'I am proud of how I handled it'. Exploring the impact of the COVID-19 pandemic and related restrictions on well-being of adults with severe mental illness using qualitative methods.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic and related restrictions globally impacted mental health, particularly for those with pre-existing severe mental illness (SMI). This qualitative study examined how adults with SMI perceived the effects of the COVID-19 pandemic and related restrictions in the Netherlands, focusing on their personal recovery, well-being and daily life, including an exploration of factors influencing these effects. METHODS: Semi-structured interviews were conducted, audio-recorded and transcribed verbatim. Reflexive thematic analysis was applied. Purposive sampling was used to ensure diversity of individuals with SMI (i.e., age, gender, diagnosis, cultural background and mental healthcare institution). RESULTS: Twenty participants (median age: 45 years [SD: 12, 8]; 11 females) were interviewed between May and July 2023. Findings revealed a wide range of experiences: while some individuals reported a negative impact on their existing psychiatric symptoms, others described adaptability, resilience and even positive effects of COVID-19 restrictions on their mental health and well-being. Factors influencing the heterogeneic perceptions of the COVID-19 pandemic and related restrictions include the availability of trusted social relationships and enduring interactions with health professionals. CONCLUSION: Personalised support, both socially and professionally, is crucial for addressing fears, building resilience, reducing isolation and encouraging positive coping strategies for individuals with SMI during external crises. In this project, a participatory research approach that integrated the lived experience perspective helped uncover the unique perceptions of people with SMI with regard to the pandemic and related restrictions. PATIENT OR PUBLIC CONTRIBUTION: The study used a participatory action research approach, with experts-by-experience involved in every stage of the project as part of the research team. This included engagement with the funding application process, recruitment strategies for interviews, developing the interview guide, piloting the interview, interpreting findings, and knowledge dissemination activities.

GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi.

BACKGROUND: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations. METHODS: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation. RESULTS: For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi. CONCLUSIONS: Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells.

Stress sensitization following a disaster: a prospective study.

BACKGROUND: According to the stress sensitization hypothesis, prior exposure to extreme stressors may lead to increased responsiveness to subsequent stressors. It is unclear whether disaster exposure is associated with stress sensitization and, if so, whether this effect is lasting or temporary. This study aimed to investigate the occurrence and duration of stress sensitization prospectively following a major disaster. METHOD: Residents affected by a fireworks disaster (n=1083) participated in surveys 2-3 weeks (T1), 18-20 months (T2) and almost 4 years (T3) after the disaster. Participants reported disaster exposure, including direct exposure, injury and damage to their home at T1, and also stressful life events (SLEs) at T2 and T3. Feelings of anxiety and depression, concentration difficulty, hostility, sleep disturbance, and intrusion and avoidance of disaster-related memories were used as indicators of distress. RESULTS: Residents whose home was completely destroyed responded with greater distress to SLEs reported 18-20 months following the disaster than residents whose home was less damaged. There were no differences in stress responsiveness almost 4 years after the disaster. CONCLUSIONS: During the first years after a disaster, stress sensitization may occur in disaster survivors who experienced extreme disaster exposure. Stress sensitization may explain the persistence or progression of distress over time following extreme stressor exposure.

Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.

BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

A socio-psychological investigation into limitations and incentives concerning reporting a clinically suspect situation aimed at improving early detection of classical swine fever outbreaks.

