Use of the Gene Expression Test Prosigna® in Premenopausal Patients with HR+, HER2- Early Breast Cancer: Correlation of the Results with the Proliferation Marker Ki-67.

Introduction: In hormone receptor-positive (ER+/PR+) and human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer (EBC), gene expression tests such as the Prosigna are increasingly used since classic clinicopathological parameters and the proliferation factor Ki-67 often do not allow a definite therapy decision regarding an adjuvant chemotherapy. While the Prosigna test has been validated for postmenopausal patients, few data are available regarding its use in premenopausal patients. The present study compared the Prosigna test with the Ki-67 index in premenopausal patients. Materials and Methods: Premenopausal patients with HR+ HER2-, pN0-1, G1-2 EBC were retrospectively enrolled (n = 55). The Prosigna assay was performed in formalin-fixed paraffin-embedded tumor samples of surgical resection specimens. Ki-67 was reassessed in original diagnostic core needle biopsy specimens and defined as low, intermediate, or high with the threshold of <10%, 10-24%, ≥25%. Results: According to Ki-67, patients were in the low (LR)-, intermediate (IR)-, and high-risk (HR) groups in 40%, 36%, and 24% of the cases. The Prosigna gene signature assay assessed the risk of recurrence as LR for 45% of the patients, IR for 35%, and HR for 20%. The most frequent intrinsic subtypes were luminal A in 73% and luminal B in 24% of the patients. A moderate correlation was found between Prosigna and Ki-67 scores with a Pearson correlation coefficient of 0.51. In the overall cohort, 47% of the Ki-67-based therapy decision would correspond to those based on the Prosigna score. After exclusion of IR patients, matching of low/low or high/high results was observed in 57% of the cases. Conclusion: According to the present study, there is only limited concordance regarding the risk group stratification between Ki-67 and Prosigna-based risk assessment. The relevance and frequency of premenopausal breast cancer emphasizes the need for further evaluation of gene expression analyses in this setting and the correlation with classic clinicopathological parameters regarding therapy decision-making.

Gait Variability at Different Walking Speeds.

Gait variability (GV) is a crucial measure of inconsistency of muscular activities or body segmental movements during repeated tasks. Hence, GV might serve as a relevant and sensitive measure to quantify adjustments of walking control. However, it has not been clarified whether GV is associated with walking speed, a clarification needed to exploit effective better bilateral coordination level. For this aim, fourteen male students (age 22.4 ± 2.7 years, body mass 74.9 ± 6.8 kg, and body height 1.78 ± 0.05 m) took part in this study. After three days of walking 1 km each day at a self-selected speed (SS) on asphalt with an Apple Watch S. 7 (AppleTM, Cupertino, CA, USA), the participants were randomly evaluated on a treadmill at three different walking speed intensities for 10 min at each one, SS - 20%/SS + 20%/ SS, with 5 min of passive recovery in-between. Heart rate (HR) was monitored and normalized as %HRmax, while the rate of perceived exertion (RPE) (CR-10 scale) was asked after each trial. Kinematic analysis was performed, assessing the Contact Time (CT), Swing Time (ST), Stride Length (SL), Stride Cycle (SC), and Gait Variability as Phase Coordination Index (PCI). RPE and HR increased as the walking speed increased (p = 0.005 and p = 0.035, respectively). CT and SC decreased as the speed increased (p = 0.0001 and p = 0.013, respectively), while ST remained unchanged (p = 0.277). SL increased with higher walking speed (p = 0.0001). Conversely, PCI was 3.81 ± 0.88% (high variability) at 3.96 ± 0.47 km·h-1, 2.64 ± 0.75% (low variability) at SS (4.94 ± 0.58 km·h-1), and 3.36 ± 1.09% (high variability) at 5.94 ± 0.70 km·h-1 (p = 0.001). These results indicate that while the metabolic demand and kinematics variables change linearly with increasing speed, the most effective GV was observed at SS. Therefore, SS could be a new methodological approach to choose the individual walking speed, normalize the speed intensity, and avoid a gait pattern alteration.

New Insights in the Era of Clinical Biomarkers as Potential Predictors of Systemic Therapy-Induced Cardiotoxicity in Women with Breast Cancer: A Systematic Review.

