Efficacy of a novel proprietary dietary supplement (TRI 360TM) on psychological symptoms and stress-related quality of life in adult subjects: A randomized controlled clinical trial.

Nowadays, diet plays an increasingly important role in normal physiology and mental health. Recently, many studies have shown that more use of dietary supplements in mental and psychological disorders. Study objective was to investigate safety and efficacy of proprietary nutraceutical combination (TRI 360TM) on psychological symptoms in adult human subjects with one or more psychological symptoms in open-label, single-center, parallel-group, randomized controlled trial. Eighty-four participants aged 20-45 years with psychological symptoms were completed this trial. Participants were randomly assigned to placebo and treatment groups. Treatment group received TRI 360TM capsules twice a day. TRI 360TM was well-tolerated and didn't show treatment-related adverse-events upto 180 days. All assessed perception scorings on psychological symptoms like fatigue, mental stress, sleep disturbance, anxiety, depression, emotional trauma, mood changes, self-confidence, willpower, and motivation were very significantly (p ≤ 0.0001) improved in TRI 360TM participants than placebo control group. Furthermore, significantly (p ≤ 0.001) increased levels of functional biomarkers: vitamin C and D3 metabolites, neurotransmitters, hormones, antiaging protein (klotho) level; and decreased proinflammatory cytokines and oxidative stress marker, malondialdehyde in TRI 360TM group than placebo. According to these findings, the use of TRI 360TM supplementation as a potentially safe therapeutic option for reducing psychological symptoms in healthy adults.

Acute and Chronic Mental Stress Both Influence Levels of Neurotransmitter Precursor Amino Acids and Derived Biogenic Amines.

Acute and chronic mental stress are both linked to somatic and psychiatric morbidity, however, the neurobiological pathways of these associations are still not fully elucidated. Mental stress is known to be immunomodulatory, which is one of the basic concepts of psychoneuroimmunology. In the present study, neurotransmitter precursor amino acid levels and derived biogenic amines were analyzed prior to and at 0, 30 and 60 minutes following an acute mental stress test (with/without chronic mental stress) in 53 healthy subjects. Psychometric measurements of mental stress, depression and anxiety were collected. Kynurenine/tryptophan was influenced by the factor acute mental stress (KYN/TRP increase), no influence of the factor chronic mental stress or any interaction was found. Phenylalanine/tyrosine was influenced by the factor acute mental stress (PHE/TYR increase) as well as by chronic mental stress (PHE/TYR decrease). Interactions were not significant. KYN/TRP correlated with state anxiety values, while PHE/TYR correlated negatively with chronic stress parameters. Kynurenic acid was significantly reduced in the acute and quinolinic acid in the chronic mental stress condition. In conclusion, neurotransmitter precursor amino acid levels and derived biogenic amines are influenced by acute and chronic mental stress. Mechanisms beyond direct immunological responses may be relevant for the modulation of neurotransmitter metabolism such as effects on enzyme function through cofactor availability or stress hormones.

Effect of astaxanthin-rich extract derived from Paracoccus carotinifaciens on the status of stress and sleep in adults.

This study investigated the effect of a dietary supplement containing astaxanthin-rich extract derived from Paracoccus carotinifaciens (astaxanthin supplement) on the status of stress and sleep in individuals aged 20-64 years. Twenty-five subjects orally administered 12 mg astaxanthin/day of astaxanthin supplement for 8 weeks (astaxanthin group) and 29 subjects given a placebo (placebo group) were evaluated with Profile of Mood States 2nd Edition for stress and Oguri-Shirakawa-Azumi Sleep Inventory for Middle-aged and Aged version for sleep. We did not observe any significant intergroup differences in the stress and sleep. A subgroup analysis was performed after dividing the subjects into two groups: those who scored >65 and those who scored ≤65 in the "Depression-Dejection" dimension of Profile of Mood States 2nd Edition. The sleep of subjects who scored >65 ("Depression-Dejection") showed significant improvement in the astaxanthin group compared with the placebo group, whereas no significant improvement was observed in stress and the other subjects. Our results indicate that people who tend to be strongly depressed may experience improved sleep after ingesting astaxanthin supplement. On the basis of the parameters tested, administration of astaxanthin supplement was not associated with any problems related to safety. Clinical registration: This study has been registered at the University Hospital Medical Information Network (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000038619) on August 24, 2018 as "A study to evaluate the effect of intake of astaxanthin on the status of stress and sleep in adults," Identification No. UMIN000033863.

Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress.

BACKGROUND: Stress is associated with activation of the sympathetic nervous system, and can lead to lasting alterations in autonomic function and in extreme cases symptoms of posttraumatic stress disorder (PTSD). Vagal nerve stimulation (VNS) is a potentially useful tool as a modulator of autonomic nervous system function, however currently available implantable devices are limited by cost and inconvenience. OBJECTIVE: The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to stress. METHODS: Using a double-blind approach, we investigated the effects of active or sham tcVNS on peripheral cardiovascular and autonomic responses to stress using wearable sensing devices in 24 healthy human participants with a history of exposure to psychological trauma. Participants were exposed to acute stressors over a three-day period, including personalized scripts of traumatic events, public speech, and mental arithmetic tasks. RESULTS: tcVNS relative to sham applied immediately after traumatic stress resulted in a decrease in sympathetic function and modulated parasympathetic/sympathetic autonomic tone as measured by increased pre-ejection period (PEP) of the heart (a marker of cardiac sympathetic function) of 4.2 ms (95% CI 1.6-6.8 ms, p < 0.01), decreased peripheral sympathetic function as measured by increased photoplethysmogram (PPG) amplitude (decreased vasoconstriction) by 47.9% (1.4-94.5%, p < 0.05), a 9% decrease in respiratory rate (-14.3 to -3.7%, p < 0.01). Similar effects were seen when tcVNS was applied after other stressors and in the absence of a stressor. CONCLUSION: Wearable sensing modalities are feasible to use in experiments in human participants, and tcVNS modulates cardiovascular and peripheral autonomic responses to stress.

Advance in Mindfulness-based Intervention for Stress-induced Autonomic Nervous System Activity (review) / 中国康复理论与实践

Mental stress may influence the autonomic nervous system (ANS) activity, and associate with the development of several chronic diseases. Mindfulness-based interventions, such as meditation, Yoga and Taiji Quan, are able to improve mental stress and ANS activity, which is probably related to its effects on the cortex to improve overall mental conditions and parasympathetic tone.

Ginger-Degraded Collagen Hydrolysate Exhibits Antidepressant Activity in Mice.

Collagen is the most abundant protein in animals. Collagen hydrolysate has been found to have multiple functions in the skin, bones, joints, muscles, and blood vessels. Recently, it has been reported that the low molecular weight fraction of collagen hydrolysate exhibited anxiolytic activity, suggesting that collagen peptides affect brain functions. In the present study, we found that oral administration of ginger-degraded collagen hydrolysate (GDCH) significantly decreased depression-like behavior in a forced swim test, suggesting that GDCH exhibited antidepressant activity in mice. The antidepressant activity of GDCH was abolished by pre-treatment with an antagonist of the dopamine receptor, but not treatment with a serotonin receptor antagonist. GDCH significantly increased gene expression of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) in the hippocampus, molecules that affect the differentiation and survival of neurons, relative to that in the control condition. Meanwhile, there were no changes in the gene expression of brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3, major factors related to depression-like behavior. We also found that GDCH exhibited antidepressant activity in corticosterone-administered mice in a model of stress. In addition, GDCH increased GDNF and CNTF expression in the stressed condition, suggesting that mechanisms of the antidepressant activity of GDCH were the same in unstressed and stressed conditions. These results imply that GDCH exhibits antidepressant activity in unstressed and stressed conditions in mice. The upregulation of neurotrophic genes in the hippocampus may contribute to the reduction of depression-like behavior via a dopamine signal pathway modulated by GDCH.

Sex-Specific Impact of Spiritual Beliefs and Sleep Quality on Degree of Psychological Distress.

The purpose of this study was to test a set of hypotheses suggesting sleep quality and spiritual beliefs differed according to degree of psychological distress and biological sex. The Pittsburgh Sleep Quality Index measured sleep quality, the Beliefs and Values Scale measured spiritual beliefs, and the Kessler-6 Psychological Distress Scale measured distress. A factorial MANOVA tested the model. Higher sleep quality and greater spiritual beliefs were associated with lower levels of distress. Women exhibited lower sleep quality than men, whereas spiritual beliefs were equivalent between sexes. To decrease psychological distress, interventions should improve sleep quality and increase spiritual engagement.

