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   Table of Contents - Current issue
October-December 2021
Volume 33 | Issue 4
Page Nos. 317-420

Online since Monday, September 27, 2021

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Indocyanine green: An old drug with novel applications p. 317
Chia-Hung Lu, Jong-Kai Hsiao
Indocyanine green (ICG), a US Food and Drug Administration-approved fluorescent compound, has been on the medical stage for more than 60 years. Current uses include hepatic function evaluation before surgical procedure and fundus evaluation. The large safety margin and near-infrared fluorescent optical advantage of the drug have proved useful in several clinical trials of intraoperative systems for tumor removal. Several nanoparticle-sized formulations for thermal ablation and photodynamic therapy have also been evaluated in animal experiments. Studies have attempted to manipulate ICG as a reporter fluorophore with initial success. In this article, we reviewed ICG's histological applications, chemical and physical properties, current clinical applications, ongoing clinical trials, and biomedical studies and prospects. We believe that ICG could be used with novel biotechnological techniques, such as fluorescent endoscopy and photoacoustic equipment, in a range of biomedical fields.
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The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia p. 323
Ding-Jyun Lin, Wen-Sen Lee, Yu-Chung Chien, Tsung-Yu Chen, Kun-Ta Yang
Catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare autosomal dominant or recessive disease, usually results in syncope or sudden cardiac death. Most CPVT patients do not show abnormal cardiac structure and electrocardiogram features and symptoms, usually onset during adrenergically mediated physiological conditions. CPVT tends to occur at a younger age and is not easy to be diagnosed and managed. The main cause of CPVT is associated with mishandling Ca2+ in cardiomyocytes. Intracellular Ca2+ is strictly controlled by a protein located in the sarcoplasm reticulum (SR), such as ryanodine receptor, histidine-rich Ca2+-binding protein, triadin, and junctin. Mutation in these proteins results in misfolding or malfunction of these proteins, thereby affecting their Ca2+-binding affinity, and subsequently disturbs Ca2+ homeostasis during excitation–contraction coupling (E-C coupling). Furthermore, transient disturbance of Ca2+ homeostasis increases membrane potential and causes Ca2+ store overload-induced Ca2+ release, which in turn leads to delayed after depolarization and arrhythmia. Previous studies have focused on the interaction between ryanodine receptors and protein kinase or phosphatase in the cytosol. However, recent studies showed the regulation signaling for ryanodine receptor not only from the cytosol but also within the SR. The changing of Ca2+ concentration is critical for protein interaction inside the SR which changes protein conformation to regulate the open probability of ryanodine receptors. Thus, it influences the threshold of Ca2+ released from the SR, making it easier to release Ca2+ during E-C coupling. In this review, we briefly discuss how Ca2+ handling protein variations affect the Ca2+ handling in CPVT.
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Regulation on tumor metastasis by Raf kinase inhibitory protein: New insight with reactive oxygen species signaling p. 332
Chi-Tan Hu, Jaya Prakash Mandal, Wen-Sheng Wu
Targeted therapy aiming at the metastatic signal pathway, such as that triggered by receptor tyrosine kinase (RTK), for the prevention of tumor progression is promising. However, RTK-based targeted therapy frequently suffered from drug resistance due to the co-expression of multiple growth factor receptors that may raise compensatory secondary signaling and acquired mutations after treatment. One alternative strategy is to manipulate the common negative regulators of the RTK signaling. Among them, Raf kinase inhibitory protein (RKIP) is highlighted and focused on this review. RKIP can associate with Raf-1, thus suppressing the downstream mitogen-activated protein kinase (MAPK) cascade. RKIP also negatively regulates other metastatic signal molecules including NF-κB, STAT3, and NOTCH1. In general, RKIP achieves this task via associating and blocking the activity of the critical molecules on upstream of the aforementioned pathways. One novel RKIP-related signaling involves reactive oxygen species (ROS). In our recent report, we found that PKCδ-mediated ROS generation may interfere with the association of RKIP with heat shock protein 60 (HSP60)/MAPK complex via oxidation of HSP60 triggered by the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. The departure of RKIP may impact the downstream MAPK in two aspects. One is to trigger the Mt→cytosol translocation of HSP60 coupled with MAPKs. The other is to change the conformation of HSP60, favoring more efficient activation of the associated MAPK by upstream kinases in cytosol. It is worthy of investigating whether various RTKs capable of generating ROS can drive metastatic signaling via affecting RKIP in the same manner.
