Serum lipids may causally affect the occurrence of alopecia areata: A Mendelian randomization study.

PURPOSE: The etiology of alopecia areata (AA) in relation to serum lipids remains unclear, thereby prompting our intention to do Mendelian study on this subject. DESIGN: Two-sample Mendelian randomization (MR) analysis was performed in the study. The inverse variance-weighted method was used as the primary method. METHODS: In our study, we integrated a set of 123 single-nucleotide polymorphisms (SNPs) into our analysis. These SNPs have been extensively studied and are known to exhibit associations with serum lipids. We sourced these SNPs from a variety of relevant studies and consortia that specifically focus on lipid-related research, such as the MRC Integrative Epidemiology Unit. These carefully curated SNPs were then utilized as instrumental variables in our analysis, allowing us to explore and evaluate the causal relationships between these genetic variants and serum lipids. By incorporating this comprehensive set of SNPs, we aimed to enhance the precision and robustness of our findings, shedding light on the intricate interplay between genetics and serum lipids. RESULTS: In the MR analysis, a higher total lipid concentration in large low-density lipoprotein (LDL) particles (odds ratio [OR] = 1.502; 95% confidence interval [CI] = 1.086-1.953; p = 0.006), a greater ratio of cholesteryl esters to total lipids in chylomicrons and extremely large very LDL (VLDL) particles (OR = 2.174; 95% CI = 1.300-2.500; p = 0.010), and a greater ratio of cholesterol to total lipids in chylomicrons and extremely large VLDL particles (OR = 2.363;95% CI = 1.556-4.438; p = 0.004), were genetically predicted to be causally associated with an increased risk of AA, while patients with a higher triglyceride to total lipids ratio in chylomicrons and extremely large VLDL particles had a lower risk of AA (OR = 0.481; 95% CI = 0.191-1.270; p = 0.002). CONCLUSION: This study found that serum lipids may be causally implicated in AA.

The role of hsa-miR-193a-5p as an important factor for control of inositol in alopecia areata.

BACKGROUND: MicroRNAs (miRNAs) are small RNA molecules that play a regulatory role in various biological processes by acting as intracellular mediators. They hold great potential as therapeutic agents for targeting human disease pathways; however, there is still much to be uncovered about their mechanism of gene regulation. Alopecia areata (AA) is a commonly occurring inflammatory condition characterized by the infiltration of T cells that specifically target the anagen-stage hair follicle. The limited understanding of its precise cellular mechanism may be the reason behind the scarcity of effective treatments for AA. AIM: The significance and function of hsa-miR-193a-5p as a genetic marker for AA and its potential influence on the advancement of the disease. SUBJECTS AND METHODS: A case-control study comprised 77 individuals diagnosed with AA who were matched with 75 healthy controls. In order to measure the expression of miR-200c-3p in both groups, the real-time PCR technique was utilized. The prediction of suitable genes for hsa-miR-193a-5p, as well as the identification of pathways and gene-gene interactions, were carried out using bioinformatic tools. RESULTS: The levels of hsa-miR-193a-5p expression were notably elevated in AA patients in comparison to healthy controls. Our prediction suggests that the involvement of hsa-miR-193a-5p in the development of AA is significant due to its influence on the inositol phosphorylation pathway and the Phosphatidylinositol signaling system, achieved through its direct impact on the IPPK gene. CONCLUSION: For the first time, our study demonstrates the significant over-expression of a new miRNA, hsa-miR-193a-5p, in the blood of AA patients compared to controls, and highlights its impact on the IPPK gene and the inositol phosphorylation and Phosphatidylinositol signaling pathways, suggesting a potential therapeutic role for hsa-miR-193a-5p in AA.

Reduced rates of substance use disorder in patients with alopecia: An all of us case-control study.

Alopecia areata (AA), depression, anxiety, and decreased quality of life are highly associated in the literature. It has been noted that there is an increased risk of substance use in those with AA to help cope with the psychological burdens and perceived stigmatization. This study aims to explore the relationship between substance use disorder (SUD) and scarring/non-scarring alopecia using the All of Us database. Of the 9,385 patients with alopecia, 8.4% had SUD of any kind. Multivariable regression revealed that alopecia is a potential protective factor against SUD when controlling for other covariates of significance, with a decreased odds of 0.73. Substance use disorder prevalence was not different between scarring and non-scarring alopecia. This may be the result of patients fearing exacerbation of hair loss, or due to increased mental health and community support in patients with alopecia. Dermatologists and primary care providers should continue to promote psychotherapy and community support to patients whose diagnosis of alopecia has a negative psychosocial impact.

