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Applications of Mobile Health Technology in Surgical Innovation. JAMA surgery Aalami, O., Ingraham, A., Arya, S. 2021
View details for DOI 10.1001/jamasurg.2020.6251

View details for PubMedID 33533899
Activity data from wearables as an indicator of functional capacity in patients with cardiovascular disease. PloS one Rens, N. n., Gandhi, N. n., Mak, J. n., Paul, J. n., Bent, D. n., Liu, S. n., Savage, D. n., Nielsen-Bowles, H. n., Triggs, D. n., Ata, G. n., Talgo, J. n., Gutierrez, S. n., Aalami, O. n. 2021; 16 (3): e0247834
Abstract

Smartphone and wearable-based activity data provide an opportunity to remotely monitor functional capacity in patients. In this study, we assessed the ability of a home-based 6-minute walk test (6MWT) as well as passively collected activity data to supplement or even replace the in-clinic 6MWTs in patients with cardiovascular disease.We enrolled 110 participants who were scheduled for vascular or cardiac procedures. Each participant was supplied with an iPhone and an Apple Watch running the VascTrac research app and was followed for 6 months. Supervised 6MWTs were performed during clinic visits at scheduled intervals. Weekly at-home 6MWTs were performed via the VascTrac app. The app passively collected activity data such as daily step counts. Logistic regression with forward feature selection was used to assess at-home 6MWT and passive data as predictors for "frailty" as measured by the gold-standard supervised 6MWT. Frailty was defined as walking <300m on an in-clinic 6MWT.Under a supervised in-clinic setting, the smartphone and Apple Watch with the VascTrac app were able to accurately assess 'frailty' with sensitivity of 90% and specificity of 85%. Outside the clinic in an unsupervised setting, the home-based 6MWT is 83% sensitive and 60% specific in assessing "frailty." Passive data collected at home were nearly as accurate at predicting frailty on a clinic-based 6MWT as was a home-based 6MWT, with area under curve (AUC) of 0.643 and 0.704, respectively.In this longitudinal observational study, passive activity data acquired by an iPhone and Apple Watch were an accurate predictor of in-clinic 6MWT performance. This finding suggests that frailty and functional capacity could be monitored and evaluated remotely in patients with cardiovascular disease, enabling safer and higher resolution monitoring of patients.

View details for DOI 10.1371/journal.pone.0247834

View details for PubMedID 33760846
Telemedicine Platforms and Their Use in the Coronavirus Disease-19 Era to Deliver Comprehensive Vascular Care. Journal of vascular surgery Lin, J. C., Humphries, M. D., Shutze, W. P., Aalami, O. O., Fischer, U. M., Hodgson, K. J. 2020
Abstract

Implementation of telemedicine for patient encounters optimizes personal safety and allows for continuity of patient care. Embracing telehealth reduces the use of personal protective equipment (PPE) and other resources consumed during in-person visits. The use of telehealth has increased to historic levels in response to the coronavirus disease 2019 (COVID-19) pandemic. Telehealth may be a key modality to fight against COVID-19, allowing us to take care of patients, conserve PPE, and protect healthcare workers all while minimizing the risk of viral spread. We must not neglect vascular health issues while the coronavirus pandemic continues to flood many hospitals and keep people confined to their homes. Patients are not immune to diseases and illnesses such as stroke, critical limb ischemia, and deep vein thrombosis while being confined to their homes and afraid to visit hospitals. Emerging from the COVID-19 crisis, incorporating telemedicine into routine medical care is transformative. By leveraging digital technology, the authors discuss their experience with the implementation, workflow, coding, and reimbursement issues of telehealth during the COVID-19 era.

View details for DOI 10.1016/j.jvs.2020.06.051

View details for PubMedID 32622075
A Distributed Registry: Smartphone-Connected Database Driven by Patient-Reported Outcomes Triggs, D., Rens, N., Savage, D. M., Nielsen-Bowles, H., Talgo, J. C., Mak, J. J., Gutierrez, S., Aalami, O. MOSBY-ELSEVIER. 2020: E259
View details for Web of Science ID 000544100700393
National assessment of availability, awareness, and utilization of supervised exercise therapy for peripheral artery disease patients with intermittent claudication. Journal of vascular surgery Dua, A., Gologorsky, R., Savage, D., Rens, N., Gandhi, N., Brooke, B., Corriere, M., Jackson, E., Aalami, O. 2019
Abstract

BACKGROUND: Supervised exercise therapy (SET) is an inexpensive, low-risk, and effective option when compared with invasive therapies for the treatment of patients with peripheral artery disease (PAD) and intermittent claudication. Randomized, controlled trials have demonstrated the benefits of SET in improving maximum walking distance in intermittent claudication patients, and society guidelines recommend SET as first-line therapy. In 2017, the Centers for Medicare & Medicaid Services (CMS) added coverage of SET. We aimed to evaluate the availability and use of SET programs, determine the awareness of SET CMS coverage in the United States, and gauge the academic interest in SET in the vascular community.METHODS: An eight-question online survey regarding SET coverage, reimbursement, barriers to prescription, and SET use was sent to 900 vascular surgeons, cardiologists, and vascular medicine physicians across the United States. The most recent 2-year programs for the Vascular Annual Meeting, Midwestern Vascular Society, Eastern Vascular Society, and Western Vascular Society were reviewed to identify SET-related abstracts and gauge academic interest and awareness for SET within the vascular surgery community.RESULTS: We received 135 physician responses (15%) to the survey. All 50 states were represented. The majority of responders (54%) stated that there was no SET program at their facility, and 5% did not know if there was a SET program available. Of those who did have a SET program available, 81% were associated with cardiac rehabilitation and 19% had a PAD-specific program. A significant number of physicians (49%) had never referred a patient for SET. Twenty-six percent were not aware that CMS covered SET sessions. Of the physicians who were aware of CMS reimbursement, 36% had never referred a patient to a SET program. Of all surveyed, 98% indicated they would refer patients to a SET program if one was available. Top barriers to use of a SET program included (1) no SET center availability and (2) significant cost or travel expense to the patient. A review of major vascular surgery meeting programs for the last 2years yielded no identification of a SET-related abstract.CONCLUSIONS: There is a lack of both availability and use of SET for patients with PAD with claudication, despite guideline recommendations and CMS reimbursement for SET sessions in the United States. When SET is offered, it is typically through cardiac rehabilitation programs which is not focused on PAD. Travel distance, lack of SET program availability, and low reimbursement rates are primary areas that could be addressed to improve use.

