Application of the National Comprehensive Cancer Network-distress thermometer in pediatric patients during autologous and allogeneic hematopoietic stem cell transplantation and relationship to blood parameters of the stress axis.

PURPOSE: Hematopoietic stem cell transplantations (HSCT) are extremely stressful procedures for pediatric patients. The activation of the hypothalamic pituitary adrenocortical axis (HPA) can influence the immune system negatively and therefore the overall outcome. The distress thermometer (DT) is an easy to use tool for the self-assessment of perceived distress. METHODS: In this prospective study, a DT with an attached problem list was used in 40 pediatric patients undergoing HSCT and in one parent of each patient. The patients were aged 10-18 years. The patients' cortisol, thyroid stimulating hormone, free triiodothyronine and thyroxine levels were measured regularly during the in-patient stay. RESULTS: After admission to the hospital, the stress levels of the pediatric patients and their parents increased and reached their maximum on the day of HSCT. The overall stress values of the parents were higher than those of their children. There was a significant difference in the parents' stress levels on the day of HSCT, as compared to their stress levels on other days. The mean cortisol values of the pediatric patients also increased after admission, reaching significant elevated levels above the upper normal limit 1 week after HSCT and on discharge day. Although the pediatric patients experienced mainly exhaustion, especially on the day of transplantation, their parents mainly felt worry and anxiety. Interestingly, the rate of worry among children increased in the post-transplant period and reached its maximum on the day of discharge. CONCLUSIONS: In summary, a significantly increased stress level is shown for both the patients and their parents. This is reflected for the patients both in the DT scores and in the increased cortisol values. For the parents, the focus is primarily on worry and anxiety, for the patients primarily on exhaustion and worry.

Swarming Multifunctional Heater-Thermometer Nanorobots for Precise Feedback Hyperthermia Delivery.

Micro-/nanorobots (MNRs) are envisioned to act as "motile-targeting" platforms for biomedical tasks due to their ability to propel and navigate in challenging, hard-to-reach biological environments. However, it remains a great challenge for current swarming MNRs to accurately report and regulate therapeutic doses during disease treatment. Here we present the development of swarming multifunctional heater-thermometer nanorobots (HT-NRs) and their application in precise feedback photothermal hyperthermia delivery. The HT-NRs are designed as photothermal-responsive photonic nanochains consisting of magnetic Fe3O4 nanoparticles arranged periodically in one dimension and encapsulated in a temperature-responsive hydrogel shell. The HT-NRs exhibit energetic and controllable swarming motions under a rotating magnetic field, while simultaneously functioning as motile nanoheaters and nanothermometers, utilizing their photothermal conversion and (photo)thermal-responsive structural color changes (photothermochromism). Consequently, the HT-NRs can be quickly deployed to a remote target area (e.g., a superficial tumor lesion) using their collective motion and selectively eliminate diseased cells in a specific targeted region by utilizing their self-reporting photothermochromism as visual feedback for precisely regulating external light irradiation. This work may inspire the development of intelligent multifunctional theranostic micro-/nanorobots and their practical applications in precise disease treatment.

Thermal Probing Techniques for a Single Live Cell.

Temperature is a significant factor in determining and characterizing cellular metabolism and other biochemical activities. In this study, we provide a brief overview of two important technologies used to monitor the local temperatures of individual living cells: fluorescence nano-thermometry and an array of micro-/nano-sized thin-film thermocouples. We explain some key technical issues that must be addressed and optimised for further practical applications, such as in cell biology, drug selection, and novel antitumor therapy. We also offer a method for combining them into a hybrid measuring system.

A systematic review of the translation and validation methods used for the national comprehensive cancer network distress thermometer in non-English speaking countries.