The aim of this study was to identify limitations and incentives in reporting clinically suspect situations, possibly caused by classical swine fever (CSF), to veterinary authorities with the ultimate aim to facilitate early detection of CSF outbreaks. Focus group sessions were held with policy makers from the veterinary authorities, and representatives of veterinary practitioners and pig farmer unions. Personal interviews with a small group of pig farmers and practitioners were held to check limitations raised and solutions proposed during the focus group sessions. An electronic questionnaire was mailed to pig farmers and practitioners to investigate perceptions and attitudes with respect to clinically suspect situations possibly caused by CSF. After triangulating the responses of veterinary authorities, veterinary practitioners and farmers, six themes emerged across all groups: (1) lack of knowledge on the early signs of CSF; (2) guilt, shame and prejudice; (3) negative opinion on control measures; (4) dissatisfaction with post-reporting procedures; (5) lack of trust in government bodies; (6) uncertainty and lack of transparency of reporting procedures. The following solutions to facilitate early detection of CSF were put forward: (a) development of a clinical decision-support system for vets and farmers, in order to get faster diagnosis and detection of CSF; (b) possibility to submit blood samples directly to the reference laboratory to exclude CSF in a clinical situation with non-specific clinical signs, without isolation of the farm and free of charge for the individual farmer; (c) decrease social and economic consequences of reporting CSF, for example by improving the public opinion on first reports; (d) better schooling of veterinary officers to deal with emotions and insecurity of farmers in the process after reporting; (e) better communication of rules and regulations, where to report, what will happen next; (f) up-to-date website with information and visual material of the clinical signs of CSF.

Episodic Src activation in uveal melanoma revealed by kinase activity profiling.

BACKGROUND: The RAS/RAF/MEK/ERK pathway is involved in the balance between melanocyte proliferation and differentiation. The same pathway is constitutively activated in cutaneous and uveal melanoma (UM) and related to tumour growth and survival. Whereas mutant BRAF and NRAS are responsible for the activation of the RAS/RAF/MEK/ERK pathway in most cutaneous melanoma, mutations in these genes are usually absent in UM. METHODS: We set out to explore the RAS/RAF/MEK/ERK pathway and used mitogen-activated protein kinase profiling and tyrosine kinase arrays. RESULTS: We identified Src as a kinase that is associated with ERK1/2 activation in UM. However, low Src levels and reduced ERK1/2 activation in metastatic cell lines suggest that proliferation in metastases can become independent of Src and RAS/RAF/MEK/ERK signalling. Inhibition of Src led to the growth reduction of primary UM cultures and cell lines, whereas metastatic cell line growth was only slightly reduced. CONCLUSION: We identified Src as an important kinase and a potential target for treatment in primary UM. Metastasis cell lines seemed largely resistant to Src inhibition and indicate that in metastases treatment, a different approach may be required.

Risk factors for physical symptoms after a disaster: a longitudinal study.

BACKGROUND: Although symptoms such as fatigue, headache and pain in bones and muscles are common after disasters, risk factors for these symptoms among disaster survivors have rarely been studied. We examined predisposing, precipitating and perpetuating factors for these physical symptoms among survivors of a man-made disaster. In addition, we examined whether risk factors for physical symptoms differ between survivors and controls. METHOD: Survivors completed a questionnaire 3 weeks (n=1567), 18 months and 4 years after the disaster. Symptoms and risk factors were measured using validated questionnaires. A comparison group was included at waves 2 and 3 (n=821). Random coefficient analysis (RCA) was used to study risk factors for symptoms. RESULTS: Female gender [beta (beta)=1.0, 95% confidence interval (CI) 0.6-1.4], immigrant status (beta=1.0, 95% CI 0.6-1.4) and pre-disaster psychological problems (beta=0.8, 95% CI 0.1-1.4) were predisposing factors for symptoms. Although disaster-related factors were predictors, the relationship between symptoms and disaster-related factors was not very strong and the magnitude of this association was reduced when perpetuating factors were added. Intrusions and avoidance, depression, anxiety and sleeping problems were important perpetuating factors for physical symptoms among survivors and mediated the association between traumatic stress and physical symptoms. Risk factors for symptoms were comparable between survivors and controls. CONCLUSIONS: The results indicate that health-care workers should be alert for physical symptoms among female survivors, immigrant survivors and individuals with a high level of psychological problems both before and after a disaster.