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Calmodulinopathy in inherited arrhythmia syndromes p. 339
Wen-Chin Tsai, Peng-Sheng Chen, Michael Rubart
Calmodulin (CaM) is a ubiquitous intracellular calcium sensor that controls and regulates key cellular functions. In all vertebrates, three CaM genes located on separate chromosomes encode an identical 149 amino acid protein, implying an extraordinarily high level of evolutionary importance and suggesting that CaM mutations would be possibly fatal. Inherited arrhythmia syndromes comprise a spectrum of primary electrical disorders caused by mutations in genes encoding ion channels or associated proteins leading to various cardiac arrhythmias, unexplained syncope, and sudden cardiac death. CaM mutations have emerged as an independent entity among inherited arrhythmia syndromes, referred to as calmodulinopathies. The most common clinical presentation associated with calmodulinopathy is congenital long QT syndrome, followed by catecholaminergic polymorphic ventricular tachycardia, both of which significantly increase the possibility of repeated syncope, lethal arrhythmic events, and sudden cardiac death, especially in young individuals. Here, we aim to give an overview of biochemical and structural characteristics of CaM and progress toward updating current known CaM mutations and associated clinical phenotypes. We also review the possible mechanisms underlying calmodulinopathy, based on several key in vitro studies. We expect that further experimental studies are needed to explore the complexity of calmodulinopathy.
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Ultrastructural changes in the underactive bladder p. 345
Han-Chen Ho, Yung-Hsiang Hsu, Jia-Fong Jhang, Yuan-Hong Jiang, Hann-Chorng Kuo
Underactive bladder (UAB) is a symptom complex suggestive of detrusor underactivity (DU). Although it implies a primary dysfunction of the detrusor muscle, many other conditions such as advanced age, neurogenic factors, and bladder outlet obstruction also lead to UAB. The current understanding of the pathophysiology directly leading to UAB is limited. We believe that by identifying the morphological changes associated with UAB might shed light on this. Therefore, we searched literature with keywords of electron microscopy, ultrastructure, UAB, and DU to review current ultrastructural evidence concerning UAB.
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Western and complementary alternative medicine treatment of uremic pruritus: A literature review Highly accessed article p. 350
Ping-Hsun Lu, Yu-Chih Tai, Min-Chien Yu, I-Hsin Lin, Ko-Lin Kuo
Uremic pruritus (UP), also called chronic kidney disease-associated pruritus (CKD-aP), is a bothersome symptom that causes sleep disturbance, anxiety, depression, and reduced quality of life. Pruritus often occurs in patients with end-stage renal disease. There is still no definite treatment for UP due to its unclear pathogenesis. We searched electronic databases (PubMed and Google Scholar) and gathered the latest clinical trials and pilot studies of Western and complementary alternative medicine (CAM) therapies for UP in English. These UP studies were separated into three main groups: systemic, topical, and others and CAM. Gabapentin, nalfurafine, acupuncture, and Chinese herbal bath therapy (CHBT) show antipruritic effects, with higher evidence grades in the meta-analysis. Emollients with additive compounds are more effective for reducing itch than emollients without additives. Supplements for deficient elements, such as zinc, omega-3, and omega-6, also show benefits for pruritus improvement. CAM therapies such as acupuncture, herbs, and herbal baths or creams all have good results for UP treatment. We summarize the treatments and suggest a treatment algorithm for UP according to severity. Some UP therapies are already supported by large-scale clinical evidence, and some new treatments can provide patients with new hope and treatment options. However, these new methods still need large population studies and further exploration.
