The impact of HIV infection on primary headache. Unexpected findings from retrospective, cross-sectional, and prospective analyses

Headache is one of the most important factors influencing the quality of life in patients infected with the human immunodeficiency virus type 1 (HIV). However, only symptomatic headache but not changes or primary headache types during HIV infection have been studied to date. Therefore, we aimed to determine the impact of an HIV infection on frequency and semiology of different primary headache types. Patients with confirmed HIV type 1 infection underwent a neurological examination, neuroimaging or EEG, and a standardized interview. Time pattern and symptoms of headaches (cross-sectional analysis), changes of headaches preexisting to their infection (longitudinal retrospective analysis), and changes of primary headaches during a 2-year follow-up (longitudinal prospective analysis) were evaluated as were the correlations between these headache patterns and different markers of HIV infection. One hundred thirty-one consecutive HIV-infected patients without evidence of a cerebral manifestation except mild encephalopathy were enrolled. The point prevalence of migraine was 16.0% (confidence interval (CI) 10.1-25.4%), of headache with a semiology of tension-type headache 45.8% (CI 33.7-62.2%), and of other headache types 6.1% (CI 3.0-12.5%). During the natural course of infection, the migraine frequency significantly decreased in the retrospective and in the prospective analyses, whereas the frequency of the headache with a semiology of tension-type headache significantly increased in all three analyses. In 20% of all patients, the tension-type headache could be considered as symptomatic due to the infection but not due to focal or general cerebral lesions. Changes of primary headache were significantly associated with different stages of the infection and with the presence of mild encephalopathy but not with antiretroviral treatment or CD4 cell count. HIV infection seems to be associated with a progressive decrease in migraine frequency and intensity which probably is related to the immunological state of the patients. Tension-type headache becomes more frequent during HIV infection. However, this can in part be related to secondary headache caused by the HIV in less than 50% of patients with tension-type headache. The progressing immunological deficiency of HIV-infected patients seems to influence pain processing of primary headache types in different ways.     

Epidemiology of fixed unilateral headaches

A fixed location unilateral headache suggests involvement of a precise nervous structure, and neuroimaging investigations are essential to seek to identify it. Nevertheless, side-locked primary headaches also occur, although they are rare. Side-locked primary headaches are more frequently found in the group of the short-lasting (≤ 4 hours) headaches but long-lasting headache forms may also present with the pain always on the same side, including migraine, tension-type headache, new daily persistent headache and cervicogenic headache. Future studies should address the issue whether patients with side-locked headache form differ from those with non-side-locked form both in terms of natural history and biological markers.
Among 63 consecutive chronic cluster headache patients seen by us from 1999 to 2007, 32 (51%) had side shift. We also found that the duration of the chronic condition was significantly longer in those with side shift than those without. The high frequency of side shift in chronic cluster headache should be considered when proposing surgical treatment for severe intractable forms of the disease.     

Lifetime prevalence and characteristics of recurrent primary headaches in a population-based sample of Swedish twins

OBJECTIVE: To examine the lifetime prevalence and other characteristics of recurrent primary headaches in twins. BACKGROUND: The twin model may provide insights into the role of genetic and environmental influences in headache disorders. However, assumptions as to whether twins are representative of the general population, and whether monozygotic and dizygotic twins are similar have rarely been addressed. METHODS: The study population consisted of a random sample of 17- to 82-year-old twins from the Swedish Twin Registry (n = 1329). Structured interviews on the telephone by lay personnel and the International Headache Society criteria were used for assessment and diagnosis of recurrent primary headaches. Prevalence data of the general population for migraine and tension-type headache was obtained from various published reports. RESULTS: A total of 372 subjects (29%) had ever had recurrent headaches. In total, 241 recurrent headache sufferers fulfilled the criteria for migraine or tension-type headache, and the lifetime prevalence was 7.1% for migraine without aura, 1.4% for migraine always with aura, 1.9% for migraine occasionally with aura, 9.4% for episodic tension-type headache, and 1.3% for chronic tension-type headache. The lifetime prevalence of all migraine and all tension-type headache, including another 84 subjects fulfilling all but one of the criteria for migraine or tension-type headache, was 13.8% and 13.5%, respectively. The corresponding prevalence risk for women was 2.4 (95% confidence interval [CI] 1.7, 3.4) and 1.5 (95% CI 1.1, 2.1), respectively. Zygosity was not a significant predictor for migraine. In tension-type headache, the prevalence risk for dizygotic twins and unlike-sexed twins as compared with monozygotic twins was 1.9 (95% CI: 1.2, 3.1) and 1.8 (95% CI: 1.1, 2.9), respectively. CONCLUSION: There is no twin-singleton or monozygotic-dizygotic difference for the risk of migraine. In tension-type headache, twins seem to have a lower risk than singletons, and this is especially true for monozygotic twins.     

