Lithiophilic Reduced Graphene Oxide/Carbonized Zeolite Imidazolate Framework-8 Composite Host for Stable Li Metal Anodes.

Lithium (Li) metal is regarded as a next-generation anode material owing to its high energy density. However, issues such as dendritic growth and volume changes during charging and discharging pose significant challenges for commercialization. We propose using lithiophilic reduced graphene oxide (rGO) and carbonized zeolite imidazolate framework-8 (C-ZIF-8) composites as host materials for Li to address these problems. The rGO/C-ZIF-8 composites are synthesized through a simple redox reaction followed by carbonization and are characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS). The roles of chemical composition, characteristics, and morphology are demonstrated. As a result of these favorable structural and functional properties, the Li symmetric cell with rGO/C-ZIF-8 exhibits a stable voltage profile for more than 100 h at 1 mA cm-2 without short-circuiting. A relatively low Li plating/stripping overpotential of ~101.5 mV at a high current density of 10 mA cm-2 is confirmed. Moreover, a rGO/C-ZIF-8-Li full cell paired with a LiFePO4 cathode demonstrates good cyclability and rate capability.

Microwave-assisted solvothermal synthesis of nanostructured Ga-Doped Li7La3Zr2O12 solid electrolyte with enhanced densification and Li-ion conductivity.

Garnet-type Li7La3Zr2O12 (LLZO) Li-ion solid electrolytes are promising candidates for safe, next-generation solid-state batteries. In this study, we synthesize Ga-doped LLZO (Ga-LLZO) electrolytes using a microwave-assisted solvothermal method followed by low-temperature heat treatment. The nanostructured precursor (<50 nm) produced by the microwave-assisted solvothermal process has a high surface energy, facilitating the reaction for preparing garnet-type Ga-LLZO powders (<800 nm) within a short time (<5 h) at a low calcination temperature (<700 °C). Additionally, the calcined nanostructured Ga-LLZO powder can be sintered to produce a high-density pellet with minimized grain boundaries under moderate sintering conditions (temperature: 1150 °C, duration: 10 h). The optimal doping concentration was determined to be 0.4 mol% Ga, which resulted significantly increased the ionic conductivity (1.04 × 10-3 S cm-1 at 25 °C) and stabilized the cycling performance over 1700 h at 0.4 mA cm-2. This approach demonstrates the potential to synthesize oxide-type solid electrolyte materials with improved properties for solid-state batteries.

Linker Encouraged Solid State Synthesis of MOF Derived Z-Scheme NiCo2O4/NiO/C toward Efficient Removal of Organic and Inorganic Pollutants from Water.

Here, we represent a solid-state route for the construction of MOF derived multifunctional Z-scheme NiCo2O4/NiO/C applied for the photocatalytic removal of methylene blue (dye) and tetracycline (drug) and the reduction of Cr(VI) (heavy metal). The developed solid-state method yielded a highly effective NiCo2O4/NiO/C catalyst by mechanically grinding independently produced Ni and Co-MOFs and subsequently pyrolyzing them. The use of different linkers in the Ni MOF (H3-BTC linker) and Co-MOF (2-methylimidazole linker) proved to be effective in constructing the NiCo2O4/NiO/C composite, ensuring a nonaggregated distribution on a carbon framework. Such a synthesized Z-scheme NiCo2O4/NiO/C composite has performed exceptionally well to achieve excellent degradation of MB (98.23% in 120 min) and TC (92.85% in 25 min) and Cr(VI) reduction (98.22% in 20 min), with excellent recyclability and stability. The NiCo2O4/NiO/C composite, synthesized using Ni and Co-MOFs prepared with different linkers, outperformed its counterpart prepared using Ni and Co-MOFs with identical linkers (either 2-methylimidazole or H3BTC). This study paves the way for the future synthesis of MOF derived bimetallic composites for photocatalytic applications.

Elevation of circulating neutrophil extracellular traps in endometrial cancer: Poor prognostic value of cell-free double-stranded DNA.