View details for DOI 10.1016/j.jvs.2019.08.238

View details for PubMedID 31699514
Mobile Engagement for Walking in Patients With Claudication Aalami, O., Savage, D., Rens, N., Meng, E., Triggs, D. MOSBY-ELSEVIER. 2019: E230
View details for DOI 10.1016/j.jvs.2019.04.336

View details for Web of Science ID 000469220300328
National Assessment of Availability, Awareness, and Utilization of Supervised Exercise Therapy for Peripheral Artery Disease in Patients With Intermittent Claudication Dua, A., Savage, D., Rens, N., Gandhi, N., Brooke, B. S., Corriere, M., Jackson, E., Aalami, O. MOSBY-ELSEVIER. 2019: E55?E56
View details for DOI 10.1016/j.jvs.2019.04.022

View details for Web of Science ID 000469220300024
Clinical validation of smartphone-based activity tracking in peripheral artery disease patients NPJ DIGITAL MEDICINE Ata, R., Gandhi, N., Rasmussen, H., El-Gabalawy, O., Gutierrez, S., Ahmad, A., Suresh, S., Ravi, R., Rothenberg, K., Aalami, O. 2018; 1
View details for DOI 10.1038/s41746-018-0073-x

View details for Web of Science ID 000452794900001
Septic Pulmonary Emboli From Peripheral Suppurative Thrombophlebitis: A Case Report and Literature Review. Vascular and endovascular surgery Ho, V. T., Rothenberg, K. A., McFarland, G., Tran, K., Aalami, O. O. 2018: 1538574418779469
Abstract

BACKGROUND: We report the case of a 90-year old woman who presented with septic pulmonary emboli due to suppurative thrombophlebitis at an old peripheral intravenous site.METHODS: After unsuccessful treatment with antibiotics, the patient was taken to the operating room for excision and drainage of the purulent superficial vein.RESULTS: We review the literature and discuss the presentation, risk factors, treatment options, and complications of this often-overlooked disease entity.CONCLUSIONS: Suppurative thrombophlebitis is a rare but morbid disease that requires a high level of clinical suspicion to diagnose.

View details for DOI 10.1177/1538574418779469

View details for PubMedID 29909751
Clinical validation of smartphone-based activity tracking in peripheral artery disease patients. NPJ digital medicine Ata, R. n., Gandhi, N. n., Rasmussen, H. n., El-Gabalawy, O. n., Gutierrez, S. n., Ahmad, A. n., Suresh, S. n., Ravi, R. n., Rothenberg, K. n., Aalami, O. n. 2018; 1: 66
Abstract

Peripheral artery disease (PAD) is a vascular disease that leads to reduced blood flow to the limbs, often causing claudication symptoms that impair patients' ability to walk. The distance walked during a 6-min walk test (6MWT) correlates well with patient claudication symptoms, so we developed the VascTrac iPhone app as a platform for monitoring PAD using a digital 6MWT. In this study, we evaluate the accuracy of the built-in iPhone distance and step-counting algorithms during 6MWTs. One hundred and fourteen (114) participants with PAD performed a supervised 6MWT using the VascTrac app while simultaneously wearing an ActiGraph GT9X Activity Monitor. Steps and distance-walked during the 6MWT were manually measured and used to assess the bias in the iPhone CMPedometer algorithms. The iPhone CMPedometer step algorithm underestimated steps with a bias of -7.2%?�?13.8% (mean?�?SD) and had a mean percent difference with the Actigraph (Actigraph-iPhone) of 5.7%?�?20.5%. The iPhone CMPedometer distance algorithm overestimated distance with a bias of 43%?�?42% due to overestimation in stride length. Our correction factor improved distance estimation to 8%?�?32%. The Ankle-Brachial Index (ABI) correlated poorly with steps (R?=?0.365) and distance (R?=?0.413). Thus, in PAD patients, the iPhone's built-in distance algorithm is unable to accurately measure distance, suggesting that custom algorithms are necessary for using iPhones as a platform for monitoring distance walked in PAD patients. Although the iPhone accurately measured steps, more research is necessary to establish step counting as a clinically meaningful metric for PAD.

View details for DOI 10.1038/s41746-018-0073-x

View details for PubMedID 31304343

View details for PubMedCentralID PMC6550212
Deepwound: Automated Postoperative Wound Assessment and Surgical Site Surveillance through Convolutional Neural Networks Shenoy, V. N., Foster, E., Aalami, L., Majeed, B., Aalami, O., Zheng, H., Callejas, Z., Griol, D., Wang, H., Hu, Schmidt, H., Baumbach, J., Dickerson, J., Zhang, L. IEEE. 2018: 1017?21
View details for Web of Science ID 000458654000179
A Cross-Sectional Study of Prominent US Mobile Health Applications: Evaluating the Current Landscape. AMIA ... Annual Symposium proceedings. AMIA Symposium Fougerouse, P., Yasini, M., Marchand, G., Aalami, O. O. 2017; 2017: 715?23
Abstract

Mobile health (mHealth) could offer unprecedented opportunity to provide medical support closer to the users. We have selected some relevant criteria to describe 100 apps from Google Play store and Apple's App Store's top suggestions in medical category. These characteristics were compared based on the paid or free nature of the apps, the target users: consumers or healthcare professionals, and the platform: Android or iOS. Seventeen provided functionalities and 27 medical subjects covered by these apps were also extracted. Our study shows that even in top rated mHealth apps, a high proportion lacks some basic criteria regarding the quality of the apps including the presence of a privacy policy, describing content sources, participation of the target users in the app development, etc. Paid apps did not ensure better quality compared to free apps. The current mHealth market is not mature enough to be used widely and recommended by healthcare professionals.

