All Publications

  • Virtual reality facilitated exercise improves pain perception: A crossover study. Journal of clinical anesthesia Rodriguez, S. T., Makarewicz, N., Wang, E. Y., Zuniga-Hernandez, M., Titzler, J., Jackson, C., Suen, M. Y., Rosales, O., Caruso, T. J. 2023; 91: 111257


    STUDY OBJECTIVE: Both virtual reality (VR) and exercise are recognized for their analgesic and anxiolytic properties. The purpose of this study is to evaluate the ability of VR-facilitated exercise to modulate pain.DESIGN: Within-subject cross-over clinical trial.SETTING: The Stanford Chariot Program conducted this study at Lucile Packard Children's Hospital Stanford (LCPHS).PATIENTS: Healthy participants meeting inclusion criteria were recruited by volunteer solicitation from LCPHS.INTERVENTIONS: Participants were randomized by hand dominance and subjected to a standardized cold pressor test with no VR or exercise. After a 5-min wash-out period, participants repeated the test on their other hand while experiencing a VR-facilitated exercise condition. Pain sensitivity, pain tolerance, and sympathetic activation data were collected during both conditions.MEASUREMENTS: Pain sensitivity was scored 0-10 and collected every 30s. Pain tolerance was recorded as the duration a participant could endure the painful stimuli. Sympathetic activation was measured by skin conductance response density (SCRD) and recorded in 30s epochs by a biosensor. In all analyses, data were nested by participant.MAIN RESULTS: Forty-one participants completed both interventions. Pain sensitivity was reduced in the VR-facilitated exercise condition (p<0.0001). There was no difference in pain tolerance between conditions. While both conditions resulted in an increase in sympathetic activity, SCRD was higher at all time points in the VR-facilitated exercise condition.CONCLUSIONS: The reduction in pain sensitivity indicates VR-facilitated exercise results in improved pain perception. VR-facilitated exercise may be especially useful for patients with chronic pain or other conditions requiring physical therapy, where pain may be exacerbated by exercise.

    View details for DOI 10.1016/j.jclinane.2023.111257

    View details for PubMedID 37708601

  • Artist's Statement: Zoom Medical School. Academic medicine : journal of the Association of American Medical Colleges Makarewicz, N. 2023; 98 (6): 679

    View details for DOI 10.1097/ACM.0000000000005199

    View details for PubMedID 37256309

  • Comparing the Outcomes and Complication Rates of Biologic vs Synthetic Meshes in Implant-Based Breast Reconstruction: A Systematic Review. Annals of plastic surgery Makarewicz, N., Perrault, D., Sharma, A., Shaheen, M., Kim, J., Calderon, C., Sweeney, B., Nazerali, R. 2023; 90 (5): 516-527


    This systematic review evaluates all published studies comparing biologic and synthetic meshes in implant-based breast reconstruction (IBBR), to determine which category of mesh produces the most favorable outcomes.Breast cancer is the most common cancer in women globally. Implant-based breast reconstruction is currently the most popular method of postmastectomy reconstruction, and recently, the use of surgical mesh in IBBR has become commonplace. Although there is a long-standing belief among surgeons that biologic mesh is superior to synthetic mesh in terms of surgical complications and patient outcomes, few studies exist to support this claim.A systematic search of the EMBASE, PubMed, and Cochrane databases was performed in January 2022. Primary literature studies comparing biologic and synthetic meshes within the same experimental framework were included. Study quality and bias were assessed using the validated Methodological Index for Non-Randomized Studies criteria.After duplicate removal, 109 publications were reviewed, with 12 meeting the predetermined inclusion criteria. Outcomes included common surgical complications, histological analysis, interactions with oncologic therapies, quality of life measures, and esthetic outcomes. Across all 12 studies, synthetic meshes were rated as at least equivalent to biologic meshes for every reported outcome. On average, the studies in this review tended to have moderate Methodological Index for Non-Randomized Studies scores.This systematic review offers the first comprehensive evaluation of all publications comparing biologic and synthetic meshes in IBBR. The consistent finding that synthetic meshes are at least equivalent to biologic meshes across a range of clinical outcomes offers a compelling argument in favor of prioritizing the use of synthetic meshes in IBBR.