Cardiotoxicity induced by breast cancer therapies is a potentially serious complication associated with the use of various breast cancer therapies. Prediction and better management of cardiotoxicity in patients receiving chemotherapy is of critical importance. However, the management of cancer therapy-related cardiac dysfunction (CTRCD) lacks clinical evidence and is based on limited clinical studies. AIM: To provide an overview of existing and potentially novel biomarkers that possess a promising predictive value for the early and late onset of CTRCD in the clinical setting. METHODS: A systematic review of published studies searching for promising biomarkers for the prediction of CTRCD in patients with breast cancer was undertaken according to PRISMA guidelines. A search strategy was performed using PubMed, Google Scholar, and Scopus for the period 2013-2023. All subjects were >18 years old, diagnosed with breast cancer, and received breast cancer therapies. RESULTS: The most promising biomarkers that can be used for the development of an alternative risk cardiac stratification plan for the prediction and/or early detection of CTRCD in patients with breast cancer were identified. CONCLUSIONS: We highlighted the new insights associated with the use of currently available biomarkers as a standard of care for the management of CTRCD and identified potentially novel clinical biomarkers that could be further investigated as promising predictors of CTRCD.

Fluctuations of entropy production of a run-and-tumble particle.

Out-of-equilibrium systems continuously generate entropy, with its rate of production being a fingerprint of nonequilibrium conditions. In small-scale dissipative systems subject to thermal noise, fluctuations of entropy production are significant. Hitherto, mean and variance have been abundantly studied, even if higher moments might be important to fully characterize the system of interest. Here, we introduce a graphical method to compute any moment of entropy production for a generic discrete-state system. Then, we focus on a paradigmatic model of active particles, i.e., run-and-tumble dynamics, which resembles the motion observed in several micro-organisms. Employing our framework, we compute the first three cumulants of the entropy production for a discrete version of this model. We also compare our analytical results with numerical simulations. We find that as the number of states increases, the distribution of entropy production deviates from a Gaussian. Finally, we extend our framework to a continuous state-space run-and-tumble model, using an appropriate scaling of the transition rates. The approach presented here might help uncover the features of nonequilibrium fluctuations of any current in biological systems operating out-of-equilibrium.

Epidemiology and Risk Factors of UTIs in Children-A Single-Center Observation.

Urinary tract infections (UTIs) are one of childhood's most common bacterial infections. The study aimed to determine the clinical symptoms, laboratory tests, risk factors, and etiology of different UTIs in children admitted to pediatric hospitals for three years. Methods: Patients with positive urine cultures diagnosed with acute pyelonephritis (APN) or cystitis (CYS) were analyzed for clinical symptoms, laboratory tests, risk factors, and etiology, depending on their age and sex. Results: We studied 948 children with UTIs (531 girls and 417 boys), with a median age of 12 (IQR 5−48 months). A total of 789 children had clinical symptoms; the main symptom was fever (63.4% of patients). Specific symptoms of UTIs were presented only in 16.3% of patients. Children with APN had shown significantly more frequent loss of appetite, vomiting, lethargy, seizures, and less frequent dysuria and haematuria than children with CYS. We found significantly higher median WBC, CRP, and leukocyturia in children with APN than with CYS. The risk factors of UTIs were presented in 46.6% of patients, of which 35.6% were children with APN and 61.7% with CYS. The main risk factor was CAKUT, more frequently diagnosed in children with CYS than APN, mainly in children <2 years. The most commonly isolated bacteria were Escherichia coli (74%). There was a higher percentage of urine samples with E. coli in girls than in boys. Other bacteria found were Klebsiella species, Pseudomonas aeruginosa, Proteus mirabilis, and Enterococcus species. Conclusions: Patients with APN were younger and had higher inflammatory markers. Often, fever is the only symptom of UTI in children, and other clinical signs are usually non-specific. The most common UTI etiology is E. coli, regardless of the clinical presentation and risk factors.

Health-related quality-of-life up to one year after myocardial infarction with non-obstructive coronary arteries.

