Harnessing polyphenol power by targeting eNOS for vascular diseases.

Vascular diseases arise due to vascular endothelium dysfunction in response to several pro-inflammatory stimuli and invading pathogens. Thickening of the vessel wall, formation of atherosclerotic plaques consisting of proliferating smooth muscle cells, macrophages and lymphocytes are the major consequences of impaired endothelium resulting in atherosclerosis, hypercholesterolemia, hypertension, type 2 diabetes mellitus, chronic renal failure and many others. Decreased nitric oxide (NO) bioavailability was found to be associated with anomalous endothelial function because of either its reduced production level by endothelial NO synthase (eNOS) which synthesize this potent endogenous vasodilator from L-arginine or its enhanced breakdown due to severe oxidative stress and eNOS uncoupling. Polyphenols are a group of bioactive compounds having more than 7000 chemical entities present in different cereals, fruits and vegetables. These natural compounds possess many OH groups which are largely responsible for their strong antioxidative, anti-inflammatory antithrombotic and anti-hypersensitive properties. Several flavonoid-derived polyphenols like flavones, isoflavones, flavanones, flavonols and anthocyanidins and non-flavonoid polyphenols like tannins, curcumins and resveratrol have attracted scientific interest for their beneficial effects in preventing endothelial dysfunction. This article will focus on in vitro as well as in vivo and clinical studies evidences of the polyphenols with eNOS modulating activity against vascular disease condition while their molecular mechanism will also be discussed.

Oral microbiota in cancer: could the bad guy turn good with application of polyphenols?

The human oral cavity is comprised of dynamic and polynomial microbes which uniquely reside in the microenvironments of oral cavities. The cumulative functions of the symbiotic microbial communities maintain normal homeostasis; however, a shifted microbiota yields a dysbiosis state, which produces local and systemic diseases including dental caries, periodontitis, cancer, obesity and diabetes. Recent research reports claim that an association occurs between oral dysbiosis and the progression of different types of cancers including oral, gastric and pancreatic ones. Different mechanisms are proposed for the development of cancer, such as induction of inflammatory reactions, production of carcinogenic materials and alteration of the immune system. Medications are available to treat these associated diseases; however, the current strategies may further worsen the disease by unwanted side effects. Natural-derived polyphenol molecules significantly inhibit a wide range of systemic diseases with fewer side effects. In this review, we have displayed the functions of the oral microbes and we have extended the report regarding the role of polyphenols in oral microbiota to maintain healthy conditions and prevention of diseases with emphasis on the treatment of oral microbiota-associated cancer.

Epidemiologic profile and outcome of primary pediatric brain tumors in Iran: retrospective study and literature review.

PURPOSE: Primary pediatric tumors are the most common solid tumors in children. There are limited reports on the management and outcome of these tumors in the developing countries. In recent years, advances have been done in the diagnosis, treatment, and outcome of these tumors. The aim of this study was to evaluate the histopathology, characteristics, and outcome of primary pediatric tumors in Iran. METHODS: This retrospective study examines primary brain tumors in children below 14 years of age who have undergone surgery. Histopathological characteristics according to WHO 2017 classification, age, sex, tumor resection rate, and patient outcome were extracted and studied. The results of the study were compared with the results of similar reports from neighboring countries and other parts of the world. RESULTS: In this study, 199 primary pediatric tumors were examined. Out of 199 cases, 114 cases were males, and 85 cases were females, and the male/female ratio was 1.34. The most common tumor group in this study was astrocytic tumors (68.3%) and the most common tumor was pilocytic astrocytoma (22.1%). In terms of malignancy, 50.7% of tumors were benign, and 49.3% were malignant. Total resection was done in 46% and subtotal resection in 35%. The mortality rate was found 19.2%. َAmong the remaining cases during follow-up, 76.6% had a good outcome without neurological deficits or mild disability and 23.4% had moderate to severe disability. CONCLUSIONS: The results of the study in terms of pathology and demographic characteristics were mainly similar to other reports. The mean age of patients was lower, and the patients' outcome was better than the other countries in the region.

Local vancomycin therapy to reduce surgical site infection in adult spine surgery: a randomized prospective study.

