Medicine and Health Sciences Commons^™

A Literature Review Of Pain Control In Osteoarthritis Patients Using Blood Flow Restriction Training, John Gericke, Dakota Pastore, Tyler Pigott

Rowan-Virtua Research Day

Background: Osteoarthritis (OA) is a degenerative disease that mainly affects articular cartilage of joints. OA most commonly affects the knees and causes pain and reduces quality of life in older adults. Blood flow restriction (BFR) occludes arterial and venous flow during exercise using a blood pressure cuff placed on the proximal lower limb. This creates an intramuscular hypoxic environment which promotes muscle hypertrophy. High load training can cause pain and inflammation in knee OA patients due to increased stress. BFR can allow patients with knee OA to use lower loads to achieve beneficial effects of rehabilitation.

Methods: Data was ascertained …

Osteoarthritis Disease Severity In The Temporomandibular Joint And The Knee Joint: A Comparative Cadaveric Study, Jessica A Immonen, Jason Ciccotelli, Linh M Nguyen, Lesley Gilmer, Landen Broadhead, Mackenzie Kitchen, Conner Paul, Jeremy James

Journal Articles

OBJECTIVE: The objective of this study was to determine the level of disease severity in a pilot cohort of temporomandibular joints (TMJs) and compare them to the pathology findings previously characterized in cadaveric knee joints.

DESIGN: Thirty-one intact TMJs from 17 cadaveric donors were harvested and arthritic lesioning seen in the knee joint was investigated on the condyle and the fossa of the TMJ. Prevalence of gross alterations was equated and disease severity was determined for sex- and age-based donor pools using a validated, osteoarthritis (OA) disease severity scale (DSS). Knee joint DSS scores were also compared to the TMJ …

Minoxidil Weakens Newly Synthesized Collagen In Fibrotic Synoviocytes From Osteoarthritis Patients, Stefan Sarkovich, Peter P. Issa, Andrew Longanecker, Davis Martin, Kaitlyn Redondo, Patrick Mcternan, Jennifer Simkin, Luis Marrero

School of Medicine Faculty Publications

Purpose: Synovial fibrosis (SFb) formation and turnover attributable to knee osteoarthritis (KOA) can impart painful stiffness and persist following arthroplasty. To supplement joint conditioning aimed at maximizing peri-operative function, we evaluated the antifibrotic effect of Minoxidil (MXD) on formation of pyridinoline (Pyd) cross-links catalyzed by Plod2-encoded lysyl hydroxylase (LH)2b that strengthen newly synthesized type-I collagen (COL1) in fibroblastic synovial cells (FSCs) from KOA patients. MXD was predicted to decrease Pyd without significant alterations to Col1a1 transcription by FSCs stimulated with transforming growth factor (TGF)β1. Methods: Synovium from 10 KOA patients grouped by SFb severity was preserved for picrosirius and LH2b …

Osteoporosis In The Setting Of Shoulder Arthroplasty: A Narrative Review, Mohammad Daher, Mohamad Fares, Peter Boufadel, Akshay Khanna, Ziad Zalaquett, Joseph A. Abboud

Rothman Institute Faculty Papers

Patients who undergo shoulder surgery are frequently affected by osteoporosis and osteopenia, and the prevalence of this association is expected to increase due to the growing number of elderly individuals undergoing these procedures. It may be advisable to conduct a preoperative DXA scan for orthopedic surgical candidates at high risk, to detect those who could benefit from early intervention and avoid any related adverse events. Some of these complications include periprosthetic fractures, infection, subsequent fragility fractures, and have an all-cause revision arthroplasty at 2 years post-op. Some studies analyzed the beneficence of antiresorptive medications pre-operatively but the latter did not …

Assessing Inflammation In The Pathology Of Knee Osteoarthritis, Zachary J. Koudys

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a joint disease that causes pain, stiffness, and loss of function. Inflammation of the synovium plays a role in the pathology of OA. Macrophages are the dominant immune cells in synovial tissue. Activated macrophages over-express the translocator protein (TSPO). [¹⁸F]FEPPA is a 2^nd generation positron emission tomography (PET) tracer that can target TSPO with high specificity. Hybrid [¹⁸F]FEPPA PET/MRI may enable accurate quantification of macrophage activity in vivo. In this work, [¹⁸F]FEPPA tracer uptake in knee synovial tissue was measured ex vivo using autoradiography and was validated to correlate to …