Spa therapy (balneotherapy) relieves mental stress, sleep disorder, and general health problems in sub-healthy people.

To investigate the relieving effects of hot spring balneotherapy on mental stress, sleep disorder, general health problems, and women's health problems in sub-healthy people, we recruited 500 volunteers in sub-health in Chongqing, and 362 volunteers completed the project, including 223 in the intervention group and 139 in the control group. The intervention group underwent hot spring balneotherapy for 5 months, while the control group did not. The two groups took questionnaire investigation (general data, mental stress, emotional status, sleep quality, general health problems, as well as some women's health problems) and physical examination (height, weight, waist circumference, blood pressure, blood lipid, blood sugar) 5 months before and after the intervention, respectively. After intervention, sleep disorder (difficulty in falling asleep (P = 0.017); dreaminess, nightmare suffering, and restless sleep (P = 0.013); easy awakening (P = 0.003) and difficulty in falling into sleep again after awakening(P = 0.016); and mental stress (P = 0.031) and problems of general health (head pain (P = 0.026), joint pain(P = 0.009), leg or foot cramps (P = 0.001), blurred vision (P = 0.009)) were relieved significantly in the intervention group, as compared with the control group. While other indicators (fatigue, eye tiredness, limb numbness, constipation, skin allergy) and women's health problems (breast distending pain; dysmenorrhea, irregular menstruation) were relieved significantly in the self-comparison of the intervention group before and after intervention (P < 0.05), but showed no statistically significant difference between two groups (P > 0.05). All indications (except bad mood, low mood, and worry or irritability) in the intervention group significantly improved, with effect size from 0.096 to 1.302. Multiple logistic regression analysis showed that the frequency, length, and location of balneotherapy in the intervention group were the factors influencing emotion, sleep, and health condition (P < 0.05). Relief of insomnia, fatigue, and leg or foot cramps was greater in old-age group than in young-aged group (P < 0.05). Physical examination found that waist circumferences in women of various ages under 55 years were significantly reduced in the intervention group (P < 0.05), while that in men did not significantly change (P > 0.05). Spa therapy (balneotherapy) relieves mental stress, sleep disorder, general health, and reduces women's waist circumferences in sub-healthy people.

A randomized, double blind, placebo controlled study of spirulina supplementation on indices of mental and physical fatigue in men.

Spirulina may increase people's ability to resist mental and physical fatigue. This study tested that hypothesis in a randomized, double blinded, placebo controlled study in men. After 1 week, a 3 g/day dose of spirulina produced a small, but statistically significant increase in exercise output (Kcals consumed in 30 min exercise on a cross trainer machine). A mathematical based mental fatigue test showed improved performance 4 h after the first time of supplementation as well as 8 weeks later. Similarly, a subjective survey for a sense of physical and mental fatigue showed improvement within 4 h of the first supplementation as well as 8 weeks later. These results show that spirulina intake can affect fatigue in men.

Viewpoint: Role of Mind-body Therapies in the Management of Cardiovascular Disorders.

Cardiovascular disorders (CVD) are the leading cause of death across the globe. The estimated cost to the National Health Service and UK economy is £30 billion. These costs continue to escalate despite major advances in pharmacotherapy and devices, which, in part, is due to improved survival, but also greater resource utilisation per patient. Hence, there is a need to develop cost-effective adjunctive therapies beyond conventional strategies. Mind-body therapies- including mindfulness and meditation, emotional regulation, practicing 'heartfelt' emotions including gratitude and compassion- may be novel low-cost approaches to reduce morbidity and mortality in CVD.

Effect of mental stress on dynamic electrophysiological properties of the endocardium and epicardium in humans.