PURPOSE: This prospective randomized controlled trial hypothesizes that intra wound vancomycin reduces postoperative infection. METHODS: In this RCT study, the patients were randomly divided into two groups of treatment and control. In the treatment group, 1-2 g of intra wound vancomycin was used, and no drug was used for the control group. SSI and the type of microorganism causing postoperative infection were assessed at a three-month follow-up. Factors affecting postoperative infection such as age, sex, site of operation, surgical levels, and risk factors affecting postoperative infection, such as diabetes, blood pressure, ischemic heart disease, smoking, blood transfusion, BMI, neurologic deficit, CSF leakage, UTI, COPD and surgery time were examined in two groups. RESULTS: In this study, 375 patients, including 187patients in the treatment group and 188 patients in the control group, were studied. Among the patients, 228 had surgery without instrumentation, and 147 had surgery with instrumentation. There were 12 cases of SSI in the treatment group and 11 in the control group, and there was no statistically significant difference between the two groups. There was no difference between the two groups with and without instrumentation in the evaluation of postoperative infection. In the subgroups with and without instruments, there was no significant difference between treatment and control groups. Due to the microorganism causing the infection, gram-negative bacteria were more common in the treatment group. CONCLUSION: Intra-wound vancomycin has no effect on SSI; in addition, it can increase the rate of gram-negative infections.

Predictive Value of Blood Markers in Pediatric Brain Tumors Using Machine Learning.

BACKGROUND: The brain tumor is the most common solid tumor in children. Blood markers in most malignancies are altered due to the effect of inflammatory mediators on the bone marrow. OBJECTIVE: This study aimed to predict the malignancy of pediatric brain tumors using blood markers. METHODS: The pediatric brain tumors were divided into benign and malignant groups. Blood markers, including RBC, WBC, neutrophil, lymphocyte, monocyte, platelet, neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio, and derived neutrophil to lymphocyte ratio were extracted. Differences in blood markers between two groups were assessed using statistical analysis. The accuracy of machine learning to determine pediatric brain tumors' malignancy was evaluated using blood markers and demographic information. RESULTS: Among 113 patients, 55 patients were in the benign tumor group, and 58 patients were in the malignant tumor group. In the statistical study of blood markers in two groups, LMR was significantly different and positively correlated with malignancy. Other blood markers were not significantly different between two groups. This study showed that support-vector machines using blood markers, age, and sex can differentiate benign and malignant pediatric brain tumors with 71.6% accuracy. CONCLUSIONS: Despite the statistically significant differences in blood markers in different grades of brain tumors in adults, their differences in pediatric brain tumors, except LMR, were not significant. Machine learning using blood markers can differentiate between benign and malignant pediatric brain tumors with 71.6% accuracy.

A minimum data set for traumatic brain injuries in Iran.

PURPOSE: Traumatic brain injury (TBI) is one of the major public health concerns worldwide. Developing a TBI registry could facilitate characterizing TBI, monitoring the quality of care, and quantifying the burden of TBI by collecting comparable and standardized epidemiological and clinical data. However, a national standard tool for data collection of the TBI registry has not been developed in Iran yet. This study aimed to develop a national minimum data set (MDS) for a hospital-based registry of patients suffering from TBI in Iran. METHODS: The MDS was designed in 2 phases, including a literature review and a Delphi study with content validation by an expert panel. After the literature review, a comprehensive list of administrative and clinical items was obtained. Through a two-round e-Delphi approach conducted by invited experts with clinical and research experience in the field of TBI, the final data elements were selected. RESULTS: A MDS of TBI was assigned to 2 parts: administrative part with 5 categories including 52 data elements, and clinical part with 9 categories including 130 data elements. CONCLUSION: For the first time in Iran, we developed a MDS specified for TBI consisting of 182 data elements. The MDS would facilitate implementing a TBI's national level registry and providing essential, comparable and standardized information.

Arglabin could target inflammasome-induced ARDS and cytokine storm associated with COVID-19.