OBJECTIVE: Neutrophils produce neutrophil extracellular traps (NETs) by releasing nuclear contents into the extracellular environment. NETs are associated with systemic inflammation and cancer development and progression. We aimed to investigate whether NET markers are associated with the prognosis of endometrial cancer. METHODS: Circulating levels of three NET markers (histone-DNA complex, cell-free double-stranded DNA (dsDNA), and neutrophil elastase) were measured in 98 patients with endometrial cancer who underwent surgery as primary treatment between January 2015 and June 2018 and 45 healthy women. Area under the receiver operating characteristic curve (AUC) analyses were conducted to investigate the diagnostic and prognostic utility of the markers for endometrial cancer. RESULTS: Patients with endometrial cancer showed significantly higher levels of the three NET markers than those in healthy controls. In discriminating endometrial cancer patients from healthy controls, the three NET markers showed AUC values in the following order: cell-free dsDNA (0.832; 95 % CI, 0.760-0.889), histone-DNA complex (0.740; 95 % CI, 0.660-0.809), and neutrophil elastase (0.689; 95 % CI, 0.607-0.764), comparable to those of CA-125 (0.741; 95 % CI, 0.659-0.813). Multivariate analysis adjusting for FIGO stage, histology, and lymphovascular space invasion, and lymph node involvement revealed that cell-free dsDNA level (cutoff: 95.2 ng/mL) was an independent prognostic marker for poor progression-free (adjusted HR, 2.75; 95 % CI, 1.096.92; P = 0.032) and overall survival (adjusted HR, 11.51; 95 % CI, 2.0664.22; P = 0.005) for patients with endometrial cancer. CONCLUSION: High levels of circulating NET markers were observed in patients with endometrial cancer. Cell-free dsDNA levels may play a role as prognostic markers for endometrial cancer.

Elevated circulating levels of neutrophil extracellular traps after cardiopulmonary bypass surgery as risk factors of postoperative atrial fibrillation and mortality.

Background: Cardiopulmonary bypass (CPB) can trigger a systemic inflammatory response during the perioperative period, which may lead to the consumption of the contact system and the production of neutrophil extracellular traps (NETs). This study attempted to determine whether the formation of NETs and contact activation are a vivid occurrence during CPB and whether they are related to post-operative atrial fibrillation (AF) and survival. Methods: A prospective observational study was conducted in 97 patients who underwent aortic valve and/or aorta replacement surgery with CPB. Circulating markers of NETs [histone-DNA complex, cell-free double stranded DNA (dsDNA), neutrophil elastase] and the contact system [prekallikrein, high molecular weight kininogen (HMWK), activated factor XII (FXIIa)] were measured at four-time points: before surgery (T0), immediately after surgery (T1), 1 day after surgery (T2), and 3 days after surgery (T3). Results: Elevated levels of circulating NETs markers were observed across post-CPB time. Significantly elevated levels of histone-DNA complex and cell-free dsDNA measured T3 were detected in patients with post-operative AF compared to those without. In logistic regression analysis, levels of histone-DNA complex and cell-free dsDNA measured at T3 were significant markers of risk for occurrence of AF. The levels of cell-free dsDNA measured T2 were significantly higher in non-survivors than in survivors. The level of cell-free dsDNA showed significant prognostic value. Conclusions: NETs markers may be useful for the assessment of risk for post-operative AF and mortality. Conduct of additional research regarding the role of NETs as clinical markers and as a therapeutic target in CPB is anticipated.

Plasma apixaban concentrations and thrombin generation assay parameters in response to dose reduction for atrial fibrillation.

AIMS: To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban. METHODS: This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n = 166); (ii) on-label reduced dose (2.5 mg twice daily, n = 55); and (iii) off-label underdose (2.5 mg twice daily, n = 153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels. RESULTS: The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P < .001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P = .005) and standard-dose (12.7%, P < .001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations. CONCLUSION: Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria.

