Electrochemical Characterization of a Novel Organoelectrocatalyst, 7-Azabicyclo[2.2.1]heptan-7-ol (ABHOL), and Its Application to Electrochemical Sensors.

Electrochemical enzyme sensors are suitable for simple monitoring methods, for example, as glucose sensors for diabetic patients; however, they have several disadvantages arising from the properties of the enzyme. Therefore, non-enzymatic electrochemical sensors using functional molecules are being developed. In this paper, we report the electrochemical characterization of a new hydroxylamine compound, 7-azabicyclo[2.2.1]heptan-7-ol (ABHOL), and its application to glucose sensing. Although the cyclic voltammogram for the first cycle was unstable, it was reproducible after the second cycle, enabling electrochemical analysis of ethanol and glucose. In the first cycle, ABHOL caused complex reactions, including electrochemical oxidation and comproportionation with the generated oxoammonium ions. The electrochemical probe performance of ABHOL was more efficient than the typical nitroxyl radical compound, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), and had similar efficiency to 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), which is activated by the bicyclic structure. The results demonstrated the advantages of ABHOL, which can be synthesized from inexpensive materials via simple methods.

The Impact of Nociception Monitor-Guided Multimodal General Anesthesia on Postoperative Outcomes in Patients Undergoing Laparoscopic Bowel Surgery: A Randomized Controlled Trial.

BACKGROUND: Excess surgical stress responses, caused by heightened nociception, can lead to elevated levels of postoperative inflammation, resulting in an increased incidence of complications after surgery. We hypothesized that utilizing nociception monitor-guided multimodal general anesthesia would exert effects on postoperative outcomes (e.g., serum concentrations of C-reactive protein (CRP) after surgery, postoperative complications). METHODS: This single-center, double-blinded, randomized trial enrolled ASA class I/II adult patients with normal preoperative CRP levels, scheduled for laparoscopic bowel surgery. Patients were randomized to receive either standard care (control group) or nociception monitor-guided multimodal general anesthesia using the nociceptive response (NR) index (NR group), where NR index was kept below 0.85 as possible. The co-primary endpoint was serum concentrations of CRP after surgery or rates of 30-day postoperative complications (defined as Clavien-Dindo grades ≥ II). MAIN RESULTS: One hundred and four patients (control group, n = 52; NR group, n = 52) were enrolled for analysis. The serum CRP level on postoperative day (POD) 1 was significantly lower in the NR group (2.70 mg·dL-1 [95% confidence interval (CI), 2.19-3.20]) than in the control group (3.66 mg·dL-1 [95% CI, 2.98-4.34], p = 0.024). The postoperative complication rate was also significantly lower in the NR group (11.5% [95% CI, 5.4-23.0]) than in the control group (38.5% [95% CI, 26.5-52.0], p = 0.002). CONCLUSIONS: Nociception monitor-guided multimodal general anesthesia, which suppressed intraoperative nociception, mitigated serum concentrations of CRP level, and decreased postoperative complications after laparoscopic bowel surgery.

Biomechanical analysis of tendon regeneration capacity of Iberian ribbed newts following transection injury: Comparison to a mouse model.

Adult mammals are known for their poor ability to regenerate tissues, including tendons. On the other hand, urodeles have become an important model in regenerative studies for their remarkable ability to regenerate various body parts and organs throughout life, such as limbs, retinas, or even the brain. However, little is known about their capacity to regenerate injured tendons. If newts can also repair tendons without scar formation, they may be a suitable animal model for tendon regeneration studies in other adult vertebrates. Therefore, the present study used Iberian ribbed newts to characterize mechanical and structural regeneration of tendons following transection, using tensile tests and multiphoton microscopy. A digital flexor tendon in a hindlimb was transected either partially or completely, and regenerated tendon was examined 6 and 12 weeks after the operation. Tensile strength of regenerated tendons was significantly less than normal at 6 weeks, but was remarkably recovered at 12 weeks, reaching levels comparable to those of uninjured tendons. On the other hand, mouse tendons demonstrated poor recovery of strength even after 12 weeks. Multiphoton microscopy revealed that tendon-like collagenous tissue bridges residual tendon stubs in newts, but disorganized scar-like tissue filled the injured location in mice. These findings highlight the remarkable capacity of newts to recover from tendon injury and confirm the utility of newts as a model to study tendon regeneration.