OBJECTIVE: The National Comprehensive Cancer Network (NCCN) distress thermometer (DT) was developed as a brief screening tool for detecting distress in cancer patients. Conceptually, distress was considered a more acceptable and inclusive term than other psychological terms such as depression or anxiety. It is used extensively in the United States and other English-speaking countries. We aim to describe the translation and validation methods of the DT and describe the recommended cutoff scores used to identify cancer patients experiencing clinically significant distress. METHODS: Nine bibliographic databases were searched using keywords to identify original research studies for non-English speaking countries' cancer patients. Full articles were independently assessed for inclusion and data extraction by two authors. RESULTS: The review of 4442 articles yielded 39 articles that validated the DT. We identified 20 languages in 25 countries. In all but one country, investigators were able to agree upon a word or phrase that meant distress in their native language that was subsequently validated against standardized instruments. Asian, Middle Eastern and European counties recommended cutoff score of 4 or 5 to identify clinically significant distress; however, European Union countries had a range of 2 to 7. CONCLUSIONS: Use of the translated DT with non-English speaking cancer patients provides a simple and quick tool to identify high distress. Similar to NCCN, the cutoff score of 4 or 5 was suggested by 78% of the studies; however, more studies of different types of cancer and within and among more countries will strengthen a recommended global DT cutoff score.

Age-stratified distress thermometers with Worry and Learning problem domains for the paediatric oncology population: Development and validation.

BACKGROUND: The long-term psychological/neuro-psychological sequalae for a minority of survivors of childhood cancer are considerable. This project aims to develop and validate a psychosocial and memory/learning distress thermometer (DT) for paediatric/young adult cancer patients. METHODS: Pilot/Development Age-appropriate versions of the DT were developed. A pilot study tested acceptability, usability, and design. VALIDATION: Seven collaborating paediatric-oncology centres with 549 participants validated the DT against Strengths and difficulties questionnaire (SDQ) and Hospital Anxiety and depression scale (HADS) for psychological issues, Utilities Index Mark 2 (HUI2) for memory/learning issues, PedsQL and SF-8 measured quality of life. RESULTS: Using a cut-off of four, sensitivity against SDQ for under 18 was 75.8%, 18plus against HADS was 94.1%. The specificity was 53.3% against the SDQ for the 18plus specificity against the HADS was 47.1%. The sensitivity against the HUI2 for all age groups was 89.0% specificity was 70.3%. CONCLUSION: The DT is a valid and reliable measure screening instrument. It can be used to identify early on those experiencing psychological distress and memory problems.

Evaluating the interchangeability of infrared and digital devices with the traditional mercury thermometer in hospitalized pediatric patients: an observational study.

Gradual replacement of the mercury thermometers with alternative devices is ongoing around the world in a bid to protect human health and the environment from the adverse effects of mercury. However, to reduce the risks of misdiagnosis, unnecessary treatments, and omission of care in pediatric populations, more evidence on the reliability of alternative thermometers is needed. The aim of this comparative observational study was to detect any differences in temperature measurements between the use of the axillary mercury thermometer and the alternative techniques. Temperature values in degree Celsius (°C) were measured in a group of Albanian children aged up to 14 years using mercury and digital axillary thermometers, as well as forehead and tympanic infrared thermometers. The digital axillary device, compared with the mercury one, showed no clinically significant difference in the mean values (- 0.04 ± 0.29 °C) and the narrowest 95% level of agreement (+ 0.53 °C to - 0.62 °C) in the paired comparisons. For cut-off point of 37.5 °C, the digital axillary thermometer showed the highest levels of sensitivity (72.5%) and specificity (99.1%) in detecting fever. This study indicates that the digital axillary thermometer may be the better option since it adequately balances accuracy, safety, and children's comfort.

A Sensitive and Reliable Organic Fluorescent Nanothermometer for Noninvasive Temperature Sensing.

Sensing temperature at the subcellular level is of great importance for the understanding of miscellaneous biological processes. However, the development of sensitive and reliable organic fluorescent nanothermometers remains challenging. In this study, we report the fabrication of a novel organic fluorescent nanothermometer and study its application in temperature sensing. First of all, we synthesize a dual-responsive organic luminogen that can respond to the molecular state of aggregation and environmental polarity. Next, natural saturated fatty acids with sharp melting points as well as reversible and rapid phase transition are employed as the encapsulation matrix to correlate external heat information with the fluorescence properties of the luminogen. To apply the composite materials for biological application, we formulate them into colloidally dispersed nanoparticles by a technique that combines in situ surface polymerization and nanoprecipitation. As anticipated, the resultant zwitterionic nanothermometer exhibits sensitive, reversible, reliable, and multiparametric responses to temperature variation within a narrow range around the physiological temperature (i.e., 37 °C). Taking spectral position, fluorescence intensity, and fluorescence lifetime as the correlation parameters, the maximum relative thermal sensitivities are determined to be 2.15% °C-1, 17.06% °C-1, and 17.72% °C-1, respectively, which are much higher than most fluorescent nanothermometers. Furthermore, we achieve the multimodal temperature sensing of bacterial biofilms using these three complementary fluorescence parameters. Besides, we also fabricate a cationic form of the nanothermometer to facilitate efficient cellular uptake, holding great promise for studying thermal behaviors in biological systems.