View details for PubMedID 29854137
Utilizing Smartphone-Based Machine Learning in Medical Monitor Data Collection: Seven Segment Digit Recognition. AMIA ... Annual Symposium proceedings. AMIA Symposium Shenoy, V. N., Aalami, O. O. 2017; 2017: 1564?70
Abstract

Biometric measurements captured from medical devices, such as blood pressure gauges, glucose monitors, and weighing scales, are essential to tracking a patient's health. Trends in these measurements can accurately track diabetes, cardiovascular issues, and assist medication management for patients. Currently, patients record their results and date of measurement in a physical notebook. It may be weeks before a doctor sees a patient's records and can assess the health of the patient. With a predicted 6.8 billion smartphones in the world by 20221, health monitoring platforms, such as Apple's HealthKit2, can be leveraged to provide the right care at the right time. This research presents a mobile application that enables users to capture medical monitor data and send it to their doctor swiftly. A key contribution of this paper is a robust engine that can recognize digits from medical monitors with an accuracy of 98.2%.

View details for PubMedID 29854226
Use of a proactive duplex ultrasound protocol for�hemodialysis access. Journal of vascular surgery Itoga, N. K., Ullery, B. W., Tran, K., Lee, G. K., Aalami, O. O., Bech, F. R., Zhou, W. 2016; 64 (4): 1042-1049 e1
Abstract

Arteriovenous fistula (AVF) creation is the preferred approach for hemodialysis access; however, the maturation of AVFs is known to be poor. We established a proactive early duplex ultrasound (DUS) surveillance protocol for evaluating AVFs before attempted access. This study determined the effect of this protocol related to improving AVF maturation.From 2008 to 2013, 153 patients received new upper extremity AVFs and an early DUS surveillance protocol at a single academic institution. The protocol involved an early DUS evaluation before hemodialysis cannulation of the AVF at 4 to 8�weeks after AVF creation. A positive DUS result was identified as a peak systolic velocity of >375�cm/s or a >50% stenosis on gray scale imaging, along with decreased velocity in the outflow vein. Patients with positive DUS findings underwent prophylactic endovascular or open intervention to assist with AVF maturation. Nature of secondary interventions, as well as AVF patency and maturation, were assessed. Overall clinical outcomes and fistula patency were investigated.During the study period, 183 upper extremity AVFs were created in 153 patients, including 82 radiocephalic, 63�brachiocephalic, and 38 brachiobasilic AVFs. A mortality rate of 43% (n�= 66) was observed in a median follow-up period of 34.5�months (interquartile range, 19.6-46.9). A total of 164 early DUS were performed at a median of 6�weeks (interquartile range, 3.4-9.6�weeks) after the initial creation. Early DUS showed nine AVFs were occluded and were excluded from further analysis. Hemodynamically significant lesions were found in 62 AVFs (40%); however, only 17 (11%) were associated with an abnormal physical examination. Positive DUS finding prompted a secondary intervention in 81% of the patients. Among those with positive early DUS findings, AVF maturation was 70% in those undergoing a secondary intervention compared with 25% in those not undergoing a prophylactic intervention (P�= .011). Primary-assisted patency for AVFs with early positive and negative DUS findings were 83% and 96% at 6�months, 64% and 89% at 1�year, and 52% and 82% at 2�years, respectively (P�< .001).Early DUS surveillance of AVFs before initial access is reasonable to identify problematic AVFs that may not be reliably detected on clinical examination. Although DUS criteria for AVFs have yet to be universally accepted, proactive early postoperative DUS interrogation assists in the early detection of dysfunctional AVFs and improvement of fistula maturation. Despite improved patency in those with positive DUS findings who undergo prophylactic secondary intervention, overall patency remains inferior to those without an abnormality detected on early DUS imaging.

View details for DOI 10.1016/j.jvs.2016.03.442

View details for PubMedID 27183858
Novel Use of Google Glass for Procedural Wireless Vital Sign Monitoring. Surgical innovation Liebert, C. A., Zayed, M. A., Aalami, O., Tran, J., Lau, J. N. 2016; 23 (4): 366-373
Abstract

This study investigates the feasibility and potential utility of head-mounted displays for real-time wireless vital sign monitoring during surgical procedures.In this randomized controlled pilot study, surgery residents (n = 14) performed simulated bedside procedures with traditional vital sign monitors and were randomized to addition of vital sign streaming to Google Glass. Time to recognition of preprogrammed vital sign deterioration and frequency of traditional monitor use was recorded. User feedback was collected by electronic survey.The experimental group spent 90% less time looking away from the procedural field to view traditional monitors during bronchoscopy (P = .003), and recognized critical desaturation 8.8 seconds earlier; the experimental group spent 71% (P = .01) less time looking away from the procedural field during thoracostomy, and recognized hypotension 10.5 seconds earlier. Trends toward earlier recognition of deterioration did not reach statistical significance. The majority of participants agreed that Google Glass increases situational awareness (64%), is helpful in monitoring vitals (86%), is easy to use (93%), and has potential to improve patient safety (85%).In this early feasibility study, use of streaming to Google Glass significantly decreased time looking away from procedural fields and resulted in a nonsignificant trend toward earlier recognition of vital sign deterioration. Vital sign streaming with Google Glass or similar platforms is feasible and may enhance procedural situational awareness.