Correction to: A combined extract containing Schisandra chinensis (SCE) reduced hepatic triglyceride accumulation in rats fed a high­sucrose diet.

[This corrects the article DOI: 10.1007/s10068-023-01464-1.].

Medial Rectus Disinsertion for the Management of Large-Angle Sensory Esotropia.

Background and Objectives: The aim of the report is to report the outcomes of the medial rectus (MR) disinsertion procedure for the management of large-angle esotropia (ET) patients. Materials and Methods: This is a retrospective case series of patients with large-angle ET who underwent an MR disinsertion procedure between March 2012 to April 2022. The procedure happened accidentally during muscle surgery. The demographic and clinical data, including sex, age, visual acuity, pre- and postoperative angle of strabismus, duction limitations, results of intraoperative forced duction tests, and follow-up duration were collected from medical records. Results: Five patients were enrolled in this study. The mean age was 62.2 ± 9.8 years, and the mean follow-up was 24.8 ± 8.7 months. The ET at the primary position of gaze was 92.0 ± 17.9 prism diopters (PD) before MR disinsertion and 38.0 ± 29.5 PD after MR disinsertion only. Abduction deficiency was -4 before after MR disinsertion, which improved to -1 at the last follow-up. Conclusions: The results of MR disinsertion were not as frustrating as anticipated. MR disinsertion may be considered in patients with large-angle sensory ET who refuse surgery on the opposite eye.

Mutational analysis of pig tissue factor pathway inhibitor α to increase anti-coagulation activity in pig-to-human xenotransplantation.

Blood coagulation mediated by pig tissue factor (TF), which is expressed in pig tissues, causes an instant blood-mediated inflammatory reaction during pig-to-human xenotransplantation. Previously, we generated a soluble pig tissue factor pathway inhibitor α fusion immunoglobulin (TFPI-Ig) which inhibits pig TF activity more efficiently than human TFPI-Ig in human plasma. In this study, we generated several pig TFPI-Ig mutants and tested the efficacy of these mutants in preventing pig-to-human xenogeneic blood coagulation. Structurally important amino acid residues of pig TFPI-Ig were changed into different residues by site-directed mutagenesis. Subsequently, a retroviral vector encoding each cDNA of several pig TFPI-Ig mutants was cloned and transduced into CHO-K1 cells. After establishing stable cell lines expressing each of the pig TFPI-Ig mutants, soluble proteins were produced and purified for evaluating their inhibitory effects on pig TF-mediated blood coagulation in human plasma. The replacement of K36 and K257 with R36 and H257, respectively, in pig TFPI-Ig more efficiently blocked pig TF activity in human plasma when compared with the wild-type pig TFPI-Ig. These results may provide additional information to understand the structure of pig TFPIα, and an improved pig TFPI-Ig variant that more efficiently blocks pig TF-mediated blood coagulation during pig-to-human xenotransplantation.

Generation of a human induced pluripotent stem cell line (YUCMi020-A) from peripheral blood mononuclear cells derived from a female with the Jr(a-) blood type.

The Jra antigen, the only antigen within the JR blood group system, is a high-prevalence red blood cell (RBC) antigen found in over 99 % of the global population. An induced pluripotent stem cell line (YUCMi020-A) was generated from peripheral blood drawn from a Jr(a-) phenotype individual, who was homozygous for a null mutation of ABCG2*01N.01 (rs72552713, c.376C>T; p.Gln126*). The generated line exhibited pluripotent characteristics and no chromosomal aberrations. This cell line will serve as a cell source, enabling us to produce RBCs with the Jr(a-) phenotype in vitro, which can be used for transfusing individuals with anti-Jra antibodies.

Differences in running biomechanics and tibiotalar cartilage T2 relaxation time between runners with and without asymptomatic tibial sesamoid bone marrow edema - clinical case series.