Managing chronic headaches in the clinic

Chronic daily headache (CDH), which is often linked to a history of migraine, tension-type headache and the abuse of headache medications, and cluster headache are the best known of the chronic headaches. These headaches may not be well recognised or well treated in primary care. This article outlines the development of management algorithms for these headache subtypes, designed for use by the primary care physician with an interest in headache. Principles of care for chronic headaches include implementation of screening procedures, differential diagnosis, tailoring of management to the individual's needs, proactive follow-up and a team approach to care. These principles can be customised to the headache subtype by the selection of appropriate therapies. The optimal treatments for CDH include physical therapy to the neck if there is any stiffness there, withdrawal of abused medications and treatment of any subsequent withdrawal symptoms and headache prophylaxis, together with the provision of acute medications as rescue therapy. Optimal treatments for cluster headache include short- and long-term prophylaxis to prevent the headaches developing and acute medications for use as rescue. If treatment is ineffective, alternative medications can be provided at follow-up, with the possibility of referral for refractory patients.     

Chronic daily headache in a paediatric headache centre

The prevalence and the clinical features of chronic daily headache (CDH) were studied in 968 children and adolescents observed during a period of one year in the Headache Centre of the Anna Meyer Paediatric Hospital of Florence. Nine hundred and fortyfour patients (97.52%) had primary headache according to ICHD-II, 24 subjects had secondary headache and 56 patients had CDH (5.93% of primary headaches). The mean age of subjects with CDH was higher than general (13.5 vs. 11.5 years), with a female preponderance (69.6% vs. 30.4%). According to the ICHD-II, headaches were classified as chronic migraine in 10 patients (1.5.2 ICHD-II), chronic tension-type headache in 36 (2.3 ICHD-II), new daily persistent headache in 8 (4.8 ICHD-II) and 2 patients reported mixed pattern (chronic migraine+chronic tension type headache). Medication overuse was not implicated in our patients.     

Side-Locked Unilaterality and Pain Localization in Long-Lasting Headaches: Migraine, Tension-Type Headache, and Cervicogenic Headache

SYNOPSIS
Side-locked unilaterality and specific localization of pain are not as well-defined clinical characteristics in long-lasting headaches (duration more than 4 hours) as they are in short-lasting forms. We examined side-locked unilaterality and pain distribution at onset and at peak headache in 74 patients with different forms of long-lasting headache: migraine and tension-type headache (IHS) and cervicogenic headache (according to Sjaastad et al). Side-locked unilaterality of pain was found in all forms, but to differing extents-20.8% in migraine, 12.5% in tension-type headache, while it was a mandatory criterion for cervicogenic headache. The pain tended to localize anteriorly, particularly at onset, in migraine; was more diffuse in tension-type headache; and always began in the occipitonuchal region in cervicogenic headache. Our results may contribute to a better clinical definition of long-lasting headaches.     

The prevalence of migraine and tension-type headaches among adolescents in Norway. The Nord-Trøndelag Health Study (Head-HUNT-Youth), a large population-based epidemiological study

