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   Table of Contents - Current issue
Coverpage
January-March 2021
Volume 33 | Issue 1
Page Nos. 1-99

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REVIEW ARTICLE - BASIC  

Modulation of microglia activation and Alzheimer's disease: CX3 chemokine ligand 1/CX3CR and P2X7R signaling p. 1
Pavithra Suresh, Sarayut Phasuk, Ingrid Y Liu
DOI:10.4103/tcmj.tcmj_144_20  
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive deficits. Two hallmarks of AD that cause chronic inflammation and lead to neuronal dysfunction and damage are tau tangles and amyloid plaques. Microglial cells, the primary immune cells of the central nervous system, maintain a homeostatic active/inactive state via a bidirectional, dynamic communication with neurons. Several studies have revealed that dysregulated microglial activation leads to AD pathology. Therefore, we reviewed the relationship between AD and two important signaling complexes, CX3 chemokine ligand 1 (CX3CL1)/CX3CR1 and ATP/P2X7R, that play critical roles in the regulation of microglial activation. CX3CL1/CX3CR1 is one important signaling which controls the microglia function. Altering this pathway can have opposite effects on amyloid and tau pathology in AD. Another important molecule is P2X7R which involves in the activation of microglia. Over activation of P2X7R is evident in AD pathogenesis. In this review, we discuss influence of the two signaling pathways at different stages of AD pathology as well as the drug candidates that can modulate CX3CL1/CX3CR1 and ATP/P2X7R.
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REVIEW ARTICLES - CLINICAL Top

Antiviral drugs against severe acute respiratory syndrome coronavirus 2 infection triggering the coronavirus disease-19 pandemic p. 7
Rashed Noor
DOI:10.4103/tcmj.tcmj_100_20  
So far, lots of analyses have been conducted to invent the appropriate therapeutic targets for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The category and the strategies for treating the virus are described in this review together with mentioning some specific drugs. Of them, saikosaponin possesses affinity of the drug toward nonstructural protein 15 and the spike glycoprotein of the SARS-CoV-2. The nucleotide inhibitors such as sofosbuvir, ribavirin, galidesivir, remdesivir, favipiravir, cefuroxime, tenofovir, and hydroxychloroquine (HCHL), setrobuvir, YAK, and IDX-184 were found to be effective in binding to SARS-CoV-2 RNA-dependent RNA polymerase. From the antimalarial and anti-inflammatory category, chloroquine and its derivative HCHL have already been approved by the U.S. Food and Drug Administration for emergency treatment of SARS-CoV-2 infection. The other drugs such as favipiravir and lopinavir/ritonavir under the antiviral category, the angiotensin-converting enzyme 2 (the renin-angiotensin system inhibitors), remdesivir (RNA polymerase inhibitor) from antiviral category, cepharanthine from anti-inflammatory category, etc., have been pointed based on the previous literature published. Besides, the assessment of the drug repositioning candidates with the related targets is also significant for the viral mitigation.
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Recurrent urinary tract infection in women and overactive bladder – Is there a relationship? p. 13
Qian-Sheng Ke, Cheng-Ling Lee, Hann-Chorng Kuo
DOI:10.4103/tcmj.tcmj_38_20  
Overactive bladder (OAB) in women has similar symptomatology with other common urologic diseases such as recurrent urinary tract infection (UTI). Recent evidence showed that chronic low-grade bacterial bladder colonization might exacerbate OAB symptoms and could be the etiology of recurrent UTI. The high prevalence of lower urinary tract dysfunction is associated with OAB. Women with urgency urinary incontinence refractory to antimuscarinic therapy had more bacteria and a more diverse urinary microbiome. The bacterial reside in the superficial urothelial cells to form intracellular bacterial community and outbreak when the host innate immunity is low. Women with recurrent UTI are found to have highly prevalent voiding dysfunction and detrusor overactivity. These functional abnormalities will further damage the urothelial barrier integrity and create vulnerable to uropathogen invasion. The defective urinary microbiota is less common in women with recurrent UTI, suggesting that the normal flora in the urine might inhibit uropathogen growth and invasion. The defective urothelial barrier function, deficient basal proliferation, and deficient maturation might be owing to chronic suburothelial inflammation, resulting in activation of sensory nerves (causing OAB) and failure elimination of intracellular bacterial communities (causing recurrent UTI). Precision diagnosis and multidisciplinary treatment of the underlying pathophysiology of OAB and recurrent UTI is necessary.