    View details for DOI 10.1097/SAP.0000000000003512

    View details for PubMedID 37146317

  • Use of Local Antibiotic Delivery Systems in Tissue Expander and Implant-Based Breast Reconstruction: A Systematic Review of the Literature. Eplasty Makarewicz, N., Lipman, K., Johnstone, T., Shaheen, M., Shah, J. K., Nazerali, R. 2023; 23: e24


    Periprosthetic infections are a debilitating complication of alloplastic breast reconstruction. Local antibiotic delivery for prophylaxis and infection clearance has been used by other surgical specialties but rarely in breast reconstruction. Because local delivery can maintain high antibiotic concentrations with lower toxicity risk, it may be valuable for infection prophylaxis or salvage in breast reconstruction.A systematic search of the Embase, PubMed, and Cochrane databases was performed in January 2022. Primary literature studies examining local antibiotic delivery systems for either prophylaxis or salvage of periprosthetic infections were included. Study quality and bias were assessed using the validated MINORS criteria.Of 355 publications reviewed, 8 met the predetermined inclusion criteria; 5 papers investigated local antibiotic delivery for salvage, and 3 investigated infection prophylaxis. Implantable antibiotic delivery devices included polymethylmethacrylate, calcium sulfate, and collagen sponges impregnated with antibiotics. Non-implantable antibiotic delivery methods used irrigation with antibiotic solution into the breast pocket. All studies indicated that local antibiotic delivery was either comparable or superior to conventional methods in both the salvage and prophylaxis settings.Despite varied sample sizes and methodologies, all papers endorsed local antibiotic delivery as a safe, effective method of preventing or treating periprosthetic infections in breast reconstruction.

    View details for DOI 10.1002/bjs5.50324

    View details for PubMedID 37187864

    View details for PubMedCentralID PMC10176462

  • En Face to the World Commentary on En Face to the World. Academic medicine : journal of the Association of American Medical Colleges Makarewicz, N. 2023

    View details for DOI 10.1097/ACM.0000000000005213

    View details for PubMedID 36972130

  • Foot Burns and Diabetes: A Systematic Review of Current Clinical Studies and Proposal of a New Treatment Algorithm. Journal of burn care & research : official publication of the American Burn Association Sharma, A., Perrault, D., Makarewicz, N. S., Pham, T., Sheckter, C., Gurtner, G. 2023


    This study aims to systematically identify studies that evaluate lower extremity burn injury in the diabetic population, evaluate their clinical course and patient outcomes, and present a treatment algorithm tailored to diabetic burn patients. Our systematic review of the PubMed and Web of Science databases yielded 429 unique articles. After exclusion and inclusion criteria were applied, 59 articles were selected for evaluation. In diabetic patients, thermal injury was largely a result of decreased awareness and education regarding heat therapies in the context of peripheral neuropathy. All non-case studies found that metrics such as hospital length of stay, ICU admission rates, rates of comorbidity, complication rates, scald injuries, infection rates, and cost of treatment was significantly increased in the diabetic burn population as compared to their nondiabetic counterparts. Where infection was present, microorganisms colonizing diabetic burn wounds were different than those found in the burn wounds of immunocompetent individuals. Operative intervention including split-skin graft, amputation, and debridement were more often utilized in diabetic burn patients. Foot burns in diabetic patients pose unique clinical risks to patients, and as such need to be an alternate treatment protocol to reflect their pathology. Education and training programs are crucial in the prevention of diabetic foot burns to avoid complications, protracted healing, and adverse outcomes. A unique algorithm can guide the unique treatment of this clinical entity.

    View details for DOI 10.1093/jbcr/irad019

    View details for PubMedID 36786194

  • Use of Antibiotic-impregnated Polymethylmethacrylate (PMMA) Plates for Prevention of Periprosthetic Infection in Breast Reconstruction PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN Johnstone, T., Lipman, K., Makarewicz, N., Shah, J., Turner, E., Posternak, V., Chang, D., Thornton, B., Nazerali, R. 2023; 11 (1)
  • Use of Antibiotic-impregnated Polymethylmethacrylate (PMMA) Plates for Prevention of Periprosthetic Infection in Breast Reconstruction. Plastic and reconstructive surgery. Global open Johnstone, T., Lipman, K., Makarewicz, N., Shah, J., Turner, E., Posternak, V., Chang, D., Thornton, B., Nazerali, R. 2023; 11 (1): e4764