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Residual hearing preservation for cochlear implantation surgery p. 359
Chung-Ching Lin, Ting Chiu, Hong-Ping Chiou, Chu-Man Chang, Chuan-Jen Hsu, Hung-Pin Wu
Cochlear implantation (CI) has developed for more than four decades. Initially, CI was used for profound bilateral hearing impairment. However, the indications for CI have expanded in recent years to include children with symptomatic partial deafness. Therefore, CI strategies to preserve residual hearing are important for both patients and otologists. The loss of residual low-frequency hearing is thought to be the result of many factors. All surgical methods have the same goal: protect the delicate intracochlear structures and preserve residual low-frequency hearing to improve speech perception abilities. Fully opening the round window membrane, a straight electrode array, slower insertion speed, and the use of corticosteroids result in a higher rate of hearing preservation. Several factors, like the way of surgical approaches, length of arrays and timing of activation, may not affect the residual hearing preservation. Therefore, the classic atraumatic technique, including the very slow and delicate insertion and administration of intraoperative corticosteroids, can improve hearing outcomes.
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Retrospective evaluation of the curative effect of traditional Chinese medicine on dry eye disease p. 365
San-Hua Su, Tsung-Jung Ho, Cheng-Chan Yang
Dry eye disease (DED) is a multifactorial illness with an increasingly high global prevalence and multiple risk factors that widely influences patients' daily lives. It is essential to identify treatments with few or no side effects for patients with DED. We have reviewed studies published from 2001 to 2020 that investigated traditional Chinese medicine (TCM) and integrated Chinese and Western medicine for DED treatment. Current Chinese medicines used in DED therapy were categorized into four types, namely anti-oxidants, anti-inflammatory agents, hormone-like agents, and cell-repairing agents. Compound herbs, including Chi-Ju-Di-Huang-Wan and Qiming granule, can effectively alleviate dry eye symptoms. Moreover, patients with DED who were treated with Western medicine combined with TCM experienced significantly magnified therapeutic effects and reasonable costs of treatment. In conclusion, TCM can be a promising approach for treating DED, and combined treatment with TCM and Western drugs may represent a new strategy for improving the curative effect.
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Two probable human leukocyte antigen haplotypes in association with human leukocyte antigen HLA-DRB1*13:50:01 identified in 41 randomized unrelated Taiwanese individuals p. 370
Nondumiso Ayanda Mazibuko, Kuo-Liang Yang
Objectives: Here, we show two probable haplotypes associated with the human leukocyte antigen (HLA) DRB1*13:50:01 allele. The haplotypes were observed from 41 randomized unrelated Taiwanese individuals among a population of 23,064 individuals tested. Materials and Methods: The samples in this study were blood samples, preserved in dipotassium ethylenediaminetetraacetic acid and/or ACD anticoagulants. The population is of donors from Tzu Chi Bone Marrow Donor Registry. Allele typing was performed using the sequence-based typing method, Sanger's sequencing. To discern the HLA-A and HLA-B alleles, exons 2 and 3 were sequenced. For DRB1 alleles, exon 2 was sequenced. Target exon sequence amplifications were done by a polymerase chain reaction and the resulting amplicons were sequenced by Bigdye Terminator Cycle Sequencing Ready Reaction kit, according to the manufacturer's protocols. Results: Two probable haplotypes that are associated with the DRB1*13:50:01 were observed among the 23,064 Taiwanese randomized unrelated individuals. One of the haplotypes is observed in 39 individuals while the other in two individuals. Conclusion: The findings in this study may be useful in studies reinforcing the understanding and clinical application of the polymorphism of HLA genes and haplotypes.