BACKGROUND: Striking temporal associations exist between ventricular arrhythmia and acute mental stress, for example, during natural disasters, or defibrillator shocks associated with stressful events. We hypothesized that electrophysiological changes in response to mental stress may be exaggerated at short coupling intervals and hence relevant to arrhythmia initiation. OBJECTIVE: The aim of this study was to determine the dynamic response in human electrophysiology during mental stress. METHODS: Patients with normal hearts and supraventricular tachycardia underwent electrophysiological studies avoiding sedation. Conditions of relaxation and stress were induced with standardized psychometric protocols (mental arithmetic and anger recall) during decremental S1S2 right ventricular (RV) pacing. Unipolar electrograms were acquired simultaneously from the RV endocardium, left ventricular (LV) endocardium (LV endo), and epicardium (LV epi), and activation-recovery intervals (ARIs) computed. RESULTS: Twelve patients ( 9 women; median age 34 years) were studied. During stress, effective refractory period (ERP) reduced from 228 ± 23 to 221 ± 21 ms (P < .001). ARIs reduced during mental stress (P < .001), with greater reductions in LV endocardium than in the epicardium or RV endocardium (LV endo -8 ms; LV epi -5 ms; RV endo -4 ms; P < .001). Mental stress depressed the entire electrical restitution curve, with minimal effect on slope. A substantial reduction in minimal ARIs on the restitution curve in LV endo occurred, commensurate with the reduction in ERP (LV endo ARI 195 ± 31 ms at rest to 182 ± 32 ms during mental stress; P < .001). Dispersion of repolarization increased sharply at coupling intervals approaching ERP during stress but not at rest. CONCLUSION: Mental stress induces significant electrophysiological changes. The increase in dispersion of repolarization at short coupling intervals may be relevant to observed phenomena of arousal-associated arrhythmia.

Responsiveness of the autonomic nervous system during paced breathing and mental stress in migraine patients.

BACKGROUND: Migraine is a stress-related disorder, suggesting that there may be sympathetic hyperactivity in migraine patients. However, there are contradictory results concerning general sympathetic activation in migraine patients. To shed more light on the involvement of the autonomic nervous system (ANS) in migraine pathophysiology, we investigated cardiac and cardiovascular reactions during vagal (paced breathing) and sympathetic activation (mental stress test). METHODS: Heart rate variability parameters and skin conductance responses were recorded interictally in 22 episodic migraine patients without aura and 25 matched controls during two different test conditions. The paced breathing test consisted of a five-minute baseline, followed by two minutes of paced breathing (6 breathing cycles per minute) and a five-minute recovery phase. The mental stress test consisted of a five-minute baseline, followed by one minute of stress anticipation, three and a half minutes of mental stress and a five-minute recovery phase. Furthermore we measured blood pressure and heart rate once daily over 2 weeks. Subjects rated their individual current stress level and their stress level during paced breathing and during the mental stress test. RESULTS: There were no significant differences between migraine patients and controls in any of the heart rate variability parameters in either time domain or frequency domain analysis. However, all parameters showed a non-significant tendency for larger sympathetic activation in migraine patients. Also, no significant differences could be observed in skin conductance responses and average blood pressure. Only heart rates during the 2-week period and stress ratings showed significantly higher values in migraine patients compared to controls. CONCLUSIONS: Generally there were no significant differences between migraine patients and controls concerning the measured autonomic parameters. There was a slight but not significant tendency in the migraine patients to react with less vagal and more sympathetic activation in all these tests, indicating a slightly changed set point of the autonomic system. Heart rate variability and blood pressure in migraine patients should be investigated for longer periods and during more demanding sympathetic activation.

Effect of inhalation aromatherapy with lavender essential oil on stress and vital signs in patients undergoing coronary artery bypass surgery: A single-blinded randomized clinical trial.

OBJECTIVES: At present, aromatherapy is used widely in medical research. This study aimed to investigate the effects of inhalation aromatherapy using lavender essential oil to reduce mental stress and improve the vital signs of patients after coronary artery bypass surgery (CABG). DESIGN: A single-blinded randomized controlled trial was conducted with 60 patients who had undergone CABG in a 2-day intervention that targeted stress reduction. PARTICIPANTS: Sixty subjects following coronary artery bypass surgery in two aromatherapy and control groups. SETTING: The study was conducted in Ekbatan Therapeutic and Educational Center, Hamadan, Iran, in 2013. INTERVENTIONS: On the second and third days after surgery, the aromatherapy group patients received two drops of 2% lavender essential oil for 20min and the control group received two drops of distilled water as a placebo. MAIN OUTCOME MEASURES: The primary outcome was mental stress, which was measured before and after the intervention using the DASS-21 questionnaire. The secondary outcomes were vital signs, including the heart rate, respiratory rate, and systolic and diastolic blood pressure, which were measured before and after the intervention. RESULTS: The individual characteristics of the aromatherapy and control groups were the same. There were no significant difference in the mean mental stress scores and vital signs of the aromatherapy and control groups on the second or third days after surgery. CONCLUSION: Inhalation aromatherapy with lavender essential oil had no significant effects on mental stress and vital signs in patients following CABG, except the systolic blood pressure.