View details for DOI 10.1177/1553350616630142

View details for PubMedID 26848138
Erratum to: 'TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial'. Trials Morris, D. R., Cunningham, M. A., Ahimastos, A. A., Kingwell, B. A., Pappas, E., Bourke, M., Reid, C. M., Stijnen, T., Dalman, R. L., Aalami, O. O., Lindeman, J. H., Norman, P. E., Walker, P. J., Fitridge, R., Bourke, B., Dear, A. E., Pinchbeck, J., Jaeggi, R., Golledge, J. 2016; 17 (1): 43-?
View details for DOI 10.1186/s13063-016-1183-x

View details for PubMedID 26791257

View details for PubMedCentralID PMC4721016
A Prospective Evaluation of Using IVUS during Percutaneous Superficial Femoral Artery Interventions ANNALS OF VASCULAR SURGERY Hitchner, E., Zayed, M., Varu, V., Lee, G., Aalami, O., Zhou, W. 2015; 29 (1): 28-33
Abstract

The outcomes of endovascular interventions of the superficial femoral artery (SFA) are variable. Completion angiography is typically performed to confirm satisfactory outcomes after SFA angioplasty and/or stenting. However, two-dimensional angiography may not accurately reflect the extent of residual stenosis. We sought to determine whether intravascular ultrasound (IVUS) can help with residual disease assessment and procedure outcome.Patients with anticipated SFA disease were prospectively recruited to the study. Patients with primary SFA disease on diagnostic angiography were included. After SFA endovascular intervention with angioplasty and/or stenting, a completion angiogram was performed to confirm satisfactory results before IVUS evaluation. IVUS-detected maximal residual stenosis, maximal residual lesion volume, and number of nonconsecutive posttreatment SFA segments with >50% residual stenosis were evaluated. Periprocedural ankle-brachial indexes (ABIs), Short Form 36 (SF-36) surveys, and Walking Impairment Questionnaires were also collected.Fifty-nine patients were prospectively enrolled. Thirty-three received angioplasty only, and 26 received angioplasty and stenting. All patients were men, mean age was 67 years, and major comorbidities included coronary artery disease (53%), active smoking (56%), hypertension (88%), and diabetes (68%). The angioplasty-only cohort had more nonconsecutive areas of >50% residual stenosis (P = 0.004), greater residual stenosis (P = 0.03), and smaller minimal lumen diameters after treatment (P = 0.01) than the angioplasty and stenting cohort. However, there was no significant difference in ABI between the 2 groups and no difference in ABI improvement after intervention. Sixty-four percent of all patients demonstrated a >0.2 increase in postintervention ABI. Improvement in ABI at 1 month after procedure significantly correlated with postintervention SF-36 survey physical scores (r = 0.435, P = 0.007).IVUS evaluation provides more-accurate intraprocedural insight on the extent of residual stenosis after SFA interventions. Future studies are warranted to determine whether IVUS-guided postangioplasty and/or stenting can impact long-term interventional outcome.

View details for DOI 10.1016/j.avsg.2014.07.026

View details for Web of Science ID 000346239900005

View details for PubMedID 25194552
TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial. Trials Morris, D. R., Cunningham, M. A., Ahimastos, A. A., Kingwell, B. A., Pappas, E., Bourke, M., Reid, C. M., Stijnen, T., Dalman, R. L., Aalami, O. O., Lindeman, J. H., Norman, P. E., Walker, P. J., Fitridge, R., Bourke, B., Dear, A. E., Pinchbeck, J., Jaeggi, R., Golledge, J. 2015; 16: 274-?
Abstract

Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.

View details for DOI 10.1186/s13063-015-0793-z

View details for PubMedID 26081587

View details for PubMedCentralID PMC4482315
Targeting of Sp1 transcription factor: a novel therapeutic approach for Keloids, an in vitro analysis EXPERIMENTAL DERMATOLOGY Mukhopadhyay, A., Khoo, A., Cheong, H. H., Chan, S. Y., Aalami, O., Lim, I. J., Phan, T. T. 2007; 16 (12): 1023-1031
Abstract

Keloid scars are fibroproliferative disorders characterized by the accumulation of extracellular matrix (ECM) components resulting in a fibrotic condition. Several ECM promoters are regulated by Sp1. Thus, our aim was to investigate the role of Sp1 in keloid pathogenesis and investigate the antiproliferative and antifibrotic effects of Wp631 and mitoxantrone, potent inhibitors of Sp1-activated transcription. An elevated level of Sp1 was observed in tissue extracts obtained from keloid tissue. Serum stimulation elevated Sp1 levels in keloid fibroblasts (KF). Under coculture conditions Sp1 seemed to be downregulated. Wp631 and mitoxanthrone in serum growth factors resulted in a reduced expression of ECM components in KF. Both Wp631 and mitoxanthrone were also able to inhibit the proliferation of normal and keloid keratinocytes and fibroblasts significantly. As Wp631 seems to be potent in downregulating the ECM components in KF and also inhibiting the proliferation of these cells it could be explored as a possible therapeutic agent in the treatment of keloids.

View details for DOI 10.1111/j.1600-0625.2007.00627.x

View details for Web of Science ID 000251189300008

View details for PubMedID 18031462
mTOR as a potential therapeutic target for treatment of keloids and excessive scars EXPERIMENTAL DERMATOLOGY Ong, C. T., Khoo, Y. T., Mukhopadhyay, A., Do, D. V., Lim, I. J., Aalami, O., Phan, T. T. 2007; 16 (5): 394-404
Abstract