[Nonspecific clinical signs in pigs and use of exclusion diagnosis for classical swine fever: a survey among pig farmers and veterinary practitioners]. / Toepassing van uitsluitdiagnostiek voor klassieke varkenspest bij aspecifieke klinische problemen op varkensbedrijven: een enquête onder varkenshouders en dierenartsen.

Outbreaks of Classical Swine Fever (CSF) occurred in spring 2006 in Germany close to the Dutch border. On 6th April Dutch pig farmers were given the possibility to submit blood samples directly via their veterinary practitioner to the National Reference Laboratory for CSF if their pigs had non-specific clinical symptoms or if pigs were being treated with antibiotics. The pig farm was not quarantined and was not visited by the veterinary authorities. Over a period of 9 weeks 156 pig farmers submitted whole blood samples via 50 different veterinary practices. All samples tested negative in the PCR test. These pig farmers and veterinary practitioners were asked to respond to a postal questionnaire with questions regarding their experience with this new diagnostic possibility, the distribution of the costs involved, a comparison with other instruments, such as official notification or use of a leukocyte count test, and their knowledge of clinical signs of CSF. 65 pig farmers (42%) and 33 veterinary practices (66%) returned the questionnaire. The main results indicated that pig farmers (72%) would use this type of exclusion diagnostics sooner than that they would approach the veterinary authorities (practitioners: 86%). Moreover the respondents considered the fact that the farm was not quarantined immediately to be an advantage (pig farmers, 79%; practitioners, 88%). 32 percent of the pig farmers were not aware that they were required to submit blood samples if pigs were being treated with antibiotics (practitioners: 11%). The majority of pig farmers and practitioners were not satisfied with the current distribution of the costs involved: in their opinion the costs of the PCR test, the costs of the veterinary practitioner and the costs for shipping the samples to the reference laboratory should be paid out of the Animal Health Fund (50% government and 50% industry) or by the government. If the current distribution of the costs is not changed, a large proportion of the pig farmers indicated that they would not use this form of exclusion diagnostics for CSF in the future. Pig farmers appeared to have a rather limited knowledge of the clinical signs of CSF: 33% of the pig farmers could mention maximally three clinical signs of CSF, and 7% could not mention a single clinical sign of CSF and said they were entirely dependent on the practitioners' ability to judge a CSF-suspect situation.

A longitudinal comparative study of the physical and mental health problems of affected residents of the firework disaster Enschede, The Netherlands.

OBJECTIVES: After the firework disaster in Enschede, The Netherlands, on 13 May 2000, a longitudinal health study was carried out. Study questions were: (1) did the health status change over this period; and (2) how is the health status 18 months after the disaster compared with controls? STUDY DESIGN: A longitudinal comparative study with two surveys at 3 weeks and 18 months after the disaster. METHODS: A control group for the affected residents was included in the second survey. Respondents filled in a set of validated questionnaires measuring their physical and mental health problems. RESULTS: The prevalence of physical and emotional role limitations, severe sleeping problems, feelings of depression and anxiety, as well as intrusion and avoidance decreased from 3 weeks to 18 months after the disaster for the affected residents. Independent of background characteristics and other life events, residents had 1.5 to three times more health problems than the control group; for example, physical role limitations (odds ratio [OR]=1.5, 95% confidence interval [CI] 1.2-2.0) and anxiety (OR=3.1, 95% CI 2.4-4.2). CONCLUSIONS: Although health problems decreased compared with 3 weeks after the disaster, 18 months after the disaster, the affected residents had more health problems than the people from the control group.

Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS.

In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours. In this study, we performed mutation analysis of the RAS and BRAF genes in a panel of 11 uveal melanoma cell lines and 19 primary uveal melanoma tumours. In addition, Western blot and immunohistochemical analyses were performed on downstream members of the MAPK pathway in order to assess the contribution of each of these components. No mutations were found in any of the three RAS gene family members and only one cell line carried a BRAF mutation (V599E). Despite this, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), ERK and ELK were constitutively activated in all samples. These data suggest that activation of the MAPK pathway is commonly involved in the development of uveal melanoma, but occurs through a mechanism different to that of cutaneous melanoma.

