Browsing by Author "Kuchibhatla, Maragatha"

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    ItemOpen Access
    A Mitochondrial Progesterone Receptor Increases Cardiac Beta-Oxidation and Remodeling.
    (Journal of the Endocrine Society, 2019-02) Dai, Qunsheng; Likes, Creighton E; Luz, Anthony L; Mao, Lan; Yeh, Jason S; Wei, Zhengzheng; Kuchibhatla, Maragatha; Ilkayeva, Olga R; Koves, Timothy R; Price, Thomas M; Price, Thomas M
    Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear action. A previously identified mitochondrial progesterone receptor (PR-M) increases cellular respiration in cell models. In these studies, we demonstrated that expression of PR-M in rat H9c2 cardiomyocytes resulted in a ligand-dependent increase in oxidative cellular respiration and beta-oxidation. Cardiac expression in a TET-On transgenic mouse resulted in gene expression of myofibril proteins for remodeling and proteins involved in oxidative phosphorylation and fatty acid metabolism. In a model of increased afterload from constant transverse aortic constriction, mice expressing PR-M showed a ligand-dependent preservation of cardiac function. From these observations, we propose that PR-M is responsible for progesterone-induced increases in cellular energy production and cardiac remodeling to meet the physiological demands of pregnancy.
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    A population-based analysis on the use of therapeutic plasma exchange and intravenous immunoglobulin in heparin-induced thrombocytopenia.
    (Thrombosis research, 2021-05) Soares Ferreira Júnior, Alexandre; Boyle, Stephen H; Kuchibhatla, Maragatha; Onwuemene, Oluwatoyosi A

    Introduction

    In heparin-induced thrombocytopenia (HIT), selected patients are treated with therapies directed at the immune response, intravenous immunoglobulin (IVIG) and therapeutic plasma exchange (TPE). To determine IVIG and TPE characteristics and outcomes in HIT, we analyzed the National Inpatient Sample (NIS) database.

    Methods

    In a population-based analysis of the NIS, we identified hospital discharges of adult patients with a HIT diagnosis. A two-level statistical analysis was performed comparing cases as follows 1) IVIG or TPE vs. none; and 2) IVIG vs. TPE. For each analysis, the primary outcome was in-hospital mortality. Secondary outcomes were thrombotic events, major bleeding, infections, hospital length of stay, and total charges.

    Results

    Among 22,152 discharges with a HIT diagnosis, 77 (0.34%) and 52 (0.23%) received TPE and IVIG, respectively. In the first level analysis of TPE or IVIG vs. no treatment, TPE or IVIG treatment was associated with a higher likelihood of in-hospital mortality (OR = 1.85; 95%CI: 1.13-3.03, p = 0.0104), major bleeding (OR = 1.91; 95%CI: 1.25-2.93, p = 0.0030), gastrointestinal bleeding (OR = 1.89; 95%CI: 1.08-3.30, p = 0.0259), and infection (OR = 1.65; 95% CI:1.13-2.41, p = 0.0095). In the second-level analysis comparing IVIG vs. TPE, there were no significant differences in patient characteristics or outcomes in both unadjusted and adjusted analyses.