Hemoglobinopathy Is Associated With Total Hip Arthroplasty Indication Even Beyond Sickle Cell Anemia, Maxwell J. Rakutt, Daniel N. Bracey, Anna Cohen-Rosenblum, Peter K. Sculco, Franco M. Sabatini, Cale A. Jacobs, Stephen T. Duncan, David C. Landy

School of Medicine Faculty Publications

Background: The extent to which hemoglobinopathies other than sickle anemia (HbSS) are associated with hip osteonecrosis is unknown. Sickle cell trait (HbS), hemoglobin SC (HbSC), and sickle/β-thalassemia (HbSβTh) may also predispose to osteonecrosis of the femoral head (ONFH). We sought to compare the distributions of indications for a total hip arthroplasty (THA) in patients with and without specific hemoglobinopathies. Methods: PearlDiver, an administrative claims database, was used to identify 384,401 patients aged 18 years or older undergoing a THA not for fracture from 2010 to 2020, with patients grouped by diagnosis code (HbSS N = 210, HbSC N = 196, …

Mesenchymal Stem Cell Use In The Treatment Of Osteoarthritis: A Literature Review, Samantha Arrizon, Nolan Barnes, Teresa Del Toro, Lei Wena Herme, Vanessa Mendoza, Thi Tran, Reeta Zamro

Physician Assistant Studies | Literature Reviews

Mesenchymal stem cell (MSC) therapies have been growing in popularity in research due to their anti-inflammatory, immunomodulatory, and regenerative properties. Many ongoing clinical trials are investigating the safety and efficacy of MSC therapies to treat osteoarthritis, also known as “wear and tear” arthritis. As the average life expectancy increases, with age people are more prone to developing this disease, therefore, increasing its prevalence. This condition is progressive and will lead to functional decline, decreased quality of life, and increased medical costs. Our focus is to discuss the efficacy of mesenchymal stem cell injections in alleviating pain, improving functionality, and slowing …

Development Of A Crosslinked Osteochondral Xenograft And A Collagen Stabilizing Intra-Articular Injection To Remediate Cartilage Focal Lesions To Prevent Osteoarthritis, Mark Lewis Mosher

Theses and Dissertations

Osteoarthritis is one of the most common causes of disability in adults in America. It is a progressive and degenerative disease where the articular cartilage is broken down and lost from the surfaces of bones causing chronic pain and swelling in the joints, and currently has no cure. The most commonly osteoarthritis starts from a focal lesion on the cartilage surface, which will expand on the surface and downwards through the thickness of the tissue. The current gold standard for correcting cartilage focal lesions is the osteochondral autograft/allograft transplantation (OAT), which replaces the defect with a fresh osteochondral graft. The …

Fibroblast Growth Factor Receptor 1-Bound Extracellular Vesicle As Novel Therapy For Osteoarthritis, Bryan Gervais De Liyis, John Nolan, Made Agus Maharjana

BioMedicine

Osteoarthritis (OA) is a joint condition that causes significant impairment of the chondrocyte. The gradual degradation of the cartilage lining of one or more freely moving joints, as well as persistent inflammation, are the causes of osteoarthritis. Current medication focus on alleviating symptoms rather than curing the condition. The aim of this review is to evaluate the potential use of fibroblast growth factor receptor 1 extracellular vesicle as novel therapy for osteoarthritis. This review article was completed by searching for the keywords “Fibroblast Growth Factor Receptor 1”, “Extracellular Vesicle”, and “Osteoarthritis” in various journals in several search engines. Of the …

The Outcomes Of Cemented Versus Cementless Total Knee Arthroplasty In Modern Day Patients With Osteoarthritis, Jordan Powelson

Capstone Showcase

Osteoarthritis (OA), the degeneration of cartilage and bone, is the most progressive musculoskeletal disease and a leading cause of disability in the United States, affecting over 27 million adults. Although conservative treatments for knee OA are available, total knee arthroplasty (TKA) is the only definitive treatment for end-stage knee OA. For the past several decades, the use of bone cement has been the gold standard for total knee arthroplasty, but the cementless TKA is being revisited as an option as the age of patients seeking TKA decreases and the average BMI increases. This review analyzes and compares the outcomes of …