Keloid is a dermal fibroproliferative disorder characterized by excessive deposition of extracellular matrix (ECM) components such as collagen, glycoproteins and fibronectin. The mammalian target of rapamycin (mTOR) is a serine/theronine kinase which plays an important role in the regulation of metabolic processes and translation rates. Published reports have shown mTOR as regulator of collagen expression and its inhibition induces a decrease in ECM deposition. Our aim was to investigate the role of mTOR in keloid pathogenesis and investigate the effect of rapamycin on proliferating cell nuclear antigen (PCNA), cyclin D1, collagen, fibronectin and alpha-smooth muscle actin (alpha-SMA) expression in normal fibroblasts (NF) and keloid fibroblasts (KF). Tissue extracts obtained from keloid scar demonstrated elevated expression of mTOR, p70KDa S6 kinase (p70S6K) and their activated forms, suggesting an activated state in keloid scars. Serum stimulation highlighted the heightened responsiveness of KF to mitogens and the importance of mTOR and p70S6K during early phase of wound healing. Application of rapamycin to monoculture NF and KF, dose- and time-dependently downregulates the expression of cytoplasmic PCNA, cyclin D1, fibronectin, collagen and alpha-SMA, demonstrating the anti-proliferative effect and therapeutic potential of rapamycin in the treatment of keloid scars. The inhibitory effect of rapamycin was found to be reversible following recovery in the expression of proteins following the removal of rapamycin from the culture media. These results demonstrate the important role of mTOR in the regulation of cell cycle and the expression of ECM proteins: fibronectin, collagen and alpha-SMA.

View details for DOI 10.1111/j.1600-0625.2007.00550.x

View details for Web of Science ID 000245605500002

View details for PubMedID 17437482
Differential gene expression between juvenile and adult dura mater: A window into what genes play a role in the regeneration of membranous bone PLASTIC AND RECONSTRUCTIVE SURGERY Wan, D. C., Aalami, O. O., Wang, Z., Nacamuli, R. P., Lorget, F., Derynck, R., Longaker, M. T. 2006; 118 (4): 851-861
Abstract

Although reossification of large calvarial defects is possible in children, adults lack this tissue engineering capacity. In this study, the authors compared the differences in gene expression between juvenile and adult dura mater using a mouse cDNA microarray with 42,000 unique elements.Non-suture-associated parietal bone was harvested from 6-day-old and 60-day-old mice. The dura mater was carefully dissected from the calvarial disk and snap-frozen. RNA was extracted from pooled dura mater for microarray analysis. The 25 most differentially expressed genes were listed, as were selected bone-related genes. In addition, quantitative real-time reverse-transcriptase polymerase chain reaction confirmation of selected genes-BMP-2, BMP-4, and BMP-7; and osteopontin (OP), osteocalcin (OC), and FGFR-1-was performed.Juvenile dura mater expressed significantly greater amounts of BMP-2 and OP. Minimal difference in OC expression was observed between juvenile and adult dura mater. Extracellular matrix proteins (Col3a1, 5a1, 6a1, and fibronectin 1), osteoblast differentiation markers (Runx2/Cbfa1, Itm2a, and FGFR-1), and the growth factor Ptn were among other genes with greater expression in juvenile dura mater. Markers of osteoclasts (Acp5, MMP9, Ctsk) and the multiple candidate gene Ntrk2 were also expressed at higher levels in the juvenile dura mater.These findings suggest a more differentiated osteoprogenitor population to exist along with a greater presence of osteoclasts in the juvenile dura mater relative to adults. In addition to establishing a baseline difference in gene expression between juvenile and adult dura mater, new genes potentially critical to the regenerative potential of juvenile calvaria were identified.

View details for DOI 10.1097/01.prs.0000232366.23897.2b

View details for Web of Science ID 000240700100004

View details for PubMedID 16980845
Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts TRANSPLANTATION Paniagua, R., Si, M. S., Flores, M. G., Rousvoal, G., Zhang, S., Aalami, O., Campbell, A., Changelian, P. S., Reitz, B. A., Borie, D. C. 2005; 80 (9): 1283-1292
Abstract

Janus Kinase (JAK) 3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cells activation and function. JAK3 inhibition with CP-690,550 prevents acute allograft rejection. To provide further insight into the mechanisms of efficacy, we investigated the immunomodulatory effects of CP-690,550 in vitro and in vivo in nonhuman primates.Pharmacodynamic assessments of lymphocyte activation, function, proliferation and phenotype were performed in three settings: in vitro in whole blood isolated from untransplanted cynomolgus monkeys (cynos), in vivo in blood from untransplanted cynos dosed with CP-690,550 for 8 days, and in vivo in blood from transplanted cynos immunosuppressed with CP-690,550. Cell surface activation markers expression, IL-2- enhanced IFN-gamma production, lymphocyte proliferation and immune cell phenotype analyzes were performed with multiparametric flow cytometry.In vitro exposure to CP-690,550 resulted in significant reduction of IL-2-enhanced IFN-gamma production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 microM) and CD71 (IC50; 1.6 microM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 microM). Similar results were observed in animals dosed with CP-690,550. In addition, transplanted animals displayed significant reduction of NK cell (90% from baseline) and T-cell numbers whereas CD8 effector memory T-cell populations were unaffected.Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.

View details for DOI 10.1097/01.tp.0000177643.05739.cd

View details for Web of Science ID 000233732600021

View details for PubMedID 16314797
Smad3 signalling plays an important role in keloid pathogenesis via epithelial-mesenchymal interactions JOURNAL OF PATHOLOGY Phan, T. T., Lim, I. J., Aalami, O., Lorget, F., Khoo, A., Tan, E. K., Mukhopadhyay, A., Longaker, M. T. 2005; 207 (2): 232-242
Abstract