The Role of 5% Minoxidil versus Platelet-Rich Plasma in Treatment of Alopecia Areata.

OBJECTIVE: To compare the efficacy of topical minoxidil and platelet-rich plasma (PRP) in the treatment of alopecia areata (AA). STUDY DESIGN: Randomised control trial. Place and Duration of the Study: Department of Dermatology, Jinnah Postgraduate Medical Centre, Karachi, Pakistan, from December 2021 to June 2022. METHODOLOGY: The study included all the patients who visited JPMC Karachi during the study period. Permission from the ERB was obtained. The inclusion criteria were any gender and age 10 to 45 years. Topical minoxidil 5% solution was applied twice daily to Group A (six pubs/time), while PRP injections were administered to Group B at baseline and every four weeks for three months. Serial photos and the severity of alopecia tool (SALT) were used to determine the clinical assessment. When comparing the effectiveness between the two groups, a p-value of <0.05 was considered significant. SPSS version 23 was used to analyse the data. RESULTS: Mean age was 23.11 ± 8.9 years in 376 patients. PRP and Minoxidil groups had mean SALT scores at three months that were 1.48 and 1.54, respectively. Both treatments were shown to be efficacious. There was no statistically significant difference in efficacy between the minoxidil solution and PRP (p = 0.483). CONCLUSION: There is no apparent difference between PRP and topical minoxidil 5% solution in the management of AA. To verify the results, additional studies are needed with a larger sample size and a longer duration of follow-up. KEY WORDS: Minoxidil, Platelet-rich plasma, Alopecia areata, Severity of alopecia tool score.

Type-2 immunity associated with type-1 related skin inflammatory diseases: friend or foe?

Chronic inflammatory skin diseases are multifactorial diseases that combine genetic predisposition, environmental triggers, and metabolic disturbances associated with abnormal immune responses. From an immunological perspective, the better understanding of their physiopathology has demonstrated a large complex network of immune cell subsets and related cytokines that interact with both epidermal and dermal cells. For example, in type-1-associated diseases such as alopecia areata, vitiligo, and localized scleroderma, recent evidence suggests the presence of a type-2 inflammation that is well known in atopic dermatitis. Whether this type-2 immune response has a protective or detrimental impact on the development and chronicity of these diseases remains to be fully elucidated, highlighting the need to better understand its involvement for the management of patients. This mini-review explores recent insights regarding the potential role of type-2-related immunity in alopecia areata, vitiligo, and localized scleroderma.

Deciphering the Complex Immunopathogenesis of Alopecia Areata.

Alopecia areata (AA) is an autoimmune-mediated disorder in which the proximal hair follicle (HF) attack results in non-scarring partial to total scalp or body hair loss. Despite the growing knowledge about AA, its exact cause still needs to be understood. However, immunity and genetic factors are affirmed to be critical in AA development. While the genome-wide association studies proved the innate and acquired immunity involvement, AA mouse models implicated the IFN-γ- and cytotoxic CD8+ T-cell-mediated immune response as the main drivers of disease pathogenesis. The AA hair loss is caused by T-cell-mediated inflammation in the HF area, disturbing its function and disrupting the hair growth cycle without destroying the follicle. Thus, the loss of HF immune privilege, autoimmune HF destruction mediated by cytotoxic mechanisms, and the upregulation of inflammatory pathways play a crucial role. AA is associated with concurrent systemic and autoimmune disorders such as atopic dermatitis, vitiligo, psoriasis, and thyroiditis. Likewise, the patient's quality of life (QoL) is significantly impaired by morphologic disfigurement caused by the illness. The patients experience a negative impact on psychological well-being and self-esteem and may be more likely to suffer from psychiatric comorbidities. This manuscript aims to present the latest knowledge on the pathogenesis of AA, which involves genetic, epigenetic, immunological, and environmental factors, with a particular emphasis on immunopathogenesis.

Epidemiological, clinical and economic burden of alopecia areata in Spain: a real-world retrospective study. The PETALO study.

