Changes in neuroactive steroids, neurotrophins and immunological biomarkers after monotherapy 8-week rTMS treatment and their relationship with neurocognitive functions in depression.

Repetitive transcranial magnetic stimulation (rTMS) has proven effective in the treatment of major depression. The underlying mechanisms of action are still poorly understood. We aimed to evaluate the changes in the levels of neuroactive steroids, neurotrophins and immunological biomarkers before and after rTMS treatment and assess the relationship of this change between clinical response and cognitive functions after monotherapy rTMS treatment. Twenty-three patients with major depressive disorder (MDD) and 25 matched healthy controls were included in the study. The Hamilton Depression Rating Scale (HDRS), Trail Making Test A and B forms and Digit Span Test were administered. Biomarkers (BDNF, TNF-α, IL-1ß, NAS) were run in the peripheral blood at the end of the first month that rTMS was administered daily and at the end of the 2nd month when that rTMS was administered once a week. Appropriate conditions were provided so that the relevant biomarkers were not affected by the biorhythm. After rTMS monotherapy, an increase in BDNF and allopregnanolone, a decrease in TNF-α, IL-1ß, DHEA, and DHEA-S levels was found to be statistically significant. The scores on cognitive tests increased with the treatment. Positive significant correlations was found between BDNF levels and cognitive tests at the end of the first and second months. Our findings suggest that the effects of rTMS treatment may be related to the neuroendocrine, neurotrophin, and immunological mechanisms. rTMS treatment is found to have positive effects on cognitive functions in the short term.

COVID-19 related mental health issues: a narrative review of psychometric properties of scales and methodological concerns in scale development.

OBJECTIVES: The global crisis of COVID-19 and its consequential strict public health measures placed around the world have impacted mental health. New scales and tools have been developed to measure these mental health effects. This narrative review assesses the psychometric properties of these scales and tools and methodological aspects of their development. METHODS: PubMed, PubMed Central, and Google Scholar were searched for articles published from 15 May 2020 to 15 August 2020. This search used three groups of terms ("tool" OR "scale" AND "mental" OR "psychological"; AND "COVID-19" OR "coronavirus"). The identified scales were further evaluated for their psychometric properties and methodological aspects of their development. RESULTS: Though the studies developing these scales (n = 12) have demonstrated their robust psychometric properties, some methodological concerns are noteworthy. Most of the scales were validated using internet-based surveys, and detailed descriptions of the mode of administration, sampling process, response rates, and augmentation strategies were missing. CONCLUSIONS: The heterogeneous and inadequate reporting of methods adopted to evaluate the psychometric properties of the identified scales can limit their utility in clinical and research settings. We suggest developing guidelines and checklists to improve the design and testing, and result in reporting of online-administered scales to assess the mental health effects of the COVID-19 pandemic.

Females with ADHD: An expert consensus statement taking a lifespan approach providing guidance for the identification and treatment of attention-deficit/ hyperactivity disorder in girls and women.

BACKGROUND: There is evidence to suggest that the broad discrepancy in the ratio of males to females with diagnosed ADHD is due, at least in part, to lack of recognition and/or referral bias in females. Studies suggest that females with ADHD present with differences in their profile of symptoms, comorbidity and associated functioning compared with males. This consensus aims to provide a better understanding of females with ADHD in order to improve recognition and referral. Comprehensive assessment and appropriate treatment is hoped to enhance longer-term clinical outcomes and patient wellbeing for females with ADHD. METHODS: The United Kingdom ADHD Partnership hosted a meeting of experts to discuss symptom presentation, triggers for referral, assessment, treatment and multi-agency liaison for females with ADHD across the lifespan. RESULTS: A consensus was reached offering practical guidance to support medical and mental health practitioners working with females with ADHD. The potential challenges of working with this patient group were identified, as well as specific barriers that may hinder recognition. These included symptomatic differences, gender biases, comorbidities and the compensatory strategies that may mask or overshadow underlying symptoms of ADHD. Furthermore, we determined the broader needs of these patients and considered how multi-agency liaison may provide the support to meet them. CONCLUSIONS: This practical approach based upon expert consensus will inform effective identification, treatment and support of girls and women with ADHD. It is important to move away from the prevalent perspective that ADHD is a behavioural disorder and attend to the more subtle and/or internalised presentation that is common in females. It is essential to adopt a lifespan model of care to support the complex transitions experienced by females that occur in parallel to change in clinical presentation and social circumstances. Treatment with pharmacological and psychological interventions is expected to have a positive impact leading to increased productivity, decreased resource utilization and most importantly, improved long-term outcomes for girls and women.