Exploration of the Relationships between Men's Healthy Life Expectancy in Japan and Regional Variables by Integrating Statistical Learning Methods.

A quantitative understanding of the relationship between comprehensive health levels, such as healthy life expectancy and their related factors, through a highly explanatory model is important in both health research and health policy making. In this study, we developed a regression model that combines multiple linear regression and a random forest model, exploring the relationship between men's healthy life expectancy in Japan and regional variables from open sources at the city level as an illustrative case. Optimization of node-splitting in each decision tree was based on the total mean-squared error of multiple regression models in binary-split child nodes. Variations of standardized partial regression coefficients for each city were obtained as the ensemble of multiple trees and visualized on scatter plots. By considering them, interaction terms with piecewise linear functions were exploratorily introduced into a final multiple regression model. The plots showed that the relationship between the healthy life expectancy and the explanatory variables could differ depending on the cities' characteristics. The procedure implemented here was suggested as a useful exploratory method for flexibly implementing interactions in multiple regression models while maintaining interpretability.

Continuous glucose monitoring-derived time in range and CV are associated with altered tissue characteristics of the carotid artery wall in people with type 2 diabetes.

AIMS/HYPOTHESIS: Previous studies have suggested that glucose variability may accelerate atherosclerosis progression in people with type 2 diabetes. Current guidelines recommend assessing glycaemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycaemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and atherosclerosis progression is not entirely clear. METHODS: This exploratory study used baseline data and data obtained after 104 weeks from an ongoing prospective, multicentre, observational study. Six hundred study participants with type 2 diabetes and no apparent history of symptomatic cardiovascular disease underwent CGM and ultrasonographic atherosclerosis measurements of the carotid arteries, including the intima-media thickness (IMT) and grey-scale median (GSM), at baseline and 104 weeks. Non-invasive ultrasonic tissue characterisation of the carotid artery wall or plaque using the GSM reflects vascular composition. Multivariate regression models were used to analyse the association between CGM-derived indices, mainly time in range (TIR) and CV, and changes in carotid atherosclerosis index values. RESULTS: Over the 104-week study period, there were modest increases in mean IMT (from 0.759±0.153 to 0.773±0.152 mm, p<0.001) and thickened-lesion GSM (from 43.5±19.5 to 53.9±23.5 units, p<0.001), but no significant changes in common carotid artery maximum-IMT (from 1.109±0.442 to 1.116±0.469 mm, p=0.453) or mean GSM (from 48.7±19.3 to 49.8±20.8 units, p=0.092). In a linear regression model with adjustment for possible atherosclerotic risk factors, including HbA1c, TIR and CV at baseline were significantly associated with the annual change in mean GSM (regression coefficient per 10% increase in TIR 0.52; 95% CI 0.06, 0.98; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.12; 95% CI -0.22, -0.02; Hochberg-adjusted p value 0.038). TIR and CV at baseline were also significantly associated with the annual change in thickened-lesion GSM (regression coefficient per 10% increase in TIR 0.95; 95% CI 0.12, 1.79; Hochberg-adjusted p value 0.038; regression coefficient per 1% increase in CV -0.19; 95% CI -0.36, -0.01; Hochberg-adjusted p value 0.038). Participants who achieved target CGM-derived metrics at baseline, as proposed by an international consensus, showed significant annual changes in mean GSM compared with those who did not (0.94±6.88 vs -0.21±6.19 units/year, p=0.007). CONCLUSIONS/INTERPRETATION: TIR and CV were significantly associated with changes in the tissue characteristics of the carotid artery wall. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, number UMIN000032325.

[Sixteen Cases of Appendiceal Mucinous Neoplasm].