Alopecia areata (AA) is a chronic autoimmune disease that causes non-scarring hair loss. Data are lacking on the epidemiology and clinical and economic burden of AA in Spain. To estimate the prevalence and incidence of AA in Spain and describe sociodemographic and clinical characteristics, treatment patterns, healthcare resource utilization (HCRU) and associated costs. This was an observational, retrospective, descriptive study based on the Health Improvement Network (THIN®) database (Cegedim Health Data, Spain). Patients with ICD9-Code 704.01 for AA, registered between 2014 and 2021, were identified. Prevalence (%) and incidence rates per 1,000 patient-years (IR) of AA were calculated and clinical characteristics, treatment characteristics and HCRU/costs were assessed. A total of 5,488 patients with AA were identified. The point prevalence of AA in 2021 was 0.44 (95% confidence interval [CI]: 0.43-0.45) overall, 0.48 (0.47-0.49) in adults, and 0.23 (0.21-0.26) in children ≤12 years. The 2021 IR for AA in adults was 0.55 (0.51-0.60). Of 3,351 adults with AA, 53.4% were female, mean (standard deviation [SD]) age was 43.1 (14.7) years, and 41.6% experienced comorbidities. Among adults, 2.7% used systemic treatment (0.5% immunosuppressants, 2.5% oral corticosteroids, 0.3% both). Laboratory tests and health care professional visits were the principal drivers of cost, which was €821.2 (1065.6)/patient in the first year after diagnosis. The epidemiology of AA in Spain is comparable with that reported for other countries, being more prevalent among adults. There is a significant burden of comorbidities and cost for patients, with limited use of systemic treatments, suggesting an unmet treatment need in this population.

Case report: Sequential therapy with dupilumab and baricitinib for severe alopecia areata with atopic dermatitis in children.

An 8-year-old female child presented with patchy hair loss for 1 year, accompanied by eyebrow loss for 6 months. Microscopic examination of the hair confirmed the features of active stage alopecia areata, with a Severity of Alopecia Tool (SALT) score of 70%. The diagnosis was severe alopecia areata. The patient had a history of atopic dermatitis since infancy, with recurrent episodes of scattered papules and pruritus for 8 years. Initial treatment involved subcutaneous injections of dupilumab 300mg every 2 weeks for 6 months, resulting in a reduction of SALT score to 20% and improvement of atopic dermatitis symptoms. Discontinuation of Dupilumab and initiation of daily oral Baricitinib at a dose of 2mg for a duration of 5 months. According to the SALT score evaluation, the severity of hair loss was less than 10% and there was significant regrowth of hair. No significant adverse reactions were observed during the treatment period.

Elucidating causal relationships of diet-derived circulating antioxidants and the risk of non-scarring alopecia: A Mendelian randomization study.

Previous observational studies revealed controversy about the effect of circulating antioxidants on risk of alopecia. In the present study, we investigated the causal relationships between diet-derived circulating antioxidants and 2 non-scarring alopecia using Mendelian randomization (MR). Instrumental variables for antioxidants (lycopene, retinol, ascorbate, ß-carotene, α-tocopherol, and γ-tocopherol) were selected from published studies. Data for alopecia areata (AA) and androgenetic alopecia (AGA) was obtained from the FinnGen study project (R9 released in 2023), including 195 cases and 201,019 controls for AGA and 682 cases and 361,140 controls for AA. We used the inverse variance weighted method as the primary MR method. Three additional methods were used as sensitivity analysis to validate the robustness of the results. We found a causal relationship between absolute ß-carotene levels and AGA risk (P = .039), but not with AA (P = .283). The results of Wald ratio showed a protective effect of absolute ß-carotene levels against AGA, with per 0.1 ln-transformed ß-carotene being associated with a 76% lower risk of AGA (OR: 0.24, 95% CI: 0.06-0.93). Based on the fixed effects inverse variance weighting results, we found that α-tocopherol was protective against both AGA (P = .026) and AA (P = .018). For each unit increase in α-tocopherol, the effects of change in AGA and AA were 0.02 (95% CI: 0.00-0.61) and 0.10 (95% CI: 0.01-0.67), respectively. The results did not reveal any other causal relationships. Our study identified 3 causal associations of antioxidants with the risk of non-scarring alopecia. These results provide new insights into the prevention of non-scarring alopecia through diet.