    Periprosthetic infections remain a major challenge for breast reconstruction. Local antibiotic delivery systems, such as antibiotic beads and spacers, have been widely used within other surgical fields, but their use within plastic surgery remains scarce. In this study, we demonstrate the use of antibiotic-impregnated polymethylmethacrylate (PMMA) plates for infection prophylaxis in tissue expander (TE)-based breast reconstruction.A retrospective review of patients who underwent immediate breast reconstruction with prepectoral TEs over the span of 5 years performed by two surgeons was completed, revealing a total of 447 patients. Data pertaining to patient demographics, operative details, and postoperative outcomes were recorded. Fifty patients underwent TE reconstruction with the addition of a PMMA plate (Stryker, Kalamazoo, Michigan) impregnated with tobramycin and vancomycin. Antibiotic plates were removed at the time of TE-to-implant exchange. Patient-matching analysis was performed using the 397 patients without PMMA plates to generate a 50-patient nonintervention cohort for statistical analysis.The intervention cohort (n = 50) and 1:1 patient-matched nonintervention cohort (n = 50) demonstrated no statistically significant differences in patient demographics or operative characteristics other than PMMA plate placement. The rate of operative periprosthetic infection was 4% in the intervention group and 14% in the nonintervention group (P = 0.047). The rate of TE explantation was also reduced in the intervention group (6% versus 18%; P = 0.036). Follow-up averaged 9.1 and 8.9 months for the intervention and nonintervention groups, respectively (P = 0.255).Local antibiotic delivery using antibiotic-impregnated PMMA plates can be safely and effectively used for infection prevention with TE-based breast reconstruction.

    View details for DOI 10.1097/GOX.0000000000004764

    View details for PubMedID 36776590

    View details for PubMedCentralID PMC9911200

  • The Impact of Oncoplastic Reduction on Initiation of Adjuvant Radiation and Need for Reexcision: A Database Evaluation. Annals of plastic surgery Shah, J. K., Lipman, K., Pedreira, R., Makarewicz, N., Nazerali, R. 2022; 89 (6): e11-e17


    INTRODUCTION: Partial breast reconstruction with oncoplastic reduction can provide breast cancer patients with improved aesthetic outcomes after breast conservation therapy. This study evaluates the implications of simultaneous oncoplastic reduction with lumpectomy on complication rates, time to adjuvant radiation therapy, and rates of margin reexcision compared with lumpectomy alone.METHODS: The Clinformatics Data Mart Database is a national deidentified commercial claims data warehouse. From 2003 to 2020, adult female patients were queried to identify patients with a breast cancer diagnosis with International Classification of Disease codes. Among those, current procedural terminology codes were used to identify those who underwent lumpectomy alone versus lumpectomy with oncoplastic reduction. Patient demographics, complications, adjuvant oncologic therapies, and need for reexcision were recorded. Patients not continuously enrolled for at least 6 months before and after the index procedure were excluded. Multivariable regression and chi 2 tests were used for statistical analysis.RESULTS: Of 53,165 patients meeting criteria (mean age, 61.4 ± 11.6 years), 1552 (2.9%) underwent oncoplastic reduction. Diagnoses of most nonsurgical complications (seroma, wound dehiscence, postoperative infection, fat necrosis, tissue necrosis, and nonspecified complications of surgical care) were significantly higher in the oncoplastic reduction group, as were rates of some surgical complications (hematoma, seroma, and tissue debridement). However, undergoing oncoplastic reduction did not impact time to adjuvant radiation ( P = 0.194) and protected against positive margins requiring repeat lumpectomy or completion mastectomy ( P < 0.001).CONCLUSIONS: In patients undergoing breast conservation therapy, simultaneous oncoplastic reduction decreased occurrence of positive margins and did not impact time to adjuvant radiation therapy despite increased rates of surgical and nonsurgical complications.