Appendiceal mucinous neoplasm is a relatively rare disease. It is classified as mucinous adenocarcinoma(MACA)and low- grade appendiceal mucinous neoplasm(LAMN). We retrospectively evaluated 16 cases of appendiceal mucinous neoplasm (LAMN: 13 cases, MACA: 3 cases)that were surgically resected in our hospital between January 2010 and July 2021. There were 7 men and 9 women, with a median age of 61 years(27-85 years). The most common chief complaint was abdominal pain(12 patients), while 3 cases were incidental findings following medical checkups for other diseases and without a chief complaint. Colonoscopy was performed for 9 cases. Of these, 5 revealed abnormal findings. The preoperative diagnosis was appendicitis in 7 patients and appendiceal tumor in 8 patients. The surgical procedures were planned for 8 cases and performed as emergencies in 8 cases. The procedures included laparoscopic surgery(n=6)and laparotomy(n=10). The resection range included appendectomy(n=9), partial cecal resection(n=4), and ileocecal resection(n=3). Surgical margins were negative in all cases. Metastases were not observed in patients who underwent lymph node dissections (2 patients with MACA and 1 patient with LAMN). The median follow-up was 17 months(1-43 months). Recurrence including peritoneal pseudomyxoma was not detected in any of the patients.

Determination of antibiotics by amperometry using nortropine N-oxyl, a highly active nitroxyl radical.

Nitroxyl radical compounds oxidize hydroxy groups and some amino groups upon application of an electric potential. The resulting anodic current depends on the concentration of these functional groups in solution. Thus, it is possible to quantify compounds containing these functional groups by electrochemical methods. Cyclic voltammetry has been used to evaluate the catalytic activity of nitroxyl radicals, and the ability of such radicals to sense biological and other compounds. In this study, we evaluated a method for quantifying compounds using constant-potential electrolysis (amperometry) of nitroxyl radicals for application in flow injection analysis and high-performance liquid chromatography as an electrochemical detector. When amperometry was performed using 2,2,6,6-tetramethylpiperidine 1-oxyl, a common nitroxyl radical compound, little change was observed even with 100 mM glucose due to its low reactivity in neutral aqueous solutions. In contrast, 2-azaadamantane N-oxyl and nortropine N-oxyl, which are highly active nitroxyl radicals, showed a concentration-dependent response in neutral aqueous solution. Responses of 33.8 and 125.9 µA, respectively, were observed. By recognition of hydroxy and amino groups, we have succeeded in the electrochemical detection of some drugs by amperometry. Streptomycin, an aminoglycoside antibiotic, was quantifiable in the range of 30-1000 µM.

Mechanism of rate controllability of water-soluble bifunctional cyclooctadiynes through cation-anion interactions.

Click reactions are used for chemoselective functionalization in many research fields. Despite the utility of small, bioinert azide groups as a counterpart, applications of strain-promoted alkyne-azide cycloaddition (SPAAC) reactions for this purpose are still limited by slow reaction kinetics. Here, we report ion-pair-guided reaction rate enhancement by the use of water-soluble cyclooctadiynes (WS-CODYs) composed of bifunctional strained alkynes and polar side chains. Arrhenius plot analysis revealed that the rate enhancement by WS-CODYs is due to a kinetic salt effect between the polar substituents and the target azide. We demonstrate the utility of these compounds for rapid protein labelling and isoelectric point-dependent labelling.

Ion-Pair-Enhanced Double-Click Driven Cell Adhesion and Altered Expression of Related Genes.

Bio-orthogonal ligations that crosslink living cells with a substrate or other cells require high stability and rapid kinetics to maintain the nature of target cells. In this study, we report water-soluble cyclooctadiyne (WS-CODY) derivatives that undergo an ion-pair enhanced double-click reaction. The cationic side chain of WS-CODY accelerated the kinetics on the azide-modified cell surface due to proximity effect. Cationic WS-CODY was able to crosslink azide-modified, poorly adherent human lung cancer PC-9 cells not only to azide-grafted glass substrates but also to other cells within 5-30 min. We discovered that cell-substrate crosslinking induced the ITGA5 gene expression, whereas cell-cell crosslinking induced the CTNNA1 gene, according to the adhesion partner. Ion-pair-enhanced WS-CODY can be applied to a wide range of cells with established azide modifications and is expected to provide a powerful tool to regulate cell-substrate and cell-cell interactions.

Neuroprotective effects of pravastatin in cerebral venous infarction in a rat model.