Assessment of Multi Fragment Melting Analysis System (MFMAS) for the Identification of Food-Borne Yeasts.

Multi Fragment Melting Analysis System (MFMAS) is a novel approach that was developed for the species-level identification of microorganisms. It is a software-assisted system that performs concurrent melting analysis of 8 different DNA fragments to obtain a fingerprint of each strain analyzed. The identification is performed according to the comparison of these fingerprints with the fingerprints of known yeast species recorded in a database to obtain the best possible match. In this study, applicability of the yeast version of the MFMAS (MFMAS-yeast) was evaluated for the identification of food-associated yeast species. For this purpose, in this study, a total of 145 yeast strains originated from foods and beverages and 19 standard yeast strains were tested. The DNAs isolated from these yeast strains were analyzed by the MFMAS, and their species were successfully identified with a similarity rate of 95% or higher. It was shown that the strains belonged to 43 different yeast species that are widely found in the foods. A clear discrimination was also observed in the phylogenetically related species. In conclusion, it might be suggested that the MFMAS-yeast seems to be a highly promising approach for a rapid, accurate, and one-step identification of the yeasts isolated from food products and/or their processing environments.

Dissociative depression among women with fibromyalgia or rheumatoid arthritis.

The aim of this study was to inquire about the possible relations of childhood trauma, anger, and dissociation to depression among women with fibromyalgia or rheumatoid arthritis. Fifty female patients diagnosed as having fibromyalgia (n = 30) or rheumatoid arthritis (n = 20) participated in the study. The Childhood Trauma Questionnaire, Somatoform Dissociation Questionnaire (SDQ), Dissociation Questionnaire (DIS-Q), Beck Depression Inventory (BDI), Spielberger State-Trait Anger Expression Inventory, and Dissociative Disorders Interview Schedule were administered to all participants. Women with a lifetime diagnosis of depressive disorder had higher scores for somatoform and psychoform dissociation than the nondepressive patients. However, childhood trauma scores did not differ between the 2 groups. In regression analysis, current severity of depression (BDI) was predicted by psychoform dissociation (DIS-Q) and lower education, and lifetime diagnosis of major depression was predicted by somatoform dissociation (SDQ). Whereas childhood emotional neglect predicted somatoform dissociation, psychoform dissociation was predicted by childhood sexual abuse. Mental processing of anger seems to be 1 of the dimensions of psychodynamics in trauma-related depressive conditions. In the context of the perceived threat of loss of control due to expressed anger and mental disintegration, somatoform dissociation seems to contribute to overmodulation of emotions in dissociative depression. Among patients suffering from physical illness with possible psychosomatic dimensions, assessment of somatoform dissociation in addition to psychoform dissociation may be helpful to understand diverse psychopathological trajectories emerging in the aftermath of childhood adversities. The recently proposed category of "dissociative depression" (Sar, 2011) seems to be a promising concept for future research on psychosomatic aspects of traumatic stress.

The European psychiatric association (EPA) - early career psychiatrists committee survey on trainees' and early-career psychiatrists' attitudes towards therapeutic drug monitoring (TDM) use and utility during antipsychotic treatment.

OBJECTIVES: This survey assessed psychiatry residents'/early-career psychiatrists' attitudes towards the utility of therapeutic drug monitoring (TDM) of antipsychotics. METHODS: A previously developed questionnaire on attitudes on TDM utility during antipsychotic treatment was cross-sectionally disseminated by national coordinators between 01/01/2022-31/12/2023. The frequency of using TDM for antipsychotics other than clozapine was the main outcome in a linear regression analysis, including sex, clinical setting, caseload, and factors generated by an exploratory factor analysis. Comparisons between residents and early-career psychiatrists, respondents working in in- and outpatient settings, and low-/middle- and high-income countries were performed. RESULTS: Altogether, 1,237 respondents completed the survey, with 37.9% having never used TDM for antipsychotics. Seven factors explained 41% of response variance; six of them were associated with frequency of TDM use (p < 0.05). Items with highest loadings for factors included clinical benefits of TDM (factors A and E: 0.7), negative expectations for beliefs of patients towards TDM (factor B: 0.6-0.7), weak TDM scientific evidence (factor C: 0.8), and TDM availability (factor D: -0.8). Respondents from low-/middle-income countries were less likely to frequently/almost always use TDM compared to high-income countries (9.4% vs. 21.5%, p < 0.001). DISCUSSION: TDM use for antipsychotics was poor and associated with limited knowledge and insufficient availability.

