Is headache a risk factor for dementia? A systematic review and meta-analysis.

OBJECTIVE: In this systematic review and meta-analysis, we critically evaluate available evidence regarding the association between primary headaches and subsequent decline of cognitive function and dementia. BACKGROUND: Recent studies suggested that headache disorders may increase the risk for dementia. However, available studies are conflicting. METHODS: To identify qualifying studies, we searched scientific databases, including Pubmed, Scopus, Web of Science, Science Direct and BMC, screening for relevant papers. In order to reduce the heterogeneity between different studies, the analyses were further subdivided according to the clinical diagnoses and the study methodologies. RESULTS: We identified 23 studies investigating the association between primary headaches and the risk of dementia. Of these, 18 met our inclusion criteria for meta-analysis (covering 924.140 individuals). Overall effect-size shows that primary headaches were associated with a small increase in dementia risk (OR = 1,15; CI 95%: 1,03-1,28; p = 0,02). Analyzing subgroups, we found that migraine was associated with both a moderate increased risk of all-cause dementia (OR = 1,26; p = 0,00; 95% CI: 1,13-1,40) as well as a moderate increased risk of Alzheimer's disease (OR = 2,00; p = 0,00; 95% CI: 1,46-2,75). This association was significant in both case-control and retrospective cohort studies but not in prospective studies. CONCLUSIONS: Our study supports the presence of a link between primary headaches and dementia. However, in the subgroup analysis, only patients with migraine showed a moderate increase risk for all-cause dementia and for Alzheimer's disease. Additional rigorous studies are needed to elucidate the possible role of primary headaches on the risk of developing cognitive impairment and dementia.

Cognitive dysfunction, social behavior disorder, cerebellar ataxia, and atypical brain FDG-PET presentation in spinocerebellar ataxia 17: a case report.

BACKGROUND: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant form of inherited ataxia, caused by heterozygous trinucleotide repeat expansions encoding glutamine in the TATA box-binding protein (TBP) gene. CASE DESCRIPTION: We describe the clinical history, neuropsychological, and neuroimaging findings of a 42-year-old patient who presented for medical attention showing prevalent behavioral and cognitive problems along with progressively worsening gait disturbances. The patient's family history indicated the presence of SCA17 in the maternal lineage. Genetic analysis confirmed a heterozygous 52-CAG pathological expansion repeat in TBP (normal interval, 25-40 CAG. Brain 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed bilateral hypometabolism in the sensorimotor cortex, with a slight predominance on the right, as well as in the striatal nuclei and thalamic hypermetabolism, a finding similar to what is observed in Huntington's disease. The patient also underwent neuropsychological evaluation, which revealed mild cognitive impairment and difficulties in social interaction and understanding other's emotions (Faux Pas Test and Reading the Mind in the Eyes Test). CONCLUSION: Our report emphasizes the importance of considering SCA17 as a possible diagnosis in patients with a prevalent progressive cognitive and behavioral disorders, even with a pattern of FDG-PET hypometabolism not primarily indicative of this disease.

Increased orexin A concentrations in cerebrospinal fluid of patients with behavioural variant frontotemporal dementia.

Orexins are hypothalamic neuropeptides that regulate several physiological functions, such as appetite, arousal, cognition, stress, sleep and metabolism. Emerging pieces of evidence suggest an orexinergic dysfunction in several neuropsychiatric disorders, including depression, anxiety and addiction. A syndromic overlap between behavioural variant frontotemporal dementia (bvFTD) and several psychiatric disorders was recently demonstrated. Therefore, we analysed cerebrospinal fluid (CSF) orexin A concentrations of 40 bvFTD and 32 non-demented patients, correlating neuropeptide concentrations with several clinical characteristics. A significant increase of orexin A concentrations was found in bvFTD patients when compared to controls (p<0.001). CSF orexin A concentration showed a correlation with Mini-Mental State Examination scores, drug assumption, history of compulsive behaviour and extrapyramidal signs. Moreover, we found a relationship between CSF markers of neurodegeneration, total tau and Aß1-42 and CSF orexin A concentrations. Our study provides evidence of an orexinergic dysfunction in bvFTD, correlating with several clinical symptoms. Further larger studies are needed to confirm our data.