Axillary Digital Thermometers uplifted a multidrug-susceptible Candida auris outbreak among COVID-19 patients in Brazil.

OBJECTIVES: To describe the first outbreak of Candida auris in Brazil, including epidemiological, clinical and microbiological data. METHODS: After the first Candida auris-colonised patient was diagnosed in a COVID-19 ICU at a hospital in Salvador, Brazil, a multidisciplinary team conducted a local C. auris prevalence investigation. Screening cultures for C. auris were collected from patients, healthcare workers and inanimate surfaces. Risk factors for C. auris colonisation were evaluated, and the fungemia episodes that occurred after the investigation were also analysed and described. Antifungal susceptibility of the C. auris isolates was determined, and they were genotyped with microsatellite analysis. RESULTS: Among body swabs collected from 47 patients, eight (n = 8/47, 17%) samples from the axillae were positive for C. auris. Among samples collected from inanimate surfaces, digital thermometers had the highest rate of positive cultures (n = 8/47, 17%). Antifungal susceptibility testing showed MICs of 0.5 to 1 mg/L for AMB, 0.03 to 0.06 mg/L for voriconazole, 2 to 4 mg/L for fluconazole and 0.03 to 0.06 mg/L for anidulafungin. Microsatellite analysis revealed that all C. auris isolates belong to the South Asian clade (Clade I) and had different genotypes. In multivariate analysis, having a colonised digital thermometer was the only independent risk factor associated with C. auris colonisation. Three episodes of C. auris fungemia occurred after the investigation, with 30-day attributable mortality of 33.3%. CONCLUSIONS: Emergence of C. auris in Salvador, Brazil, may be related to local C. auris clade I closely related genotypes. Contaminated axillary monitoring thermometers may facilitate the dissemination of C. auris reinforcing the concept that these reusable devices should be carefully cleaned with an effective disinfectant or replaced by other temperature monitoring methods.

Reaching Deeper: Absolute In Vivo Thermal Reading of Liver by Combining Superbright Ag2S Nanothermometers and In Silico Simulations.

Luminescent nano-thermometry is a fast-developing technique with great potential for in vivo sensing, diagnosis, and therapy. Unfortunately, it presents serious limitations. The luminescence generated by nanothermometers, from which thermal readout is obtained, is strongly distorted by the attenuation induced by tissues. Such distortions lead to low signal levels and entangle absolute and reliable thermal monitoring of internal organs. Overcoming both limitations requires the use of high-brightness luminescent nanothermometers and adopting more complex approaches for temperature estimation. In this work, it is demonstrated how superbright Ag2S nanothermometers can provide in vivo, reliable, and absolute thermal reading of the liver during laser-induced hyperthermia. For that, a new procedure is designed in which thermal readout is obtained from the combination of in vivo transient thermometry measurements and in silico simulations. The synergy between in vivo and in silico measurements has made it possible to assess relevant numbers such as the efficiency of hyperthermia processes, the total heat energy deposited in the liver, and the relative contribution of Ag2S nanoparticles to liver heating. This work provides a new way for absolute thermal sensing of internal organs with potential application not only to hyperthermia processes but also to advanced diagnosis and therapy.

Tympanic thermometers support fast and accurate temperature monitoring in acute and alternative care.

This article explores body temperature and the physiological process of thermoregulation. Normal body temperature and body temperature changes are discussed, including comorbidities associated with body temperature and signs of hyperthermia and hypothermia, and the factors that affect intraoperative temperature regulation. The evidence base behind thermometry is discussed and is applied to contemporary clinical conditions and symptoms, including: sepsis and suspected COVID-19. After discussing clinical considerations and regulations that encompass thermometry, three case studies present the use of the Genius 3 Tympanic Thermometer in clinical practice, with user feedback supporting its benefits, which include speed, accuracy and ease of use.

Non-contact infrared versus axillary and tympanic thermometers in children attending primary care: a mixed-methods study of accuracy and acceptability.