Smad signalling plays important roles in developmental and cancer biology as well as in fibropathogenesis. Its role in keloid biology is not known. Epithelial-mesenchymal interactions, originally described in normal skin, have recently been established to play a significant role in keloid pathogenesis, and demonstrate the important influence of keratinocyte paracrine factor signalling on fibroblast behaviour. The present study investigated the role of downstream Smad cascade induction in this interaction. Normal fibroblasts (NF) and keloid fibroblasts (KF) were co-cultured in serum-free medium with normal keratinocytes (NK) or keloid keratinocytes (KK) for 5 days, after which fibroblast cell lysates were subjected to western blot and immunoprecipitation analysis to quantify the levels of Smad and Smad2/3/4 binding complex. In another set of experiments, wild-type (wt), Smad2-null (Smad2-/-) and Smad3-null (Smad3-/-) mouse embryonic fibroblasts (MEF) were assayed for cell proliferation and collagen production after serum-free co-culture with KK or exposure to conditioned media collected from serum-free KK/KF co-culture. Compared to normal skin, keloids expressed high basal levels of TGFbetaR1 and TGFbetaR2, Smad2, 3 and 4 and phospho-Smad2. Upregulation of TGFbetaR1 and TGFbetaR2, Smad3 and p-Smad2 was observed in KF co-cultured with KK, together with enhanced Smad3 phosphorylation and Smad2/3/4 binding complex production. When MEF-wt, MEF-Smad2-/- or MEF-Smad3-/- were co-cultured with KK or exposed to KK/KF co-culture conditioned media, enhanced proliferation and collagen production were seen in MEF-wt and MEF-Smad2-/- but not in MEF-Smad3-/- cells. The activation of Smad signalling, importantly that of Smad3, appears to be one facet of the complex epithelial-mesenchymal interactions in keloid pathogenesis, resulting in active KF proliferation and collagen-ECM production in co-culture with KK. This finding suggests the suppression of Smad signalling as a novel approach in keloid therapy.

View details for DOI 10.1002/path.1826

View details for Web of Science ID 000232213500012

View details for PubMedID 16052471
Differential transcriptional expression profiles of juvenile and adult calvarial bone PLASTIC AND RECONSTRUCTIVE SURGERY Aalami, O. O., Nacamuli, R. P., Salim, A., Fong, K. D., Lenton, K. A., Song, H. M., Fang, T. D., Longaker, M. T. 2005; 115 (7): 1986-1994
Abstract

It has widely been observed that young children are capable of reossifying large calvarial defects, while adults lack this endogenous tissue-engineering capacity. The ability of juvenile animals to regenerate calvarial defects has been investigated in multiple animal models, including mice. In this study, the authors used cDNA microarrays to investigate the expression of osteogenesis-associated genes upstream and downstream of Runx2 in juvenile and adult mouse calvaria.Nonsuture-associated parietal bone discs were harvested from 6-day-old (n = 50) and 60-day-old (n = 35) male CD-1 mice. After separation of the underlying dura mater and overlying pericranium, the calvarial discs were snap-frozen and RNA was extracted from pooled samples of calvaria for microarray analysis. Genes analyzed included cytokines, receptors, and cell-surface and matrix proteins both upstream and downstream of Runx2.Genes associated with the Runx2 pathway had notably higher levels in the juvenile versus adult calvaria. All genes except for osteocalcin were expressed at least twofold higher in the juvenile calvaria. This pattern was validated with quantitative real-time polymerase chain reaction. In addition, mRNA for potent osteoinductive growth factors was present at higher levels in the juvenile compared with the adult calvaria.These findings reflect a genomic environment of active osteoblast differentiation and ossification in the juvenile calvaria compared with the adult "quiescent" calvarial tissue. These data suggest that a decreased osteogenic potential of adult calvarial osteoblasts may, in part, explain the inability of adult animals to heal calvarial defects.

View details for DOI 10.1097/01.PRS.0000163323.66318.73

View details for Web of Science ID 000229497700025

View details for PubMedID 15923847
Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover TISSUE ENGINEERING Cowan, C. M., Aalami, O. O., Shi, Y. Y., Chou, Y. F., Mari, C., Thomas, R., Quarto, N., Nacamuli, R. P., Contag, C. H., Wu, B., Longaker, M. T. 2005; 11 (3-4): 645-658
Abstract

Reconstruction of craniofacial defects presents a substantial biomedical burden, and requires complex surgery. Interestingly, children after age 2 years and adults are unable to heal large skull defects. This nonhealing paradigm provides an excellent model system for craniofacial skeletal tissueengineering strategies. Previous studies have documented the in vivo osteogenic potential of adipose-derived stromal (ADS) cells and bone marrow-derived stromal (BMS) cells. This study investigates the ability to accelerate in vivo osteogenesis on ex vivo recombinant human bone morphogenetic protein 2 (BMP-2) and retinoic acid stimulation. Mouse osteoblasts, ADS cells, and BMS cells were seeded onto apatite-coated PLGA scaffolds, stimulated with rhBMP-2 and retinoic acid ex vivo for 4 weeks, and subsequently implanted into critically sized (4 mm) calvarial defects. Samples were harvested after 2, 4, 8, and 12 weeks. Areas of complete bony bridging were noted as early as 2 weeks in vivo; however, osteoclasts were attracted to the scaffold as identified by calcitonin receptor staining and tartrate-resistant acid phosphatase activity staining. Although the optimal method of in vitro osteogenic priming for mesenchymal cells remains unknown, these results provide evidence that BMP-2 and retinoic acid stimulation of multipotent cells ex vivo can subsequently induce significant quantities of bone formation within a short time period in vivo.

View details for PubMedID 15869441
Applications of a mouse model of calvarial healing: Differences in regenerative abilities of juveniles and adults PLASTIC AND RECONSTRUCTIVE SURGERY Aalami, O. O., Nacamuli, R. P., Lenton, K. A., Cowan, C. M., Fang, T. D., Fong, K. D., Shi, Y. Y., Song, H. M., Sahar, D. E., Longaker, M. T. 2004; 114 (3): 713-720
Abstract

Young children are capable of healing large calvarial defects, whereas adults lack this endogenous osseous tissue-engineering capacity. Despite the important clinical implications, little is known about the molecular and cell biology underlying this differential ability. Traditionally, guinea pig, rabbit, and rat models have been used to study the orchestration of calvarial healing. To harness the research potential of knockout and transgenic mice, the authors developed a mouse model for calvarial healing. Nonsuture-associated parietal defects 3, 4, and 5 mm in diameter were made in both juvenile (6-day-old, n = 15) and adult (60-day-old, n = 15) mice. Calvariae were harvested after 8 weeks and analyzed radiographically and histologically. Percentage of healing was quantified using Scion Image software analysis of calvarial radiographs. A significant difference in the ability to heal calvarial defects was seen between 6-day-old and 60-day-old mice when 3-, 4-, or 5-mm defects were created. The authors' analysis revealed that juvenile mice healed a significantly greater percentage of their calvarial defects than adult mice (juvenile mean percentage of healing: 3-mm defects, 59 percent; 4-mm defects, 65 percent; 5-mm defects, 44 percent; adult mean percentage of healing: <5 percent in all groups; p < 0.05). All three defect sizes were found to be critical in the adult, whereas significant healing was seen regardless of the size of the defect in juvenile mice. The establishment of this model will facilitate further, detailed evaluation of the molecular biology underlying the different regenerative abilities of juvenile versus adult mice and enhance research into membranous bone induction by making available powerful tools such as knockout and transgenic animals.