Ictal kissing behavior: neurological and psychodynamic overview.

This study is based on the psychodynamic and neurological analysis of three Turkish patients who displayed ictal kissing automatism during their seizures. To unveil the probable underlying causes of their kissing behaviors, all patients underwent psychiatric interviews after being evaluated by ictal video-EEG recordings. The group consisted of two females (ages 35 and 29) and one male (age 26). In addition to prominent oral automatisms, each patient also displayed behaviors of kissing or blowing kisses to individuals at close proximity. Seizures were related to the right temporal lobe in two patients and the left temporal lobe in one patient. Magnetic resonance imaging showed mesial temporal sclerosis in two of the patients (one left, one right) and was normal in one. According to the DSM-IV-TR criteria, each of the three patients also suffered from major depression, while the psychodynamic interviews revealed traumatic childhood histories and intense unfulfilled affective needs.

The role of gender as a barrier to the professional development of psychiatrists.

BACKGROUND: Despite efforts toward greater gender equality in clinical and academic psychiatry in recent years, more information is needed about the challenges in professional development within psychiatry, and how these may vary with gender. METHODS: A cross-sectional 27-item online survey was conducted with psychiatrists and psychiatric trainee members of the European Psychiatric Association. RESULTS: A total of 561 psychiatrists and psychiatric trainees from 35 European countries participated representing a response rate of 52.8% for women and 17.7% for men from a total sample of 1,580. The specific challenges that women face in their professional development fall into two categories. One comprised women's negative attitudes concerning their abilities in self-promotion and networking. The other identified environmental barriers related to lack of opportunity and support and gender discrimination. Compared to men, women reported higher rates of gender discrimination in terms of professional advancement. Women were less likely to agree that their institutions had regular activities promoting inclusion, diversity, and training to address implicit gender bias. Working in high-income countries compared to middle-income countries relates to reporting institutional support for career progression. CONCLUSIONS: These findings are an open call to hospital leaders, deans of medical schools, and department chairs to increase efforts to eradicate bias against women and create safer, inclusive, and respectful environments for all psychiatrists, a special call to women psychiatrists to be aware of inner tendencies to avoid self-promotion and networking and to think positively and confidently about themselves and their abilities.

Subjective cognitive assessments and N-back are not correlated, and they are differentially affected by anxiety and depression.

Cognitive function (CF) is a core feature related to all psychiatric disorders. However, self-report scales of CF (SRSC) may not always correlate with CF's objective measures and may have different mediators. Tools to select for evaluating CF in diverse psychiatric populations and their determinants need to be studied. In this study, we aimed to assess the association of SRSC (Perceived Deficit Questionnaire-Depression (PDQ-D), and World Health Organization's Adult Attention Deficit Hyperactivity Disorder Self-Report Scale (ASRS) and its inattentiveness subscale) with Letter-N-back as an objective measure of CF, and to analyze their association with psychopathology. Two hundred nine (131 nonclinical, and 78 clinical with a psychiatric diagnosis of ICD10 F31-39 [mood disorders excluding Bipolar I] or F40-F49 [neurotic, stress-related or psychosomatic disorder] categories) participants were evaluated with PDQ-D, ASRS, Beck Depression Inventory (BDI), and Beck's Anxiety Inventory (BAI), and N-back. Both groups' data were included in the analysis. PDQ-D showed a small correlation with N-back scores, whereas ASRS showed no correlation. PDQ-D and ASRS showed a large correlation. Age and BAI scores significantly predicted both PDQ-D and ASRS, whereas the cognitive subscale of BDI predicted PDQ-D, but not ASRS. Only BAI scores predicted N-back results. The mediation model revealed that 2-back scores of N-back task directly affects PDQ-D scores, independent of BDI scores. However, the cognitive subscale of BDI moderated 2-back and PDQ-D association. On the contrary, BAI scores significantly mediated the association of 2-back scores with PDQ-D. The direct effect of 2-back scores in PDQ-D was insignificant in the mediation of BAI scores. Our study validates the discordance between SRSC and an objective measurement of CF. Anxiety may affect both self-report and objective measurement of CF, whereas depressive thought content may lead to higher cognitive dysfunction reports in nondemented participants.