Possible role of ß-hydroxybutyrate in inducing inflammation in alopecia areata.

Alopecia areata (AA) is an autoimmune inflammatory disease characterized by non-scarring hair loss due to an immune response that targets hair follicles. The current treatment approach for AA involves the use of immunosuppressants and immunomodulators to reduce cytokine levels around affected hair follicles. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as potential anti-inflammatory agents with diverse beneficial effects in various medical conditions. This study investigates the role of beta-hydroxybutyrate (BHB), a ketone body produced during SGLT2 inhibition, in the pathogenesis of AA. Serum BHB levels were found to be significantly elevated in patients with AA compared with healthy controls, with higher levels correlating with severity of hair loss. BHB treatment increased inflammatory cytokine production in outer root sheath (ORS) cells, mimicking the inflammatory conditions seen in AA. The results suggest that elevated BHB levels may exacerbate the inflammatory immune response in AA patients and may be associated with chronic hair loss and resistance to treatment. Serum BHB levels may serve as a potential marker of poor prognosis in patients with severe AA. Further research is needed to elucidate the precise role of BHB in the pathogenesis of AA and its implications for disease management.

Elucidating the role of T-Reg related cytokines: serum transforming growth factor beta and interleukin-35 in alopecia areata.

Previous studies demonstrated that Th1 cytokines like IL-2, IL-12 and IFN-γ have initiatory role in alopecia areata (AA) and positive correlation with disease severity. They informed that serum levels of Th17 cytokines, IL-17, IL-22, IL-23 increased in active AA patients and corelated, particularly IL-17, with disease severity. In recent reports it was showed the balance between Th17 and Treg cells is crucial for maintaining tolerance to self-antigens, and an imbalance towards Th17 may contribute to the development of autoimmune diseases like AA. But research on serum Treg markers in AA is limited. It was aimed to investigate whether the Treg cells have a role in the pathogenesis of AA analyzing the serum levels of Treg cytokines IL-35 and TGF-ß in the patients with AA. 42 AA patients and 38 healthy controls were enrolled. Patient demographics, clinical data, disease severity assessed by Severity of Alopecia Tool (SALT) scores were recorded. Serum samples were collected and analyzed for TGF-ß and IL-35 levels using ELISA kits. The cytokine levels in both groups were statistically compared. Their relation with parameters of demographic and severity of disease was evaluated. The patient and control groups had no statistically significant difference, there was 71.4% males and 28.6% females in patient group, while the control group had 63.2% males and 36.8% females, Severity analysis classified 18 patients with mild AA, 19 with moderate AA, and 5 with alopecia totalis/areata universalis. While TGF-ß levels exhibited no significant difference between groups, IL-35 levels were significantly elevated in AA patients (p = 0.002). Logistic regression identified IL-35 as a significant parameter influencing disease status (OR = 1.055). Correlation analysis revealed a weak positive correlation between patient age and IL-35 levels (r = 0.436; p = 0.004). Notably, IL-35 levels displayed a significant decrease in individuals with antinuclear antibody (ANA) positivity. No correlations were identified between cytokine levels and disease severity, prognosis, or disease activity. Elevated IL-35 levels suggest that IL-35 and specific Treg cell subsets can play a role in AA pathogenesis. The nuanced roles of TGF-ß and IL-35 highlight the need for comprehensive studies to interpret their implications in the complex immunopathogenesis of AA. These findings open avenues for further research, positioning IL-35 as a prospective target for investigating and potentially intervening in AA pathogenesis.

Parenting styles and psychological effects on children with alopecia areata: exploring family dynamics, anxiety, and depression.

Alopecia areata (AA) is an autoimmune disease that develops due to inflammation and causes sudden hair loss. Ithas been observed that family circumstances may contribute to the development of AA. This study aims to assessthe relationship between the development of alopecia areata in children, family functions, and depression andanxiety levels in their parents.Thirty-nine participants diagnosed with AA and 41 healthy controls (HC), agedbetween 8 and 18 years, and their parents participated in the study. The assessment of the children included thecompletion of a socio-demographic data form, the Parenting Style Scale (PSS), and the Revised Children's Anxietyand Depression Scale (RCADS). The parents provided information on a sociodemographic form, the BeckDepression Inventory (BDI), and the Beck Anxiety Inventory (BAI). The children in the control group scoredsignificantly higher on the PSS acceptance/ involvement subscale than those with AA. In the AA group, the numberof authoritative and indulgent (PSS) families was statistically significantly lower than that of the families in the HC,and the number of neglectful families was statistically significantly higher than those of the control group. Totalanxiety and depression t scores (RCADS) were statistically significantly higher in the AA children than in theHC. Our study demonstrates the importance of considering familial factors and parental mental health tounderstand and address alopecia areata in children. Our findings support the psychosomatic component of AA.Implementing comprehensive treatment strategies that target psychological well-being and family dynamics couldprove crucial.