Arglabin (l(R),10(S)-epoxy-5(S),5(S),7(S)-guaia-3(4),ll(13)-dien-6,12-olide), is a natural sesquiterpene γ-lactone which was first isolated from Artemisia glabella. The compound has been shown to possess anti-inflammatory activity through inhibition of the NLR Family pyrin domain-containing 3 (NLRP3) inflammasome and production of proinflammatory cytokines including interleukin (IL)-1ß and IL-18. A more hydrophilic derivative of the compound also exhibited antitumor activity in the breast, colon, ovarian, and lung cancer. Some other synthetic derivatives of the compound have also been synthesized with antitumor, cytotoxic, antibacterial, and antifungal activities. Since both NLRP3 inflammasome and cytokine storm are associated with the pathogenesis of COVID-19 and its lethality, compounds like arglabin might have therapeutic potential to attenuate the inflammasome-induced acute respiratory distress syndrome and/or the cytokine storm associated with COVID-19.

Predictive value of the preliminary findings in the severity of COVID-19 disease and the effect on therapeutic approaches.

In this retrospective multicenter case series study, the predictive value of initial findings of confirm COVID-19 cases in determining outcome of the disease was assessed. Patients were divided into two groups based on the outcome: low risk (hospitalization in the infectious disease ward and discharge) and high risk (hospitalization in ICU or death). A total of 164 patients with positive PCR-RT were enrolled in this study. About 36 patients (22%) were in the high-risk group and 128 (78%) were in the low-risk group. Results of statistical analysis revealed a significant relationship between age, fatigue, history of cerebrovascular disease, organ failure, white blood cells (WBC), neutrophil-to-lymphocyte ratio (NLR), and derived neutrophil-to-lymphocyte ratio (dNLR) with increased risk of disease. The artificial neural network (ANN) could predict the high-risk group with an accuracy of 87.2%. Preliminary findings of COVID-19 patients can be used in predicting their outcome and ANN can determine the outcome of patients with appropriate accuracy (87.2%). Most treatment in Covid-19 are supportive and depend on the severity of the disease and its complications. The first step in treatment is to determine the severity of the disease. This study can improve the treatment of patients by predicting the severity of the disease using the initial finding of patients and improve the management of disease with differentiating high-risk from low-risk groups.

Comparison of the effects of 2 ventilatory strategies using tidal volumes of 6 and 8 ml/kg on pulmonary shunt and alveolar dead space volume in upper abdominal cancers surgery.

Background: High tidal volume leads to inflammation, and low tidal volume leads to atelectasia and hypoxemia. This study was conducted to compare the effect of 6 mL/kg with positive end-expiratory pressure (PEEP) and 8 mL/kg without PEEP on pulmonary shunt and dead space volume. Methods: This clinical trial was done on 36 patients aged 20 to 65 years old with ASA I-II. They were candidates for upper abdominal surgery and divided randomly into 2 groups. One group were ventilated with the tidal volume = 8 mL/kg without PEEP (TV8). The other group received the tidal volume = 6 mL/kg with low PEEP = 5 cm H2O (TV6). Arterial and central venous blood gases were taken after intubation and 2 hours later. Additionally, the vital signs of the patients were checked every 30 minutes. Data analysis was performed using t test, chi-square test, and repeated measures analysis of variance with SPSS software, version 16 (SPSS Inc). P value less than.05 were meaningful. Results: There was no significant difference on the preanesthesia parameters. The pulmonary shunt was 13.5±0.1% and 18.6±0.2% in the groups TV6 and TV8, respectively (p=0.132), which slightly decreased after 2 hours in both groups without any significant difference (p=0.284). Prior to the ventilation, the ratios of dead space to tidal volume were 0.25±0.2 and 0.14±0.1 in the TV6 and TV8 groups, respectively (p=0.163), and after 2 hours, they were 0.23±0.11 and 0.16±0.1 in the TV6 and TV8 groups, respectively (p=0.271). There was no significant difference between the groups for blood pressure and peripheral and arterial oxygenation changes. Conclusion: The tidal volume of 6 mL/kg with the PEEP of 5 mmHg was similar to the tidal volume of 8 mL/kg without PEEP for hemodynamic and pulmonary changes (oxygenation, shunt, and dead space).

Evaluation of Intravenous Infusion of Ibuprofen with Paracetamol-Morphine in Pain and Satisfaction of Patients Undergoing Supratentorial Brain Surgery.