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Updates on the diagnosis and management of multicentric Castleman disease p. 22
Ya-Ju Wu, Kuei-Ying Su
DOI:10.4103/tcmj.tcmj_15_20  
Multicentric Castleman disease (MCD) is an uncommon systemic lymphoproliferative disease. The diagnosis of this disease is typically challenging and requires collaboration between clinicians and pathologists. Moreover, it is important to exclude other diseases (such as malignancies, autoimmune diseases, and infectious diseases) that have similar clinical manifestations and pathological findings. Patients with untreated severe MCD have high mortality due to devastating cytokine storms. Thus, early diagnosis and prompt treatment is a key imperative. The diagnosis of MCD is based on the clinical signs of systemic inflammation, serological tests, and typical pathological features. In this review article, we provide an overview of MCD with a focus on the emerging evidence pertaining to its diagnosis and treatment.
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Spinal cord stimulation for spinal cord injury patients with paralysis: To regain walking and dignity p. 29
Sheng-Tzung Tsai, Yu-Chen Chen, Hung-Yu Cheng, Chun-Hsiang Lin, Huan-Chen Lin, Chich-Haung Yang, Chung-Chao Liang, Shin-Yuan Chen
DOI:10.4103/tcmj.tcmj_53_20  
Spinal cord injury (SCI) usually leads to disconnection between traversing neuronal pathway. The impairment of neural circuitry and its ascending and descending pathway usually leave severe SCI patients with both motor disability and loss of sensory function. In addition to poor quality of life, SCI patients not only have disabling respiratory function, urinary retention, impaired sexual function, autonomic dysregulation but also medical refractory neuropathic pain in the long term. Some translational studies demonstrated that spinal networks possess a dynamic state of synaptic connection and excitability that can be facilitated by epidural spinal cord stimulation. In addition, preliminary human studies also confirmed that spinal cord stimulation enables stepping or standing in individuals with paraplegia as well. In this review, we examined the plausible interventional mechanisms underlying the effects of epidural spinal cord stimulation in animal studies. Following the success of translational research, chronic paralyzed subjects due to SCI, defined as motor complete status, regained their voluntary control and function of overground walking and even stepping for some. These progresses lead us into a new hope to help SCI patients to walk and regain their independent life again.
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Vascular calcification of chronic kidney disease: A brief review p. 34
Bang-Gee Hsu, Jen-Pi Tsai
DOI:10.4103/tcmj.tcmj_36_20  
Vascular calcification (VC) is highly prevalent among patients with chronic kidney disease (CKD). There is growing evidence that there is more underlying this condition than the histological presentation of atherosclerotic plaque and arteriosclerosis and that the risk of cardiovascular disease in the context of CKD might be explained by the presence of VC. While VC has been observed in the absence of overt abnormal mineral metabolism, this association is coupled to abnormal homeostasis of minerals in patients with CKD, due to hyperphosphatemia and hypercalcemia. Furthermore, recent studies have shown that the differentiation of vascular smooth muscle cells into an osteogenic phenotype is highly regulated by pro-calcifying and anti-calcifying factors. There are several imaging modalities currently used in clinical practice to evaluate the extent and severity of VC; each has different advantages and limitations. Although there is no universally accepted method for the treatment of VC, there is growing evidence of the beneficial effects of medical therapy for the condition. This study discusses the mechanism underlying VC, imaging modalities used for evaluation of the condition, and possible treatments.