    Conclusions

    In this population-based analysis of HIT, we found similar outcomes of IVIG and TPE-treated cases. Given the small sample size, future studies are needed to confirm this observation.
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    Auditory-Perceptual Speech Features in Children With Down Syndrome.
    (American journal on intellectual and developmental disabilities, 2019-07) Jones, Harrison N; Crisp, Kelly D; Kuchibhatla, Maragatha; Mahler, Leslie; Risoli, Thomas; Jones, Carlee W; Kishnani, Priya
    Speech disorders occur commonly in individuals with Down syndrome (DS), although data regarding the auditory-perceptual speech features are limited. This descriptive study assessed 47 perceptual speech features during connected speech samples in 26 children with DS. The most severely affected speech features were: naturalness, imprecise consonants, hyponasality, speech rate, inappropriate silences, irregular vowels, prolonged intervals, overall loudness level, pitch level, aberrant oropharyngeal resonance, hoarse voice, reduced stress, and prolonged phonemes. These findings suggest that speech disorders in DS are due to distributed impairments involving voice, speech sound production, fluency, resonance, and prosody. These data contribute to the development of a profile of impairments in speakers with DS to guide future research and inform clinical assessment and treatment.
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    Bleeding is associated with intravenous immunoglobulin and therapeutic plasma exchange use in heparin-induced thrombocytopenia: A propensity matched analysis.
    (EJHaem, 2021-08) Soares Ferreira Júnior, Alexandre; Boyle, Stephen H; Kuchibhatla, Maragatha; Onwuemene, Oluwatoyosi A
    Intravenous immunoglobulin (IVIG) and therapeutic plasma exchange (TPE) are used in select cases with heparin-induced thrombocytopenia (HIT). In a cross-sectional analysis, a propensity matched sample was generated by IVIG or TPE treatment status to assess the primary outcome of mortality. In 500 HIT cases, IVIG or TPE was not associated with increased mortality (OR = 1.46; 95% CI: 0.81-2.63, p = 0.2052) but was associated with a higher likelihood of major bleeding (OR = 1.75; 95% CI: 1.03-2.96, p = 0.0376). The use of IVIG or TPE in HIT cases with bleeding contraindications to standard therapies should be further investigated.
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    Bleeding outcomes of inpatients receiving therapeutic plasma exchange: A propensity-matched analysis of the National Inpatient Sample.
    (Transfusion, 2022-02) Soares Ferreira Júnior, Alexandre; Boyle, Stephen H; Kuchibhatla, Maragatha; Onwuemene, Oluwatoyosi A

    Background

    Although therapeutic plasma exchange (TPE) is associated with hemostatic abnormalities, its impact on bleeding outcomes is unknown. Therefore, the main study objective was to determine bleeding outcomes of inpatients treated with TPE.

    Study design and methods

    In a cross-sectional analysis of the National Inpatient Sample (NIS), discharges were identified with 10 common TPE-treated conditions. A 1:3 propensity-matched analysis of TPE- to non-TPE-treated discharges was performed. The primary outcome was major bleeding and secondary outcomes were packed red blood cell (PRBC) transfusion, mortality, disposition, hospital length of stay (LOS), and charges. Multivariable regression analyses were used to examine the association between TPE and study outcomes.

    Results

    The study population was 15,964 discharges, of which 3991 were TPE- treated. The prevalence of major bleeding was low (5.4%). When compared to non-TPE discharges, TPE had a significant and positive association with major bleeding (OR = 1.37, 95% CI: 1.16-1.63, p = .0003). TPE was also associated with PRBC transfusion (OR = 1.66, 95% CI: 1.42-1.94, p < .0001), in-hospital mortality (OR = 1.45, 95% CI: 1.10-1.90, p = .0008), hospital length of stay (12.45 [95% CI: 11.95-12.97] vs. 7.38 [95% CI: 7.12-7.65] days, p < .0001) and total charges, ($125,123 [95% CI: $119,220-$131,317] vs. $61,953 [95% CI: $59,391-$64,625], p < .0001), and disposition to non-self-care (OR = 1.29, 95% CI: 1.19-1.39, p < .0001).

    Discussion

    The use of TPE in the inpatient setting is positively associated with bleeding; however, with low prevalence. Future studies should address risk factors that predispose patients to TPE-associated bleeding.
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    Central venous catheters are associated with thrombosis among adult inpatients undergoing therapeutic plasma exchange.
    (Journal of clinical apheresis, 2022-08) Soares Ferreira Júnior, Alexandre; Boyle, Stephen H; Kuchibhatla, Maragatha; Onwuemene, Oluwatoyosi A

    Background

    For inpatients undergoing therapeutic plasma exchange (TPE) in the United States, the primary mode of venous access is the central venous catheter (CVC). To evaluate the impact of CVC on thrombosis outcomes of patients undergoing TPE, we analyzed the National Inpatient Sample (NIS) database.

    Study design and methods

    In a cross-sectional analysis of the NIS, we identified hospital discharges of adult patients treated with TPE. Cases were classified into two groups based on CVC status. The primary outcome was thrombosis. Secondary outcomes were major bleeding, packed red blood cell (PRBC) transfusion, in-hospital mortality, hospital length of stay (LOS), and charges.