Polymorphisms of the Proinflammatory Cytokine Genes Modulate the Response to NSAIDs but Not to Triptans in Migraine Attacks.

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (IL-1α, IL-1ß, IL-1RN; IL-6 and TNF-α) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the TNF-α promoter (−308 A/G) and a lack of efficacy after NSAID administration (p < 0.01, OR 2.51, 95% CI: 1.33 < OR < 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the TNF-α gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack.

Impact of COVID-19 on chronic migraine treated with erenumab: a case report.

BACKGROUND: Headache is a frequent symptom of the novel coronavirus 19 disease (COVID-19). To date, there are limited information on how COVID-19 affects migraine and its treatment. CASE DESCRIPTION: A 47-year-old patient, suffering from chronic migraine and medication-overuse headache, in September 2020 started erenumab at 70 mg once monthly. Two months later, monthly migraine days decreased from 20 to 5. On the third month, the patient developed mild COVID-19 symptoms, experiencing extreme fatigue, hyposmia, and attention deficit, resulting positive for SARS-Cov-2 RNA. A significant increase in migraine attacks frequency was reported. Brain MRI and EEG were normal. Erenumab was increased to 140 mg/month, and attacks decreased to 3 monthly migraine days and remained stable. All the headaches experienced by our patient during the infection fulfilled the criteria of the migraine attacks, without tensive-like features. CONCLUSION: We report the first case showing the effects of SARS-CoV-2 infection in a patient with chronic migraine and medication-overuse headache treated with erenumab. Our case description suggests that inflammatory processes induced by SARS-CoV-2 infection may increase the frequency of migraine attacks, probably through an activation of the trigeminovascular system. Whether treatment with CGRP receptor antagonist may influence COVID is still debated. Additional studies regarding anti-CGRP monoclonal antibodies in COVID-19 patients are warranted.

Intimate Partner Violence and Alexithymia: Do Emotions Matter? A Systematic Review and Meta-Analysis.

Intimate partner violence (IPV) encompasses physical, sexual, or psychological abuse. Recent evidence suggests that victims and perpetrators might share some common psychological characteristics. Particularly, high levels of alexithymia, a difficulty in identifying and expressing emotions, and an externally oriented thinking style were found in both victims and perpetrators when compared to the general population. This systematic review and meta-analysis aimed to quantify the levels of alexithymia in victims and perpetrators of IPV and compare these levels to controls. We systematically searched PubMed, PsycINFO, Web of Science, and Scopus databases, using the following strings: ("intimate partner violence" OR "IPV" OR "partner abuse") AND ("alexithymia" OR "alexithymic"). The inclusion criteria were: adult perpetrators or victims of IPV; with or without a rehabilitation program; having or not a comparison group from the general population; alexithymia as outcome; all types of study design. Seventeen studies met the inclusion criteria. Data were meta-analyzed with random-effects models. Results showed comparable levels of alexithymia in victims and perpetrators of IPV (mean = 55.92 vs. 55.15, respectively). Furthermore, we found increased alexithymia in victims (Hedges' g, 0.87 [95% CI 0.43, 1.31]) and perpetrators (Hedges' g, 0.94 [95% CI 0.77, 1.12]) compared to controls. These results highlight that both perpetrators and victims exhibited high levels of alexithymia. A deeper understanding of this psychological dimension can help professionals to plan better-tailored interventions, in which all relevant factors associated with IPV are considered.

A Novel PSEN1 Variant Leading to Posterior Cortical Atrophy: A Case Report.

We describe a 52-year-old patient with a progressive visuospatial disorder and apraxia. Neuropsychological assessment, neuroradiological findings, and Alzheimer's disease (AD) core biomarker assay on cerebrospinal fluid led to a diagnosis of posterior cortical atrophy due to AD. We performed a next generation sequencing dementia-gene panel and found the c.1301 C>T p.(Ala434Val) variant in the Presenilin1 (PSEN1) gene. The missense change affects the PAL (Pro433-Ala434-Leu435) motif critical for catalytic activity of the macromolecular γ-secretase complex. Evolutionary and integrated bioinformatic tools predicted a deleterious effect of the variant supporting its role in the AD pathogenesis.