Background: The pain experienced following supratentorial brain surgery is usually defined as moderate to severe. Therefore, pain-management approaches, including narcotics, are an integral part of treatment regimens that cause respiratory complications or seizures, and reducing this pain level and increasing patient satisfaction is vital. Methods: This randomized, double-blind clinical trial study to evaluate the pain level and satisfaction in patients undergoing surgery for supratentorial brain neoplasms was performed on two groups with a sample size of 50 patients. In group I, after removal of the brain lesion (at the beginning of dura closure), 400 mg of ibuprofen solution was infused intravenously over 30 minutes. In group II, morphine 0.07 mg/kg intravenously with 1000 mg paracetamol was infused over 30 minutes. After injecting ibuprofen and paracetamol morphine, the patient's pain level and satisfaction with the process were checked. Results: Patients' satisfaction score in the first 6 hours in the ibuprofen group was 1.67 ± 0.72, and in the other group was 2.27 ± 0.7, which was statistically different (P-value = 0.029). The mean of VAS in the first, second, third, and fourth hours was not statistically different. In the comparative analysis of the laboratory indicators of platelet function analysis in the two groups, none of the measured items had a significant difference between the two groups in the three measurement periods (P > 0.05). Conclusions: Administration of ibuprofen led to pain relief and patient satisfaction comparable to morphine and paracetamol, and after the surgery for supratentorial brain tumors, ibuprofen did not affect the patients' blood clotting functions.

Emerging Novel Approaches for the Enhanced Delivery of Natural Products for the Management of Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis, and prion disease affect any part of the brain. The complete mechanism of ND is unknown, but there are some molecular mechanism and chemical process. Natural compounds have better compatibility with the human body along with lesser side effects. Moreover, several studies showed that various natural compounds have significant neuroprotective, potent antioxidant, and anti-inflammatory properties, which are effective for treating the different type of ND. In ND, natural compounds act by various mechanisms such as preventing the generation of reactive oxygen species (ROS), eliminating destructed biomolecules before their accumulation affects cell metabolism, and improving the disease conditions. But due to the presence of the blood-brain barrier (BBB) layer and unfavorable pharmacokinetic properties of natural compounds, their delivery into the brain is limited. To minimize this problem and enhance drug delivery into the brain with an effective therapeutic dose, there is a need to develop a practical novel approach. The various studies showed that nanoformulations and microneedles (MN) containing natural compounds such as quercetin, curcumin, resveratrol, chrysin, piperine, ferulic acid, huperzine A, berberine, baicalein, hesperetin, and retinoic acid effectively improved many ND. In this review, the effect of such natural drug-loaded nanoformulation and MN patches on ND management is discussed, along with their merits and demerits. This review aims to introduce different novel approaches for enhancing natural drug delivery into the brain to manage various neurodegenerative diseases.

Pharmacotherapy consideration of thrombolytic medications in COVID-19-associated ARDS.

BACKGROUND: In late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is responsible for coronavirus disease (COVID-19), was identified as the new pathogen to lead pneumonia in Wuhan, China, which has spread all over the world and developed into a pandemic. Despite the over 1 year of pandemic, due to the lack of an effective treatment plan, the morbidity and mortality of COVID-19 remains high. Efforts are underway to find the optimal management for this viral disease. MAIN BODY: SARS-CoV-2 could simultaneously affect multiple organs with variable degrees of severity, from mild to critical disease. Overproduction of pro-inflammatory mediators, exacerbated cellular and humoral immune responses, and coagulopathy such as Pulmonary Intravascular Coagulopathy (PIC) contributes to cell injuries. Considering the pathophysiology of the disease and multiple microthrombi developments in COVID-19, thrombolytic medications seem to play a role in the management of the disease. Beyond the anticoagulation, the exact role of thrombolytic medications in the management of patients with COVID-19-associated acute respiratory distress syndrome (ARDS) is not explicit. This review focuses on current progress in underlying mechanisms of COVID-19-associated pulmonary intravascular coagulopathy, the historical use of thrombolytic drugs in the management of ARDS, and pharmacotherapy considerations of thrombolytic therapy, their possible benefits, and pitfalls in COVID-19-associated ARDS. CONCLUSIONS: Inhaled or intravenous administration of thrombolytics appears to be a salvage therapy for severe ARDS associated with COVID-19 by prompt attenuation of lung injury. Considering the pathogenesis of COVID-19-related ARDS and mechanism of action of thrombolytic agents, thrombolytics appear attractive options in stable patients without contraindications.

A perspective on the applications of furin inhibitors for the treatment of SARS-CoV-2.