Vaccine-induced inflammation attenuates the vascular responses to mental stress.

Inflammation is associated with poorer vascular function, with evidence to suggest that inflammation can also impair the vascular responses to mental stress. This study examined the effects of vaccine-induced inflammation on vascular responses to mental stress in healthy participants. Eighteen male participants completed two stress sessions: an inflammation condition having received a typhoid vaccination and a control (non-inflamed) condition. Tumor necrosis factor-alpha and interleukin-6 (p's<.001) increased following vaccination, confirming modest increases in inflammation. Mental stress increased blood flow, blood pressure, heart rate, and cardiac output in both conditions (all p's<.001), but the blood flow response to stress was attenuated having received the vaccination compared to the control condition (p's<.05). These results further implicate the interaction between inflammation and the vasculature as a mechanism through which stress may trigger myocardial infarction.

Yoga and health.

Yoga has been the subject of research in the past few decades for therapeutic purposes for modern epidemic diseases like mental stress, obesity, diabetes, hypertension, coronary heart disease, and chronic obstructive pulmonary disease. Individual studies report beneficial effect of yoga in these conditions, indicating that it can be used as nonpharmaceutical measure or complement to drug therapy for treatment of these conditions. However, these studies have used only yoga asana, pranayama, and/ or short periods of meditation for therapeutic purposes. General perception about yoga is also the same, which is not correct. Yoga in fact means union of individual consciousness with the supreme consciousness. It involves eight rungs or limbs of yoga, which include yama, niyama, asana, pranayama, pratyahara, dharana, dhyana, and samadhi. Intense practice of these leads to self-realization, which is the primary goal of yoga. An analytical look at the rungs and the goal of yoga shows that it is a holistic way of life leading to a state of complete physical, social, mental, and spiritual well-being and harmony with nature. This is in contrast to purely economic and material developmental goal of modern civilization, which has brought social unrest and ecological devastation.

Brief training of psychoneuroendocrinoimmunology-based meditation (PNEIMED) reduces stress symptom ratings and improves control on salivary cortisol secretion under basal and stimulated conditions.

CONTEXT: Meditation is proposed as an anti-stress practice lowering allostatic load and promoting well-being, with brief formats providing some of the benefits of longer interventions. OBJECTIVES: PsychoNeuroEndocrinoImmunology-based meditation (PNEIMED) combines the teaching of philosophy and practice of Buddhist meditation with a grounding in human physiology from a systemic and integrative perspective. We evaluated the effects of four-day PNEIMED training (30 h) on subjective and objective indices of stress in healthy adults. DESIGN: A non-randomized, controlled, before-and-after study was conducted. Participants (n = 125, mostly health practitioners) answered a questionnaire rating stress symptom before (T0) and after (Tf) a PNEIMED course. In an additional sample (n = 40; smokers, overweight persons, women taking contraceptives, and subjects with oral pathologies were excluded), divided into PNEIMED-attending (intervention, n = 21) and non-meditating (control, n = 19) groups, salivary cortisol was measured upon awakening and during a challenging mental task. RESULTS: Self-rated distress scores were highly reduced after the PNEIMED course. In the intervention group, improvement of psychological well-being was accompanied by decrease in cortisol levels at awakening. No T0-vs-Tf changes in distress scores and morning cortisol were found in controls. Based on baseline-to-peak increment of cortisol response at T0, 26 subjects (n = 13 for each group) were classified as task-responders. The amplitude and duration of the cortisol response decreased after PNEIMED, whereas no effects were found in controls. CONCLUSIONS: Brief PNEIMED training yields immediate benefits, reducing distress symptoms and adrenocortical activity under basal and stimulated conditions. PNEIMED may represent an effective practice to manage stress and anxiety, particularly among subjects facing a multitude of job-related stressors, such as healthcare workers.