    Results

    Among 9863 TPE-treated discharges, CVC was used in 5988 (60%). These numbers correspond to weighted national estimates of 49 315 and 29 940, respectively. There was a positive and significant association between CVC and thrombosis (OR = 1.23, 95% 1.04-1.46, P = 0.0174), PRBC transfusion (OR = 1.15, 95% 1.03-1.29, P = 0.0121), in-hospital mortality (OR = 1.36, 95% 1.10-1.68, P = 0.0043), hospital LOS (15.63 vs 12.45 days, P < 0.0001) and hospital charges ($166 387 vs. $132 655, P < 0.0001).

    Conclusion

    In hospitalized patients undergoing TPE, CVC use is associated with increased rates of thrombosis. Future studies are needed to investigate strategies to decrease CVC use and/or prevent CVC-associated complications in TPE-treated inpatients.
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    Comparison of superior-level facet joint violations during open and percutaneous pedicle screw placement.
    (Neurosurgery, 2012-11) Babu, Ranjith; Park, Jong G; Mehta, Ankit I; Shan, Tony; Grossi, Peter M; Brown, Christopher R; Richardson, William J; Isaacs, Robert E; Bagley, Carlos A; Kuchibhatla, Maragatha; Gottfried, Oren N

    Background

    Superior-level facet joint violation by pedicle screws may result in increased stress to the level above the instrumentation and may contribute to adjacent segment disease. Previous studies have evaluated facet joint violations in open or percutaneous screw cases, but there are no reports describing a direct institutional comparison.

    Objective

    To compare the incidence of superior-level facet violation for open vs percutaneous pedicle screws and to evaluate patient and surgical factors that affect this outcome.

    Methods

    We reviewed 279 consecutive patients who underwent an index instrumented lumbar fusion from 2007 to 2011 for degenerative spine disease with stenosis with or without spondylolisthesis. We used a computed tomography grading system that represents progressively increasing grades of facet joint violation. Patient and surgical factors were evaluated to determine their impact on facet violation.

    Results

    Our cohort consisted of 126 open and 153 percutaneous cases. Percutaneous procedures had a higher overall violation grade (P = .02) and a greater incidence of high-grade violations (P = .006) compared with open procedures. Bivariate analysis showed significantly greater violations in percutaneous cases for age < 65 years, obesity, pedicle screws at L4, and 1- and 2-level surgeries. Multivariate analysis showed the percutaneous approach and depth of the spine to be independent risk factors for high-grade violations.

    Conclusion

    This study demonstrates greater facet violations for percutaneously placed pedicle screws compared with open screws.
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    Cultured thymus tissue implementation promotes donor-specific tolerance to allogeneic heart transplants.
    (JCI insight, 2020-04-30) Kwun, Jean; Li, Jie; Rouse, Clay; Park, Jae Berm; Farris, Alton B; Kuchibhatla, Maragatha; Turek, Joseph W; Knechtle, Stuart J; Kirk, Allan D; Markert, M Louise
    Eighty-six infants born without a thymus have been treated with allogeneic cultured thymus tissue implantation (CTTI). These infants, who lack T cells and are profoundly immunodeficient at birth, after CTTI from an unmatched donor develop genetically-recipient T cells that are tolerant to both their own major histocompatibility antigens and those of the donor. We tested use of CTTI with the goal of inducing tolerance to unmatched heart transplants in immunocompetent rats. We thymectomized and T cell depleted Lewis rats. The rats were then given Lewis x Dark Agouti (LWxDA) CTTI under the kidney capsule and vascularized DA heart transplants in the abdomen. Cyclosporine was administered for 4 months. The control group did not receive CTTI. Recipients with CTTI showed repopulation of naïve and recent thymic emigrant CD4 T cells; controls had none. Recipients of CTTI did not reject DA cardiac allografts. Control animals did not reject DA grafts, due to lack of functional T cells. To confirm donor-specific unresponsiveness, MHC-mismatched Brown Norway (BN) hearts were transplanted 6 months after the initial DA heart transplant. LW rats with (LWxDA) CTTI rejected the third-party BN hearts (mean survival time 10d; n=5). Controls did not (n=5). CTTI recipients produced antibody against third party BN donor but not against the DA thymus donor demonstrating humoral donor-specific tolerance. Taken together, F1(LWxDA) CTTI given to Lewis rats resulted in specific tolerance to the allogeneic DA MHC expressed in the donor thymus with resulting long-term survival of DA heart transplants after withdrawal of all immunosuppression.
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    Experience with intrawound vancomycin powder for spinal deformity surgery.
    (Spine, 2014-01) Martin, Joel R; Adogwa, Owoicho; Brown, Christopher R; Bagley, Carlos A; Richardson, William J; Lad, Shivanand P; Kuchibhatla, Maragatha; Gottfried, Oren N

    Study design

    Retrospective cohort study.