Objectives: Pravastatin sodium is reported to have multiple beneficial effects in cerebral atherosclerosis and neuronal injury; however, the preventive effects on cerebral venous ischemia are still unknown. Herein, we aimed to examine the neuroprotective effects of transoral prior administration of pravastatin sodium against cerebral cortical venous ischemia with suppression of apoptosis. Methods: Thirty 8-week-old male Wistar rats were divided equally into two study groups (n = 15 vs. n = 15); the pravastatin group was fed 1% pravastatin sodium with their usual diet for 2 weeks, while the control group only received the usual diet. Two-vein occlusion (2VO) model was applied for this study, and two adjacent cortical veins in each animal were permanently occluded photochemically with rose bengal dye. During photo-thrombosis, regional changes of the cerebral blood flow (CBF) in area of the venous ischemia were recorded. At 48-h after 2VO, animals were euthanized using perfusion fixation, and we histologically measured ratios of infarcted area to contralateral hemisphere, and counted Bax- and Bcl-2-positive cells in the penumbra to investigate the implications for apoptosis. Results: The ratio of infarcted area was significantly decreased in the pravastatin group compared to the control group (P < 0.01). The number of Bax-positive cells also decreased significantly in the pravastatin group (P < 0.01). In contrast, immunolabeling for Bcl-2 was essentially negative in all areas in both groups. There were also no significant differences in regional CBF changes after 2VO between the two groups (P = 0.13). Conclusions: Pre-emptive administration of pravastatin sodium mixed in the food has neuroprotective effects against cerebral cortical venous ischemia with suppression of apoptosis associated with inhibition of Bax expression but has little influence on regional CBF.

Electrochemical reactions of highly active nitroxyl radicals with thiol compounds.

Nitroxyl radicals are known to electrochemically oxidize thiols as well as alcohols and amines. In this study, a preliminary investigation of the electrochemical reaction of thiols with 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), 2-azaadamantane N-oxyl (AZADO), and nortropine N-oxyl (NNO), which are highly active due to their bicyclo structures, for use in electrochemical analysis was performed and the results were compared with those for a typical nitroxyl radical compound, 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO). Mercaptopropane sulfonic acid (MPS) was used as a model compound to investigate the electrochemical response in aqueous solution. In addition, electrochemical detection of glutathione, a biological thiol molecule, was performed.

Tranexamic acid and blood loss in pancreaticoduodenectomy: TAC-PD randomized clinical trial.

BACKGROUND: Tranexamic acid (TXA) may reduce intraoperative blood loss, but it has not been investigated in pancreaticoduodenectomy (PD). METHODS: A pragmatic, multicentre, randomized, blinded, placebo-controlled trial was conducted. Adult patients undergoing planned PD for biliary, duodenal, or pancreatic diseases were randomly assigned to TXA or placebo groups. Patients in the TXA group were administered 1 g TXA before incision, followed by a maintenance infusion of 125 mg/h TXA. Patients in the placebo group were administered the same volume of saline as those in the placebo group. The primary outcome was blood loss during PD. The secondary outcomes included perioperative blood transfusions, operating time, morbidity, and mortality. RESULTS: Between September 2019 and May 2021, 218 patients were randomly assigned and underwent surgery (108 in the TXA group and 110 in the placebo group). Mean intraoperative blood loss was 659 ml in the TXA group and 701 ml in the placebo group (mean difference -42 ml, 95 per cent c.i. -191 to 106). Of the 218 patients, 202 received the intervention and underwent PD, and the mean blood loss during PD was 667 ml in the TXA group and 744 ml in the placebo group (mean difference -77 ml, 95 per cent c.i. -226 to 72). The secondary outcomes were comparable between the two groups. CONCLUSION: Perioperative TXA use did not reduce blood loss during PD. REGISTRATION NUMBER: jRCTs041190062 (https://jrct.niph.go.jp).

Removing part of the pancreas is an operation with a risk of major blood loss. Tranexamic acid is a drug thought to reduce blood loss. This study asked the question, 'Does tranexamic acid reduce blood loss during surgery on the pancreas?' Half of patients received tranexamic acid during surgery. The other half received only standard care. This study showed that tranexamic acid did not decrease the blood loss during the surgery and may have little effect in patients having a pancreaticoduodenectomy.