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ORIGINAL ARTICLE - BASIC RESEARCH Top

Effects of different electrodes used in bone-guided extracochlear implants on electrical stimulation of auditory nerves in guinea pigs p. 42
Chien-Hao Liu, Yung-Shan Lu, Po-Chun Chen, Chia-Fone Lee
DOI:10.4103/tcmj.tcmj_46_20  
Objective: Conventional cochlear implants provide patients who are deaf with hearing via electrical intracochlear stimulations. Stimulation electrodes are inserted into the cochlea through a cochleostomy or round window membrane (RWM) approach. However, these methods might induce cochlear ossificans and loss of residual hearing by damaging inner ear structures. To avoid an invasive electrode insertion, we developed a novel bone-guided extracochlear implant that stimulated the auditory nerves between the cochlear bones and the RWM to prevent cochlea damage. Power consumption plays an important role in wireless implantable electronic devices. Therefore, we aimed to investigate the effects of different electrodes on the stimulating threshold currents of the auditory nerve and the power consumption of bone-guided extracochlear implants using a commercial stimulator. Materials and Methods: Inert aurum (Au) electrodes were compared with biocompatible platinum (Pt) and iridium oxide (IrOx) electrodes in practical implantable applications. IrOxelectrodes were used for their high-charge storage capacity, low impedance, and biocompatibility. The electrodes were fabricated via sputtering and were experimentally characterized with cyclic voltammetry and then examined using in vivo tests. Results: Based on electrical auditory brainstem responses, IrOxelectrodes yielded lower acoustic nerve-stimulating threshold currents (132 μA) compared with Au electrodes (204 μA). IrOxelectrodes also had a lower acoustic nerve stimulating threshold current (132 μA) compared with Pt electrodes (168 μA). Conclusion: As expected, IrOxelectrodes were beneficial in the development of multielectrode bone-guided extracochlear implants, with the lowest acoustic nerve-stimulating threshold and current consumptions compared with Au and Pt electrodes.
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ORIGINAL ARTICLES - CLINICAL RESEARCH Top

Prevalence and predictors of low bone mineral density in treatment-naive HIV-infected patients and its correlation with CD4 cell counts p. 49
Pulin Kumar Gupta, Sanchit Singh, Subodh Kumar Mahto, Ankita Sheoran, Umesh Chand Garga, Ashok Kumar Lal, Piyush Jain, Sujata Elizabeth Mathews
DOI:10.4103/tcmj.tcmj_177_19  
Objective: HIV virtually affects every organ system of the body. The skeletal system is no exception, and antiretroviral therapy (ART) has been implicated in bone diseases. However, not many studies have been done to evaluate bone disease in treatment (ART) naive HIV-infected patients, and hence, the present study was executed. Materials and Methods: One hundred and twenty HIV-infected ART-naive patients and 80 age- and sex-matched healthy controls were recruited for this study. A thorough history and physical examination was done followed by laboratory investigations after an overnight fasting. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry scan at the level of lumbar spine, femur, and forearm. Results: Of 120 ART-naive HIV-infected cases, the prevalence of osteoporosis and osteopenia was 13% and 41%, respectively, as compared to 0% and 17.5% in controls (P < 0.001). The mean BMD in cases was 0.842 g/cm2 which was approximately 25% lesser than that in controls. Hypovitaminosis-D was seen in 100% of cases as compared to 65% of controls (P < 0.01). A significant association of low BMD was seen with HIV-infection per se (P < 0.001), low CD4 cell counts (P < 0.001), low Vitamin D levels (P < 0.001), long duration of disease (P < 0.04), history of opportunistic infections (P < 0.03), and history of tuberculosis in the past (P < 0.05). Conclusion: Bone diseases such as osteoporosis and osteopenia characterized by low BMD are very common in HIV-infected patients. Virus per se, along with low CD4 cell counts and low Vitamin D levels are major predictors of pathological fractures in these individuals.