AIMS: Patients with Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) are a heterogenous group and previous studies indicate a decreased Health-related quality-of-life (HRQoL) compared with patients with myocardial infarction with obstructive coronary artery disease and healthy individuals. However, longitudinal data are scarce. Therefore, the aim was to explore HRQoL among patients with MINOCA during a one-year period after the acute event in comparison with a group of healthy individuals and to describe HRQoL in patients with Takotsubo Syndrome (TTS). METHODS AND RESULTS: Patients with MINOCA were recruited from five hospitals in the Stockholm region (SMINC-2 study, clinical trials: NCT2318498). Patients responded to the HRQoL questionnaire RAND-36 between days 2-4, after 6 and 12 months respectively. A sample of population-based individuals was used as a comparison group. A total of 142 MINOCA patients, (70% women) mean age of 56 years, responded. A population-based sample of 317 volunteers (66% women) mean age of 57 years. Patients with MINOCA scored lower than the comparison group in the domains role functioning physical, social functioning, and role functioning emotional (P = 0.01-0.02) at 12 months. In these domains of HRQoL there was no improvement in MINOCA patients during 12 months follow-up. In the domains of energy/fatigue vitality and emotional well-being the scores improved and were similar to the comparison group at 12 months. Patients with TTS scored generally lower on RAND-36 than MINOCA patients without TTS. CONCLUSION: Physical, social, and emotional functioning did not improve during the first year after MINOCA, indicating a need for increased follow-up including psychological support.

ABC transporters are billion-year-old Maxwell Demons.

ATP-Binding Cassette (ABC) transporters are a broad family of biological machines, found in most prokaryotic and eukaryotic cells, performing the crucial import or export of substrates through both plasma and organellar membranes, and maintaining a steady concentration gradient driven by ATP hydrolysis. Building upon the present biophysical and biochemical characterization of ABC transporters, we propose here a model whose solution reveals that these machines are an exact molecular realization of the autonomous Maxwell Demon, a century-old abstract device that uses an energy source to drive systems away from thermodynamic equilibrium. In particular, the Maxwell Demon does not perform any direct mechanical work on the system, but simply selects which spontaneous processes to allow and which ones to forbid based on information that it collects and processes. In its autonomous version, the measurement device is embedded in the system itself. In the molecular model introduced here, the different operations that characterize Maxwell Demons (measurement, feedback, resetting) are features that emerge from the biochemical and structural properties of ABC transporters, revealing the crucial role of allostery to process information. Our framework allows us to develop an explicit bridge between the molecular-level description and the higher-level language of information theory for ABC transporters.

Neurodevelopment Outcome in Children with Fetal Growth Restriction at Six Years of Age: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to describe neurodevelopment in fetal growth restriction children at the age of six. Secondly, we tried to demonstrate influencing factors that can improve or exacerbate this development, as well as predictive factors that might select a population at risk to assist with early childhood support. METHOD: It was a study of 70 children affected with FGR. FGR was based on these definitions: birth weight below the 3rd percentile or birth weight below the 10th percentile with an abnormal hemodynamic Doppler study. Neurodevelopment was assessed at 6 years old by means of Batelle Development Inventory. A global development quotient under a 100 score was considered a neurodevelopment delay. All variables regarding pregnancy care, delivery episode, postpartum, neonatal care, sociodemographic issues, and the need for support in the first years were studied. RESULTS: The mean gestational age at diagnosis was 33.14 weeks (standard deviation (SD = 4.31), with 32.9% of early-onset diagnoses. The mean gestational age at delivery was 35.61 (SD = 3.21), and the cesarean rate was 64.3%. The average age of the children at the moment of the evaluation was 76.20-month-old (SD = 3.70). The mean global development quotient was 97.28 (SD = 13.97). We were able to record a 57.1% of global development delay. In the cases of cognition, only 17.1% of the children registered a delay. Motor and communication skills were the most frequently affected. We discovered that socioeconomic status was positively related to the global development quotient, as well as both gestational age at delivery and middle cerebral artery pulsatility index was positively related to the global development quotient. CONCLUSIONS: We found a higher neurodevelopment delay rate (57.1%). We could relate a higher gestational age at delivery and a higher MCA percentile with better global neurodevelopment quotients.

Information-driven transitions in projections of underdamped dynamics.

Low-dimensional representations of underdamped systems often provide useful insights and analytical tractability. Here, we build such representations via information projections, obtaining an optimal model that captures the most information on observed spatial trajectories. We show that, in paradigmatic systems, the minimization of the information loss drives the appearance of a discontinuous transition in the optimal model parameters. Our results raise serious warnings for general inference approaches, and they unravel fundamental properties of effective dynamical representations impacting several fields, from biophysics to dimensionality reduction.