Aß42 as a Biomarker of Alzheimer's Disease: Is Saliva a Viable Alternative to Cerebrospinal Fluid?

The identification of reliable biomarkers in biological fluids is paramount to optimizing the diagnosis of Alzheimer's disease (AD). Measurement of Aß42, t-tau, and p-tau in cerebrospinal fluid (CSF) is the most accepted method to support the diagnosis of AD. However, lumbar puncture represents an invasive investigation, whereas saliva is one of the most accessible body fluids. The aim of our study was to investigate salivary concentrations in AD and evaluate the correlation between salivary and CSF Aß42 concentrations in AD patients, patients with non-AD dementias, and controls. We recruited 100 subjects: 18 AD patients, 64 patients with non-AD dementias, and 18 controls. The mean saliva Aß42 concentrations in AD patients were higher than in controls (p < 0.001), and to patients with non-AD dementias (p = 0.001). A significant negative correlation between salivary and CSF Aß42 concentrations was found in the overall group (r = −0.562, p < 0.001) and in non-AD patients (r = −0.443, p < 0.001). Salivary Aß42 concentrations positively correlated with CSF t-tau (r = 0.321, p = 0.001) and p-tau (r = 0.297, p = 0.001). Our study showed that in AD patients' saliva, Aß42 concentrations are specifically increased, and we found an interesting negative correlation between CSF and salivary Aß42 concentrations that warrants further investigation.

Decreased resistin plasmatic concentrations in patients with Alzheimer's disease: A case-control study.

Previous studies suggested a role for adipokines in ageing and in several age-related diseases. The purpose of our study was to further elucidate adipokines involvement in neurodegeneration, investigating adiponectin, leptin and resistin in Alzheimer's disease (AD) and Frontotemporal Dementia (FTD). We enrolled for the study 70 subjects: 26 AD, 21 FTD, and 23 with other neurological (but not neurodegenerative) conditions (CTR, control group). According to a standardized protocol, we measured adipokines plasmatic levels, blood parameters of glucidic and lipidic metabolism, ESR, cerebrospinal fluid (CSF) markers of neurodegeneration (beta-amyloid, total-Tau, phosphorylated-Tau) and anthropometric parameters. In comparison with control group, we found lower resistin concentrations in patients with dementia, and in particular in AD (p < 0.001). In multivariate analysis, AD relative risk was reduced by resistin, when controlling for sex, age and anthropometric/metabolic parameters (RR = 0.71, P < 0.0001). Considering CSF biomarkers, we found a direct correlation between resistin and Aß1-42 CSF concentration in patients (p < 0.001, r = 0.50). Lower resistin characterized AD patients in our study and AD, but not FTD, diagnosis risk was found to be inversely associated with resistin when controlling for confounders. We hypothesize that resistin-linked metabolic profile has to be reconsidered and further investigated in AD.

Analysis of the DNA methylation pattern of the promoter region of calcitonin gene-related peptide 1 gene in patients with episodic migraine: An exploratory case-control study.

Recent studies suggested that epigenetic mechanisms, including DNA methylation, may be involved in migraine pathogenesis. The calcitonin gene-related peptide (CGRP), encoded by calcitonin gene-related peptide 1 (CALCA) gene, plays a key role in the disease. The aim of the study was to evaluate DNA methylation of CALCA gene in patients with episodic migraine. 22 patients with episodic migraine (F/M 15/7, mean age 39.7 ± 13.4 years) and 20 controls (F/M 12/8, mean age 40.5 ± 14.8 years) were recruited. Genomic DNA was extracted from peripheral blood. Cytosine-to-thymine conversion was obtained with sodium bisulfite. The methylation pattern of two CpG islands in the promoter region of CALCA gene was analyzed. No difference of methylation of the 30 CpG sites at the distal region of CALCA promoter was observed between migraineurs and controls. Interestingly, in patients with episodic migraine the methylation level was lower in 2 CpG sites at the proximal promoter region (CpG -1461, p = 0.037, and -1415, p = 0.035, respectively). Furthermore, DNA methylation level at different CpG sites correlates with several clinical characteristics of the disease, as age at onset, presence of nausea/vomiting, depression and anxiety (p < 0.05). In conclusion, we found that DNA methylation profile in two CpG sites at the proximal promoter region of CALCA is lower in migraineurs when compared to controls. Intriguingly, the -1415 hypomethylated unit is located at the CREB binding site, a nuclear transcription factor. In addition, we found a correlation between the level of CALCA methylation and several clinical features of migraine. Further studies with larger sample size are needed to confirm these results.