Gut Permeability And Osteoarthritis, Towards A Mechanistic Understanding Of The Pathogenesis: A Systematic Review, Giorgio Guido, Guido Ausenda, Veronica Iascone, Emanuele Chisari

Rothman Institute Faculty Papers

Osteoarthritis (OA) is the most common condition affecting human joints. Along with mechanical and genetic factors, low-grade inflammation is increasingly supported as a causal factor in the development of OA. Gut microbiota and intestinal permeability, via the disruption of tight junction competency, are proposed to explain a gut-joint axis through the interaction with the host immune system. Since previous studies and methods have underestimated the role of the gut-joint axis in OA and have only focussed on the characterisation of microbiota phenotypes, this systematic review aims to appraise the current evidence concerning the influence of gut permeability in the pathogenesis …

Use Of Ultrasound-Guided Platelet-Rich Plasma In The Treatment Of Carpometacarpal Osteoarthritis, Manuel Britto, Siraaj Dawood, Siyang Lu, Martin Canillas

HCA Healthcare Journal of Medicine

Introduction

Osteoarthritis (OA) is the most common form of arthritis and can severely affect function and quality of life. Platelet-rich plasma (PRP) is derived from a patient’s own blood and has potential as an adjunct to treat OA. However, research has been limited for small joints such as the carpometacarpal (CMC) joint.

Clinical Findings

A 65-year-old Caucasian male complained of bilateral wrist and neck pain after a motor vehicle accident. His initial exam noted swelling, tenderness and pain with movement at the bilateral thumb CMC joints and anatomic snuffboxes. However, there was no strength, range of motion or tactile deficits …

A Pilot Study Of Knee And Hip Osteoarthritis Patient Experience With Telemedicine During The Covid-19 Pandemic, Rondy M. Lazaro, Kyle J. Smith, Mohammad H. Bawany, Nathan Barford, Jennifer H. Paul

Advances in Clinical Medical Research and Healthcare Delivery

Objective: The purpose of this pilot study is to examine patients' experience and satisfaction using telemedicine for knee and hip osteoarthritis care during the COVID-19 pandemic.

Methods: Adult patients seen via telemedicine for knee and/or hip osteoarthritis pain completed surveys through the REDCap online platform or pen/paper evaluating their experiences and satisfaction with telemedicine, assessed using yes/no and Likert scale questions. Demographic information was collected from the electronic medical record (EMR).

Results: 32 subjects (9 males, 23 females, mean age 63.2 years [SD = 12.2 years]) completed surveys. 90.6% of subjects stated that they were satisfied with the audio/video quality …

Functional Outcomes And Complications Of Total Hip Arthroplasty With Dual Mobility Cup : An Audit, Muhammad Younus Khan Durrani, Javeria Saeed, Masood Umer, Pervaiz Hashmi

Section of Orthopaedic Surgery

Objective: To determine the functional outcomes in total hip arthroplasty with a dual mobility cup, performed in our hospital.
Methods: After receiving an exemption from the Ethics review committee of the hospital, data collection for audit was started in January 2019. Records from July 2016 to June 2018 were included. All patients who underwent total hip arthroplasty with dual mobility prosthesis without any age limit were included. A proforma was prepared to collect the required information. Data was entered and analyzed on SPSS v. 21.
Results: Two hundred and ten patients were included, 114 females and 96 males. Of the …

Weight Reduction Motivation In Osteoarthritis Patients Through Nurse Practitioner Driven Education And Follow-Up: A Pilot Project, Caoilfhionn Mulvey, Martha Fuller Phd

Doctor of Nursing Practice Final Manuscripts

Purpose of Project: The ultimate goal of this short-term pilot project is for

overweight or obese osteoarthritis patients to increase their knowledge on the benefits of

weight loss and physical activity. Research shows that for every kilogram of weight lost,

2.2–4.0 kilograms of weight is taken off of the joint and could reduce joint pain up to

thirty to fifty percent and improve quality of life. Following education from the provider,

patients will understand the correlation of osteoarthritis symptom management with

weight loss.