    Objective

    To evaluate the ability of local vancomycin powder to prevent deep wound infection after thoracolumbar and lumbar spinal fusion for open deformity cases.

    Summary of background data

    Recent studies report that local delivery of vancomycin powder is associated with a decrease in spinal surgical site infection (SSI). This study compares deformity fusion cases before and after the routine application of spinal vancomycin powder.

    Methods

    Posterior spinal deformity surgical procedures by a single institution were reviewed from January 2011 to April 2013. Routine application of vancomycin powder started in April 2012. Inclusion criteria included adult patients who underwent posterior fusion for deformity pathologies, including spondylolisthesis, kyphosis, sagittal imbalance, and scoliosis. Each cohort's baseline characteristics including infection risk factors, operative data, and rates of wound infection were compared. Associations between infection and vancomycin powder, with and without propensity score adjustment for risk factors were determined using logistic regression.

    Results

    A total of 306 patients were included in the study. All measured baseline and operative variables were statistically similar between untreated (n = 150) and those who received vancomycin powder (n = 156). No significant change in deep wound infection rate was seen between the control (5.3%) and intervention group (5.1%, P = 0.936). Logistic regression with and without propensity score adjusted for risk factors demonstrated that the use of vancomycin powder did not impact the development of SSI (odds ratio [95% confidence interval]: 1.01 [0.36-2.79], P = 0.9910) and (odds ratio [95% confidence interval]: 0.87 [0.31-2.42], P = 0.7876), respectively.

    Conclusion

    The local application of powdered vancomycin was not associated with a significant difference in the rate of deep SSI after spinal deformity surgery, and other treatment modalities are necessary to limit infection for this high-risk group. This study is in contrary to prior studies, which have reported a decrease in SSI with vancomycin powder.

    Level of evidence

    2.
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    ItemOpen Access
    Gastroesophageal Reflux Predicts Utilization of Dehydration Treatments After Bariatric Surgery.
    (Obesity surgery, 2021-02) Seymour, Keri A; Turner, Megan C; Kuchibhatla, Maragatha; Sudan, Ranjan

    Background

    Dehydration treatments (DT) provide intravenous fluids to patients in the outpatient setting; however, the utilization of DT is not well-described. We characterize the cohort receiving DT, the first year it was recorded in a bariatric-specific database.

    Setting

    A retrospective cohort analysis of patients undergoing bariatric surgery between January 1, 2016, and December 31, 2016, in 791 centers in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program data file.

    Methods

    Patients ≥ 18 years with a body mass index (BMI) ≥ 35 kg/m2 who underwent laparoscopic adjustable gastric band (LAGB), sleeve gastrectomy (LSG), Roux-en-Y gastric bypass (LRYGB), and biliopancreatic diversion with duodenal switch (LBPD/DS) were identified. Unadjusted and adjusted rates of DT were analyzed. In addition, adjusted rates and indication for readmission were reviewed.

    Results

    The overall rate of dehydration treatments was 3.5% for the 141,748 bariatric surgery cases identified. Patient comorbidities of gastroesophageal reflux (GERD) (odds ratio (OR) 1.49; 95% CI, 1.40-1.59), insulin-dependent diabetes (OR = 1.19; 95% CI, 1.07-1.33), and LRYGB (OR = 1.45; 95% CI, 1.36-1.54) were associated with higher odds of DT. DT only had the highest odds of readmission (OR = 6.22; 95% CI, 5.55-6.98) compared to other outpatient visits. Nausea and vomiting, or fluid, electrolyte, or nutritional depletion was the most common indication for readmission in all groups.