Digitalising mental health care: Practical recommendations from the European Psychiatric Association.

The digitalisation of mental health care is expected to improve the accessibility and quality of specialised treatment services and introduce innovative methods to study, assess, and monitor mental health disorders. In this narrative review and practical recommendation of the European Psychiatric Association (EPA), we aim to help healthcare providers and policymakers to navigate this rapidly evolving field. We provide an overview of the current scientific and implementation status across two major domains of digitalisation: i) digital mental health interventions and ii) digital phenotyping, discuss the potential of each domain to improve the accessibility and outcomes of mental health services, and highlight current challenges faced by researchers, clinicians, and service users. Furthermore, we make several recommendations meant to foster the widespread adoption of evidence-based digital solutions for mental health care in the member states of the EPA. To realise the vision of a digitalised, patient-centred, and data-driven mental health ecosystem, a number of implementation challenges must be considered and addressed, spanning from human, technical, ethical-legal, and economic barriers. The list of priority areas and action points our expert panel has identified could serve as a playbook for this process.

The Effects of Transcranial Focused Ultrasound Stimulation of Nucleus Accumbens on Neuronal Gene Expression and Brain Tissue in High Alcohol-Preferring Rats.

We investigated the effect of low-intensity focused ultrasound (LIFU) on gene expression related to alcohol dependence and histological effects on brain tissue. We also aimed at determining the miRNA-mRNA relationship and their pathways in alcohol dependence-induced expression changes after focused ultrasound therapy. We designed a case-control study for 100 days of observation to investigate differences in gene expression in the short-term stimulation group (STS) and long-term stimulation group (LTS) compared with the control sham group (SG). The study was performed in our Experimental Research Laboratory. 24 male high alcohol-preferring rats 63 to 79 days old, weighing 270 to 300 g, were included in the experiment. LTS received 50-day LIFU and STS received 10-day LIFU and 40-day sham stimulation, while the SG received 50-day sham stimulation. In miRNA expression analysis, it was found that LIFU caused gene expression differences in NAc. Significant differences were found between the groups for gene expression. Compared to the SG, the expression of 454 genes in the NAc region was changed in the STS while the expression of 382 genes was changed in the LTS. In the LTS, the expression of 32 genes was changed in total compared to STS. Our data suggest that LIFU targeted on NAc may assist in the treatment of alcohol dependence, especially in the long term possibly through altering gene expression. Our immunohistochemical studies verified that LIFU does not cause any tissue damage. These findings may lead to new studies in investigating the efficacy of LIFU for the treatment of alcohol dependence and also for other psychiatric disorders.

Sociodemographic and Clinical Factors Affecting Treatment Adherence in Adults with Attention Deficit and Hyperactivity Disorder.

Background: This study aims to explore sociodemographic and clinical factors affecting medication adherence in adults with attention deficit and hyperactivity disorder and elicit dysfunctional domains and comorbidities with a focus on gender differences. Methods: Patients were recruited from 2 specialty clinics using chart records in a natural treatment design. Adult attention deficit and hyperactivity disorder self-report scale, Diagnostic Interview for attention deficit and hyperactivity disorder in adults, was applied. Adherence is defined if the patient declared ≥80% adherence to medication throughout the last 8-12 weeks. Results: From 205 attention deficit and hyperactivity disorder patients (male = 112 female = 93 (age (median) min-max = 29 (18-56)), 29% were non-adherent to attention deficit and hyperactivity disorder medication. In the multivariate analysis, having 2 or more comorbid disorders (P = .009), dysfunctions in academic/work (P = .049), and dysfunctions in family and other relationships (P = .047) increased the likelihood of adherence. Adherence rates did not significantly differ between methylphenidate and atomoxetine (P = .405). Women were more likely to have 2 or more comorbid psychiatric disorders (P = .004) and dysfunctions in social relationships (P = .001), free time activities, hobbies (P < .001), self-confidence, and self-image (P < .001). Results: Nearly one-third of adult patients with attention deficit and hyperactivity disorder did not adhere to medication treatment. Comorbid psychiatric disorders and dysfunctions in life domains appear to increase the likelihood of adherence to attention deficit and hyperactivity disorder medications, possibly through increasing motivation for treatment. The effect of cognitive-behavioral therapy on compliance with attention deficit and hyperactivity disorder medication should further be explored with prospective controlled studies. Conclusion: We suggest that future longitudinal studies use objective measures of adherence and confirm the role of dysfunctional life domains and comorbid psychiatric disorders as correlates of medication adherence.