EBP Model/Frameworks: This project utilizes the Iowa Model of Evidence-Based

Practice to Promote Quality Care. This addresses …

Development Of A Mind Body Program For Obese Knee Osteoarthritis Patients With Comorbid Depression, Cale A. Jacobs, Ryan A. Mace, Jonathan Greenberg, Paula J. Popok, Mira Reichman, Christian Lattermann, Jessica L. Burris, Eric A. Macklin, Ana-Maria Vranceanu

Orthopaedic Surgery and Sports Medicine Faculty Publications

Knee osteoarthritis (OA) is the most common joint disorder in the U.S. and a leading cause of disability. Depression and obesity are highly comorbid among knee OA patients, and the combination of obesity and depression is associated with decreased physical activity, higher pain and disability, and more rapid cartilage degradation. Depression, obesity and OA exacerbate one another and share a common pathophysiology involving systemic inflammation and pro-inflammatory cytokines, reflecting a complex mind-body interaction. Current treatments for knee OA offer little to no benefit over placebo, and do not emphasize mind-body practices or physical activity to target the underlying pathophysiology. Mind-body …

Acupuncture Therapy In The Treatment Of Osteoarthritis Of The Knee, Reece Bartell

Capstone Showcase

Abstract

Introduction: Osteoarthritis (OA) is a chronic condition that affects the joints of the body, most commonly the knees; it has the potential to cause debilitating pain, and stiffness and decrease quality of life. The current management involves lifestyle modifications of a healthy diet and exercise as well as analgesics like NSAIDs or acetaminophen to manage symptoms. Long-term use of these medications has been associated with many side effects affecting the GI and CV system. This review analyzes the use of acupuncture therapy (I) for symptom management (O) in patients aged 60-80 years old suffering from mild to moderate …

Reducing Length Of Stay After Total Hip And Knee Arthroplasty: Assessing Cost-Effectiveness, Caregiver Involvement And Surgical Approach, Bryn O. Zomar

Electronic Thesis and Dissertation Repository

Purpose

The overall purpose of this dissertation was to evaluate factors related to reducing length of stay after total hip and knee arthroplasty (THA and TKA).

Methods

Study 1 was a randomized controlled trial (RCT) to investigate the cost-effectiveness of outpatient THA compared to standard overnight stay. Study 2 was a prospective cohort study to assess patient- and caregiver-related factors and how they may relate to caregiver strain and level of assistance when caring for patients undergoing THA and TKA. Finally, Study 3 was a 2x2 factorial RCT to compare the trajectory of early functional recovery between the medial parapatellar …

A Comparison Of 4-Year Total Medical Care Costs, Adverse Outcomes, And Opioid/Prescription Analgesic Use For 3 Knee Osteoarthritis Pain Treatments: Intra-Articular Hyaluronic Acid, Intra-Articular Corticosteroids, And Knee Arthroplasty., John Mackowiak, John T Jones, Vinod Dasa

School of Medicine Faculty Publications

To compare the medical costs associated with treatments for knee osteoarthritis (OA): intra-articular corticosteroids (ICS) and intra-articular hyaluronic acid (IHA) primarily, and ICS/IHA vs knee arthroplasty (TKA) secondarily. This was a retrospective analysis of an insurance claims database. Eligible members had diagnosed OA and no claims for ICS, IHA, or TKA during the 6–18-month look-back period. Cohorts of interest over the 4-year observation period were: patients who received ICS only, those who received IHA only, and those who received TKA only. Outcomes assessed included: (1) total allowed medical costs, (2) claims for pre-specified, treatment-related adverse outcomes and costs, and (3) …

Joint Protection Programs For People With Hand Arthritis, Pavlos Bobos

Electronic Thesis and Dissertation Repository

The fact that Joint Protection Programs (JPP) can reduce pain and improve function is based on small, but definitive Randomized Controlled Trials (RCTs), conducted in the 1980s. However, changes over time in the nature of hand use, the rapid expansion of technology, and improvements in our understanding of health literacy mean that these programs are now outdated. Further, problems with adherence to JPP are well documented. The purpose of this thesis was 1) to conduct a scoping review to map all the available evidence around joint protection programs in published and unpublished studies 2) to evaluate the effectiveness of joint …

Comparison Of Non-Nsaid Pain Management In The Treatment Of Patients With Symptomatic Knee Osteoarthritis, Nicholas Schmitz

Theses and Graduate Projects

Objective: To compare the efficacy of other modalities and interventions versus standard first-line therapy of nonsteroidal anti-inflammatory drugs for pain management in patients with symptomatic knee osteoarthritis

Methods: Perform literature reviews outlining patients suffering from Grade II or higher KOA using the Kellgren-Lawrence classification system and currently experiencing symptoms of pain, stiffness, and impaired physical functioning. Use data and results from various studies to compare improvement of symptoms from these modalities versus improvement of NSAIDs alone.