    Conclusions

    Patients with GERD utilized dehydration treatments after bariatric surgery. DT was highly associated with readmissions, and a better understanding of the clinical application of DT will allow bariatric centers to develop programs to further optimize outpatient treatments.
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    Ideal high sensitivity troponin baseline cutoff for patients with renal dysfunction.
    (The American journal of emergency medicine, 2022-06) Limkakeng, Alexander T; Hertz, Julian; Lerebours, Reginald; Kuchibhatla, Maragatha; McCord, James; Singer, Adam J; Apple, Fred S; Peacock, William F; Christenson, Robert H; Nowak, Richard M
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    Impact of Hearing Aid Use on Falls and Falls-Related Injury: Results From the Health and Retirement Study.
    (Ear and hearing, 2022-03) Riska, Kristal M; Peskoe, Sarah B; Kuchibhatla, Maragatha; Gordee, Alexander; Pavon, Juliessa M; Kim, Se Eun; West, Jessica S; Smith, Sherri L

    Objectives

    Falls are considered a significant public health issue and falls risk increases with age. There are many age-related physiologic changes that occur that increase postural instability and the risk for falls (i.e., age-related sensory declines in vision, vestibular, somatosensation, age-related orthopedic changes, and polypharmacy). Hearing loss has been shown to be an independent risk factor for falls. The primary objective of this study was to determine if hearing aid use modified (reduced) the association between self-reported hearing status and falls or falls-related injury. We hypothesized that hearing aid use would reduce the impact of hearing loss on the odds of falling and falls-related injury. If hearing aid users have reduced odds of falling compared with nonhearing aid users, then that would have an important implications for falls prevention healthcare.

    Design

    Data were drawn from the 2004-2016 surveys of the Health and Retirement Study (HRS). A generalized estimating equation approach was used to fit logistic regression models to determine whether or not hearing aid use modifies the odds of falling and falls injury associated with self-reported hearing status.

    Results

    A total of 17,923 individuals were grouped based on a self-reported history of falls. Self-reported hearing status was significantly associated with odds of falling and with falls-related injury when controlling for demographic factors and important health characteristics. Hearing aid use was included as an interaction in the fully-adjusted models and the results showed that there was no difference in the association between hearing aid users and nonusers for either falls or falls-related injury.

    Conclusions

    The results of the present study show that when examining self-reported hearing status in a longitudinal sample, hearing aid use does not impact the association between self-reported hearing status and the odds of falls or falls-related injury.
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    Impact of Kidney Function on Effects of the Dietary Approaches to Stop Hypertension (Dash) Diet.
    (J Hypertens (Los Angel)) Tyson, Crystal C; Kuchibhatla, Maragatha; Patel, Uptal D; Pun, Patrick H; Chang, Alex; Nwankwo, Chinazo; Joseph, Michael A; Svetkey, Laura P
    OBJECTIVES: Although the Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure in adults with hypertension, how kidney function impacts this effect is not known. We evaluated whether Estimated Glomerular Filtration Rate (eGFR) modifies the effect of the DASH diet on blood pressure, markers of mineral metabolism, and markers of kidney function. METHODS: Secondary analysis of the DASH-Sodium trial, a multicenter, randomized, controlled human feeding study that evaluated the blood pressure lowering effect of the DASH diet at three levels of sodium intake. Data from 92 participants with pre-hypertension or stage 1 hypertension during the 3450 mg /day sodium diet assignment contributed to this analysis. Stored frozen plasma and urine specimens were used to measure kidney related laboratory outcomes. RESULTS: Effects of the DASH diet on blood pressure, phosphorus, intact parathyroid hormone, creatinine, and albuminuria were not modified by baseline eGFR (mean 84.5 ± 18.0 ml/min/1.73 m(2), range 44.1 to 138.6 ml/min/1.73 m(2)) or the presence of chronic kidney disease (N=13%). CONCLUSIONS: The impact of the DASH diet on blood pressure, markers of mineral metabolism, and markers of kidney function does not appear to be modified by eGFR in this small subset of DASH-Sodium trial participants with relatively preserved kidney function. Whether greater reduction in eGFR modifies the effects of DASH on kidney related measures is yet to be determined. A larger study in individuals with more advanced kidney disease is needed to establish the efficacy and safety of the DASH diet in this patient population.
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    Opportunity Cost of Surgical Management of Craniomaxillofacial Trauma: A Longitudinal Study.
    (Craniomaxillofacial trauma & reconstruction, 2024-10) Issa, Khalil; Frisco, Nicholas A; Kilpatrick, Kayla W; Kuchibhatla, Maragatha; Barrett, Dane M; Powers, David B; Woodard, Charles R

    Study design

    Single-institution retrospective financial analysis.