COVID-19 infection, vaccine status, and avoidance behaviors in adults with attention deficit and hyperactivity disorder: A cross-sectional study.

Objective: We aim to examine infection risk and vaccine status of COVID-19 in attention deficit and hyperactivity disorder and evaluate the impact of demographic, clinical, and COVID-19-related factors on the infection status and behavioral avoidance of COVID-19. Methods: This cross-sectional study assessed adults with attention deficit and hyperactivity disorder recruited from an outpatient psychiatry clinic. Patients and healthy controls completed a survey on sociodemographic data, COVID-19 infection status, and vaccine status. COVID-19 Disease Perception Scale, COVID-19 Avoidance Attitudes Scale, Attitudes toward COVID-19 Vaccine Scale, Adult Attention Deficit and Hyperactivity Disorder Self-report Screening Scale for DSM-5, Adult Attention Deficit and Hyperactivity Disorder Self-Report Scale Symptoms Checklist, Patient Health Questionnaire-9, and State-Trait Anxiety Inventory were applied. Results: Ninety patients and 40 healthy controls participated. Patients did not differ from controls in COVID-19 infection and vaccine status, and behavioral avoidance of COVID-19. No demographic and clinical factor significantly affected the COVID-19 infection status. Patients scored higher than controls in the perception of COVID-19 as contagious (p = 0.038), cognitive avoidance of COVID-19 (p = 0.008), and positive attitudes toward the COVID-19 vaccine (p = 0.024). After adjustment of possible factors, a positive perception of the COVID-19 vaccine and a perception of COVID-19 as dangerous were the two factors significantly affecting behavioral avoidance of COVID-19 [R 2 = 0. 17, F(2) = 13.189, p < 0.0001]. Conclusion: Infection and vaccine status of COVID-19 in patients did not significantly differ from controls. No demographic and clinical factor significantly affected the COVID-19 infection status. Approximately four-fifths of the patients were fully vaccinated as recommended by national and global health organizations. This has increased the knowledge base showing that the COVID-19 vaccine is acceptable and receiving the vaccine is endorsed by ADHD patients. Attention deficit and hyperactivity disorder itself may provoke no kind of mental disturbance in sense of perception of the danger of this disease. Our findings have increased the knowledge base showing that the COVID-19 vaccine is acceptable and the actual practice of receiving the vaccine is endorsed in this population. Our message for practice would be to take into account not only the core symptoms and the comorbidities of the disorder but also the perception of the disease while exploring its link with COVID-19.

Assessment of loneliness in patients with inflammatory arthritis.

AIM: This study aimed to explore loneliness and associated factors in Turkish patients with inflammatory arthritis. METHOD: Adult patients with rheumatoid arthritis (RA) (n = 58), ankylosing spondylitis (AS) (n = 53), and psoriatic arthritis (PsA) (n = 30), respectively, were included in the study. A single-item visual analog scale (VAS) for loneliness, UCLA Loneliness Scale-8 (ULS-8), Beck depression inventory (BDI), Beck anxiety inventory (BAI), revised multidimensional scale of perceived social support, Health Assessment Questionnaire-Disability Index (HAQ-DI) were used for the psychometric and functional assessments. Multiple regression models were generated for predicting the ULS-8 and HAQ-DI scores. RESULTS: There was no difference between disease groups in terms of the ULS-8 and HAQ-DI scores. Among demographic and clinical parameters, only the education status and number of drugs used had associations with the ULS-8 score. Single-item VAS score for loneliness did not predict the ULS-8 score well. There were significant correlations between the ULS-8 and HAQ-DI, depression, anxiety, social support, and physician global VAS scores. Only the education status significantly predicted (ß = -0.208) the ULS-8 score in multiple regression analysis (adjusted R2  = 0.15, P < .001). Beck depression, anxiety, and patient global VAS scores remained significant for predicting the HAQ-DI after multiple regression with the covariates ULS-8, depression, anxiety, social support, patient and physician global VAS scores, and the number of drugs used (adjusted R2  = 0.53, P < .001). Disease activity and the ULS-8 scores were not found to be associated in any disease group. CONCLUSION: Loneliness is associated with depression, anxiety, lack of social support, disability, higher number of drugs used, and lower education but not with disease activity in Turkish patients with RA, AS, and PsA. Perception and expression of loneliness vary according to the cultural background. Single-item scales for loneliness may lack reliability compared to the more comprehensive ULS-8.