Mutual information in changing environments: Nonlinear interactions, out-of-equilibrium systems, and continuously varying diffusivities.

Biochemistry, ecology, and neuroscience are examples of prominent fields aiming at describing interacting systems that exhibit nontrivial couplings to complex, ever-changing environments. We have recently shown that linear interactions and a switching environment are encoded separately in the mutual information of the overall system. Here we first generalize these findings to a broad class of nonlinear interacting models. We find that a new term in the mutual information appears, quantifying the interplay between nonlinear interactions and environmental changes, and leading to either constructive or destructive information interference. Furthermore, we show that a higher mutual information emerges in out-of-equilibrium environments with respect to an equilibrium scenario. Finally, we generalize our framework to the case of continuously varying environments. We find that environmental changes can be mapped exactly into an effective spatially varying diffusion coefficient, shedding light on modeling of biophysical systems in inhomogeneous media.

Etiopathogenesis of ovarian cancer. An inflamm-aging entity?

Ovarian cancer is one of the most common gynecologic cancers and has the highest mortality rate. The risk/protective factors of ovarian cancer suggest that its etiology is multifactorial. Several factors are involved in age-related increases in carcinogenesis, including the accumulation of senescent cells, inflammaging (a chronic inflammatory state that persists in the elderly), and immunosenescence (aging of the immune system) changes associated with poor immune surveillance. At sites of inflammation, exposure to high levels of inflammatory mediators, such as reactive oxygen species, cytokines, prostaglandins, and growth factors, contributes to increased cell division and genetic and epigenetic changes. These exposure-induced changes promote excessive cell proliferation, increased survival, malignant transformation, and cancer development. Furthermore, the proinflammatory tumor microenvironment contributes to ovarian cancer metastasis and chemoresistance. This narrative review of the literature was carried out to delineate the possible role of inflammaging in the etiopathogenesis of ovarian cancer development. We discuss the current carcinogenic hypotheses, sites of origin, and etiological factors of ovarian cancer. Treatment of inflammation may represent an attractive strategy for both the prevention and therapy of ovarian cancer.

Management of genitourinary syndrome of menopause in breast cancer survivors: An update.

There is increasing attention about managing the adverse effects of adjuvant therapy (Chemotherapy and anti-estrogen treatment) for breast cancer survivors (BCSs). Vulvovaginal atrophy (VVA), caused by decreased levels of circulating estrogen to urogenital receptors, is commonly experienced by this patients. Women receiving antiestrogen therapy, specifically aromatase inhibitors, often suffer from vaginal dryness, itching, irritation, dyspareunia, and dysuria, collectively known as genitourinary syndrome of menopause (GSM), that it can in turn lead to pain, discomfort, impairment of sexual function and negatively impact on multiple domains of quality of life (QoL). The worsening of QoL in these patients due to GSM symptoms can lead to discontinuation of hormone adjuvant therapies and therefore must be addressed properly. The diagnosis of VVA is confirmed through patient-reported symptoms and gynecological examination of external structures, introitus, and vaginal mucosa. Systemic estrogen treatment is contraindicated in BCSs. In these patients, GSM may be prevented, reduced and managed in most cases but this requires early recognition and appropriate treatment, but it is normally undertreated by oncologists because of fear of cancer recurrence, specifically when considering treatment with vaginal estrogen therapy (VET) because of unknown levels of systemic absorption of estradiol. Lifestyle modifications and nonhormonal treatments (vaginal moisturizers, lubricants, and gels) are the first-line treatment for GSM both in healthy women as BCSs, but when these are not effective for symptom relief, other options can be considered, such as VET, ospemifene, local androgens, intravaginal dehydroepiandrosterone (prasterone), or laser therapy (erbium or CO2 Laser). The present data suggest that these therapies are effective for VVA in BCSs; however, safety remains controversial and a there is a major concern with all of these treatments. We review current evidence for various nonpharmacologic and pharmacologic therapeutic modalities for GSM in BCSs and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research. We include recommendations for an approach to the management of GSM in women at high risk for breast cancer, women with estrogen-receptor positive breast cancers, women with triple-negative breast cancers, and women with metastatic disease.