BACKGROUND: Guidelines recommend measuring temperature in children presenting with fever using electronic axillary or tympanic thermometers. Non-contact thermometry offers advantages, yet has not been tested against recommended methods in primary care. AIM: To compare two different non-contact infrared thermometers (NCITs) to axillary and tympanic thermometers in children aged ≤5 years visiting their GP with an acute illness. DESIGN AND SETTING: Method comparison study with nested qualitative component. METHOD: Temperature measurements were taken with electronic axillary (Welch Allyn SureTemp®), electronic tympanic (Braun Thermoscan®), NCIT Thermofocus® 0800, and NCIT Firhealth Forehead. Parents rated acceptability and discomfort. Qualitative interviews explored parents' experiences of the thermometers. RESULTS: In total, 401 children were recruited (median age 1.6 years, 50.62% male). Mean difference between the Thermofocus NCIT and axillary thermometer was -0.14°C (95% confidence interval [CI] = -0.21 to -0.06°C); lower limit of agreement was -1.57°C (95% CI = -1.69 to -1.44°C) and upper limit 1.29°C (95% CI = 1.16 to 1.42°C). A second NCIT (Firhealth) had similar levels of agreement; however, the limits of agreement between tympanic and axillary thermometers were also wide. Parents expressed a preference for the practicality and comfort of NCITs, and were mostly negative about their child's experience of axillary thermometers. But there was willingness to adopt whichever device was medically recommended. CONCLUSION: In a primary care paediatric population, temperature measurements with NCITs varied by >1°C compared with axillary and tympanic approaches. But there was also poor agreement between tympanic and axillary thermometers. Since clinical guidelines often rely on specific fever thresholds, clinicians should interpret peripheral thermometer readings with caution and in the context of a holistic assessment of the child.

Development of hypothermia measurable fiber radiometric thermometer for thermotherapy.

Temperature monitoring is extremely important during thermotherapy. Fiber-optic temperature sensors are preferred because of their flexibility and immunity to electromagnetic interference. Although many types of fiber-optic sensors have been developed, clinically adopting them remains challenging. Here, we report a silica fiber-based radiometric thermometer using a low-cost extended InGaAs detector to detect black body radiation between 1.7 and 2.4 µm. For the first time, this silica fiber-based thermometer is capable of measuring temperatures down to 35°C, making it suitable for monitoring hyperthermia during surgery. In particular, the thermometer has potential for seamless integration with current silica fiber catheters, which are widely used in laser interstitial thermotherapy. The feasibility, capability and sensitivity of tracking tissue temperature variation were proved through ex vivo tissue studies. After further improvement, the technology has the potential to be translated into clinics for monitoring tissue temperature.

Cancer-Related Distress: Revisiting the Utility of the National Comprehensive Cancer Network Distress Thermometer Problem List in Women With Gynecologic Cancers.

PURPOSE: The Distress Thermometer (DT) includes a measure of cancer-related distress and a list of self-reported problems. This study evaluated the utility of the DT problem list in identifying concerns most associated with distress and poorer quality of life (QOL) in survivors of gynecologic cancer. METHODS: Demographic, clinical, psychosocial functioning, and DT data were described among 355 women participating in a gynecologic cancer cohort. Problems from the DT list were ranked by prevalence, distress, and QOL. Logistic regression models explored factors associated with problems that were common (≥ 25% prevalence) and associated with distress and QOL. RESULTS: The average age of participants was 59.9 years (standard deviation [SD], 10.8 years). Most participants were non-Hispanic white (97%) and had ovarian (44%) or uterine (42%) cancer. The mean DT score was 2.7 (SD, 2.7); participants reported a mean of 7.3 problems (SD, 5.9 problems). The most common problems were fatigue (53.6%), worry (49.9%), and tingling (46.3%); least common problems were childcare (2.1%), fevers (2.1%), and substance abuse (1.1%). Report of some common problems, including tingling, sleep, memory, skin issues, and appearance, was not associated with large differences in distress or QOL. In contrast, some rarer problems such as childcare, treatment decisions, eating, housing, nausea, and bathing/dressing were associated with worse distress or QOL. Younger age, lower income, and chemotherapy were risk factors across common problems that were associated with worse distress or QOL (fatigue, nervousness, sadness, fears, and pain). CONCLUSION: The DT problem list did not easily identify concerns most associated with distress and low QOL in patients with gynecologic cancer. Adaptations that enable patients to report their most distressing concerns would enhance clinical utility of this commonly used tool.