View details for DOI 10.1097/01.PRS.0000131016.12754.30

View details for Web of Science ID 000223436200015

View details for PubMedID 15318051
Adipose-derived adult stromal cells heal critical-size mouse calvarial defects NATURE BIOTECHNOLOGY Cowan, C. M., Shi, Y. Y., Aalami, O. O., Chou, Y. F., Mari, C., Thomas, R., Quarto, N., Contag, C. H., Wu, B., Longaker, M. T. 2004; 22 (5): 560-567
Abstract

In adults and children over two years of age, large cranial defects do not reossify successfully, posing a substantial biomedical burden. The osteogenic potential of bone marrow stromal (BMS) cells has been documented. This study investigates the in vivo osteogenic capability of adipose-derived adult stromal (ADAS) cells, BMS cells, calvarial-derived osteoblasts and dura mater cells to heal critical-size mouse calvarial defects. Implanted, apatite-coated, PLGA scaffolds seeded with ADAS or BMS cells produced significant intramembranous bone formation by 2 weeks and areas of complete bony bridging by 12 weeks as shown by X-ray analysis, histology and live micromolecular imaging. The contribution of implanted cells to new bone formation was 84-99% by chromosomal detection. These data show that ADAS cells heal critical-size skeletal defects without genetic manipulation or the addition of exogenous growth factors.

View details for DOI 10.1038/nbt958

View details for PubMedID 15077117
Mechanisms of murine cranial suture patency mediated by a dominant negative transforming growth factor-beta receptor adenovirus PLASTIC AND RECONSTRUCTIVE SURGERY Song, H. J., Fong, D., Nacamuli, R. P., Warren, S. M., Fang, T. D., Mathy, J. A., Cowan, C. M., Aalami, O. O., Longaker, M. T. 2004; 113 (6): 1685-1697
Abstract

Using a physiologic model of mouse cranial suture fusion, the authors' laboratory has previously demonstrated that transforming growth factor (TGF)-betas appear to be more abundantly expressed in the suture complex of the fusing posterior frontal compared with the patent sagittal suture. Furthermore, the authors have shown that by blocking TGF-beta signaling with a replication-deficient adenovirus encoding a defective, dominant negative type II TGF-beta receptor (AdDN-TbetaRII), posterior frontal suture fusion was inhibited. In this study, the authors attempt to further elucidate the role of TGF-beta in cranial suture fusion by investigating possible mechanisms of AdDN-TbetaRII-mediated cranial suture patency using both an established organ culture model and a novel in vitro co-culture system that recapitulates the in vivo anatomic dura mater/cranial suture relationship. In this article, the authors demonstrate that blocking TGF-beta signaling with the AdDN-TbetaRII construct led to inhibition of cellular proliferation in the suture mesenchyme and subjacent dura mater during the early period of predicted posterior frontal suture fusion. Interestingly, co-culture experiments revealed that transfecting osteoblasts with AdDN-TbetaRII led to alterations in the gene expression levels of two important bone-related molecules (Msx2 and osteopontin). Inhibiting TGF-beta signaling prevented time-dependent suppression of Msx2 and prevented induction of osteopontin, thereby retarding osteoblast differentiation. Furthermore, the authors demonstrated that the AdDN-TbetaRII construct was capable of blocking TGF-beta -mediated up-regulation of collagen IalphaI, an extracellular matrix molecule important for bone formation. Collectively, these data strongly suggest that AdDN-TbetaRII maintains posterior frontal patency, in part by altering early events in de novo bone formation, including cellular proliferation and early extracellular matrix production.

View details for DOI 10.1097/001.PRS.000117363.43699.5B

View details for Web of Science ID 000221141000019

View details for PubMedID 15114130
In vitro murine posterior frontal suture fate is age-dependent: Implications for cranial suture biology PLASTIC AND RECONSTRUCTIVE SURGERY Song, H. J., Sahar, D. E., Fong, K. D., Nacamuli, R. P., Fang, T. D., Mathy, J. A., Aalami, O. O., Warren, S. M., Longaker, M. T. 2004; 113 (4): 1192-1204
Abstract

In CD-1 mice, the posterior frontal suture (analogous to the human metopic suture) fuses while all other cranial sutures remain patent. In an in vitro organ culture model, the authors previously demonstrated that posterior frontal sutures explanted immediately before the onset of suture fusion (at 25 days old) mimic in vivo physiologic fusion. In the first portion of this study, the authors defined how early in development the posterior frontal suture fuses in their tension-free, serum-free organ culture system by serially analyzing posterior frontal suture fusion from calvariae explanted at different stages of postnatal development. Their results revealed a divergence of suture fate leading to abnormal patency or physiologic fusion between the first and second weeks of life, respectively, despite viability and continued growth of the calvarial explants in vitro. From these data, the authors postulated that the gene expression patterns present in the suture complex at the time of explant may determine whether the posterior frontal suture fuses or remains patent in organ culture. Therefore, to elucidate potentially important differences in gene expression within this "window of opportunity," they performed a cDNA microarray analysis on 5-day-old and 15-day-old posterior frontal and sagittal whole suture complexes corresponding to the age ranges for unsuccessful (1 to 7 days old) and successful (14 to 21 days old) in vitro posterior frontal suture fusion. Overall, their microarray results reveal interesting differential expression patterns of candidate genes in different categories, including angiogenic cytokines and mechanosensitive genes potentially important in cranial suture biology.