Antiphospholipid antibodies in patients with myocardial infarction with and without obstructive coronary arteries.

BACKGROUND: Recent studies demonstrate that prothrombotic antiphospholipid antibodies (aPL) are overrepresented in patients with myocardial infarction (MI) due to coronary artery disease (MICAD). However, it is not known whether aPL differ between the two subsets of MI: MICAD and MI with nonobstructive coronary arteries (MINOCA). OBJECTIVES: To determine whether aPL are associated with MINOCA or MICAD, or with hypercoagulability as assessed by activated protein C-protein C inhibitor (APC-PCI) complex. METHODS: Well-characterized patients with MINOCA (n = 98), age- and gender-matched patients with MICAD (n = 99), and healthy controls (n = 100) were included in a cross-sectional case-control study. Autoantibodies (IgA/G/M) targeting cardiolipin and ß2 glycoprotein-I and specific nuclear antigens were analyzed by multiplexed bead technology. The concentration of APC-PCI was determined as a measure of hypercoagulability by an immunofluorometric sandwich assay. RESULTS: Both prevalence and titers of aPL of the IgG isotype (anti-cardiolipin and/or anti-ß2 glycoprotein-I) were higher in patients with MINOCA and MICAD than in controls. aPL IgG positivity was twice as frequent among patients with MICAD than MINOCA (11% vs. 6%, nonsignificant). We observed no group differences regarding aPL IgA/M or antibodies targeting specific nuclear antigens. Levels of APC-PCI were elevated in aPL IgG-positive compared to aPL IgG-negative MICAD patients. CONCLUSIONS: aPL IgG, but not IgA/M, are enriched particularly in patients with MICAD but also in patients with MINOCA, as compared to controls. Interestingly, signs of hypercoagulability-measured by increased levels of the APC-PCI complex-were present in aPL IgG-positive MICAD patients, indicating an association with functional disturbances of the coagulation system.

Measuring Resilience in Women with Endometriosis.

Endometriosis is a multifactorial disease with pathophysiological factors not yet well known; it also presents a wide symptomatic range that makes us think about the need for multidisciplinary management. It is a chronic disease in which there is no definitive treatment, and is associated in a large majority of cases with psychological pathology. Connecting comorbidities and multimorbidities on a neurobiological, neuropsychological, and pathophysiological level could significantly contribute to their more successful prevention and treatment. In our study, resilience is analyzed as an adjunctive measure in the management of endometriosis. Methods: A multi-centre, cross-sectional study was performed to analyse resilience levels in a sample of Spanish women suffering from endometriosis. CDRIS-25, CDRIS-10, BDI, the STAI, and the SF-36 Health Questionnaire were used for assessments. A representative group of 202 women with endometriosis was recruited by consecutive sampling. Exploratory and confirmatory factor analyses were performed for both resilience scales. Results: Mean CDRIS-25 and CDRIS-10 scores were 69.58 (SD 15.1) and 29.37 (SD 7.2), respectively. Women with adenomyosis and without signs of deep endometriosis showed the lowest scores. The best predictive model included women's age, years of endometriosis evolution, number of pregnancies, and history of fertility problems as the best predictive factors. Conclusions: Women build resilience as the number of years of evolution of the disease increases. Symptoms such as dyspareunia and continued abdominal pain were more prevalent among less resilient women.

Mutual Information Disentangles Interactions from Changing Environments.

Real-world systems are characterized by complex interactions of their internal degrees of freedom, while living in ever-changing environments whose net effect is to act as additional couplings. Here, we introduce a paradigmatic interacting model in a switching, but unobserved, environment. We show that the limiting properties of the mutual information of the system allow for a disentangling of these two sources of couplings. Further, our approach might stand as a general method to discriminate complex internal interactions from equally complex changing environments.

Correlates of Sexual Function in a Sample of Spanish Women with Endometriosis.