The aim of this study was to examine the prevalence of headache and primary headache disorders like migraine and tension-type headaches among adolescents, and to explore the differences in headache prevalence and frequency by gender and age. This cross-sectional study was conducted in Nord-Tr?ndelag county, Norway, during the years 1995-97. In total, 8984 (88%) out of 10 202 invited adolescents aged 12-19 years participated in the youth part of the Nord-Tr?ndelag Health Study [Helseunders?kelsen i Nord-Tr?ndelag (HUNT)]. The total study population in this study consisted of 8255 individuals after exclusion of invalid questionnaires and students outside the target range of 13-18 years of age. The students completed a comprehensive questionnaire, and one of the questions was whether the students had experienced any headaches during the last 12 months. In addition, 5847 of these students were also subject to an interview in which they were asked whether they had experienced recurring headaches during the last year and, if so, were they classified as migraine (MI), tension-type headache (TTH) or non-classifiable headache. In the total questionnaire-based population, 76.8% reported having had headaches during the last 12 months (69.4% boys and 84.2% girls). Among those who also were interviewed, 29.1% reported having recurrent headaches (21.0% boys and 36.5% girls). The overall 1-year prevalence of migraine was 7%, of tension-type headache 18%, and of non-classifiable headache 4.8%. Higher prevalence rates were found for girls in all age groups and for all headache categories. The overall frequency of recurrent headaches did not vary significantly with age, but girls had significantly more frequent headaches than boys. We concluded that headache in general, and recurrent primary headache disorders like migraine and tension-type headaches, are common somatic complaints among Norwegian adolescents, especially among girls.     

Is a de novo whiplash-associated pain most commonly cervicogenic headache?

Whiplash is a controversial concept. The real nature and prevalence of whiplash-related headaches are not known. To address this issue, the history of severe trauma was collected from occipital/nuchal headache-cervicogenic headache, migraine and tension-type headache patients attending a neurology office. The two last groups of patients had significantly less history of trauma in their medical records, with longer time span between the injury and the headache onset. Whiplash may induce preferably cervicogenic and tension-type headaches.     

Quantification of Headache Disability: A Diagnostic-Based Approach

The quantification of the social and economic handicaps caused by headache is a complex problem, especially given the great variability of headache patients' clinical pictures. In the present study, 400 patients, consecutively admitted to Headache Centers in Pavia and Milan, were interviewed on the relationship between headache and their work and social activities, in order to evaluate their socioeconomic handicap due to headache. The analysis of the data primarily focused on attack-type headaches (migraine, cluster headache, and episodic tension-type headache) and chronic or daily headaches (chronic tension-type headache and migraine combined with tension-type headache). These latter types were often characterized by the daily use or abuse of analgesics.
The overall profile which emerged from the study reveals relatively low levels of handicap or disability in work and social activities. These low levels can be mainly attributed to timely, and at times excessive, use of analgesics.     

Botulinum Toxin A, Adjunctive Therapy for Refractory Headaches Associated With Pericranial Muscle Tension

Pericranial muscle tension may contribute to the development of facial discomfort, chronic daily headache, and migraine-type headache. Elimination of pericranial muscle tension may reduce associated myalgia and counteract influences that can trigger secondary headaches which fall within the migraine continuum. Four patients with chronic, predominantly tension-type headaches and associated pericranial muscles tension failed prolonged conventional treatment and, therefore, symptomatic areas were treated with botulinum toxin A. This alleviated myalgia and reduced the severity and frequency of migraine-type headaches with a concomitant reduction in subsequent medical and physical therapy interventions. Judicious use of botulinum toxin A into defined areas of pericranial muscle tension may be useful for reducing primary myalgia and secondary headache.     

Psychosocial Functioning in Schoolchildren With Recurrent Headaches

The psychosocial functioning of 113 schoolchildren (8 to 15 years old) reporting headaches at least once a month was compared to a group of headache-free control subjects matched for sex and age. Thirteen percent of the headache sufferers had migraine headaches, 28% had episodic tension-type headaches, 30% had chronic tension-type headaches, and 29% had migraine coexisting with tension-type headaches.
Overall, the headache sufferers experienced more somatic complaints, stress, and psychological symptoms, in addition to being absent from school (due to illness), more often and reported fewer caring persons as compared to headache-free controls. Although few differences between the four headache groups emerged in the children's psychosocial functioning levels, children with migraine coexisting with tension-type headaches had significantly more frequent somatic complaints than those having episodic tension-type headaches. In addition, children with migraine or migraine coexisting with tension-type headaches were more often absent from school than those having tension-type headaches only. A significant but weak relationship between children's headache severity and their somatic complaints was noted.     