    View details for DOI 10.1097/SAP.0000000000003313

    View details for PubMedID 36416687

  • Maternal Exercise-Induced SOD3 Reverses the Deleterious Effects of Maternal High-Fat Diet on Offspring Metabolism Through Stabilization of H3K4me3 and Protection Against WDR82 Carbonylation DIABETES Kusuyama, J., Makarewicz, N. S., Albertson, B. G., Alves-Wagner, A., Conlin, R. H., Prince, N. B., Alves, C. R., Ramachandran, K., Kozuka, C., Xiudong, Y., Xia, Y., Hirshman, M. F., Hatta, T., Nagatomi, R., Nozik, E. S., Goodyear, L. J. 2022; 71 (6): 1170-1181


    Preclinical studies reveal maternal exercise as a promising intervention to reduce the transmission of multigenerational metabolic dysfunction caused by maternal obesity. The benefits of maternal exercise on offspring health may arise from multiple factors and have recently been shown to involve DNA demethylation of critical hepatic genes leading to enhanced glucose metabolism in offspring. Histone modification is another epigenetic regulator, yet the effects of maternal obesity and exercise on histone methylation in offspring are not known. Here, we find that maternal high-fat diet (HFD; 60% kcal from fat) induced dysregulation of offspring liver glucose metabolism in C57BL/6 mice through a mechanism involving increased reactive oxygen species, WD repeat-containing 82 (WDR82) carbonylation, and inactivation of histone H3 lysine 4 (H3K4) methyltransferase leading to decreased H3K4me3 at the promoters of glucose metabolic genes. Remarkably, the entire signal was restored if the HFD-fed dams had exercised during pregnancy. WDR82 overexpression in hepatoblasts mimicked the effects of maternal exercise on H3K4me3 levels. Placental superoxide dismutase 3 (SOD3), but not antioxidant treatment with N-acetylcysteine was necessary for the regulation of H3K4me3, gene expression, and glucose metabolism. Maternal exercise regulates a multicomponent epigenetic system in the fetal liver resulting in the transmission of the benefits of exercise to offspring.

    View details for DOI 10.2337/db21-0706

    View details for Web of Science ID 000905183300002

    View details for PubMedID 35290440

    View details for PubMedCentralID PMC9163554

  • Grandmaternal exercise improves metabolic health of second-generation offspring MOLECULAR METABOLISM Alves-Wagner, A. B., Kusuyama, J., Nigro, P., Ramachandran, K., Makarewicz, N., Hirshman, M. F., Goodyear, L. J. 2022; 60: 101490


    A major factor in the growing world-wide epidemic of obesity and type 2 diabetes is the increased risk of transmission of metabolic disease from obese mothers to both first (F1) and second (F2) generation offspring. Fortunately, recent pre-clinical studies demonstrate that exercise before and during pregnancy improves F1 metabolic health, providing a potential means to disrupt this cycle of disease. Whether the beneficial effects of maternal exercise can also be transmitted to the F2 generation has not been investigated.C57BL/6 female mice were fed a chow or high-fat diet (HFD) and housed in individual cages with or without running wheels for 2 wks before breeding and during gestation. Male F1 offspring were sedentary and chow-fed, and at 8-weeks of age were bred with age-matched females from untreated parents. This resulted in 4 F2 groups based on grandmaternal treatment: chow sedentary; chow trained; HFD sedentary; HFD trained. F2 were sedentary and chow-fed and studied up to 52-weeks of age.We find that grandmaternal exercise improves glucose tolerance and decreases fat mass in adult F2 males and females, in the absence of any treatment intervention of the F1 after birth. Grandmaternal exercise also improves F2 liver metabolic function, including favorable effects on gene and miRNA expression, triglyceride concentrations and hepatocyte glucose production.Grandmaternal exercise has beneficial effects on the metabolic health of grandoffspring, demonstrating an important means by which exercise during pregnancy could help reduce the worldwide incidence of obesity and type 2 diabetes.

    View details for DOI 10.1016/j.molmet.2022.101490

    View details for Web of Science ID 000793587800005

    View details for PubMedID 35398278

    View details for PubMedCentralID PMC9036117

  • Reinforced Biologic Mesh Reduces Postoperative Complications Compared to Biologic Mesh after Ventral Hernia Repair. Plastic and reconstructive surgery. Global open Sivaraj, D., Henn, D., Fischer, K. S., Kim, T. S., Black, C. K., Lin, J. Q., Barrera, J. A., Leeolou, M. C., Makarewicz, N. S., Chen, K., Perrault, D. P., Gurtner, G. C., Lee, G. K., Nazerali, R. 2022; 10 (2): e4083