BACKGROUND: In the present study, we aim to report on the sexual function of women experiencing symptoms of endometriosis, analysing the clinical and psychosocial factors that may be associated. METHODS: A multicentre cross-sectional study was performed to analyse the sexual function in a sample of 196 Spanish women with endometriosis, using the Female Sexual Function Inventory. RESULTS: The Female Sexual Function Inventory (FSFI) was validated in our endometriosis study group. The mean FSFI score for the sample was 22.5 (SD 6.6), with 20.9 and 26.9 being in the 25th and 75th percentiles, respectively. Although physical sexual pain and dyspareunia were factors that influenced the sexual function of women with endometriosis, our results show that the impairment was multifactorial. CONCLUSIONS: We found impaired sexual function in women diagnosed with endometriosis. The final model included deep endometriosis, depression, age, and unemployment as strongest predictive factors for poor (deteriorated) sexual function.

Sexual Dysfunction in Postmenopausal Women with Breast Cancer on Adjuvant Aromatase Inhibitor Therapy.

INTRODUCTION: The aim of this study was to investigate whether postmenopausal women with breast cancer (BC) on adjuvant aromatase inhibitor (AI) therapy have a higher prevalence of female sexual dysfunction (FSD). Second, the aim was to determine the quality of life (QoL) and level of anxiety depending on whether or not they are AI users. METHODS: A prospective cross-sectional study involving 168 patients was performed. Three questionnaires were carried out: sexual functioning was evaluated with the Female Sexual Function Index (FSFI), while the EORTC QLQ-BR23 measures to study QoL in patients with BC and the State-Trait Anxiety Inventory (STAI) questionnaire (trait and status) were used to assess anxiety status in patients under treatment with AIs or not. RESULTS: 47.6% (80/168) of the postmenopausal BC survivors were not sexually active (mean time after surgery: 48.6 months) despite a relatively low mean age (56.43 years). Postmenopausal AI-treated women had significantly worse sexual function as measured by the FSFI (23.40 ± 5.26 vs. 30.16 ± 2.24; p = 0.000). There were significant differences between both groups in all domains, except orgasm. The QoL score was 37.67 ± 7.38 in AI users versus 39.00 ± 1.44 among nonusers (p = 0.053). Patients under endocrine treatment also presented STAI scores significantly higher (25.83 ± 4.99 vs. 19.00 ± 7.12; p = 0.000). Trait anxiety was high in both groups, but this was not statistically significant. CONCLUSIONS: We observed a high prevalence of sexual inactivity among BC survivors regardless of AI use. Patients with AI use presented significantly higher prevalence of FSD, worse QoL, and greater anxiety.

Plasma catecholamine levels in the acute and subacute stages of takotsubo syndrome: Results from the Stockholm myocardial infarction with normal coronaries 2 study.

AIMS: It is well-accepted that takotsubo syndrome (TS) is characterized by a massive surge of plasma catecholamines despite lack of solid evidence. The objective of this study was to examine the hypothesis of a massive catecholamine elevation in TS by studying plasma-free catecholamine metabolites in patients participating in the Stockholm myocardial infarction (MI) with normal coronaries 2 (SMINC-2) study where TS constituted more than one third of the patients. METHODS AND RESULTS: The patients included in the SMINC-2 study were classified, according to cardiac magnetic resonance (CMR) imaging findings (148 patients), which was performed at a median of 3 days after hospital admission. Plasma-free catecholamine metabolites; metanephrine, normetanephrine, and methoxy-tyramine were measured on day 2-4 after admission. Catecholamine metabolite levels were available in 125 patients. One hundred and ten (88%) of the 125 patients included in SMINC-2 study, and 38 (86.4%) of the 44 patients with TS had completely normal plasma metanephrine and normetanephrine levels. All patients had normal plasma methoxy-tyramine levels. Fourteen (11.2%) of the 125 patients included in SMINC-2 study, and 5 (11.6%) of the 43 patients with TS had mild elevations (approximately 1.2 times the upper normal limits) of either plasma metanephrine or normetanephrine. One patient with pheochromocytoma-triggered TS had marked elevation of plasma metanephrine and mild elevation of plasma normetanephrine. There were no significant differences between the number or degree of catecholamine metabolite elevations between the different groups of patients with CMR imaging diagnosis included in SMINC-2 study. CONCLUSION: There was no evidence of massive catecholamine elevations in the acute and subacute stages of TS apart from one patient with pheochromocytoma-induced TS. Most of the TS patients had normal catecholamine metabolites indicating that blood-borne catecholamines do not play a direct role in the pathogenesis of TS.