The impact of asymptomatic bone marrow edema (BME) in sesamoids on running biomechanics remains largely unknown, but exploring this relationship could aid early detection of forefoot-related injuries with cost-effective modalities. This study aimed to compare the running biomechanics of runners with asymptomatic BME in the tibial sesamoids with that of healthy controls. Four runners with asymptomatic BME in tibial sesamoids and four healthy runners participated. Lower extremity joint kinetics and kinematics were assessed along with plantar pressure while running at a self-selected speed. The T2 relaxation time of the tibiotalar cartilage was measured using MRI-derived T2 maps. Compared to the non-injured group, the injured group exhibited significantly lower plantar pressure under the hallux (p = 0.001), increased peak ankle rotation angles (p = 0.025), reduced ankle power generation (p = 0.049), and increased knee extension torque (p = 0.015). No significant differences in T2 values of the tibiotalar cartilage were observed. It appears that runners with asymptomatic BME adapted their running strategies by modifying their ankle biomechanics and reducing plantar pressure, even in the absence of pain. While the precise implications of these biomechanical alterations warrant further investigation, this study provides valuable insights into the relationship between asymptomatic BME and running biomechanics.

Sublethal Effects of Spirotetramat, Cyantraniliprole, and Pymetrozine on Aphis gossypii (Hemiptera: Aphididae).

The toxicity and sublethal effects of three insecticides (spirotetramat, cyantraniliprole, and pymetrozine) on Aphis gossypii, a major agricultural pest, were investigated. The nymphal stage showed greater susceptibility than the adult stage to all the insecticides, with a difference of up to 8.9 times at the LC50 of spirotetramat. The effects of sublethal concentrations (LC10, LC30, LC50, and LC70) of the insecticides on the on the developmental period, survival rate, adult longevity, fecundity, and deformity rate were compared with those of the control. Compared with the control, cyantraniliprole and pymetrozine did not significantly affect the developmental period in the parental or F1 generation when applied at the nymphal stage at any concentration. Nonviable nymphs occurred in the F1 generation when both nymphs and adults were treated with spirotetramat and cyantraniliprole but not in the F2 generation. The age-specific maternity (lxmx) of A. gossypii treated with sublethal concentrations (LC10, LC30) decreased with increasing concentration. Spirotetramat at the LC30 resulted in significant differences in all life table parameters (R0, rm, λ, T, DT) compared with those of the control. Similarly, compared with that of the control (43.8), the net reproductive rate (R0) significantly decreased for all the insecticides except cyantraniliprole at the LC10 (37.5). Therefore, this study indicated that sublethal concentrations (over the LC30) of spirotetramat, cyantraniliprole, or pymetrozine might be useful for the density management of A. gossypii.

A combined extract containing Schisandra chinensis (SCE) reduced hepatic triglyceride accumulation in rats fed a high-sucrose diet.

Excessive hepatic lipid accumulation is closely linked to inflammation, insulin resistance, and metabolic syndromes. We hypothesized that a combined extract containing Schisandra chinensis (SCE) could alleviate hepatic lipid accumulation. Male Sprague-Dawley rats fed a high-sucrose diet (HSD) were randomly assigned to three groups (n = 6): normal diet (ND), HSD (60% kcal from sucrose), and HSD + SCE (HSD with 2.44% SCE). Liquid chromatography-tandem mass spectrometry revealed that SCE contains chlorogenic acid (5.514 ± 0.009 mg/g) and schisandrin (0.179 ± 0.002 mg/g) as bioactive components. SCE did not alter the body weight, fat mass, lean mass, or glucose levels. Strikingly, SCE effectively reduced the plasma triglyceride (TG) and hepatic TG levels compared to the HSD group. Adiposity reduction is due to decreased activity of hepatic de novo lipogenic enzymes. These results indicated that SCE has nutraceutical potential for the prevention and treatment of hepatic steatosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01464-1.

Comparative analysis of adverse drug reactions associated with new antiseizure medications from the Korea Adverse Event Reporting System database.