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Extreme horseshoe and circumanal anal fistulas-challenges in diagnosis and management p. 374
Pankaj Garg, Baljit Kaur, Vipul D Yagnik, Geetha R Menon
Objectives: Extreme horseshoe anal fistulas are rare, and there are little data on the diagnosis and management of these fistulas. Materials and Methods: Patients with horseshoe anal fistula, in which the fistula tract encircled more than 75% of the anal circumference were included in the study. All patients were assessed by a preoperative magnetic resonance imaging (MRI). The patients were managed by a sphincter-sparing procedure. The continence was evaluated by an objective continence scoring system (Vaizey's scores). Results: 1059 anal fistula patients were operated on over 7-years with a median follow-up of 36 months (range: 5–79 months). There were 47/1059 (4.4%) patients with extreme horseshoe anal fistulas. In 4/47 patients, the fistulas were complete circumanal (encircling anal canal completely). The mean age was 39.5 ± 10.9 years, M/F-41/6. The fistula was supralevator in 12/47 (25.5%), had an associated abscess in 28/47 (59.6%), and was recurrent in 33/47 (70.2%) patients. The tracts were intersphincteric in 27/47, transsphincteric in 2/47, and both (intersphincteric and transsphincteric) in 18/47 patients. All patients (n = 47) were managed by a sphincter-sparing procedure. Four patients were lost to follow-up. The fistula healed completely in 34/43 (79%) patients. There was no significant difference between preoperative and postoperative Vaizey's continence scores 0.031 ± 0.17 and 0.033 ± 0.18 respectively (P=0.90, Mann–Whitney U-test). Conclusion: Extreme horseshoe fistulas are rare, with an incidence of about 4% (in a referral practice). The missed diagnosis of circumferential tracts could lead to a recurrence. MRI was pivotal to confirm the diagnosis. Proper identification and management of internal opening and adequate drainage of all tracts were crucial for successfully treating extreme horseshoe fistulas.
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Effectiveness of individual audio-visual coaching, respiratory modulated stereotactic body radiotherapy for localized hepatocellular carcinoma: Analysis of 29 cases from a single academic radiotherapy center p. 380
Liang-Cheng Chen, Hon-Yi Lin, Moon-Sing Lee, Wen-Yen Chiou, Li-Wen Huang, Chia-Hui Chew, Feng-Chun Hsu, Shih-Kai Hung
Objectives: Recently, Stereotactic Body Radiotherapy (SBRT) has been suggested for managing hepatocellular carcinoma (HCC) curatively. Thus, we conducted this clinical study to evaluate retrospectively the effect of individualized audio-visual (AV) coaching, respiratory modulated SBRT. Materials and Methods: Between 2014 and 2018, 29 patients with inoperable Barcelona Clinic Liver Cancer (BCLC) stage 0-B HCC received AV coaching, respiratory-modulated SBRT. We constructed a task-oriented multidisciplinary team to establish a standard operation process of respiratory modulation procedures and developed our AV coaching devices. In the training period, a goodness-of-fit test was applied individually. SBRT was delivered with a total dose of 40–54 Gy in 5–6 fractions individually. Freedom from local progression (FFLP) and overall survival (OS) were estimated using SPSS (version 17, SPSS Inc., Chicago, IL, USA) life tables. Results: The patient characteristics were as follows: 32.7 ± 16 mm in maximum tumor diameter (range 11–94); BCLC stage 0: 3.4%, BCLC A: 48.3%, BCLC B: 48.3%; Child-Pugh classification A: 86.2%, Child-Pugh classification B: 13.8%, and a median of 2 prior liver-directed treatments (range 0–7). One-, 2-, and 3-year rates of FFLP of SBRT were 96.6%, 96.6%, and 96.6%, respectively. One-, 2-, and 3-year rates of OS were 81.5%, 72.4%, and 67.2%, respectively. No adverse event (AE) occurred in 41.4% of patients, 48.3% developed grade (G) 1–2 AE, 10.3% had G3 AE and none had G4-5 AE. Conclusion: Respiration-modulated SBRT is a promising noninvasive treatment option for patients with inoperable and localized HCC. Our data show that SBRT provides comparable tumor control to historical curative options like surgery and radiofrequency ablation of localized tumors. Thus, we are conducting a further prospective clinical trial with the intent to demarcate the clinical effectiveness of SBRT in a larger population of patients with HCC.