Gene expression profiling identifies tumour markers potentially playing a role in uveal melanoma development.

Microarray is a powerful tool to compare the gene expression of different tumour specimens and cell lines simultaneously and quantitatively. To get a better insight into genes that are involved in uveal melanoma tumorigenesis, we compared the gene expression profiles of 12 different uveal melanoma cell lines with three melanocyte cell cultures obtained from healthy donor eyes. Gene expression profiles were obtained by nylon filter arrays, containing 1176 gene spots related to cancer development. The expression levels of selected genes were validated on cell lines and primary uveal melanomas by real time RT-PCR, and were subsequently included in cluster analysis. Four candidate tumour markers, Laminin Receptor 1, Endothelin 2, Von Hippel Lindau Binding protein 1 and Cullin 2, have been selected from genes that were differentially expressed in the uveal melanoma cell lines compared to the normal uveal melanocytes. In primary uveal melanomas, these four markers could discriminate between two classes of uveal melanoma, which may be indicative of a differential disease process.

Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma.

Germline mutations of the cell-cycle regulator p16 (also called "CDKN2A") in kindreds with melanoma implicate this gene in susceptibility to malignant melanoma. Most families with familial atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden dermatology clinic share the same p16-inactivating deletion (p16-Leiden). Incomplete penetrance and variable clinical expression suggest risk modification by other genetic and/or environmental factors. Variants of the melanocortin-1 receptor (MC1R) gene have been shown to be associated with red hair, fair skin, and melanoma in humans. Carriers of the p16-Leiden deletion in Dutch families with FAMMM show an increased risk of melanoma when they also carry MC1R variant alleles. The R151C variant is overrepresented in patients with melanoma who are from families with the p16-Leiden mutation. Although some of the effect of the R151C variant on melanoma risk may be attributable to its effect on skin type, our analyses indicate that the R151C variant contributes an increased melanoma risk even after statistical correction for its effect on skin type. These findings suggest that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway.

Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma.

Tumors often display unrestricted cell cycling attributable to a dysfunctional G(1)-S checkpoint. One of the mechanisms leading to such a defect is the inactivation of the cyclin-dependent kinase inhibitor p16(INK4a). Although inactivation of p16(INK4a) is observed in a wide range of tumors, including cutaneous melanoma, genetic alteration of p16(INK4a) is reportedly uncommon in uveal melanoma. Here we show that the p16(INK4a) promoter is hypermethylated in 6 of 12 uveal melanoma cell lines and in 7 of 22 primary uveal melanomas analyzed. Five of seven patients with a methylated primary tumor died of metastatic disease compared with 2 of 15 patients with a nonmethylated primary tumor. We also show that all uveal melanoma cell lines with a hypermethylated p16(INK4a) promoter have lost p16(INK4a) expression but have maintained the expression of p14(ARF). Treatment of uveal melanoma cell lines with 5-aza-2'-deoxycytidine results in demethylation of p16(INK4a) and in reexpression of p16(INK4a) mRNA, which is maintained upon withdrawal of the 5-aza-2'-deoxycytidine. In conclusion, p16(INK4a) promoter methylation appears to be a common event in uveal melanoma and is accompanied by the loss of p16(INK4a) expression.

Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden).