Headache in Behçet's disease

The aim of this study was to investigate the characteristics of headache in patients with Beh?et's disease (BD) seeking neurological consultation. Consecutive patients with BD seen within 1 year at the neuro-Beh?et's out-patient clinic were studied using an electronic database according to the classification criteria of the International Headache Society. During a 12-month period 118 BD patients were admitted, and 98 had headaches. Migraine was the most common type of primary headache diagnosed in 45 patients (46.4%) in the whole headache group, followed by tension-type headache (TTH) in 26 cases (26.8%). Thirty-seven patients had secondary headaches mainly due to cerebral venous thrombosis or parenchymal neurological involvement of BD. Of these patients, 15 had both primary and secondary headaches. The primary headaches of 13 patients were exacerbated with systemic BD flare-ups, and four patients had migraine attacks triggered only by systemic BD activation which showed a good response to the treatment of systemic inflammation. The majority of the headaches of patients with BD do not indicate any neurological involvement; they are usually due to migraine or TTH. In a minority of patients, migraine associated with systemic inflammation of BD is notable.     

Headache in a Population-Based Elderly Cohort. An Ancillary Study to the Italian Longitudinal Study of Aging (ILSA)

The aims of this ancillary study to the Italian Longitudinal Study of Aging were: (1) to provide reliable prevalence data on headache in an elderly population, (2) to classify the subtypes of headache according to International Headache Society criteria, and (3) to identify possible risk factors and associated pathologies in the elderly.
A total of 312 subjects were examined, 148 women and 164 men, with a mean age of 73 years (SD 5.5). For 236 subjects (75.7%), 141 men (85.9%) and 95 women (64.2%), headache had never been a problem; 57 subjects (18.3%), 21 men (12.8%) and 36 women (24.3%), reported troublesome headache only in the past. Nineteen subjects (6%), 6 men (3.6%) and 13 women (8.8%), reported current headache: in this group tension-type headache was the most prevalent, accounting for 2.6%; secondary headaches ranked second, accounting for 2.2%; and only 1% had current migraine.
Our data indicate female sex and younger age as risk factors for headache, and associate migraine and secondary headaches with hypertension, tension-type headaches and secondary headaches with diabetes, and tension-type headaches with myocardial ischemia.     

Disability is the major determinant of the severity of depressive symptoms in primary headaches but not in low back pain

Pain syndromes are often associated with depression. In a prospective study we analysed if determinants of depression differ among patients with different primary headaches and between headaches and non-headache pain. During a 2-year period between 1 February 2002 and 31 January 2004, 635 subjects (migraine n = 231; tension-type headache n = 176; cluster headache n = 11; patients with low back pain n = 103; and healthy subjects n = 114) seen by two neurologists filled in a questionnaire on pain characteristics, the MIDAS questionnaire and the Beck Depression Inventory. A multivariate general regression model was used to identify independent predictors of the severity of depressive symptoms. Pain was most frequent in chronic tension-type headache and most intense in the cluster subgroup (P < 0.001, Kruskal-Wallis ANOVA). In univariate tests gender, age, pain frequency, pain intensity and disability were all significantly associated with the severity of depressive symptoms. In the multivariate model disability was the most important independent determinant of the severity of depressive symptoms in the pooled headache group as well as in the migraine and tension-type headache subgroups. In contrast to patients with headache, pain frequency and pain intensity were the significant independent predictors of the severity of depressive symptoms in patients with low back pain. In a multivariate model, after controlling for other factors, determinants of the severity of depressive symptoms were different in headache and non-headache pain subjects, suggesting a different mechanism for developing depression in primary headaches and in other pain syndromes.     

Application of the ICHD-II criteria to the diagnosis of primary chronic headaches via a computerized structured record