    The use of biologic mesh to reinforce the abdominal wall in ventral hernia repair has been proposed as a viable alternative to synthetic mesh, particularly for high-risk patients and in contaminated settings. However, a comparison of clinical outcomes between the currently available biologic mesh types has yet to be performed.We performed a retrospective analysis of 141 patients who had undergone ventral hernia repair with biologic mesh, including noncross-linked porcine ADM (NC-PADM) (n = 51), cross-linked porcine ADM (C-PADM) (n = 17), reinforced biologic ovine rumen (RBOR) (n = 36), and bovine ADM (BADM) (n = 37) at the Stanford University Medical Center between 2002 and 2020. Postoperative donor site complications and rates of hernia recurrence were compared between patients with different biologic mesh types.Abdominal complications occurred in 47.1% of patients with NC-PADM, 52.9% of patients with C-PADM, 16.7% of patients with RBOR, and 43.2% of patients with BADM (P = 0.015). Relative risk for overall complications was higher in patients who had received NC-PADM (RR = 2.64, P = 0.0182), C-PADM (RR = 3.19, P = 0.0127), and BADM (RR = 2.11, P = 0.0773) compared with those who had received RBOR. Furthermore, relative risk for hernia recurrence was also higher in all other mesh types compared with RBOR.Our data indicate that RBOR decreases abdominal complications and recurrence rates after ventral hernia repair compared with NC-PADM, C-PADM, and BADM.

    View details for DOI 10.1097/GOX.0000000000004083

    View details for PubMedID 35141102

    View details for PubMedCentralID PMC8820910

  • Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue DIABETES Nigro, P., Middelbeek, R. W., Alves, C. R., Rovira-Llopis, S., Ramachandran, K., Rowland, L. A., Moller, A. B., Takahashi, H., Alves-Wagner, A. B., Vamvini, M., Makarewicz, N. S., Albertson, B. G., Hirshman, M. F., Goodyear, L. J. 2021; 70 (6): 1250-1264


    Recent studies demonstrate that adaptations to white adipose tissue (WAT) are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal WAT (iWAT) in male mice, including decreasing fat mass, improving mitochondrial function, inducing beiging, and stimulating the secretion of adipokines. In this study, we find that despite performing more voluntary wheel running compared with males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor coactivators is upregulated in iWAT from trained male mice and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex specificity also occurs in the secretome profile, as we identify cysteine-rich secretory protein 1 (Crisp1) as a novel adipokine that is only secreted from male iWAT in response to exercise. Crisp1 expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.

    View details for DOI 10.2337/db20-0790

    View details for Web of Science ID 000671940300007

    View details for PubMedID 33563587

    View details for PubMedCentralID PMC8275891

  • Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health CELL METABOLISM Kusuyama, J., Alves-Wagner, A., Conlin, R. H., Makarewicz, N. S., Albertson, B. G., Prince, N. B., Kobayashi, S., Kozuka, C., Moller, M., Bjerre, M., Fuglsang, J., Miele, E., Middelbeek, R. W., Xiudong, Y., Xia, Y., Garneau, L., Bhattacharjee, J., Aguer, C., Patti, M., Hirshman, M. F., Jessen, N., Hatta, T., Ovesen, P., Adamo, K. B., Nozik-Grayck, E., Goodyear, L. J. 2021; 33 (5): 939-+


    Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.

    View details for DOI 10.1016/j.cmet.2021.03.004

    View details for Web of Science ID 000647203900011

    View details for PubMedID 33770509

    View details for PubMedCentralID PMC8103776

  • Grand-Maternal Exercise Improves Glucose Tolerance in Second Generation Offspring Wagner, A. A., Kusuyama, J., Nigro, P., Makarewicz, N. S., Hirshman, M. F., Goodyear, L. J. AMER DIABETES ASSOC. 2020

    View details for DOI 10.2337/db20-695-P

    View details for Web of Science ID 000554509801443

  • Mechanism for the Beneficial Effects of Maternal Exercise to Improve Offspring Metabolic Health Kusuyama, J., Wagner, A. B., Conlin, R. H., Makarewicz, N. S., Moller, M., Miele, E. M., Middelbeek, R., Jessen, N., Ovesen, P. G., Hirshman, M. F., Adamo, K. B., Grayck, E. N., Goodyear, L. J. AMER DIABETES ASSOC. 2020

    View details for DOI 10.2337/db20-700-P

    View details for Web of Science ID 000554509801448