OBJECTIVE: This study aimed to compare and characterize the safety profiles of new antiseizure medications (ASMs) using a nationwide pharmacovigilance database from a long-term perspective in Korea. METHODS: We reviewed adverse event reports from the Korea Adverse Event Reporting System database between January 2013 and December 2022 for descriptive analysis of six new ASMs (lacosamide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, and zonisamide). We investigated the frequency and characteristics of adverse drug reactions (ADRs) based on the MedDRA terminology, system organ classes, and modified WHO classification. RESULTS: We identified 5,733 reported cases of ADRs. The commonly reported ADRs associated with total ASMs were rash/urticaria (1,822, 31.8 %), dizziness (409, 7.1 %), somnolence/drowsiness (311, 5.4 %), and hepatotoxic effects (273, 4.8 %). Type B (idiosyncratic) effects (2,932; 51.1 %) were more commonly reported than Type A (related to known drug mechanisms) effects (2,613; 45.6 %). Skin and subcutaneous tissue disorders and type B effects were most commonly reported for lamotrigine and oxcarbazepine, whereas nervous system disorders and type A effects were most commonly reported for lacosamide, topiramate, and zonisamide. The pediatric group (<18 years) exhibited skin and subcutaneous tissue disorders and type B effects relatively more frequently than the adult and older adult groups. CONCLUSION: Hypersensitivity skin reactions and type B effects remained significant ADRs in the new ASMs; however, type A effects were more commonly reported in some ASMs. The pediatric group showed a higher rate of type B effects. Overall, new ASMs should also be used with caution.

Evaluating the TaqMan Jra-Genotyping Method for Rapidly Predicting the Presence of Anti-Jra Antibodies.

Background: The Jra antigen is a high-prevalence red blood cell (RBC) antigen. Reports on cases of fatal hemolytic disease of the fetus and newborn and acute hemolytic transfusion reactions suggest that antibodies against Jra (anti-Jra) have potential clinical significance. Identifying anti-Jra is challenging owing to a lack of commercially available antisera. We developed an alternative approach to rapidly predict the presence of anti-Jra using the TaqMan single-nucleotide polymorphism (SNP)-genotyping method. Methods: Residual peripheral blood samples from 10 patients suspected of having the anti-Jra were collected. Two samples with confirmed Jr(a-) RBCs and anti-Jra were used to validate the TaqMan genotyping assay by comparing the genotyping results with direct sequencing. The accuracy of the assay in predicting the presence of anti-Jra was verified through crossmatching with in-house Jr(a-) O+ RBCs. Results: The TaqMan-genotyping method was validated with two Jr(a-) RBC- and anti-Jra-confirmed samples that showed concordant Jra genotyping and direct sequencing results. Jra genotyping for the remaining samples and crossmatching the serum samples with inhouse Jr(a-) O+ RBCs showed consistent results. Conclusions: We validated a rapid, simple, accurate, and cost-effective method for predicting the presence of anti-Jra using a TaqMan-based SNP-genotyping assay. Implementing this method in routine practice in clinical laboratories will assist in solving difficult problems regarding alloantibodies to high-prevalence RBC antigens and ultimately aid in providing safe and timely transfusions and proper patient care.

CEBPA double mutations associated with ABO antigen weakness in hematologic diseases.

ABSTRACT: ABO antigen weakness is rarely observed in ABO typing for transfusion. Hematologic diseases and associated gene mutations have been suggested as potential causes of this phenomenon, yet the precise etiology has not been elucidated. Through ABO typing and genetic analysis data conducted over 7 years, we have reconfirmed the association between ABO antigen weakness and hematologic diseases, especially acute myeloid leukemia (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.12-5.83) and myelodysplastic syndrome (OR, 6.94; 95% CI, 2.86-16.83), and discovered previously unidentified candidate genes, CEBPA (OR, 43.70; 95% CI, 18.12-105.40), NRAS (OR, 3.37; 95% CI, 1.46-7.79), U2AF1 (OR, 8.12; 95% CI, 2.86-23.03), and PTPN11 (OR, 4.52; 95% CI, 1.51-13.50), seemingly associated with this phenomenon. Among these, CEBPA double mutations displayed a significant association, with ABO antigen weakness being observed in 20 of the 25 individuals (80.0%) possessing these mutations. From this study, new factors associated with ABO antigen weakness have been identified.