    Objective

    Trauma care is consistently linked to inadequate reimbursement, posing a significant financial burden for large trauma centers. Data show that declining Medicare reimbursement rates have indirectly led to declining payment for all procedures covered by insurance. The goals of this study are to investigate the opportunity cost associated with contemporary surgical management of CMF trauma at our institution and to evaluate longitudinal financial trends.

    Methods

    Patients with operative facial fractures between 2015 and 2022 at Duke University Medical Center were included and compared to patients undergoing general otolaryngology, plastic surgery and oral surgery operations in the same period. Procedural codes, payor type, charges billed, collections, relative value units (RVUs) and other financial data were obtained and analyzed among the 2 patient populations. Comparative analysis was performed to assess the financial trends in data reported previously from 2007-2015.

    Results

    The collection rate at Duke University Medical Center for operatively managed CMF fractures remains significantly lower than non-CMF counterparts. Interestingly, the collection rate gap between CMF and non-CMF surgeries has narrowed when comparing to the data from 2007-2013. This is largely due to a decrease in collection rates for non-CMF procedures from 29.61% (2007-2013) to 26.57% (2015-2022) [P = 0.0001] and an increase in collection rates for CMF procedures from 17.25% (2007-2013) to 18.05% (2015-2022) [P = 0.0001].

    Conclusions

    Despite a slight improvement of the gap in reimbursement rates for CMF and non-CMF surgeries over the last several years, trauma care continues to have a negative financial impact on health care institutions.
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    Predictors of Stress-Delta High-Sensitivity Troponin T in Emergency Department Patients Undergoing Stress Testing.
    (Cureus, 2022-09) White, Emily J; Susman, Stephen J; Bouffler, Andrew; Leahy, J Clancy; Griffin, S Michelle; Christenson, Robert; Newby, L Kristin; Gordee, Alexander; Kuchibhatla, Maragatha; Limkakeng, Alexander T
    Background and objective Elevations in high-sensitivity troponin T (hs-TnT) are frequently observed following extreme physical exercise. In light of this, we sought to determine whether specific clinical characteristics are associated with this phenomenon in patients undergoing cardiac exercise tolerance testing (ETT). Methods We conducted a retrospective analysis of a prospectively collected biospecimen repository of 257 patients undergoing a stress echocardiogram for possible acute coronary syndrome (ACS). Ischemic electrocardiogram (ECG) changes during ETT and the presence or absence of ischemia on imaging were determined by a board-licensed cardiologist. N-terminal pro-brain natriuretic peptide (NT-proBNP) and hs-TnT assays were obtained immediately before and two hours following ETT. We developed linear regression models including several clinical characteristics to predict two-hour stress-delta hs-TnT. Variable selection was performed using the least absolute shrinkage and selection operator (LASSO). Results The mean age of the patients was 52 years [standard deviation (SD): 11.4]; 125 (48.6%) of them were men, and 88 (34.2%) were African-American. Twenty-two patients (8.6%) had ischemia evident on echocardiography, and 31 (12.1%) had ischemic ECG changes during exercise. The mean baseline hs-TnT was 5.6 ng/L (SD: 6.4) and the mean two-hour hs-TnT was 7.1 ng/L (SD: 10.2). Age and ischemic ECG changes were associated with two-hour stress-delta hs-TnT values. Conclusions Based on our findings, ischemic changes in stress ECG and age were associated with an increase in hs-TnT levels following exercise during a stress echo.
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    Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): A protocol for a sham-controlled clinical trial.
    (Molecular genetics and metabolism, 2019-08) Jones, Harrison N; Kuchibhatla, Maragatha; Crisp, Kelly D; Hobson Webb, Lisa D; Case, Laura; Batten, Milisa T; Marcus, Jill A; Kravitz, Richard M; Kishnani, Priya S

    Introduction

    Morbidity and mortality in adults with late-onset Pompe disease (LOPD) results primarily from persistent progressive respiratory muscle weakness despite treatment with enzyme replacement therapy (ERT). To address this need, we have developed a 12-week respiratory muscle training (RMT) program that provides calibrated, individualized, and progressive pressure-threshold resistance against inspiration and expiration. Our previous results suggest that our RMT regimen is safe, well-tolerated, and results in large increases in respiratory muscle strength. We now conduct an exploratory double-blind, randomized control trial (RCT) to determine: 1) utility and feasibility of sham-RMT as a control condition, 2) the clinically meaningful outcome measures for inclusion in a future efficacy trial. This manuscript provides comprehensive information regarding the design and methods used in our trial and will aid in the reporting and interpretation of our future findings.