Synaptic Proteins as Fluid Biomarkers in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Synaptic disruption precedes neuronal death and correlates with clinical features of Alzheimer's disease (AD). The identification of fluid biomarkers of synaptic damage is emerging as a goal for early and accurate diagnosis of the disease. OBJECTIVE: To perform a systematic review and meta-analysis to determine whether fluid biomarkers of synaptic damage are impaired in AD. METHODS: PubMed, Scopus, EMBASE, and Web of Science were searched for articles reporting synaptic proteins as fluid biomarkers in AD and cognitively unimpaired (CU) individuals. Pooled effect sizes were determined using the Hedge G method with random effects. Questions adapted from the Quality Assessment of Diagnostic Accuracy Studies were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42021277487). RESULTS: The search strategy identified 204 articles that were assessed for eligibility. A total of 23 studies were included in the systematic review and 15 were included in the meta-analysis. For Neurogranin, 827 AD and 1,237 CU subjects were included in the meta-analysis, showing a significant increase in cerebrospinal fluid of patients with AD compared to CU individuals, with an effect size of 1.01 (p < 0.001). A significant increase in SNAP-25 and GAP-43 levels in CSF of patients with AD was observed. CONCLUSION: Neurogranin, SNAP-25, and GAP-43 are possible biomarkers of synaptic damage in AD, and other potential synaptic biomarkers are emerging. This meta-analysis also revealed that there are still relatively few studies investigating these biomarkers in patients with AD or other dementias and showed wide heterogeneity in literature.

Investigating p62 Concentrations in Cerebrospinal Fluid of Patients with Dementia: A Potential Autophagy Biomarker In Vivo?

Several studies have revealed defects in autophagy in neurodegenerative disorders including Alzheimer's disease (AD) and frontotemporal dementia (FTD). SQSTM1/p62 plays a key role in the autophagic machinery and may serve as a marker for autophagic flux in vivo. We investigated the role of p62 in neurodegeneration, analyzing its concentrations in the CSF of AD and FTD patients. We recruited 76 participants: 22 patients with AD, 28 patients with FTD, and 26 controls. CSF p62 concentrations were significantly increased in AD and FTD patients when compared to controls, which persisted after adjusting for age (p = 0.01 and p = 0.008, respectively). In female FTD patients, p62 positively correlated with the neurodegenerative biomarkers t-Tau and p-Tau. A significant correlation between CSF p62 concentrations and several clinical features of AD was found. Our data show that p62 is increased in CSF of AD and FTD patients, suggesting a key role of autophagy in these two disorders. The levels of p62 in CSF may reflect an altered autophagic flux, and p62 could represent a potential biomarker of neurodegeneration.

Effects of Circadian Phase Tailored Light Therapy on Sleep, Mood, and Cognition in Alzheimer's Disease: Preliminary Findings in a Pivotal Study.

It is shown that the circadian system is affected in patients with Alzheimer's disease (AD) even at an early stage of the disease and that such dysfunction may be detrimental to sleep, mood, and cognitive functioning. Light is a strong central modulator of the circadian rhythms and is potentially beneficial to mood and cognitive functioning via a direct effect or indirectly via its modulating effects on circadian rhythms. This study focuses on tracking the effect of light therapy on sleep quality, mood, and cognition in AD of mild/moderate severity. We performed a single-blind randomized controlled trial to investigate the effects of a light therapy treatment tailored to the individual circadian phase as measured by dim light melatonin onset (DLMO). Such a treatment induced an objective circadian phase shift consistent with the melatonin phase response curve to light exposure, led to a shortening of the phase angle DLMO-falling asleep time, and was associated with an improvement in subjective sleep quality and cognitive performance.