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Androgen deprivation therapy and the risk of subsequent keratitis p. 55
Dai-Wei Liu, Ren-Jun Hsu, Sheng-Yao Huang, Yen-Hsiang Liao, Chen-Ta Wu, Wen-Lin Hsu
DOI:10.4103/tcmj.tcmj_31_20  
Objectives: The objective of the study was to determine the risk of subsequent keratitis in prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT). Materials and Methods: Three thousand three hundred and nine patients with PCa were identified using data from Taiwan’s National Health Insurance Research Database for 2001 through 2013. Among those patients, 856 treated with ADT comprised the study group, while 856 non-ADT-treated patients matched with 1:1 propensity-score-matched analysis comprised the control group. The demographic characteristics and comorbidities of all the patients were analyzed, and Cox proportional hazards regression was utilized to determine the hazard ratios (HRs) for subsequent keratitis. Results: A total of 157 (9.2%) patients had newly diagnosed keratitis. Compared to the non-ADT-treated patients, the ADT-treated patients had a reduced risk of subsequent keratitis, with an adjusted HR of 0.38 (95% confidence interval: 0.27–0.55; P < 0.001). Conclusion: ADT treatment apparently decreased the risk of subsequent keratitis in the investigated PCa patients, but the clinical significance of this finding should be further assessed in additional studies.
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Multiparametric positron emission tomography/magnetic resonance imaging in nasopharyngeal carcinoma: Correlations between magnetic resonance imaging functional parameters and18F-fluorodeoxyglucose positron emission tomography imaging biomarkers and their predictive value for treatment failure p. 61
Sheng-Chieh Chan, Shu-Hang Ng, Chih-Hua Yeh, Kai-Ping Chang
DOI:10.4103/tcmj.tcmj_4_20  
Objectives: The clinical significance of positron emission tomography/magnetic resonance imaging (PET/MRI) functional parameters in nasopharyngealcarcinoma (NPC) remains unclear. The purpose of this prospective study was two-fold: (1) to investigate the associations between simultaneously acquired PET/MRI perfusion, diffusion, and glucose metabolism parameters in patients with NPC and (2) to analyze their predictive value with respect to treatment failure. Materials and Methods: We enrolled 85 patients with primary NPC who simultaneously underwent18F-fluorodeoxyglucose PET/CT and PET/MRI before definitive treatment. The following variables were determined: (1) functional parameters from the MRI component, including perfusion values (Ktrans,kep,ve, and initial area under the enhancement curve) and apparent diffusion coefficient (ADC) values, and (2) PET parameters, including metabolic tumor volume (MTV). The reciprocal interrelationships between these parameters and their correlations with treatment failure were examined. Results: We observed significant negative associations between Ktransand ADC (r = −0.215, P = 0.049) as well as between veand ADC (r = −0.22, P = 0.04). Correlations between PET and MRI functional parameters were not statistically significant. Treatment failures were observed in 21.2% of patients without distant metastases. Multivariate analysis identified ve as a significant independent predictor for treatment failure (P = 0.022), whereas MTV showed a borderline significance (P = 0.095). Patients in whom both veand MTV values were increased had a significantly higher rate of treatment failure (62.5%) than those with either one (21.9%) or no (7.7%) increased parameter (P = 0.004). Conclusion: Correlation analyses revealed complex interrelationships among PET and MRI indices measured in patients with NPC. These parameters may have a complementary role in predicting treatment failure in this clinical setting.