Familial atypical multiple mole melanoma (FAMMM) is an autosomal dominant disease characterized by the familial occurrence of malignant melanoma of the skin and multiple atypical precursor lesions. Germline mutations in the p16 (CDKN2A) gene have been reported in at least a quarter of such families. An association has been reported between p16 mutations and pancreatic cancer. The aim of this study was to assess the risk of developing pancreatic and other cancers in Dutch FAMMM families with a 19 bp deletion in exon 2 of the p16 gene (p16-Leiden). Mutation analysis was performed in 27 families suspected of FAMMM. Clinical and pathological data were collected from all relatives affected with cancer. A p16-Leiden mutation was identified in 19 families. These families included 86 patients with melanoma. The second most frequent cancer was pancreatic cancer, which was observed in 15 patients from 7 families. The mean age at diagnosis of pancreatic cancer was 58 years (range 38-77 years). The estimated cumulative risk of developing pancreatic cancer in putative mutation carriers by age 75 years was 17%. In 8 p16-Leiden-negative families, no cases of pancreatic cancer occurred. p16 mutation carriers have a considerable risk of developing pancreatic cancer. Further studies should evaluate the value of surveillance of the pancreas in these high-risk families.

Value of estrogenic recruitment before chemotherapy: first randomized trial in primary breast cancer.

PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node-positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE(2)). FAC (500, 50, and 500 mg/m(2), respectively) was administered intravenously once every 4 weeks for four cycles. EE(2) (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence-free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.

Familial melanoma; CDKN2A and beyond.

The most common hereditary melanoma susceptibility disorder is the familial atypical multiple mole-melanoma (FAMMM) syndrome. FAMMM is regarded as an ideal natural model to study the very complex pathologic mechanism of melanoma. In 1994, cloning of the melanoma susceptibility gene CDKN2A was thought to give answers to many questions on genotype-phenotype correlations in familial melanoma. Today, 4 y later, germline mutations cosegregate with melanoma in only 40%-50% of the families predisposed to this disease. The hunt for genes and modifying genes is on again. Through the years the very well-characterized Dutch FAMMM families have proven to be valuable study subjects in melanoma research. This paper describes over 10 y of melanoma research illustrated by research performed in the Dutch FAMMM families.

A locus linked to p16 modifies melanoma risk in Dutch familial atypical multiple mole melanoma (FAMMM) syndrome families.

The CDKN2A gene that encodes the cell cycle inhibitor p16 shows mutations in many but not all 9p21-linked melanoma families. Most Dutch melanoma families segregate for a unique founder mutation (p16-Leiden), encoding a truncated nonfunctional p16 protein. The highly variable risk for p16-Leiden carriers to develop melanoma suggests a role for other genetic and/or environmental factors. We hypothesized that a 9p21 gene other than CDKN2A may be relevant in the remaining 9p21-linked melanoma families without p16 mutations but may also act as a risk modifier in p16-Leiden carriers. Haplotype analysis for 9p21 was performed using microsatellite markers in six p16-Leiden families originating from a founder population. p16-Leiden carriers in two families shared an unexpectedly large founder haplotype ( approximately 20-cM) around CDKN2A, mostly in proximal direction. Melanoma-positive p16-Leiden carriers from these families showed this extensive proximal haplotype compared with melanoma-negative p16-Leiden carriers from the same families. Additional p16-Leiden families less heavily affected with melanoma showed shorter haplotypes sharing, excluding the region proximally of CDKN2A. The presence of a gene involved in melanoma susceptibility proximal of CDKN2A is corroborated by somatic deletions of 9p in tumors, which frequently do not include CDKN2A but a more proximal chromosomal area instead. Our results provide a candidate region for further gene mapping in p16-negative 9p21-linked melanoma families and guide the search for risk modifiers in melanoma development.

Genetics of familial atypical multiple mole-melanoma (FAMMM) syndrome in The Netherlands: how far have we come?

By the genetic localization of the first melanoma susceptibility gene on chromosome 1p we thought that the puzzle on familial melanoma families would soon be solved. Now, almost fifteen years later we have learned that inherited melanoma is not a simple genetic disorder and that multiple genes, modifying genes and environmental factors might be involved. This paper outlines the current understanding of the genetics of melanoma and the relationship to atypical nevi based on more than ten years of genetic analysis in the Dutch familial atypical multiple mole-melanoma (FAMMM) syndrome families.