Medulloblastoma in adults: an analysis of clinico-pathological, molecular and treatment factors.

BACKGROUND: Medulloblastoma is a highly malignant, embryonal tumor, which is rare in adults, and shows distinct clinical, histopathological, molecular and treatment response features. METHODS: We retrospectively investigated 44 adults (age 17-48 years) with an histological diagnosis of medulloblastoma, and in 23 immunohistochemistry was used to identif y the molecular subgroups. We analyzed demographic, diagnostic, therapeutic and cognitive data, and correlated with PFS (progression-free-survival) and OS (overall survival). RESULTS: We observed a male prevalence and a median age of 31 years. Symptoms at onset were related to infratentorial location, while myeloradicular and/or cranial nerve involvement was rare. Histological examination showed the classic variant in 75% of patients, the desmoplastic/nodular in 23% and the anaplastic in one. As for molecular diagnosis, 17 patients were SHH and 6 non-WNT/non-SHH (5 group 4 and 1 group 3), while no WNT subgroup was found. The SHH subgroup had a prevalence of high-risk patients and leptomeningeal involvement. Patients underwent grosstotal or subtotal/partial resection, and craniospinal irradiation, followed in 20 cases by adjuvant chemotherapy. Median OS and PFS were 16.9 and 12 years, respectively. Metastatic disease at presentation and subtotal/partial resection were associated with worse prognosis, while the addition of chemotherapy did not yield a significant advantage over radiotherapy alone. Cognitive impairment in long-term survivors was limited and late relapses occurred in 15% of patients. CONCLUSIONS: Future studies with adequate sample size and long-term follow-up should prospectively investigate the role of surgery and adjuvant therapies across the different molecular subgroups to see whether a personalized approach is feasible.

Migraine during COVID-19: Data from Second Wave Pandemic in an Italian Cohort.

OBJECTIVES: The study aims to assess the impact of the second COVID-19 pandemic wave on migraine characteristics. METHODS: This is an observational cross-sectional study conducted on migraine patients previously interviewed during the first Italian pandemic outbreak. A second structured telephone interview was conducted between 20 November 2020 and 18 January 2021. We compared migraine characteristics among T0 (before pandemic), T1 (during the first pandemic phase), and T2 (during the second pandemic phase). RESULTS: Among the 433 patients interviewed during the first pandemic phase, 304 cases were finally considered. One hundred forty-eight patients had a control visit between March 2020 and December 2020, 120 had an in-person visit, 14 by phone, the remainder used telemedicine software provided by the hospital. Frequency of headache, number of symptomatic drugs and headache intensity worsened during T2, compared to T0 and T1, especially in episodic migraine. Headache intensity increased relating to the negative emotional impact of the pandemic. Migraine management during the pandemic did not influence the clinical outcome. CONCLUSION: The prolongation of the pandemic seems to have a negative impact on migraine evolution. The arousal and negative psychological behavior toward the COVID-19 outbreak seem to worsen migraine.

Migraine pathways and the identification of novel therapeutic targets.

Introduction: Migraine is a chronic neurovascular disorder characterized by recurrent headache attacks associated with neurological and autonomic symptoms. The pathophysiological mechanisms of the disease are extremely complex, involving hypothalamic and trigeminovascular activation, cortical spreading depression, release of pro-inflammatory peptides, peripheral and central sensitization. The underlying cellular and molecular mechanisms have been scarcely investigated. Recently, genetic studies have suggested that different metabolic pathways could be involved in the pathogenesis of migraine.Areas covered: This review focuses on cellular and molecular mechanisms involved in migraine, suggesting a role for circadian clocks, ion channels, synaptic plasticity, vascular factors, ion metal homeostasis, and impaired glucose metabolism in the pathogenesis of the disease. Accordingly, the article proposes new therapeutic targets that may be of particular relevance for disease prevention.Expert opinion: Several complex molecular mechanisms are involved in setting the genetic threshold for migraine and the pathogenesis of headache attacks. Most promising new therapeutic targets are the modulation of hypothalamic activity and ion channels involved in pain transmission. Further studies in animals and humans are necessary to enhance the elucidation of the molecular mechanisms of migraine and open new avenues for disease prevention.