Currently, the world is facing a pandemic of the new coronavirus SARS-CoV-2 that causes COVID-19. Identifying key targets in the viral infection lifecycle is urgently needed for designing therapeutic strategies to combat the virus. Furin is a subtilisin-like proprotein convertase with diverse cellular functions. Emerging evidence suggests that furin plays a critical role in the activation and/or infectivity of SARS-CoV-2. In this perspective, we discuss the potential role of furin in the entry SARS-CoV-2 into host cells. Furthermore, we evaluate available peptide and non-peptide furin inhibitors and potential outcomes, including immune responses.

Shaping the gut microbiota by bioactive phytochemicals: An emerging approach for the prevention and treatment of human diseases.

The human digestive tract is the cottage to trillions of live microorganisms, which regulate health and illness. A healthy Gut Microbiota (GM) is necessary for preventing microbial growth, body growth, obesity, cancer, diabetes, and enhancing immunity. The equilibrium in GM's composition and the presence/absence of critical species enable specific responses to be essential for the host's better health condition. Research evidences revealed that the dietary plants and their bioactive phytochemicals (BPs) play an extensive and critical role in shaping the GM to get beneficial health effects. BPs are also known to improve gastrointestinal health and reduce the risk of several diseases by modulating GM-mediated cellular and molecular processes. Regular intake of BPs-rich vegetables, fruits, and herbal preparations promotes probiotic bacteria, including Bifidobacteria and Lactobacillus species, while inhibiting unwanted gut residents' development Escherichia coli, and Salmonella typhimurium etc. Upon consumption, BPs contact the GM that gets transformed before being absorbed from the gastrointestinal tract. Biotransformation of BPs by GM is linked with the enhancement of bioactivity/toxicity diminishment of the BPs compared to parental phytochemicals. Therefore, the current review focuses on the role of BPs in shaping GM for the prevention and treatment of human diseases.

Illuminating the Molecular Intricacies of Exosomes and ncRNAs in Cardiovascular Diseases: Prospective Therapeutic and Biomarker Potential.

Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Accumulating evidences have highlighted the importance of exosomes and non-coding RNAs (ncRNAs) in cardiac physiology and pathology. It is in general consensus that exosomes and ncRNAs play a crucial role in the maintenance of normal cellular function; and interestingly it is envisaged that their potential as prospective therapeutic candidates and biomarkers are increasing rapidly. Considering all these aspects, this review provides a comprehensive overview of the recent understanding of exosomes and ncRNAs in CVDs. We provide a great deal of discussion regarding their role in the cardiovascular system, together with providing a glimpse of ideas regarding strategies exploited to harness their potential as a therapeutic intervention and prospective biomarker against CVDs. Thus, it could be envisaged that a thorough understanding of the intricacies related to exosomes and ncRNA would seemingly allow their full exploration and may lead clinical settings to become a reality in near future.

Himalayan Ficus palmata L. Fruit Extract Showed In Vivo Central and Peripheral Analgesic Activity Involving COX-2 and Mu Opioid Receptors.

Analgesic drugs like morphine and non-steroidal anti-inflammatory drugs exhibit several harmful effects. Here, we show for the first time the analgesic activity of Ficus palmata L. fruit extract (FPFE) on different analgesic rat models along with the in silico studies of some of the main phytochemicals of this plant. We performed in vivo pain models, along with in silico docking studies against the active site of COX-2 protein and mu-opioid receptors. A significant (p < 0.05) analgesic effect of FPFE was observed, and it was found that rutin has good pose and score as compared to diclofenac and morphinan antagonist (X-ligand), and psoralen has binding affinity almost equal to diclofenac, but a lower binding affinity as compared to rutin. The results proved that F. palmata fruits have the potential to ameliorate painful conditions.

Aromatic hydrocarbon receptors in mitochondrial biogenesis and function.