View details for DOI 10.1097/01.PRS.0000110203.90911.63

View details for Web of Science ID 000220618600011

View details for PubMedID 15083020
Postoperative rhabdomyolysis following laparoscopic gastric bypass in the morbidly obese ARCHIVES OF SURGERY Khurana, R. N., Baudendistel, T. E., Morgan, E. F., Rabkin, R. A., Elkin, R. B., Aalami, O. O. 2004; 139 (1): 73-76
Abstract

Laparoscopic approaches for weight reduction in the morbidly obese have become common with more than 50,000 bariatric surgical procedures being performed in 2001. The objective of this article is to raise awareness among surgeons of a new complication of rhabdomyolysis from this frequent procedure.Case series extracted from surgical database from January 2, 2001, through December 31, 2002.We identified 5 cases of postoperative rhabdomyolysis in morbidly obese patients who underwent laparoscopic duodenal switch procedures with parietal gastrectomy. The cause, pathogenesis, and clinical features are reviewed and discussed.Postoperative rhabdomyolysis developed in 5 of 353 morbidly obese patients who underwent consecutive laparoscopic duodenal switch procedures, an incidence of 1.4%. All 5 patients were male, had a mean peak serum creatine kinase level of 19 680 U/L, and reported muscle pain in either the buttock, hip, or shoulder regions during the early postoperative period.We hypothesized that morbidly obese patients develop critical surface and deep tissue pressures during bariatric surgery, increasing their risk for tissue injury and rhabdomyolysis. Unexplained elevations in the serum creatinine level or reports of buttock, hip, or shoulder pain in the postoperative period should raise the possibility of rhabdomyolysis and prompt clinical investigation. We recommend routine preoperative and postoperative measurements of the serum creatine kinase and serum creatinine levels to aid detection. Surgeons need to keep a low index of suspicion because early diagnosis and treatment are the cornerstones of successful management of rhabdomyolysis.

View details for Web of Science ID 000187998500017

View details for PubMedID 14718280
Physiological features of aging persons ARCHIVES OF SURGERY Aalami, O. O., Fang, T. D., Song, H. M., Nacamuli, R. P. 2003; 138 (10): 1068-1076
View details for Web of Science ID 000186075900006

View details for PubMedID 14557122
Roles of periosteum, dura, and adjacent bone on healing of cranial osteonecrosis - Discussion JOURNAL OF CRANIOFACIAL SURGERY Aalami, O. O., Nacamuli, R. P., Longaker, M. T. 2003; 14 (3): 380-382
View details for Web of Science ID 000183221300017
Microarray analysis of regional patterning of suture-specific dura mater 10th International Congress of the International-Society-of-Craniofacial-Surgery Nacamuli, R. P., Song, H. M., Fang, T. D., Fong, K. D., Aalami, O. O., Salim, A., Sahar, D. E., Chi, J. T., Longaker, M. T. MEDIMOND PUBLISHING CO. 2003: 459?460
View details for Web of Science ID 000227470500094
Establishment of a young-versus-adult mouse calvarial defect model 10th International Congress of the International-Society-of-Craniofacial-Surgery Aalami, O. O., Nacamuli, R. P., Fong, K. D., Fang, T. D., Song, H. M., Sahar, D. E., Lenton, K. A., Cowan, C. M., Longaker, M. T. MEDIMOND PUBLISHING CO. 2003: 375?377
View details for Web of Science ID 000227470500067
A mouse model of mandibular distraction osteogenesis 10th International Congress of the International-Society-of-Craniofacial-Surgery Fang, T. D., Nacamuli, R. P., Song, H. M., Thomas, R., Fong, K. D., Aalami, O. O., Longaker, M. T. MEDIMOND PUBLISHING CO. 2003: 397?398
View details for Web of Science ID 000227470500074
Cranial suture fate in an in vitro organ culture model 10th International Congress of the International-Society-of-Craniofacial-Surgery Sahar, D. E., Song, H. M., Fong, K. D., Nacamuli, R. P., Warren, S. M., Mathy, J. A., Fang, T. D., Aalami, O., Longaker, M. T. MEDIMOND PUBLISHING CO. 2003: 473?475
View details for Web of Science ID 000227470500098
Analysis of de novo bone formation by dura-derived TGF-beta signaling 10th International Congress of the International-Society-of-Craniofacial-Surgery Song, H. M., Nacamuli, R. P., Fong, K. D., Fang, T. D., Aalami, O. A., Warren, S. M., Longaker, M. T. MEDIMOND PUBLISHING CO. 2003: 489?491
View details for Web of Science ID 000227470500102
The osteogenic antagonist BMP-3 is down-regulated during programmed suture fusion in the rat 10th International Congress of the International-Society-of-Craniofacial-Surgery Fong, K. D., Nacamuli, R. P., Lenton, K., Fang, T. D., Song, H. M., Salim, A., Shi, Y. Y., Aalami, O. O., Longaker, M. T. MEDIMOND PUBLISHING CO. 2003: 399?401
View details for Web of Science ID 000227470500075
Microarray analysis comparing juvenile and adult dura mater 10th International Congress of the International-Society-of-Craniofacial-Surgery Aalami, O. O., Fong, K. D., Nacamult, R. P., Fang, T. D., Song, H. M., Sahar, D. E., Lenton, K. A., Cowan, C. M., Chi, J. T., Longaker, M. T. MEDIMOND PUBLISHING CO. 2003: 373?374
View details for Web of Science ID 000227470500066

Oliver O. Aalami, MD

Clinical Associate Professor, Surgery - Vascular Surgery

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