PhD, Director of Research in the Department of Anesthesiology, Critical Care and Pain Management at HSS and lead author of the study.

The analysis found that most patients’ questions focused on risks, complications, and details surrounding medications, awareness during sedation, nerve block duration, and the recovery process. The study also found that while the overall quality of information accessed during Google searches was accurate, the source of that information was not always clear.

Anesthesiologists see patients in the clinic for a short period to prepare them for surgery and manage expectations.

“There’s so much information being conveyed during that limited time that sometimes patients forget what to ask, or they don’t even know what they should be asking during the visit,” explains Dr. Poeran. “Our study results will help us anticipate some of their questions and give us a starting point when we sit down with them so it’s not so much of a guessing game.”

The researchers entered seven search terms into Google Web Search: “regional nerve block,” “regional anesthesia,” “peripheral nerve block,” “pain block,” “neuraxial anesthesia,” “epidural anesthesia,” and “spinal anesthesia.” The top 200 questions in the “People Also Ask” section and its associated websites were collected, totaling 1,400 question and website combinations.

The authors then used AI to categorize themes and assess website quality. They found that most questions pertained to facts around risks and complications, comparisons between different techniques and approaches, technical details, and indications.

“We were expecting questions around risks and complications, but it was surprising that so many patients were looking at technical details, specifically around sedation,” notes Dr. Poeran. “They were not always aware that you can be awake for a peripheral nerve block, for example.”

Because patients’ questions are linked to specific websites, researchers also wanted to know where patients were being referred to and how reliable the information presented was. The AI analysis found that 55% of websites were academic, 19% were government, and 11% were public/social media sources. Information on government and academic/hospital websites scored the highest in terms of accuracy, and medical practice websites scored the lowest.

Dr. Poeran cautioned that some patients’ questions are nuanced, and online information can bias a person in the wrong direction.

“For example, if you ask whether regional anesthesia is better than general anesthesia you will be able to get generic information about those approaches online, but you need to talk to your doctor to get a more personalized recommendation based on your specific circumstances,” says Dr. Poeran.

While the study revealed important questions, it’s not all-encompassing. “There will be questions that aren’t captured by this study, but anesthesiologists can use this data to guide their consultations with patients scheduled for surgery, provide more-informative patient education materials, and refer them to the most reliable websites for more information,” notes Dr. Poeran.

He plans to continue leveraging AI in his future research endeavors.

“Based on the information we gathered, we will update our educational materials with the questions we now know patients ask most often and may even provide it in different languages and reading levels,” says Dr. Poeran. “We can then use AI to see how that information is perceived and understood by patients, study differences in search terms entered in different languages, etc.”

HSS is the world’s largest academic medical center specialized in musculoskeletal health, spanning orthopedics, rheumatology and related disciplines. The HSS Research Institute maintains 20 laboratories dedicated to solving debilitating orthopedic and rheumatic conditions such as arthritis, bone and soft tissue injuries, autoimmune diseases, and musculoskeletal pain and deformities. There, more than 300 dedicated personnel focus on tissue repair, improving surgical outcomes, autoimmunity and inflammation, genomics, new treatments, and precision medicine.

“HSS has a long history of contributing to the collective base of clinical and basic science knowledge and finding healthcare solutions for complex conditions,” said Louis A. Shapiro, President and CEO, HSS. “We’re proud that through the joint efforts of our institution and philanthropic support, we will have the ability to make a strong impact on this growing and vital area of research.”

“As experts in inflammatory disorders and in the development of interventions for overactive immune responses, the clinicians and researchers at HSS are well-positioned to investigate many of the adverse effects of COVID-19,” says Lionel B. Ivashkiv, MD, Chief Scientific Officer at the HSS Research Institute. “This includes studying the causes of these adverse effects as well as how to prevent and treat them.”What follows are descriptions of the first group of funded projects in basic/translational research:

Activation of pDCs by SARS-CoV-2 and Its Impact on Macrophage Response

Principal Investigator: Franck Barrat, PhD

Co-Investigator: Marie-Dominique Ah Kioon, PhD

This project will study cell types that are responsible for cytokine storm syndrome — the hyperactive immune response seen in people with COVID-19 — by looking at how certain immune cells are activated by SARS-CoV-2. Research in mice infected with SARS-CoV, a coronavirus similar to the one that causes COVID-19, has suggested that plasmacytoid dendritic cell precursors (pDCs) are key to the immune response to infection. These pDCs activate macrophages, which in turn secrete cytokines. In the SARS-CoV research, depletion of pDCs appeared to protect the mice from lethal lung injury. Using blood samples from donors, the investigators will study the pathway by which pDCs activate macrophages and look at ways to therapeutically block that process.

Inhibiting RNA Polymerase II Transcription Complexes in Macrophages to Target COVID-19–Associated Cytokine Storm

Principal Investigator: Inez Rogatsky, PhD

Co-Investigators: Steven Josefowicz, PhD, and Robert P. Fisher, MD, PhD

This pilot project will dissect the role of macrophages in SARS-CoV-2-induced acute respiratory distress syndrome (ARDS), the main driver of COVID-19-associated mortality. We will test small-molecule inhibitors of RNA Polymerase II (Pol II) transcription complexes for their ability to modulate type I interferon and inflammatory pathways in monocytes/macrophages. This research will be done using cultured macrophages as well as donor blood and blood from COVID-19 patients.

Mechanisms of Cytokine Storm in Patients with COVID-19

Principal Investigator: Mary K. Crow, MD

Co-Investigators: Mikhail Olferiev, MD, and Lionel B. Ivashkiv, MD

The objectives of this study are to describe the process of the cytokine storm in people with COVID-19 and to identify biologic predictors of a favorable outcome in patients with severe cases of the disease. The project aims to characterize immune cell populations seen in COVID-19 patients who experience cytokine storm and compare them to those patients who do not, to compare the immune response before and after patients are given the anti-inflammatory drug anakinra, and to identify measures that suggest patients are more likely to decline and eventually require mechanical ventilation. The research will employ blood samples from HSS patients who are being treated for COVID-19 at New York–Presbyterian Hospital and who meet certain other qualifications.

What follows are descriptions of the first group of funded projects in the areas of clinical and health outcomes research:

Response to and Recovery from TKA in Patients with Antibodies to SARS-CoV-2

Principal Investigator: Miguel Otero, PhD

Co-Investigators: Meghan Kirksey, MD, PhD, and Peter K. Sculco, MD

It is unknown if people who have been exposed to COVID-19 may be at higher risk of experiencing an abnormal immune response following surgery, resulting in poor outcomes. This study will evaluate the response to and recovery from total knee arthroplasty (TKA) in people who have antibodies to COVID-19 — a marker of exposure. This study will include both patients who have COVID-19 antibodies and those who don’t, to act as controls. Patients will be followed for six weeks after surgery and evaluated for the presence of certain immune markers in the blood, as well as symptoms of inflammation including pain and stiffness in the joint.

SARS-CoV-2 Exposure and the Role of Vitamin D Among Hospital Employees

Principal Investigator: Emily M. Stein, MD, MS

Co-Investigators: Theresa T. Lu, MD, PhD; Andy O. Miller, MD; Jeri Nieves, PhD; and Alana Serota, MD

It is unknown if people with vitamin D deficiency may be more likely to become infected with COVID-19. This study will investigate vitamin D status and associated immune markers as risk factors for COVID-19 infection in a cohort of healthcare workers. Healthcare workers are at higher risk of contracting COVID-19 than the general population, making them a good group to study. Vitamin D is critical for immune function and is known to be protective against respiratory-tract infection and tuberculosis. This prospective, observational study will follow healthcare workers at HSS and at other healthcare facilities for one year, to determine whether levels of vitamin D and certain immune cells in the blood make someone more susceptible to COVID-19 infection.