Aftermath of 3/11: earthquakes and involuntary attentional orienting to sudden ambient sounds.

Due to the Great East Japan Earthquake on 11 March 2011 and the following long-term earthquake swarm, many people living in the earthquake-affected areas have developed mental stress, even though clinically-diagnosable symptoms may not be apparent. Concurrently, many unusual reports have emerged in which persons complain of abnormally increased sensitivity to sudden ambient sounds during their daily lives (e.g., the sound of the washing machine on spin cycle). By recording event-related potentials to various sudden ambient sounds from young adults living in the affected areas, we found that the level of earthquake-induced mental stress, as indexed by the hyperarousal symptoms of posttraumatic stress disorder, was positively related to the magnitude of P3a to sudden ambient sounds. These results reveal a strong relationship between mental stress and enhanced involuntary attentional orienting in a large majority of trauma-exposed people without diagnosable symptoms.

Management of stress and stress-related diseases: Emerging computer-based technologies and the rationale for clinical laboratory assessment.

BACKGROUND: Over the years, the issue of stress management in mental health has been discussed without reference to the clinical laboratory perspectives. Translational research and the vast array of emerging diagnostic technologies in alternative medical practice are now bridging the gap. While it would be scientific arrogance for the clinical practitioner and scientist to ignore the trend, the new technologies seeking clinical acceptability necessarily require expatiation of the scientific aspects of their products. AIMS: This commentary builds on a comparative critical review to further our hypothesis that oxidative stress is the biochemical basis of the emerging computer-based diagnostic technologies. MATERIALS #ENTITYSTARTX00026; METHOD: The available information on Computer Meridian Diagnostics, Neuropattern and Virtual Scanning technologies were critically reviewed. The differences and similarities were articulated. RESULTS: The technologies seem different, but have similarities that have not been articulated before. The seemingly different theories are traceable to Russian scientists and are based upon stress-induced adrenal secretions and the associated effect on glucose metabolism. The therapeutic effects of antioxidant nutrition, exercise or relaxation that are inherent in the technologies are highlighted. CONCLUSION: This commentary furthers explanation of the alterations in antioxidant activities as a result of biofeedback, oxidative stress and/or physiological effects as the biochemical basis of the technologies. The place for antioxidant indices and whole blood viscosity are also highlighted. This provides a rationale for the evaluation of available clinical diagnostic tests both to validate the technologies and as clinical laboratory correlates in stress management.

Investigation of the relationship between allergic rhinitis and personality traits using semeiometry.

Mind-body interactions have been well recognized and are extendedly studied in the medical literature. There is evidence that the mind and body communicate with each other in a multidirectional flow of information by means of hormones, neurotransmitters/neuropeptides, cytokines, and semaphorines. There are consistent and convincing reports of links between stress and disease onset and progression, e.g. asthma. Growing evidence in the field of psychoneuroimmunology contributes to the understanding of the mechanisms by which stressful events affect physical health. The psychoneuroendocrine system can influence the immune response and thereby the capacity of the organism to cope with illness, and the immune system can have an impact on neuroendocrine function. Such cross-talk among systems is dependent upon feedback loops working to maintain homeostatic equilibrium. The immune system is capable of producing factors, which serve to integrate immune-neuroendocrine circuits with immunoregulatory and metabolic consequences for the organism. The interaction of the immune, nervous and endocrine system may drive an individual to a well recognized biological hypersensitivity and the creation of allergic symptoms (allergic rhinitis, asthma, atopic dermatitis, etc), followed by distinct behavioural patterns characterized as affective hypersensitivity. Semeiometry is a proper tool for large scale investigation of the psychological profile of patients with allergic rhinitis. Statistical analysis of semeiometry questionnaires processed by Greek adult patients in Crete island during 2005, showed that there is relation between occupation and allergy. Housewives, public services employees and private employees appear to be allergic in significantly higher percentage than others. With semeiometry we can find evidence of the bi-directional immunoendocrine--nervous system interactions in patients with allergic rhinitis.