Near-infrared photothermal immunoassay for pancreatic cancer biomarker CA 19-9 on a digital thermometer.

A near-infrared (NIR) photothermal immunoassay was designed for the sensitive monitoring of CA 19-9 on the capture antibody-coated microplate, coupling a 3D-printed device with a digital thermometer in this work. Prussian blue nanoparticles (PBNPs)-encapsulated CaCO3 microspheres were not only utilized for labeling of detection antibody, but used as the photo-heat conversion materials for the signal amplification. With the sandwiched immunocomplex, the as-released PBNPs under acidic conditions adsorbed and converted NIR-light wavelength to heat under 808-nm laser irradiation, thereby resulting in the temperature change of the detection solution. Under optimum conditions, a linear range from 1.0 U mL-1 to 100 U mL-1 and a detection limit of 0.83 U mL-1 were acquired for the CA 19-9 detection on the portable photothermal immunosensing platform with PBNP-CaCO3-labeling system. Relative standard deviations for reproducibility were ≤9.7% for intra-assay and ≤11.9% for inter-assay. High specificity, long-time storage stability (>10 months) and good accuracy (relative to gold standard with commercial human ELISA kit) with the photothermal immunoassay were encountered for the evaluation of target CA 19-9 in complex system.

Broken thermometer in foot: a source of mercury poisoning.

A 17-year-old boy was referred after jumping from a ladder onto the ground, crushing a medical thermometer with his right foot. Some days later, he complained of loss of appetite and weakness. A radiograph of the affected foot demonstrated radiopaque densities. Blood and 24-h urine assays for mercury demonstrated toxic levels. Chelation therapy cured the patient dramatically.

Temperature dissociation of liquids in reusable thermoplastic containers-An eco-friendly scald risk?

Recent global concern regarding the impact of plastic waste on the environment has resulted in efforts to utilise reusable drink containers. Research is lacking regarding temperature dissociation of drinks in reusable thermoplastic cups. This study aimed to compare the cooling time of two common hot drinks sold at a UK retailer, in the three vessels they are sold; ceramic, disposable paper (with and without lid) and reusable thermoplastic cups (with and without lid). All temperatures were collated from 250 ml volumes of black Americano coffee or café latte in the three different containers. The cooling time was measured every sixty seconds using a standardised digital thermocouple thermometer until a threshold liquid temperature of 43 °C was reached. All experiments were performed in triplicate and temperatures converted to a dimensionless logarithmic scale prior to statistical analysis. Cooling time was significantly slower for lidded cups irrespective of material. Unlidded thermoplastic cups significantly slowed cooling times for both black Americano coffee and café latte compared to ceramic and unlidded disposable paper cups. The growing trend in reusable cups does not in itself pose an increased risk of scald injury. However, we consider that the potentially increased ambulatory behaviour associated with using a lidded rather than unlidded cup may increase scald risk. We propose that further consumer guidance should be disseminated regarding the use of any lidded takeaway container to prevent scalds in both adults and children.

Dynamics of sleep oscillations is coupled to brain temperature on multiple scales.

KEY POINTS: Sleep spindle frequency positively, duration negatively correlates with brain temperature. Local heating of the thalamus produces similar effects in the heated area. Thalamic network model corroborates temperature dependence of sleep spindle frequency. Brain temperature shows spontaneous microfluctuations during both anesthesia and natural sleep. Larger fluctuations are associated with epochs of REM sleep. Smaller fluctuations correspond to the alteration of spindling and delta epochs of infra-slow oscillation. ABSTRACT: Every form of neural activity depends on temperature, yet its relationship to brain rhythms is poorly understood. In this work we examined how sleep spindles are influenced by changing brain temperatures and how brain temperature is influenced by sleep oscillations. We employed a novel thermoelectrode designed for measuring temperature while recording neural activity. We found that spindle frequency is positively correlated and duration negatively correlated with brain temperature. Local heating of the thalamus replicated the temperature dependence of spindle parameters in the heated area only, suggesting biophysical rather than global modulatory mechanisms, a finding also supported by a thalamic network model. Finally, we show that switches between oscillatory states also influence brain temperature on a shorter and smaller scale. Epochs of paradoxical sleep as well as the infra-slow oscillation were associated with brain temperature fluctuations below 0.2°C. Our results highlight that brain temperature is massively intertwined with sleep oscillations on various time scales.