Research trends in alopecia areata: a cross-sectional bibliometric analysis of the top cited studies.

In the field of alopecia areata research, various focuses including risk factors, epidemiology, molecular pathways, and treatment were constantly improving. However, to date, a bibliometric analysis summarizing the research trend is not available to date. The main objective of this study was to provide researchers with an overview of the research trend on alopecia areata in the past two decades. In Web of Science database, screening and extraction of studies related to alopecia areata has been performed. Within studies related to alopecia areata, the most cited 100 studies were appraised and the information of articles, including the citation amounts, keywords and publication types, was extracted for analyses. On average, each study in the top 100 list was cited 104.72 times. Within the top 100 list, the most focused fields were on the management of alopecia areata (34%), molecular mechanisms (28%) and epidemiological issues (23%). Approximately one third of the management-associated studies focused on Janus kinase (JAK) inhibitors (10 studies) and 5 studies focused on the efficacy of corticosteroids for alopecia areata. According to the results of the keyword analysis, JAK inhibitors had become the most mentioned keywords in the field of alopecia areata research since 2016. The top 100 most referenced papers in the field of alopecia areata mostly focused on essential aspects such as treatment options, pathogenesis, risk factors, and comorbidities. The results of the current study could be considered a potential resource for future research and patient care information.

Low rates of vaccination among atopic dermatitis, alopecia areata, psoriasis, and psoriatic arthritis patients on biologics.

Biologics and Janus kinase (JAK) inhibitors are immunomodulating and immunosuppressing medications utilized to treat atopic dermatitis (AD), psoriasis (PSO), psoriatic arthritis (PsA), and alopecia areata (AA). Special recommendations must be considered when prescribing vaccinations in this population, as the pneumococcal and herpes zoster vaccine are recommended to patients ≥ 19-years-old (rather than ≥ 65-years-old and ≥ 50-years-old as in the general population, respectively), along with a yearly influenza and up to date COVID-19 vaccination. Additionally, TNF-α and JAK-inhibitors may increase the risk of latent Hepatitis B virus (HBV) reactivation among high-risk patients. Prior to prescribing these medications, a quantitative HepB Surface Antibody (HepB SA) test is performed to determine immunity. This study utilized the SlicerDicer function on EPIC Medical Records to search for any patient ≥ 19-years-old prescribed a biologic or JAK inhibitor for AD, PSO, PsA, or AA between 10/2003 and 10/2023 at a large tertiary institution. Vaccination rates among patients on biologics and JAK inhibitors were low, with rates being significantly lower in patients 19-64 years-old, compared to those ≥ 65 years-old for most disease states (p < 0.01). Among AD, PSO/PsA, and AA patients, on average, 9.39% were vaccinated for influenza, 6.76% for herpes zoster, 16.56% for pneumococcal pneumonia, and 63.98% for COVID-19. Only 3.16% of patients were adequately vaccinated for HepB after an abnormal HepB SA test. Here, extremely low rates of vaccination among patients on biologics and JAK inhibitors at our institution were highlighted, emphasizing the imperative need for ensuring vaccination in this group.

Evaluating the sources and types of dietary and nutritional advice for patients with alopecia areata.