Association of Immunomodulatory Medication Use and Social Determinants of Health with COVID-19 Infection in Systemic Rheumatic Disease Patients in New York City

Principal Investigator: Medha Barbhaiya, MD, MPH

Co-Investigators from HSS: Lisa Mandl, MD, MPH; Catherine MacLean, MD, PhD; Vinicius Antao, MD, PhD; Jane Salmon, MD; and Mayu Sasaki, MPH

Other Co-Investigators: Candace Feldman, MD, MPH (of Brigham and Women’s Hospital); Debra D’Angelo, MS (of Weill Cornell Medicine)

Using data from the INSIGHT Clinical Research Network, a central repository containing longitudinal electronic health data for residents of New York City, investigators will assemble a cohort of patients being treated with immunomodulatory medications for rheumatic disease. This patient population will then be used to study the effect of these medications on COVID-19 incidence and outcomes. Retrospective data will be used to evaluate the incidence and severity of COVID-19 in these patients. Patients will also be studied prospectively to determine whether there’s a relationship between COVID-19 infection and future rheumatic disease as well as to study connections between infection and future psycho-social issues.

Assessment of Surgical Outcomes in the COVID-19 Pandemic Era

Principal Investigator: Andy O. Miller, MD

Co-Investigators: Scott A. Rodeo, MD, and Mark Fontana, PhD

Investigators will implement a patient registry to evaluate how COVID-19 affects outcomes and complication rates after orthopedic surgery. This registry, along with COVID-19 screening procedures, will provide the tools to address specific research questions. Among these questions are determining the incidence of current and prior infection among the HSS surgical population, the clinical features associated with current and prior infections in this patient population, and whether COVID-19 status affects short-term complication rates.

What follows is a description of an integrated multidisciplinary study being undertaken jointly by the Adult Reconstruction and Joint Replacement (ARJR) Perioperative Research Group, Anesthesiology and Rheumatology:

Prediction and Prevention of Postoperative Blood Clots in COVID-19 Patients

Principal Investigators: Friedrich Boettner, MD; Kethy M. Jules-Elysee, MD; Lisa A. Mandl, MD, MPH

Co-Investigators: ARJR surgeons: Alejandro Gonzalez Della Valle, MD; Jason Blevins, MD; David J. Mayman, MD; Peter K. Sculco, MD; Geoffrey H. Westrich, MD and Thomas P. Sculco, MD

Medicine/Rheumatology: Medha Barbhaiya, MD, MPH; Doruk Erkan, MD, MPH; Deanna Jannat-Khah, DrPH

Pathology: Thomas W. Bauer, MD, PhD

Anesthesiology: Stavros G. Memtsoudis, MD, PhD, MBA; Alexandra Sideris, PhD

ARJR: Amethia Joseph, MHA; Ethan Krell, MS

Weill Cornell Medicine: Raymond David Pastore, MD

Recent literature suggests that one of the major complications seen in people with COVID-19 is thrombosis (the formation of blood clots) due to endothelial dysfunction, persistent inflammation and potentially antiphospholipid antibodies. As elective surgeries resume, those with prior exposure to SARS-CoV-2 will inevitably present for treatment, and some may have perioperative management considerations related to their risk of deep-vein thrombosis. This project will use, a noninvasive device that can determine clotting risks, to investigate whether people who have had COVID-19 have a more dysfunctional endothelium preoperatively and at 24 hours after surgery. The investigators will measure antiphospholipid antibodies and inflammatory markers, and evaluate the prevalence of asymptomatic post-operative deep-vein thrombosis in people who undergo TKR and have SARS-CoV-2 antibodies.

COVID-19 Translational Research Core at HSS

Principal Investigator: Theresa Lu, MD, PhD

Co-Investigators: Jessica Andrés-Bergós, PhD; Miguel Otero, PhD and Emily M. Stein, MD, MS

The COVID-19 Translational Research Core (TRC) was designed to fill critical gaps in the resources needed to promote the broad range of COVID-19–related clinical and translational research at HSS. The TRC will provide consultation on the design and implementation of COVID-19 research in the areas of orthopedics, rheumatology and metabolic bone disease; support for a COVID-19 biobank; and technical expertise and facilities required for clinical and translational researchers working on COVID-19–related projects. The TRC staff will help to acquire, house, and track biospecimens from investigator-initiated COVID-19–related research studies.