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Can preoperative neutrophil-to-lymphocyte ratio predict in-hospital mortality in postoperative patients with Stanford type A aortic dissection? Evidence-based appraisal by meta-analysis and GRADE p. 388
Bing-Ru Chung, Yen-Ta Huang, Pei-Chun Lai
Objectives: In-hospital mortality in postoperative patients with type A aortic dissection (AAD) is high. Neutrophil-to-lymphocyte ratio (NLR) is a novel predictor of adverse outcomes in many cardiovascular diseases. We examine NLR as a predictive tool in AAD in this meta-analysis. Materials and Methods: We systematically searched in four databanks. Risk of bias was appraised using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. The midas and metandi commands in Stata 15 were used for the meta-analysis. The certainty of evidence was assessed by the Grading of Recommendations, Assessment, Development, and Evaluation methodology (GRADE). Results: Four studies with 502 cases in total were included. Pooled sensitivity and specificity were 0.71 (95% confidence interval [CI] = 0.52–0.79) and 0.64 (95% CI = 0.55–0.71), respectively. Area under the hierarchical summary receiver operating characteristic curve yielded 0.73 (95% CI = 0.68–0.76). The diagnostic odds ratio was 4.42 (95% CI = 2.56–7.62). Pooled positive and negative likelihood ratios yielded 1.98 (95% CI = 1.53–2.55) and 0.45 (95% CI = 0.32–0.62), respectively. When the pretest probabilities were 25%, 50%, and 75%, the positive posttest probabilities were 40%, 66%, and 86%, and the negative posttest probabilities were 13%, 31%, and 57%, respectively, according to the Fagan's nomogram plot. The overall certainty of evidence in GRADE was low and very low in sensitivity and specificity, respectively. Conclusion: The pooled diagnostic values of preoperative NLR, an inexpensive and routine laboratory examination, provide a practicable help for predicting in-hospital mortality for patients with postoperative AAD in our meta-analysis.
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Correlation between intraoperative mapping and monitoring and functional outcomes following supratentorial glioma surgery p. 395
Han-Lin Wu, Po-Cheng Hsu, Sanford P C Hsu, Chun-Fu Lin, Kwong-Kum Liao, Kai-Ming Yang, Chen-Liang Chou, Tsui-Fen Yang
Objectives: Intraoperative neurophysiological monitoring (IONM) has long been regarded as the “gold standard” when resecting a supratentorial glioma, as it facilitates the goals of maximal tumor resection and preservation of sensorimotor function. The purpose of the present study was to evaluate the ability of motor evoked potentials (MEPs) monitoring or subcortical mapping (SCM), alone or in combination, to predict postoperative functional outcomes in glioma surgery. Materials and Methods: We retrospectively reviewed patients with supratentorial glioma that underwent craniotomy for tumor removal with IONM. Statistical analyses were used to evaluate whether the following criteria correlated with postoperative functional outcomes: Reduced amplitude (>50% reduction) or disappearance of MEPs (criterion 1), SCM with a stimulation intensity threshold less than 3 mA (criterion 2), the presence of both two phenomena (criterion 3), or either one of the two phenomena (criterion 4). Results: Ninety-two patients were included in this study, of whom 15 sustained new postoperative deficits, 4 experienced improved functional status, and 73 were unchanged. Postoperative functional status correlated significantly with all four criteria, and especially with criterion 3 (r = 0.647, P = 0.000). Sensitivity of IONM was better if using criteria 2 and 4, but specificity was better if using criteria 1 and 3. Criterion 3 had the most favorable overall results. Conclusion: Using statistical methodology, our study indicates that concomitant interpretation of MEPs and SCM is the most accurate predictor of functional outcomes following supratentorial glioma surgery. However, accurate interpretations of the monitoring results by experienced neurophysiologists are essential.
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Rapid screening for mutations associated with malignant hyperthermia using high-resolution melting curve analysis p. 399
I-Min Su, Po-Kai Wang, Chun-Yu Chen, Hsien-Tse Huang, Yuan-Ji Day
Objectives: The diagnosis of malignant hyperthermia (MH) is based on clinical signs or laboratory testing. The gold standard laboratory test is the in vitro contracture test, although it is invasive, expensive, and only performed at specialized centers. Genetic diagnosis is another option, although direct mutation screening is a laborious task. Therefore, we evaluated whether high-resolution melting (HRM) curve analysis could be used as a rapid screening tool to target MH-associated mutations. Materials and Methods: The feasibility of HRM analysis was evaluated using plasmids that were constructed by cloning wild-type or mutated versions of the ryanodine receptor 1 (RYR1) gene into the pCR2.1 plasmid. We obtained engineered plasmids and patient DNA extracted from blood samples with known wild-type or mutated sequences that are associated with MH. Amplicon lengths were kept relatively short (<250 bp) to improve discrimination between the engineered and patient plasmids. Real-time polymerase chain reaction (PCR) cycling and HRM analysis of the engineered plasmids and patient DNA were performed using the LightCycler 480 System (Roche). Results: The HRM results were clearly different from those obtained using real-time PCR. Furthermore, the HRM analysis provided sufficient resolution to identify two single-nucleotide variants in the tested RYR1 exons. Conclusion: We conclude that HRM analysis can provide high resolution for identifying single-nucleotide variants in RYR1, which might be useful for predicting the risk of MH in the preanesthesia setting.