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Postpartum depression burden and associated factors in mothers of infants at an urban primary health center in Delhi, India p. 70
Saurav Basu, Nidhi Budh, Suneela Garg, Mongjam Meghachandra Singh, Akashdeep Sharma
DOI:10.4103/tcmj.tcmj_190_19  
Objective: Postpartum depression is a nonpsychotic mental health condition that impairs both the immediate and long-term health of both the mother and her child. Materials and Methods: We conducted a cross-sectional study from January to June 2019 at a primary care clinic in Delhi, India, to estimate the burden of postpartum depression in women having an infant child. The Hindi version of the Edinburgh Postnatal Depression Scale was used to screen for the depression in the participants. Data were analyzed with IBM SPSS software version 25. P <0.05 was considered statistically significant. Results: A total of 210 women were screened, and 61 (29%) were detected with postpartum depression. On multivariate analysis, women reporting low and medium levels of perceived social support had significantly higher odds of having postpartum depression. However, depressive symptoms were not associated with the sex and age of the infant or even the sex composition of the women's other children. Conclusion: Postpartum depression represents a major public health challenge in India. Regular, mandatory screening for postpartum depression is needed at primary health facilities in resource-constrained settings for an extended period postchildbirth.
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Elevated serum leptin levels are associated with low muscle strength and muscle quality in male patients undergoing chronic hemodialysis p. 74
Bang-Gee Hsu, Chih-Hsien Wang, Yu-Hsien Lai, Chiu-Huang Kuo, Yu-Li Lin
DOI:10.4103/tcmj.tcmj_20_20  
Objectives: Low muscle strength and poor muscle quality are highly prevalent in patients with chronic hemodialysis (HD), which lead to an increased risk of poor clinical outcomes. Leptin dysregulation is common in HD patients. Given that leptin receptors are abundant in skeletal muscle, there may be a link between leptin and muscle strength. The cross-sectional study aimed to explore the correlation of serum leptin levels with muscle strength and muscle quality in patients with chronic HD. Materials and Methods: A total of 118 chronic HD patients were included in this study. Basic characteristics, handgrip strength, body composition were assessed, and blood samples for serum leptin levels and other biochemical test were obtained. We defined skeletal muscle index (SMI) as skeletal muscle mass/height2 (kg/m2) and muscle quality as handgrip strength divided by mid-arm muscle circumference (MAMC). Patients were classified into tertile groups, according to sex-specific leptin levels. Results: We observed that patients in the higher leptin tertile tend to have a higher body weight, body mass index (BMI), body fat mass, MAMC, and SMI, while the handgrip strength and muscle quality were significantly lower. Bodyweight (r = 0.30; P = 0.001), BMI (r = 0.45; P = 0.001), body fat mass (r = 0.57;P < 0.001), and SMI (r = 0.22; P = 0.018) were positively and handgrip strength (r = −0.27; P = 0.003) and muscle quality (r = −0.35;P < 0.001) were negatively correlated with serum leptin levels, respectively. After adjusting multiple confounding factors, logarithmically transformed serum leptin levels were independently associated with handgrip strength (β = −3.29, P = 0.005) and muscle quality (β = −0.14, P = 0.009). However, gender-stratified models showed the associations were observed only in male, but not in female. Conclusion: We concluded that higher serum leptin levels are associated with low handgrip strength and poor muscle quality in male patients on chronic HD. Further studies are needed to clarify the gender differences and to evaluate the casual relationship between circulating leptin levels and muscle strength.
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Vitamin D, C-reactive protein, and oxidative stress markers in chronic obstructive pulmonary disease p. 80
Sarika Pandey, Rajiv Garg, Surya Kant, Priyanka Gaur
DOI:10.4103/tcmj.tcmj_198_19  
Objective: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Systemic inflammation and oxidant/antioxidant imbalance has been seen to play a key role in pathogenesis of COPD. The present study investigated the levels of inflammatory and antioxidant/oxidative stress biomarker in COPD patients and healthy subjects. Materials and Methods: The present study enrolled seventy COPD patients and seventy healthy controls from Department of Respiratory Medicine at a tertiary care hospital. Vitamin D, C-reactive protein (CRP), superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) levels were measured in both cases and control. GraphPad PRISM version 6.01 was used for analysis of data. Results: The levels of Vitamin D, SOD, Catalase, were found to be significantly lower among the COPD patients in comparison to healthy controls while levels of MDA and CRP were significantly higher (P = 0.0001). Conclusion: The results showed oxidant/antioxidant imbalance and Vitamin D deficiency in COPD patients. Higher levels of CRP and oxidative stress markers were observed in COPD patients in comparison to healthy controls. A biomarker based study testing the efficacy of novel antioxidant or other agents will be helpful that can modify the course of this disease.