How do Physicians Manage Functional Neurological Symptom Disorder and Somatic Symptom Disorder in the Emergency Department? A Vignette Study.

INTRODUCTION: We aimed to explore how physicians from different specialties approach the management of functional neurological symptom (conversion) and somatic symptom disorders in the emergency department compared with pulmonary embolism and how physicians' professional and personal characteristics influence their diagnostic preferences. METHODS: Using a vignette methodology, and cross-sectional design, three emergency department case vignettes of possible functional neurological symptom, somatic symptom disorder, and pulmonary embolism were presented to physicians from internal medicine, emergency medicine, and psychiatry. A structured survey including questions on diagnosis and management of these cases, and physicians' professional and personal characteristics (childhood trauma, attachment style) was conducted. RESULTS: Physicians from internal medicine and emergency medicine tended to consider functional neurological symptom disorder as 'malingering' while psychiatrists tended to diagnose the pulmonary embolism case as a psychiatric condition. Emergency medicine physicians preferred to manage functional neurological symptom disorder themselves, while other doctors endorsed recommending a psychiatric consultation. In the univariable model, being a physician from psychiatry, emergency medicine, or internal medicine; being a specialist, history of childhood sexual abuse, dismissive, and fearful attachment styles of doctors were significant predictors of diagnosing functional neurological symptom disorder as malingering. Being a psychiatrist stayed as the only significant predictor in the multivariable model. CONCLUSION: Objectively-aberrant functional neurological symptoms and subjective somatic symptoms may be creating different reactions in physicians. In the emergency department, physicians' diagnostic and treatment preferences of conversion disorder may be influenced by lack of training in conversion disorder, rather than their personal characteristics.

Risk and protective factors for mental disorders with onset in childhood/adolescence: An umbrella review of published meta-analyses of observational longitudinal studies.

The patho-etiology of mental disorders with onset in childhood or adolescence remains largely unknown. We conducted an umbrella review of meta-analyses (MAs) on environmental factors associated with mental disorders with onset in childhood/adolescence. We searched Pubmed-MEDLINE/EMBASE/PsycInfo databases, last search April 29th, 2020. Quality of MAs was measured with AMSTAR-2. Out of 6851 initial references, ten articles met inclusion criteria, providing 23 associations between 12 potential environmental factors and nine disorders (cases: 8884; N = 3,660,670). While almost half of the associations were nominally significant, none of them met criteria from either convincing or highly suggestive evidence. A single association was supported by suggestive evidence (maternal exposure to lithium or antipsychotics with neuromotor deficits), but it was affected by confounding by indication. Ten more associations had weak evidence, and 12 associations were not statistically significant. Quality of meta-analyses was rated as high in two, moderate in one, low in four, critically low in two, and not pertinent in one (individual participant data). Methodologically-sound research is needed in this field.

How to overcome barriers to publication in low- and middle-income countries: Recommendations from early career psychiatrists and researchers from around the world.

There is an increasing movement toward international collaboration and global discussion in mental health. If provided with the right opportunities, early career psychiatrists (ECPs) and researchers in mental health can contribute meaningfully to this discussion. However, they often experience multiple barriers when attempting to add their voices via academic publications. We represent a diverse group of ECPs and researchers from all six World Health Organization regions. In this piece, we discuss these barriers, grounded in our first-hand experiences, and put forth a series of recommendations. The most potentially beneficial and immediate way forward is ensuring a much-needed mentorship and support, particularly for low- and middle-income countries. In this regard, international organizations, especially those with a particular focus on education, such as the Section on Education in Psychiatry of the World Psychiatric Association, can play a pivotal role.