Metacognitive impairment in patients with episodic and chronic migraine.

Migraine is one of the most common medical disorder in the world. Metacognition is the ability to monitor one's own cognitive functioning and consequently direct one's behavior. In adult migraine patients, the neuropsychological profile has been poorly investigated, and metacognitive functions have never been assessed. The aim of the present study was therefore to evaluate executive metacognitive abilities in patients with episodic and chronic migraine. Sixty-four migraine patients (male/female = 18/46; mean age = 45.65 ± 11.61 years): 27 patients with episodic migraine without aura (male/female = 9/18; mean age ± SD = 45.11 ± 12.18 years) and 37 patients with chronic migraine and medication-overuse headache (male/female = 9/28; mean age ± SD = 46.05 ± 11.32 years) were selected for the study. Twenty-nine controls (male/female = 12/17; mean age ± SD = 42.86 ± 14.78 years) were also enrolled in the research. Metacognitive and executive skills were assessed using the metacognitive version of Wisconsin Card Sorting Test. Migraine patients exhibited a lower performance in metacognitive tasks in respect to controls in term of worse outcomes in accuracy score (p = 0.012), global monitoring (p = 0.015), monetary gains (p = 0.022), and control sensitivity (p = 0.027). A reduction in accuracy score (p = 0.001), free-choice improvement (p = 0.002), global monitoring (p = 0.003), monetary gains (p = 0.009), and control sensitivity (p < 0.001) was also found in patients with chronic migraine and medication-overuse headache in respect to patients with episodic migraine. Our study supports the hypothesis that migraine patients show metacognitive dysfunctions that become worse with the chronicization of the disease and the increase of medication use.

Investigating the Effects of COVID-19 Quarantine in Migraine: An Observational Cross-Sectional Study From the Italian National Headache Registry (RICe).

Background: Previous studies during SARS and Ebola pandemics have shown that quarantine is associated with several negative psychological effects, such as post-traumatic stress symptoms, confusion, and anger. These conditions may affect the course of many diseases, including migraine. Although it is possible that the quarantine measures for the current COVID-19 pandemic affect migraine burden, no information is currently available on this issue. Aim: In this study, we aimed to: (1) explore the possible changes in migraine frequency, severity, and days with acute medication intake during quarantine period; (2) evaluate possible differences in migraine outcomes in consideration of lifestyle changes, emotions, pandemic diffusion, and COVID-19 infection. Methods: We interviewed patients who were included in the observational Italian Headache Registry (Registro Italiano Cefalee, RICE), retrospectively collecting information on main headache features, lifestyle factors, emotions, individual infection status, and perception of COVID-19 for 2 months before (pre-quarantine) and after the beginning of the quarantine (quarantine). Inclusion criteria were: age > 18, diagnosis of migraine without aura, migraine with aura and chronic migraine, last in-person visit more than 3 months preceding the beginning of quarantine. Results: A total of 433 migraine subjects agreed to be interviewed. We found an overall reduction in headache frequency (9.42 ± 0.43 days with headache vs. 8.28 ± 0.41) and intensity (6.57 ± 0.19 vs. 6.59 ± 0.21) during the quarantine, compared to pre-quarantine. There was a correlation between improvement and number of days of stay-at-home. When results were stratified for geographic area, we found a tendency toward worsening of headache frequency in northern Italy. Disgust regarding viral infection corresponded to a minor improvement in migraine. Conclusions: Migraine patients showed a mild improvement of migraine features, probably attributable to resilient behavior toward pandemic distress. Disgust regarding the contagion whereas potentially favoring defensive behavior, could potentially worsen migraine. The spontaneous limitation of migraine burden during quarantine could favor patient follow-up via the use of telemedicine visits, reliable diaries, and frequent remote contacts.