    Methods

    Twenty-eight adults with LOPD will be randomized (1:1) in blocks of 4 to RMT (treatment) or sham-RMT (control). Assessments will be conducted at pretest, posttest, 3-months detraining, and 6-months detraining. The primary outcome is maximum inspiratory pressure (MIP). Secondary outcomes include maximum expiratory pressure (MEP), 6-min walk test (6MWT), Gait, Stairs, Gowers, and Chair test (GSGC), peak cough flow (PCF), and patient-reported life activity/social participation (Rasch-built Pompe-specific Activity scale [R-Pact]). Exploratory outcomes include quantitative measures from polysomnography; patient reported measures of fatigue, daytime sleepiness, and sleep quality; and ultrasound measures of diaphragm thickness. This research will use a novel tool to provide automated data collection and user feedback, and improve control over dose.

    Ethics and dissemination

    The results of this clinical trial will be promptly analyzed and submitted for publication. Results will also be made available on clinicaltrials.gov. ClinicalTrials.gov: NCT02801539, R21AR069880.
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    Respiratory muscle training in late-onset Pompe disease: Results of a sham-controlled clinical trial.
    (Neuromuscular disorders : NMD, 2020-11) Jones, Harrison N; Kuchibhatla, Maragatha; Crisp, Kelly D; Hobson-Webb, Lisa D; Case, Laura; Batten, Milisa T; Marcus, Jill A; Kravitz, Richard M; Kishnani, Priya S
    To address progressive respiratory muscle weakness in late-onset Pompe disease (LOPD), we developed a 12-week respiratory muscle training (RMT) program. In this exploratory, double-blind, randomized control trial, 22 adults with LOPD were randomized to RMT or sham-RMT. The primary outcome was maximum inspiratory pressure (MIP). Secondary and exploratory outcomes included maximum expiratory pressure (MEP), peak cough flow, diaphragm ultrasound, polysomnography, patient-reported outcomes, and measures of gross motor function. MIP increased 7.6 cmH2O (15.9) in the treatment group and 2.7 cmH2O (7.6) in the control group (P = 0.4670). MEP increased 14.0 cmH2O (25.9) in the treatment group and 0.0 cmH2O (12.0) in the control group (P = 0.1854). The only statistically significant differences in secondary/exploratory outcomes were improvements in time to climb 4 steps (P = 0.0346) and daytime sleepiness (P = 0.0160). The magnitude of changes in MIP and MEP in the treatment group were consistent with our pilot findings but did not achieve statistical significance in comparison to controls. Explanations for this include inadequate power and baseline differences in subject characteristics between groups. Additionally, control group subjects appeared to exhibit an active response to sham-RMT and therefore sham-RMT may not be an optimal control condition for RMT in LOPD.
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    Therapeutic plasma exchange for management of heparin-induced thrombocytopenia: Results of an international practice survey.
    (Journal of clinical apheresis, 2019-10) Onwuemene, Oluwatoyosi A; Zantek, Nicole D; Rollins-Raval, Marian A; Raval, Jay S; Kiss, Joseph E; Ipe, Tina S; Kuchibhatla, Maragatha; Pagano, Monica B; Wong, Edward CC
    INTRODUCTION:Anti-heparin/platelet factor 4 antibody immune complexes resulting from heparin-induced thrombocytopenia (HIT) are removed by therapeutic plasma exchange (TPE). We sought to define TPE in HIT practice patterns using an international survey. METHODS:A 31-item online survey was disseminated through the American Society for Apheresis. After institutional duplicate responses were eliminated, a descriptive analysis was performed. RESULTS:The survey was completed by 94 respondents from 78 institutions in 18 countries. Twenty-nine institutions (37%) used TPE for HIT (YES cohort) and 49 (63%) did not (NO cohort). Most NO respondents (65%) cited "no requests received" as the most common reason for not using TPE. Of the 29 YES respondents, 10 (34%) gave incomplete information and were excluded from the final analysis, leaving 19 responses. Of these, 18 (95%) treated ≤10 HIT patients over a 2-year period. The most common indications were cardiovascular surgery (CS; 63%) and HIT-associated thrombosis (HT; 26%). The typical plasma volume processed was 1.0 (63% CS and 58% HT). For CS, the typical replacement fluid was plasma (42%) and for HT, it was determined on an individual basis (32%). For CS, patients were treated with a set number of TPE procedures (37%) or laboratory/clinical response (37%). For HT, the number of TPE procedures typically depended on laboratory/clinical response (42%). CONCLUSION:In a minority of responding institutions, TPE is most commonly used in HIT to prophylactically treat patients who will undergo heparin re-exposure during CS. Prospective studies are needed to more clearly define the role of TPE in HIT.
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    Tongue weakness and atrophy differentiates late-onset Pompe disease from other forms of acquired/hereditary myopathy.
    (Molecular genetics and metabolism, 2021-07) Jones, Harrison N; Hobson-Webb, Lisa D; Kuchibhatla, Maragatha; Crisp, Kelly D; Whyte-Rayson, Ashley; Batten, Milisa T; Zwelling, Paul J; Kishnani, Priya S
    Late-onset Pompe disease (LOPD) is an inherited autosomal recessive progressive metabolic myopathy that presents in the first year of life to adulthood. Clinical presentation is heterogeneous, differential diagnosis is challenging, and diagnostic delay is common. One challenge to differential diagnosis is the overlap of clinical features with those encountered in other forms of acquired/hereditary myopathy. Tongue weakness and imaging abnormalities are increasingly recognized in LOPD. In order to explore the diagnostic potential of tongue involvement in LOPD, we assessed tongue structure and function in 70 subjects, including 10 with LOPD naive to treatment, 30 with other acquired/hereditary myopathy, and 30 controls with neuropathy. Tongue strength was assessed with both manual and quantitative muscle testing. Ultrasound (US) was used to assess tongue overall appearance, echointensity, and thickness. Differences in tongue strength, qualitative appearance, echointensity, and thickness between LOPD subjects and neuropathic controls were statistically significant. Greater tongue involvement was observed in LOPD subjects compared to those with other acquired/hereditary myopathies, based on statistically significant decreases in quantitative tongue strength and sonographic muscle thickness. These findings provide additional evidence for tongue involvement in LOPD characterized by weakness and sonographic abnormalities suggestive of fibrofatty replacement and atrophy. Findings of quantitative tongue weakness and/or atrophy may aid differentiation of LOPD from other acquired/hereditary myopathies. Additionally, our experiences in this study reveal US to be an effective, efficient imaging modality to allow quantitative assessment of the lingual musculature at the point of care.
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    ItemOpen Access
    Use of therapeutic plasma exchange in heparin-induced thrombocytopenia: A population-based study.
    (Journal of clinical apheresis, 2021-06) Soares Ferreira Júnior, Alexandre; Boyle, Stephen H; Kuchibhatla, Maragatha; Akinyemiju, Tomi; Onwuemene, Oluwatoyosi A