Mitochondria are ubiquitous membrane-bound organelles that not only play a key role in maintaining cellular energy homeostasis and metabolism but also in signaling and apoptosis. Aryl hydrocarbons receptors (AhRs) are ligand-activated transcription factors that recognize a wide variety of xenobiotics, including polyaromatic hydrocarbons and dioxins, and activate diverse detoxification pathways. These receptors are also activated by natural dietary compounds and endogenous metabolites. In addition, AhRs can modulate the expression of a diverse array of genes related to mitochondrial biogenesis and function. The aim of the present review is to analyze scientific data available on the AhR signaling pathway and its interaction with the intracellular signaling pathways involved in mitochondrial functions, especially those related to cell cycle progression and apoptosis. Various evidence have reported the crosstalk between the AhR signaling pathway and the nuclear factor κB (NF-κB), tyrosine kinase receptor signaling and mitogen-activated protein kinases (MAPKs). The AhR signaling pathway seems to promote cell cycle progression in the absence of exogenous ligands, whereas the presence of exogenous ligands induces cell cycle arrest. However, its effects on apoptosis are controversial since activation or overexpression of AhR has been observed to induce or inhibit apoptosis depending on the cell type. Regarding the mitochondria, although activation by endogenous ligands is related to mitochondrial dysfunction, the effects of endogenous ligands are not well understood but point towards antiapoptotic effects and inducers of mitochondrial biogenesis.

Complete Versus Incomplete Surgical Resection in Intramedullary Ependymomas: A Systematic Review and Meta-analysis.

STUDY DESIGN: Systematic review. OBJECTIVE: To compare outcomes of complete versus incomplete resection in primary intramedullary spinal cord ependymoma. METHODS: A comprehensive search of the MEDLINE, CENTRAL, and Embase databases was conducted by 2 independent investigators. Random-effect meta-analysis and meta-regression with seven covariates were performed to evaluate the reason for the heterogeneity among studies. We also used individual patient data in the integrative analysis to compare complete and incomplete resection based on 4 outcomes: progression-free survival (PFS), overall survival (OS), postoperative neurological improvement (PNI), and follow-up neurological improvement (FNI). RESULTS: A total of 23 studies were identified, including 407 cases. Significant heterogeneity among included studies was observed in risk estimates (I2 for PFS, FNI, and PNI were 49.5%, 78.3%, and 87.2%, respectively). The mean follow-up time across cases was 48.6 ± 2.35 months. Cox proportional multivariable analysis revealed that the complete resection can prolong PFS (model, hazard ratio = 0.18, CI 0.05-0.54, P = .004,) and improve the FNI (binary logistic regression, adjusted odds ratio = 16.5, CI 1.6-171, P = .019). However, PNI and OS were similar in patients with incomplete resected spinal cord ependymoma compared with complete resection (binary logistic regression respectively and Cox multivariable analysis, P > .5). CONCLUSION: The data presented in this study showed that OS was not significantly affected by the degree of surgery. However, complete resection of intramedullary ependymomas provides the optimal outcomes with longer PFS and better long-term neurological outcomes than incomplete resection.

Functional Outcome of Surgical versus Conservative Therapy in Patients with Traumatic Thoracolumbar Fractures and Thoracolumbar Injury Classification and Severity Score of 4; A Non-randomized Clinical Trial.

OBJECTIVE: To compare the effectiveness of surgical intervention to conservative treatment in patients with thoracolumbar fracture and thoracolumbar injury classification and severity score (TLICS) of 4. METHODS: Twenty-five patients with TLICS 4 were enrolled in this non-randomized clinical trial. Based on clinical symptoms and radiologic findings, patients were considered under surgical or conservative treatments. The JOA Back Pain Evaluation Questionnaire (JOABPEQ) was assessed at baseline and at 3, 6, 12 months after treatment. A 20-point improvement from the baseline JOABPEQ scores was considered as clinical success in both the conservative and surgery groups. Additionally, residual canal, angulations and height loss were determined in all patients. RESULTS: Eight patients received conservative and 17 surgical treatment. Both study groups were comparable regarding the baseline characteristics. Both study demonstrated treatment success, regarding functional recovery when compared to baseline (p<0.001). However, those undergoing surgical intervention had significantly better JOABPEQ score (p<0.001) and higher residual canal (p=0.042) when compared to those receiving conservative therapy. The success rate of treatment was comparable between the two study groups in 6- (p=0.998) and 12-month (p=0.852) intervals; however, surgical therapy had significantly higher success arte in 3-month interval (p=0.031). CONCLUSION: Our findings revealed that surgical treatment was preferred more in comparison to conservative treatment in patients with TLICS 4. Additionally, residual canal might be a modifying factor to decide the ideal therapeutic approach.