Results: Weight loss and physical activity should remain the mainstay of early osteoarthritis treatment to help slow disease progression and symptoms of KOA. Duloxetine …

Assessment Of The Composition And Biologic Activity Of Platelet Rich Plasma And Its Relationship To Clinical Outcomes In Patients With Knee Osteoarthritis, Daniel Nemirov, Bijan Dehghani, Habib Zahir, Xiaoning Yuan, Christine Kim, Reyna Bhandhari, Patrick Fava, Yurii Chinenov, Joseph Nguyen, Laura Donlin, Brian Halpern, Scott Rodeo, Miguel Otero

Phase 1

Recent studies suggest positive clinical outcomes associated with platelet-rich-plasma (PRP) administration to treat knee osteoarthritis (OA). However, the results remain inconclusive in part because of the high variability in PRP preparations and the limited information regarding the relevant biologically active components of PRP. We hypothesize that the variability in clinical response is driven by the heterogeneous composition of PRP. In this study we evaluated the composition and biological activity of PRP and further correlated our findings to clinical outcomes in patients receiving intra-articular injections for knee OA. After IRB approval and patient consent, we enrolled 51 patients (mean age: 57.9 …

Outcomes Of Bilateral Shoulder Arthroplasties: A Comparison Of Bilateral Total Shoulder Arthroplasties And Bilateral Reverse Shoulder Arthroplasties., Ryan Matthew Cox, Tyler James Brolin, Eric Michael Padegimas, Mark D. Lazarus, Charles Lonnie Getz, Matthew Lee Ramsey, Gerald Ross Williams, Joseph Albert Abboud

Rothman Institute Faculty Papers

Background: The purpose of this study was to compare outcomes of patients who underwent bilateral total shoulder arthroplasties (TSAs) for osteoarthritis (OA) versus bilateral reverse shoulder arthroplasties (RSAs) for cuff tear arthropathy (CTA).

Methods: Inclusion criteria were patients who underwent bilateral TSAs for OA or bilateral RSAs for CTA with at least 2 years of follow-up. Twenty-six TSA patients (52 shoulders) were matched 2 to 1 with 13 RSA patients (26 shoulders) by sex, age at first surgery, and time between surgeries. Outcomes measured were shoulder range of motion (ROM), complications, and patient-reported scores.

Results: Preoperatively, TSA patients had significantly …

Wearable Sensors And Total Knee Arthroplasty: Assessing Quantitative Function To Improve The Patient Experience, Megan Fennema

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a chronic degenerative disease for which the only long-term solution is total knee arthroplasty (TKA), though many patients are not satisfied with their TKA. Satisfaction in TKA patients is not well understood. Subjective questionnaires and objective functional tests have been previously used to assess TKA outcomes, but both have disadvantages. Wearable sensors have facilitated affordable biomechanical measurement in OA and TKA populations. The objective of this work was to use wearable sensors alongside functional tests with TKA patients to identify quantitative function that related to subjective function and satisfaction. A wearable sensor-setup was validated before implementation in …

A Review Of Mesenchymal Stem Cell Injections For Osteoarthritis, Ammar Qureshi, Jill Goodwin, Franklin D. Shuler, Timothy Wilson-Byrne, John J. Jasko, Charles Giangarra

Charles Giangarra

Mesenchymal stem cell (MSC) injections for osteoarthritis is reviewed.

Methods- PubMed search identifying articles in English from 2003-2018 that used intra- articular injection (IA), cartilage repair, cartilage regeneration, chondral injury, adipose stem cells, bone marrow stem cells, mesenchymal stem cells, or autologous stem cells.

Results – 388 patients receiving IA MSC injections are discussed with data obtained from 10 case reports or case series, 4 randomized clinical trials (RCT), 1 cohort study, and 3 case controlled therapeutic studies.