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The workload of obstetric doctors working in different modes at a medical center p. 87
I-Min Su, Dah-Ching Ding
DOI:10.4103/tcmj.tcmj_41_20  
Objective: The workload of obstetric and gynecologic (OB-GYN) physicians has been an unprecedented increase because of the decrease in the number of such physicians. This study aimed to demonstrate that the hospitalist mode was the best mode for the work-life balance of OB-GYN physicians. Materials and Methods: This was a retrospective study in a tertiary academic hospital. Patients were admitted to the labor ward for delivery. The number of deliveries performed by each OB-GYN physician in different working modes was measured. We reviewed the medical charts of women admitted for delivery as well as the shift schedule of OB-GYN physicians from January 1, 2018, to June 30, 2018. We classified deliveries into three modes: the traditional mode (patient designation), on-call mode, and the hospitalist mode. Traditional mode was the work mode currently. On-call mode and the hospitalist mode were simulated conditions. The number of deliveries and the total OB-GYN physician worked time for their shift were recorded. The differences between the three modes and between OB-GYN physicians were assessed using analysis of variance. Results: In total, 237 deliveries were recorded over 6 months (3 deliveries were excluded from our data); these deliveries were performed by four OB-GYN physicians named A to D. Significant differences in workload were noted between OB-GYN physicians working in the traditional mode and those in the on-call mode, but no significant differences were noted among those working in the hospitalist mode. All OB-GYN physicians worked an average of seven shifts, and no significant differences among them were noted. Conclusion: The hospitalist mode might be the optimal mode for OB-GYN physicians to achieve a favorable work-life balance if their original main jobs are obstetric practice.
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CASE REPORTS Top

Noninvasive ventilator prevents intubation in thyrotoxic hypokalemic periodic paralysis-associated respiratory failure: A case report and literature review p. 91
Shu-Ya Hung, Wen-Jing Liu, Pei-Chan Wu, Mei-Chen Yang, Yao-Kuang Wu, Chou-Chin Lan
DOI:10.4103/tcmj.tcmj_248_19  
Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism, often presents with limb muscle paralysis, hypokalemia with elevated-free T3, T4, and low thyroid-stimulating hormone (TSH). We herein reported an unusual presentation of TPP with acute hypercapnic respiratory failure. A 28-year-old female had complaints of nausea and vomiting. Laboratory investigations showed a serum potassium level of 1.2 mEq/L. Thyroid function test revealed the TSH level of 0.021 μlU/mL and free T4 at 2.01 ng/dL. She suddenly suffered from dyspnea and drowsiness. Acute hypercapnic respiratory failure with CO2retention was found. Noninvasive ventilation was used. Rapid correction of hypokalemia and administration of propylthiouracil, propranolol, and 5% Lugol's solution were performed. After the normalization of potassium levels, the patient's respiratory pattern stabilized and noninvasive ventilator (NIV) use was discontinued. Respiratory failure is an unusual but lethal complication of TPP. Rapid correction of hypokalemia and temporarily NIV can successfully avoid endotracheal intubation for respiratory failure.
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IMAGES IN CLINICAL MEDICINE Top

Idiopathic intracranial calcification p. 96
Kalyan Mansukhbhai Shekhda, Paul Tobin, Surendra Kumar Gupta, PS Sridhar
DOI:10.4103/tcmj.tcmj_127_20  
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LETTER TO THE EDITOR Top

Research publications during public health emergencies p. 98
Malcolm Koo
DOI:10.4103/tcmj.tcmj_40_20  
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