Smart All-in-One Thermometer-Heater Nanoprobe Based on Postsynthetical Functionalization of a Eu(III)-Metal-Organic Framework.

Real-time temperature feedback in tissue based on photothermal therapy is an urgent problem to be solved in cancer treatment. Herein, a smart all-in-one nanoprobe THA@Eu-NMOF@Fe/TA was designed and assembled by postsynthetical functionalization of an Eu(III)-based nanoscale metal-organic framework (Eu-NMOF) with a two-photon-absorbing ß-diketonate ligand 4,4,4-trifluoro-1-(9-hexylcarbazol-3-yl)-1,3-butanedione (HTHA) and Fe(III)/tannic acid assembly (Fe/TA). Such a functionalized material can simultaneously achieve the temperature-sensing and optical heating under a single beam of near-infrared (NIR) light. Under 808 nm laser excitation, real-time feedback of temperature by monitoring thermoresponsive fluorescence emission ratio ( I616/ I590) and fluorescence lifetime of Eu(III) ions were realized. Meantime, Fe/TA served as the photothermal agent and antibacterial agent to implement photothermal therapy (PTT) and antibacteria simultaneously. The functions of the nanoprobe were proved with ex vivo experiments, and the antibacterial activity against Gram-positive and Gram-negative bacteria of the probe was also elaborately evaluated. Our work paves a new avenue for engineering a new cancer treatment probe which can achieve real-time temperature sensing feedback during PTT and antibacterial process.

Validation of Noninvasive Ultrasound Temperature Measurement System Through Experiments Using Resonant Cavity Applicator.

We developed a resonant cavity applicator for noninvasive deep hyperthermia treatment of osteoarthritis. In previous studies, we confirmed its viability by heating agar phantoms and conducting computer simulations. To evaluate the heating performance of this system on human subjects, it is necessary to develop a new noninvasive temperature measurement system. In this study, we developed a new temperature measurement system utilizing ultrasound imaging techniques. After heating an agar phantom with our resonant cavity applicator, temperature measurements from both our custom-made noninvasive ultrasonic thermometer and an optical fiber thermometer were collected and compared. Both temperature distributions showed a reliable trend, with heat energy concentrated at the center of the agar phantom. Average error rates were less than 13% for temperatures. The results of this study describe the viability of the temperature measurement system and the resonant cavity applicator for clinical applications.

Heating and Cooling Rates With an Esophageal Heat Exchange System.

BACKGROUND: The Esophageal Cooling Device circulates warm or cool water through an esophageal heat exchanger, but warming and cooling efficacy in patients remains unknown. We therefore determined heat exchange rates during warming and cooling. METHODS: Nineteen patients completed the trial. All had general endotracheal anesthesia for nonthoracic surgery. Intraoperative heat transfer was measured during cooling (exchanger fluid at 7°C) and warming (fluid at 42°C). Each was evaluated for 30 minutes, with the initial condition determined randomly, starting at least 40 minutes after induction of anesthesia. Heat transfer rate was estimated from fluid flow through the esophageal heat exchanger and inflow and outflow temperatures. Core temperature was estimated from a zero-heat-flux thermometer positioned on the forehead. RESULTS: Mean heat transfer rate during warming was 18 (95% confidence interval, 16-20) W, which increased core temperature at a rate of 0.5°C/h ± 0.6°C/h (mean ± standard deviation). During cooling, mean heat transfer rate was -53 (-59 to -48) W, which decreased core temperature at a rate of 0.9°C/h ± 0.9°C/h. CONCLUSIONS: Esophageal warming transferred 18 W which is considerably less than the 80 W reported with lower or upper body forced-air covers. However, esophageal warming can be used to supplement surface warming or provide warming in cases not amenable to surface warming. Esophageal cooling transferred more than twice as much heat as warming, consequent to the much larger difference between core and circulating fluid temperature with cooling (29°C) than warming (6°C). Esophageal cooling extracts less heat than endovascular catheters but can be used to supplement catheter-based cooling or possibly replace them in appropriate patients.