BACKGROUND: The authors recently developed a software program designed to analyze clinical data from patients affected by primary headache. The program is based exclusively on the International Classification of Headache Disorders 2nd edition (ICHD-II) criteria. This software examines all the diagnoses of primary headaches on the basis of the variables needed to fulfill these mandatory criteria. METHODS: We tested the software, Primary Headaches Analyser 1.0 INT (PHA), by entering and analyzing clinical data from 200 consecutive patients affected by primary chronic headaches and evaluating the corresponding output diagnoses. RESULTS: The diagnosis of chronic migraine (1.5.1) was obtained in 68 cases (34 %) and that of probable chronic migraine (1.6.5) plus probable medication-overuse headache (8.2.8) in 46 (23%). Chronic tension-type headache (2.3) and probable chronic tension-type headache (2.4.3) plus probable medication-overuse headache (8.2.8) were diagnosed in 24 (12%) and 2 (1%) patients, respectively. Moreover, 4 and 12 patients, respectively, received both the diagnosis of chronic migraine (1.5.1) plus chronic tension-type headache (2.3) and of probable migraine (1.6.1) without aura plus chronic tension-type headache (2.3). In the remaining 44 cases (22%), none of the chronic primary headaches disorders defined by ICHD-II received an output diagnosis from the program. This was due mainly to the fact that the criteria fulfilled were insufficient for the diagnoses of migraine without (1.1) aura plus chronic migraine or, more infrequently, chronic tension-type headache. CONCLUSIONS: Our software program permitted diagnoses of chronic migraine, chronic tension-type or their probable forms (with or without MOH) in 78% of 200 patients with headache 15 or more days per month. In the remaining cases the inability to provide a specific diagnosis may be explained in part by the fact that the criteria for both diagnoses are too stringent and do not accurately reflect variations of the headache pattern in these chronic forms.     

Acute and interictal allodynia in patients with different headache forms: an Italian pilot study

OBJECTIVE: To investigate allodynia in patients with different primary headaches. BACKGROUND: Many migraineurs have allodynia during headache attacks; some may have allodynia outside attacks; allodynia may also be associated with other primary headaches. METHODS: A total of 260 consecutive primary headache patients presenting for the first time at a headache center, and 23 nonheadache controls answered written questions (subsequently repeated verbally) to determine the presence of acute and interictal allodynia. RESULTS: We divided the patients into: episodic migraine (N = 177), subdivided into only migraine without aura (N = 114) and those sometimes or always reporting migraine with aura (N = 63); episodic tension-type headache (N = 28); chronic headaches (headache > or = 15 days/month, N = 52), including chronic migraine, chronic tension-type headache, and medication-overuse headache; and other headache forms (N = 3). Acute allodynia was present in 132 (50.7%), significantly more often in patients sometimes or always suffering migraine with aura, and those with chronic headache forms, compared to patients with migraine without aura and episodic tension-type headache. Interictal allodynia was present in 63 (24.2%) patients, with significantly higher frequency in those having migraine with aura attacks than controls and common migraine patients. CONCLUSIONS: Allodynia is not specific to migraine but is frequent in all headache patients: acute allodynia was reported in half those interviewed and in over a third of patients in each headache category; interictal allodynia was reported by nearly 25%.     

Clinical features of headache patients with fibromyalgia comorbidity

Our previous study assessed the prevalence of fibromyalgia (FM) syndrome in migraine and tension-type headache. We aimed to update our previous results, considering a larger cohort of primary headache patients who came for the first time at our tertiary headache ambulatory. A consecutive sample of 1,123 patients was screened. Frequency of FM in the main groups and types of primary headaches; discriminating factor for FM comorbidity derived from headache frequency and duration, age, anxiety, depression, headache disability, allodynia, pericranial tenderness, fatigue, quality of life and sleep, and probability of FM membership in groups; and types of primary headaches were assessed. FM was present in 174 among a total of 889 included patients. It prevailed in the tension-type headache main group (35%, p < 0.0001) and chronic tension-type headache subtype (44.3%, p < 0.0001). Headache frequency, anxiety, pericranial tenderness, poor sleep quality, and physical disability were the best discriminating variables for FM comorbidity, with 81.2% sensitivity. Patients presenting with chronic migraine and chronic tension-type headache had a higher probability of sharing the FM profile (Bonferroni test, p < 0.01). A phenotypic profile where headache frequency concurs with anxiety, sleep disturbance, and pericranial tenderness should be individuated to detect the development of diffuse pain in headache patients.     