Breast angiosarcoma after primary breast cancer surgery: A systematic review.

BACKGROUND: A potentially fatal disease of breast angiosarcoma (AS) can occur after breast cancer treatments, and previous studies have revealed that lymphedema is a risk factor of AS development. However, little is known, and there is no systematic review focusing on the relationship between lymphedema and breast AS. This systematic review aimed to evaluate all publications on breast AS after primary breast cancer surgery to identify prognostic factors and evaluate treatment modalities. METHODS: Databases were searched for articles with published individual patient data on prognostic factors, treatment, and follow-up of patients with breast AS after primary breast cancer surgery. Statistical analysis was performed to test the prognostic values of age, gender, location, tumor-node-metastasis classification of primary breast cancer (tumor and node), stage of primary breast cancer, treatment for primary breast cancer, breast cancer recurrence, post-operative lymphedema, latent period from primary breast cancer to AS, treatment for AS, AS recurrence, and time until death or last follow-up. RESULTS: Twenty articles were included, representing data on 41 patients. In these articles, 15 patients were referred to post-operative lymphedema. Eleven patients of them had post-operative lymphedema. As for this research, post-operative lymphedema was not a significant prognostic factor. AS recurrence was significant as a prognostic factor (P-value < 0.001) in univariate analysis for follow-up status; patients who had AS recurrence had a shorter time until death. CONCLUSION: In this systematic review, AS recurrence was of prognostic value for breast AS patients after primary breast cancer surgery. There are only a few articles that refer post-operative breast lymphedema.

The Importance of Continuous Glucose Monitoring-derived Metrics Beyond HbA1c for Optimal Individualized Glycemic Control.

CONTEXT: Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM) and hemoglobin A1c (HbA1c) measurement. OBJECTIVE: This study aimed to clarify the characteristics of patients who might benefit from CGM metrics in addition to HbA1c monitoring. METHODS: CGM metrics, specifically time in range (TIR), time below range (TBR), and time above range (TAR), were determined in 999 outpatients with type 2 diabetes and compared between HbA1c categories (HbA1c < 53 mmol/mol [7.0%, HbA1c <  53], HbA1c 53-63 mmol/mol [7.0-7.9%, HbA1c 53-63], HbA1c 64-74 mmol/mol [8.0-8.9%, HbA1c 64-74], and HbA1c ≥ 75 mmol/mol [9.0%, HbA1c ≥  75]) and between patients with identical HbA1c categories who were stratified by age, types of antidiabetic agents, and renal function. RESULTS: For HbA1c <  53 category, patients aged ≥ 65 years had a significantly higher nocturnal TBR than those aged < 65 years. For HbA1c <  53 and HbA1c 53-63 categories, patients receiving insulin and/or sulfonylureas had a significantly higher TAR and TBR, and a lower TIR than those not receiving these drugs, and for HbA1c 64-74 category, they had a significantly higher TBR. For HbA1c <  53, HbA1c 53-63, and HbA1c 64-74 categories, patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 had a significantly higher TBR during some periods than those with an eGFR ≥ 60. CONCLUSION: Higher HbA1c levels do not always protect against hypoglycemic episodes. Our data demonstrate that using CGM metrics to complement HbA1c monitoring is beneficial, especially in older people, users of insulin and/or sulfonylureas, and patients with chronic kidney disease.

Transition-Metal-Free Synthesis of Unsymmetrical Diaryl Tellurides via SH2 Reaction of Aryl Radicals on Tellurium.

Although diaryl tellurides are parent organotellurium compounds, their synthesis methods, especially for unsymmetrical ones, are limited. This may be due to the instability of diaryl tellurides and their synthesis intermediates under reaction conditions. Radical reactions are known to exhibit excellent functional group selectivity; therefore, we focused on a bimolecular homolytic substitution (SH2) reaction between the aryl radical and diaryl ditelluride. Aryl radicals are generated from arylhydrazines in air and captured by diaryl ditellurides, resulting in a selective formation of unsymmetrical diaryl tellurides with high yields. The electronic effects of the substituents on both arylhydrazines and diaryl ditellurides on the SH2 reaction of tellurium are also discussed in detail.