Although there are now two Food and Drug Administration (FDA)-approved treatments for severe alopecia areata (AA), many patients still resort to non-medical therapies and lifestyle modifications such as diet and nutrition. The goal of this study was to evaluate the sources and types of dietary and nutritional advice for patients with AA. We distributed a cross-sectional national survey using the National Alopecia Areata Foundation's email list-serv between August 2022 and January 2023. Most respondents were White (76.3%), employed (58.3%) females (84.4%) with a mean age of 52 years. 163 (19.1%) respondents reported receiving diet and/or nutritional advice and 418 (49.5%) respondents reported searching for diet and/or nutritional advice to help with their AA; the most common source of advice was online. The most common dietary changes were the use of vitamins or supplements (30.6%), adherence to diets (23.2%), and the addition of specific foods (21.4%). 209 (50.2%) respondents reported no change in their disease and 197 (47.4%) respondents reported no change in how they felt about their disease compared to before they tried the change. Many AA patients search for or receive unsolicited dietary and nutritional advice and subsequently modify their behavior to manage their disease. However, the efficacy of these changes is unclear. Providers should be mindful of the sources through which patients obtain treatment information as well as the lifestyle changes patients make to counsel patients with evidence-based information. Further investigation is needed to better characterize the direct and indirect costs of dietary and nutritional modification in the treatment of AA.

Hair growth-promoting effects of Enz_MoriL on human dermal papilla cells through modulation of the Wnt/ß-Catenin and JAK-STAT signaling pathways.

Enz_MoriL is a naturally occurring substance extracted from the leaves of Morus alba L. through enzymatic conversion. Historically, M. alba L. has been recognized for its potential to promote hair regrowth. However, the precise mechanism by which Enz_MoriL affects human hair follicle dermal papilla cells (hDPCs) remains unclear. The aim of this study was to investigate the molecular basis of Enz_MoriL's effect on hair growth in hDPCs. Interferon-gamma (IFN-γ) was used to examine the effects of Enz_MoriL on hDPCs during the anagen and catagen phases, as well as under conditions mimicking alopecia areata (AA). Enz_MoriL demonstrated the ability to promote cell proliferation in both anagen and catagen stages. It increased the levels of active ß-catenin in the catagen stage induced by IFN-γ, leading to its nuclear translocation. This effect was achieved by increasing the phosphorylation of GSK3ß and decreasing the expression of DKK-1. This stimulation induced proliferation in hDPCs and upregulated the expression of the Wnt family members 3a, 5a, and 7a at the transcript level. Additionally, Enz_MoriL suppressed JAK1 and STAT3 phosphorylation, contrasting with IFN-γ, which induced them in the catagen stage. In conclusion, Enz_MoriL directly induced signals for anagen re-entry into hDPCs by affecting the Wnt/ß-catenin pathway and enhancing the production of growth factors. Furthermore, Enz_MoriL attenuated and reversed the interferon-induced AA-like environment by blocking the JAK-STAT pathway in hDPCs.

Evaluating the Cost Burden of Alopecia Areata Treatment: A Comprehensive Review for Dermatologists.

Alopecia areata (AA) is managed with prolonged medical treatments and cosmetic therapies, whose cost can be burdensome. We sought to identify the costs of AA treatment and consolidate the available data for the practicing dermatologist by performing a PubMed search of articles indexed for MEDLINE. Ten studies including approximately 16,000 patients with AA across a range of Oxford Centre for Evidence-Based Medicine Levels of Evidence were included. Studies showed that despite the limited efficacy of many AA therapies, patients incurred substantial expenses to manage their AA.

To evaluate the role of interleukin-6 in alopecia areata.

Objective: TTo investigate the level of interleukin-6 in alopecia areata patients. METHODS: The exploratory study was conducted from September to December 2021 at the Sindh Institute of Skin Disease, Karachi, and comprised alopecia areata patients regardless of age and gender in group A, while healthy controls matched for age and gender formed group B. Alopecia areata classification and severity were done using the Severity of Alopecia Tool. Serum interleukin-6 was measured using enzyme-linked immune sorbent assay. Data was analysed using R statistical software v4.2.1. RESULTS: Of the 100 subjects, 50(50%) with mean age 15.52±10.14 years were cases in group A; 26(52%) females with mean age 16.78±10.77 years, and 24(48%) males with mean age 16.44±10.3 years. The remaining 50(50%) were controls in group B. Interleukin-6 concentration was significantly higher in group A (p<0.05). The concentration was not significantly different between the genders (p>0.05). The concentration was the highest in patients aged 11-20 years, followed by 21-30 years, 31-40 years and 1-10 years. Conclusion: The concentration of circulatory pro-inflammatory interleukin-6 was significantly higher in alopecia areata patients than in the healthy controls.