Effect of MIND diet on cognitive function in elderly: a narrative review with emphasis on bioactive food ingredients.

As the world becomes a super-aged society, cognitive decline is public health problems that are increasing rapidly. A healthy diet has great potential for maintaining cognitive health. A diet that could delay the onset of neurodegenerative diseases has been developed: the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, a hybrid form of the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet. In this review, the effects of the MIND diet on improving cognitive function, including memory, are summarized. In most studies, the higher the adherence to the MIND diet, the higher the cognitive function evaluation score, and the lower the incidence of dementia. This is because of the anti-inflammatory and antioxidant effects of the major nutritional components of the MIND diet: folate, carotenoids, polyphenols, and polyunsaturated fatty acids. Adherence to the MIND diet, containing various bioactive food ingredients, is related to cognitive improvement in the elderly population.

Decision-making experiences regarding kidney transplant among older adults in South Korea: A qualitative descriptive study.

OBJECTIVES: To explore the decision-making experiences of older patients with end-stage renal disease who chose to undergo kidney transplantation. METHODS: This was a qualitative descriptive study.Twelve participants aged over 60 years who underwent kidney transplantation were recruited from a kidney transplant clinic in a hospital in South Korea. Individual in-depth interviews were conducted from March to April 2021. The data were analysed using inductive thematic analysis. RESULTS: Four main themes were identified: 1) hesitation towards complex and risky kidney transplant, 2) internal suffering due to social prejudice and limits, 3) taking a step back from the decision-making process, and 4) being rushed into a decision on the brink of death. CONCLUSION: Older patients with end-stage renal disease experience hesitation and difficulties and are passive in the decision-making process for a kidney transplant. They lacked sufficient relevant information and decided to receive transplant surgery, feeling pressured by the recommendations of family and healthcare providers. PRACTICE IMPLICATIONS: Healthcare professionals should help older patients with end-stage renal disease make proactive decisions by providing tailored education programs and improving communication between the patients and their family members. Changing negative social perceptions and implementing supportive policies are necessary to resolve the difficulties experienced by such patients. PATIENT OR PUBLIC CONTRIBUTION: Patients were involved in the data collection as interview participants in this study.

Cardiovascular risk trajectory and its associated factors among candidates on the waiting list for deceased-donor kidney transplantation: A longitudinal study.

BACKGROUND: Cardiovascular disease is a significant cause of morbidity and mortality for wait-listed kidney transplant candidates. Since cardiovascular risk is related to a variety of factors and may change with time, longitudinal changes in cardiovascular risk and related factors in candidates need to be investigated. OBJECTIVES: This study aimed to examine the trajectory of the cardiovascular risk score and its related factors in patients on the waiting list for deceased-donor kidney transplantation (DDKT). METHODS: This longitudinal study enrolled 144 patients who were registered as candidates for a DDKT at a transplant center in South Korea. During the 5-year follow-up period, 3 candidates on the waiting list were transferred to other hospitals, 19 candidates died, and 31 candidates received kidney transplantation. RESULTS: Approximately 26.6 % of the candidates had a high level of cardiovascular risk, and this increased to 53.2 % after 5 years. A high risk of psychosocial status (ß=0.351, p=.026) was the most significant predictor of cardiovascular risk, followed by higher comorbidity (ß=0.263, p<.001). Comorbidities were a significant factor associated with cardiovascular risk throughout the 5-year period, whereas the duration of dialysis and waiting time were significant only within 1 year after baseline. CONCLUSION: Cardiovascular risk during 5 years on the waiting list for DDKT was associated with multidimensional factors, including psychosocial status before transplantation, comorbidity, waiting time for transplantation, and the duration of dialysis. In addition to managing comorbid conditions, shortening the waiting time and duration of dialysis is important for reducing cardiovascular risk during the long-term care of candidates on the waiting list for DDKT.