Awake Surgery for Local Recurrence of Brain Metastasis in the Precentral Gyrus After Fractionated Stereotactic Radiotherapy: A Technical Case Report.

BACKGROUND: To avoid permanent neurologic deficits and preserve brain function, intraoperative electrical stimulation mapping (IESM) is essential for surgical resection. CASE REPORT: A 59-year-old right-handed woman with ovarian cancer who had undergone stereotactic radiotherapy for brain metastasis two years before, was introduced due to progressive left upper paresis. Magnetic resonance imaging showed a recurrence of the lesion. We performed awake surgery using IESM. Thus, the sensorimotor site was elicited on the precentral and postcentral gyrus. However, IESM elicited no disturbance of motor function on the surface of the posterior part of the precentral gyrus. We made a safe corticotomy on it, and performed the resection of recurrent BM. Preserving the motor and sensory function, we achieved the resection of BM. After surgery, she experienced a significant improvement in motor function. CONCLUSION: IESM is a useful tool to make a safe approach via the precentral gyrus avoiding permanent sensorimotor deficits.

Investigations into the Potential of Using Open Source CFD to Analyze the Differences in Hemodynamic Parameters for Aortic Dissections (Healthy versus Stanford Type A and B).

BACKGROUND: The objective of this study was to develop a method to evaluate the effects of an aortic dissection on hemodynamic parameters by conducting a comparison with that of a healthy (nondissected) aorta. Open-source software will be implemented, no proprietary software/application will be used to ensure accessorily and repeatability, in all the data analysis and processing. Computed tomography (CT) images of aortic dissection are used for the model geometry segmentation. Boundary conditions from literature are implemented to computational fluid dynamics (CFD) to analyze the hemodynamic parameters. METHODS: A numerical simulation model was created by obtaining accurate 3-dimensional geometries of aortae from CT images. In this study, CT images of 8 cases of aortic dissection (Stanford type-A and type-B) and 3 cases of healthy aortae are used for the actual aorta model geometry segmentation. These models were exported into an open-source CFD software, OpenFOAM, where a simplified pulsating flow was simulated by controlling the flow pressure. Ten cycles of the pulsatile flow (0.50 sec/cycle) conditions, totaling 5 sec, were calculated. RESULTS: The pressure distribution, wall shear stress (WSS) and flow velocity streamlines within the aorta and the false lumen were calculated and visualized. It was found that the flow velocity and WSS had a high correlation in high WSS areas of the intermittent layer between the true and false lumen. Most of the Stanford type-A dissections in the study showed high WSS, over 38 Pa, at the systole phase. This indicates that the arterial walls in type-A dissections are more likely to be damaged with pulsatile flow. CONCLUSIONS: Using CFD to estimate localized high WSS areas may help in deciding to treat a type-A or B dissection with a stent graft to prevent a potential rupture.

Quantitative evaluation of the effects of interscalene block on physiological responses to the balance between nociception and anti-nociception among inpatients undergoing total shoulder arthroplasty under general anesthesia.

Although the suppression of physiological responses to the balance between nociception caused by surgical trauma and anti-nociception due to anesthesia during total shoulder arthroplasty (TSA) is relevant for better perioperative managements, quantitative evaluations of the effects of ultrasound-guided interscalene brachial plexus block (ISB) on physiological responses have not been performed. Physiological responses were assessed using the nociceptive response (NR) index. In this multi-institutional observational study, associations between ISB and NR values were examined among inpatients undergoing TSA under general anesthesia between March 2019 and January 2021. The effects of ISB on acute postoperative pain and major complications within 30 days after surgery were also examined. NR values after skin incision clearly showed significant suppressions of physiological responses in patients undergoing TSA with ISB (n = 60), compared to those without ISB (n = 24). Acute postoperative pain on the day of surgery was also significantly less in patients with ISB than in those without ISB. Postoperative complications, classified by Clavien-Dindo grades, showed no significant differences between patients with and without ISB. A propensity score-matched sensitivity analysis confirmed the same results in patients with (n = 21) and without ISB (n = 21). In conclusion, suppression of physiological responses to the balance between nociception and anti-nociception by ISB can be quantitatively evaluated by NR index during TSA.