Conclusions – MSC injections may be an effective adjunct in the management of osteoarthritis and a variety of cartilage related pathologies.

A Review Of Mesenchymal Stem Cell Injections For Osteoarthritis, Charles Giangarra, Jill Goodwin, Franklin D. Shuler, Timothy Wilson-Byrne, John J. Jasko

Timothy Wilson-Byrne MD

Mesenchymal stem cell (MSC) injections for osteoarthritis is reviewed.

Methods- PubMed search identifying articles in English from 2003-2018 that used intra- articular injection (IA), cartilage repair, cartilage regeneration, chondral injury, adipose stem cells, bone marrow stem cells, mesenchymal stem cells, or autologous stem cells.

Results – 388 patients receiving IA MSC injections are discussed with data obtained from 10 case reports or case series, 4 randomized clinical trials (RCT), 1 cohort study, and 3 case controlled therapeutic studies.

Conclusions – MSC injections may be an effective adjunct in the management of osteoarthritis and a variety of cartilage related pathologies.

A Review Of Mesenchymal Stem Cell Injections For Osteoarthritis, Charles Giangarra, Jill Goodwin, Franklin D. Shuler, Timothy Wilson-Byrne, John J. Jasko

John J. Jasko

Mesenchymal stem cell (MSC) injections for osteoarthritis is reviewed. Methods- PubMed search identifying articles in English from 2003-2018 that used intra- articular injection (IA), cartilage repair, cartilage regeneration, chondral injury, adipose stem cells, bone marrow stem cells, mesenchymal stem cells, or autologous stem cells. Results – 388 patients receiving IA MSC injections are discussed with data obtained from 10 case reports or case series, 4 randomized clinical trials (RCT), 1 cohort study, and 3 case controlled therapeutic studies. Conclusions – MSC injections may be an effective adjunct in the management of osteoarthritis and a variety of cartilage related pathologies.

A Review Of Mesenchymal Stem Cell Injections For Osteoarthritis, Ammar Qureshi, Jill Goodwin, Franklin D. Shuler, Timothy Wilson-Byrne, John J. Jasko, Charles Giangarra

Marshall Journal of Medicine

Mesenchymal stem cell (MSC) injections for osteoarthritis is reviewed.

Methods- PubMed search identifying articles in English from 2003-2018 that used intra- articular injection (IA), cartilage repair, cartilage regeneration, chondral injury, adipose stem cells, bone marrow stem cells, mesenchymal stem cells, or autologous stem cells.

Results – 388 patients receiving IA MSC injections are discussed with data obtained from 10 case reports or case series, 4 randomized clinical trials (RCT), 1 cohort study, and 3 case controlled therapeutic studies.

Conclusions – MSC injections may be an effective adjunct in the management of osteoarthritis and a variety of cartilage related pathologies.

Multimodality Minimally Invasive Treatment Of Large Joint Osteoarthritis: A Pilot Trial Of Stromal Vascular Fraction From Autologous Fat Combined With Platelet-Rich Plasma, Phil Giddings, Insiyah Campwala, Subhas Gupta

Loma Linda University Student Journal

Osteoarthritis (OA) is a degenerative joint disease that can cause severe pain in those affected. Currently, there are no therapeutic drugs available to treat osteoarthritis. While total joint arthroplasties (TJA) allow for improved function, there are no less invasive, yet effective procedures that can be done for patients unwilling or unable to undergo major surgery.

Platelet-rich plasma (PRP) has been shown to reduce the symptoms of OA when injected into the affected joint. Patients treated by this method alone have improved self-reported pain (at least a 50% reduction from original value) as well as lower extremity function. While the effects …

Motor Learning And Adaptation In People With Knee Osteoarthritis And Chronic Pain, Heather Turcotte, Katherine S. Rudolph

Osteopathic Medicine Student Research Posters

Osteoarthritis (OA) affects an estimated 50 million people in the US, and approximately 43% have limitations in daily function due to arthritis pain.3 Individuals with knee osteoarthritis (OA) have heightened sensitization to pain2,5 as well as reduced strength, diminished function and quality of life1 that prompts them to seek care from health care providers. Physical therapists commonly work with patients to improve function and quality of life by helping them learn to move without pain. Unfortunately, chronic pain causes changes to the nervous system that may impact the ability to learn new ways but the extent to which chronic pain …