    Background

    Heparin-induced thrombocytopenia (HIT) is characterized by anti-heparin/platelet factor 4 immune complexes, which are removed by therapeutic plasma exchange (TPE). Our main objective was to study TPE outcomes in HIT using a large administrative claims database.

    Study design and methods

    We used the National Inpatient Sample (NIS) to identify hospital discharges of adult patients (≥18) with a primary or secondary diagnosis of HIT. Cases were classified into two groups based on TPE use. The primary outcome was in-hospital mortality. Secondary outcomes were thrombotic events, major bleeding, hospital length of stay (LOS), and charges. Multivariable regression analysis, controlling for age and medical comorbidities, was used to examine the association of TPE with study outcomes.

    Results

    A HIT diagnosis was made in 22 165 discharges, of which 90 (0.4%) received TPE. Corresponding national estimates are 106 435 and 439, respectively. TPE was not associated with decreased in-hospital mortality (OR = 1.72; 95%CI: 0.93-3.17, P = .085). However, TPE was associated with a higher likelihood of major bleeding (OR = 2.35; 95%CI: 1.40-3.68, P = .0009), primarily driven by gastrointestinal bleeding (OR = 2.21; 95%CI: 1.17-4.17, P = .015). TPE was also associated with higher hospital LOS (20.5 vs 10 day, P < .0001) and charges (USD 211181 vs USD 81654, P < .0001).

    Conclusion

    TPE's association with increased bleeding and a prolonged hospital course indicates that it is being used in HIT cases with a severe clinical phenotype. Future studies are needed to better characterize the HIT phenotype that will most benefit from TPE.