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Evaluation of patient satisfaction and masticatory performance in mandible single implant-assisted overdenture p. 406
Swati Kashyap, Sanjeev Mittal, Navneet Sharma, Urvashi Sukhija, Mohit Kamra, Nitika Gupta
Objectives: Many authors' have advocated a minimum of two implants to support a mandibular overdenture, but financial restraints specifically among the geriatric population in developing countries made this treatment plan economically difficult. Hence, this study was planned to assess the symphyseal (midline) single implant-assisted complete overdenture for patient satisfaction and masticatory performance. Materials and Methods: In this clinical study, 12 edentulous first-time denture wearers underwent placement of a single implant in the mandibular symphyseal region. After 1 week, new complete dentures were fabricated and delivered to the patients. Post 3 months, the denture was fixed with a nylon cap-ball attachment to the anchor implant. Patients were questioned about comparison in the level of satisfaction and complaint before loading the implant (control group) and after 1 week, 1 month, and 3 months. The implant-assisted overdenture was fabricated with the help of a questionnaire. Masticatory performance was calculated with the help of a bite force measuring device at the same time intervals. SPSS 17.0 statistical software was used to analyze the data. Results: It was found that single implant anchorage of the mandibular complete denture resulted in a significant increase (P < 0.05) in patient's subjective satisfaction and a decrease (P < 0.05) in complaints at the end of 3 months. There was a significant (P < 0.01) increase in bite force in implant overdenture after 3 months (5.459 kgf) as compared to that of the complete denture (3.406 kgf). Conclusion: Single implant-assisted overdenture can be an appropriate treatment modality to treat edentulousness in the geriatric population. It insinuates the remarkable improvement of prosthesis function and oral comfort with minor surgical procedures.
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Perioperative exercise intervention in patients with lung cancer: A systematic literature review of randomized controlled trials p. 412
Chun-Hou Huang, Tai-Chu Peng, Yi-Tso Cheng, Yen-Ta Huang, Bee-Song Chang
Objectives: During perioperative, lung cancer (LC) patients are often left to experience debilitating disease-related symptoms, impaired physical activity and health-related quality of life (HRQoL), and social difficulties, despite the progress achieved in terms of treatment efficacy. Nonpharmacological intervention, such as exercise, has been identified as an effective strategy in LC patients before and after lung resection. Therefore, we aimed to assess evidence of the effect of perioperative exercise among patients with LC. Materials and Methods: Seven databases were searched from January 1998 to September 2020. All randomized controlled trials (RCTs) that evaluated the effect of exercise on the physical and psychological status of patients with LC during the perioperative period were reviewed. Two reviewers independently assessed the quality of all studies included here using the revised Cochrane risk of bias tool for RCTs. Results: Seventeen RCTs (1199 participants) published between 2011 and 2019 met for this literature review. The outcome measures that emerged from these studies included subjective outcomes, such as HRQoL, pain score, fatigue, and objective effects, such as cardiorespiratory fitness, pulmonary function, physical activity, and biological markers. Overall, these studies suggest that exercise should be an optimal option for LC; however, its efficacy and effectiveness regarding HRQoL should be investigated further. Conclusion: Perioperative exercise could be included in the rehabilitation program of patients with LC. More extensive, high-quality RCTs evidence is needed on the ideal exercise type, duration, intensity, and timing across the LC perioperative care.
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Asymptomatic paraganglioma of urinary bladder p. 419
Tai-Li Chen, Yuan-Hong Jiang, Yung-Hsiang Hsu
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