2000 Wolfe Award. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study

BACKGROUND: Migraineurs experience a spectrum of headaches: migraine, migrainous, and episodic tension-type as defined by the International Headache Society (IHS). OBJECTIVE: To evaluate the effectiveness of sumatriptan, 50-mg tablets, in treating the spectrum of headaches in IHS-diagnosed migraineurs. DESIGN/METHODS: Migraineurs with severe disability (Headache Impact Questionnaire score 250 or greater) were enrolled in a randomized, double-blind, placebo-controlled, crossover study. Patients treated up to 10 headaches with sumatriptan, 50 mg, or placebo (4:1). Headache features, recorded prior to treatment, were used to classify each headache using IHS criteria. Headache response (moderate or severe pain reduced to mild or no pain) and pain-free response were recorded at 2 and 4 hours postdose (primary endpoint). Because patients treated multiple attacks, statistical methods controlling for within-subject correlation were used. RESULTS: Two hundred forty-nine migraineurs treated 1576 moderate or severe headaches: migraine (n = 1110), migrainous (n = 103), and tension-type (n = 363). Sumatriptan was superior to placebo for headache response 4 hours postdose (primary endpoint) across all headache types (migraine, 66% versus 48%; P<.001; migrainous, 71% versus 39%; P<.01; tension-type, 78% versus 50%, P<.001). Sumatriptan was also superior to placebo for pain-free response 4 hours postdose for migraine (41% versus 24%, P<.001) and tension-type headaches (56% versus 36%, P =.001). Sumatriptan provided superior pain-free response 2 hours postdose for migraine (18% versus 7%, P<.0001) and tension-type headache (28% versus 14%, P =.0005) compared with placebo. CONCLUSION: Sumatriptan, 50-mg tablets, are effective for the full spectrum of headaches experienced by patients with disabling migraine due to a sumatriptan-responsive mechanism.     

Dextroamphetamine pilot crossover trials and n of 1 trials in patients with chronic tension-type and migraine headache

OBJECTIVE: To examine the preventive effects of dextroamphetamine in select small groups of patients with chronic tension-type and migraine headache. BACKGROUND: Neither amphetamine nor methylphenidate is used as a headache preventive. This study was undertaken after a chance observation led one of us to prescribe dextroamphetamine with apparent successes in specific patients with chronic tension-type or migraine headaches. METHODS: Two pilot trials were done. Trial 1 tested patients who were taking dextroamphetamine, while Trial 2 tested patients who had never taken this drug. Each trial obtained full data on eight subjects with chronic tension-type headache and eight subjects with migraine headache. A randomized, double-blinded, controlled, multiple-crossover design was used. Subjects took capsules containing dextroamphetamine or equi-stimulatory caffeine (the control) during four alternating 20-day periods. Trial 1 subjects took their pretrial dextroamphetamine dose at breakfast and lunch. Trial 2 subjects took 10 mg at these times. Subjects recorded the integer from 0 to 3 that represented their headache intensity during the previous 24 hours. The subject's data were the average daily headache grade for the two dextroamphetamine periods and for the two caffeine periods. The differential effect of amphetamine and caffeine on each group of eight subjects and on each individual was analyzed by t-tests. RESULTS: In both trials, the tension-type and migraine groups had lower mean daily headache grades in the amphetamine than in the caffeine periods. P values for these differences indicated that there were real drug effects, on the average, in the migraine groups (P<.05) and suggestive but inconclusive effects in the tension-type groups (P<.10). The individual n of 1 analyses showed that five tension-type and three migraine subjects in Trial 1 and three tension-type and three migraine subjects in Trial 2 had considerably lower mean daily headache grades on amphetamine with P values indicating, at various levels of significance (from P<.05 to P<.001), real amphetamine effects. Twelve of the remaining 18 patients had lower, albeit not significant, mean daily grades with amphetamine. No subject in either trial had a significantly lower mean daily headache grade on caffeine. CONCLUSIONS: Dextroamphetamine had real preventive effects on chronic tension-type and migraine headaches in some subjects. These results should encourage other investigators to study its effects on these headaches.     

Chronic post-traumatic headaches classified and compared with natural headaches

This study sought to determine whether chronic post-traumatic headaches are different from or identical to the naturally occurring headaches. The chronic post-traumatic headaches of 48 patients were classified, as if they were natural headaches, by the diagnostic criteria of the International Headache Society. Thirty-six patients' headaches (75%) were chronic tension-type headache, 10 (21%) were migraine without aura , and 2 (4%) were unclassifiable. The characteristics and accompaniments of the headaches within each diagnostic group were then compared to those in a control group with natural headaches of the same type. No notable differences between the post-traumatic and control groups were found. Hence, chronic post-traumatic headaches have no special features, but are symptomatically identical to either chronic tension-type headache or migraine without aura (in this series of patients). This identity suggests that post-traumatic headaches are generated by the same processes causing the natural headaches, not by intracranial derangement from head blows or jolts.