Understanding quality of life issues in patients with advanced melanoma: Phase 1 and 2 in the development of the EORTC advanced melanoma module.

AIMS: We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) melanoma receiving immune checkpoint inhibitors or targeted therapy. METHODS: Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module. RESULTS: Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates. Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items. CONCLUSION: We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma.

Is the road to burnout paved with perfectionism? The prevalence of obsessive-compulsive personality disorder in a clinical longitudinal sample of female patients with stress-related exhaustion.

OBJECTIVES: Few studies have investigated the relationship between stress-related mental health problems and obsessive-compulsive personality disorder (OCPD). Similarly, little research has focused on the moderating effect of OCPD on recovery in clinical patients with stress-related mental health problems. The general aim of this study was to investigate the prevalence of OCPD and the associations between OCPD and level of burnout, anxiety, and depression symptoms, during a 7-years follow-up in a clinical longitudinal sample of female patients with stress-related exhaustion. METHOD: The included patients (n = 84) were referred to a specialist outpatient clinic for patients with stress-related exhaustion between 2006 and 2011. Data was collected at the initial examination and during a 7-year treatment follow-up. RESULTS: OCPD was the most common personality disorder in the present clinical sample, with 40% of patients fulfilling the criteria. There was a significant association between OCPD and the degree of burnout symptoms as well as the degree of depression, both at baseline and during the 7-year follow-up. No significant association between OCPD and levels of anxiety was observed. CONCLUSION: The results support the hypothesis that there might be an association between OCPD and stress-related exhaustion, including preservation of symptoms over time. OCPD and its related traits, such as perfectionism, may be important factors to consider when constructing effective treatment and rehabilitation plans for these patients.

A latent class analysis of mental disorders, substance use, and aggressive antisocial behavior among Swedish forensic psychiatric patients.

BACKGROUND: Patients in the forensic mental health services (FMHS) with a mental disorder, a co-occurring substance use disorder (SUD), and high risk of aggressive antisocial behavior (AAB) are sometimes referred to as the 'triply troubled'. They suffer poor treatment outcomes, high rates of criminal recidivism, and increased risk of drug related mortality. To improve treatment for this heterogeneous patient group, more insight is needed concerning their co-occurring mental disorders, types of substances used, and the consequent risk of AAB. METHODS: A three-step latent class analysis (LCA) was used to identify clinically relevant subgroups in a sample of patients (n = 98) from a high-security FMHS clinic in Sweden based on patterns in their history of mental disorders, SUD, types of substances used, and AAB. RESULTS: A four-class model best fit our data: class 1 (42%) had a high probability of SUD, psychosis, and having used all substances; class 2 (26%) had a high probability of psychosis and cannabis use; class 3 (22%) had a high probability of autism and no substance use; and class 4 (10%) had a high probability of personality disorders and having used all substances. Both polysubstance classes (1 and 4) had a significantly more extensive history of AAB compared to classes 2 and 3. Class 3 and class 4 had extensive histories of self-directed aggression. CONCLUSIONS: The present study helps disentangle the heterogeneity of the 'triply troubled' patient group in FMHS. The results provide an illustration of a more person-oriented perspective on patient comorbidity and types of substances used which could benefit clinical assessment, treatment planning, and risk-management among patients in forensic psychiatric care.

Implementing clinical guidelines for co-occurring substance use and major mental disorders in Swedish forensic psychiatry: An exploratory, qualitative interview study with mental health care staff.

INTRODUCTION: Patients with substance use disorders (SUD) and co-occurring mental disorders (COD) within forensic psychiatric care often suffer poor treatment outcomes and high rates of criminal recidivism, substance use, and psychiatric problems. This study aimed to describe the conditions for, and mental health care staff's experiences with, implementing integrated SUD-focused clinical guidelines, including assessment and treatment for patients with COD at a high-security forensic mental health services (FMHS) facility in Sweden. METHODS: Study staff conducted nineteen semi-structured interviews with health care staff experienced in administering the new SUD assessment and treatment. The study conducted a thematic analysis to describe the health care staff's experiences with these guidelines and suggestions for improvement. RESULTS: Most participants reported appreciation for the implementation of clinical guidelines with an SUD focus, an area they considered to have previously been neglected, but also noted the need for more practical guidance in the administration of the assessments. Participants reported the dual roles of caregiver and warden as difficult to reconcile and a similar, hindering division was also present in the health care staff's attitudes toward SUD. Participants' reports also described an imbalance prior to the implementation, whereby SUD was rarely assessed but treatment was still initiated. One year after the implementation, an imbalance still existed, but in reverse: SUD was more frequently assessed, but treatment was difficult to initiate. CONCLUSIONS: Despite indications of some ambivalence among staff regarding the necessity of the assessment and treatment guidelines, many participants considered it helpful to have a structured way to assess and treat SUD in this patient group. The imbalance between frequent assessment and infrequent treatment may have been due to difficulties transitioning patients across the "gap" between assessment and treatment. To bridge this gap, mental health services should make efforts to increase patients' insight concerning their SUD, flexibility in the administration of treatment, and the motivational skills of the health care staff working with this patient group. Participants considered important for enhancing treatment quality a shared knowledge base regarding SUD, and increased collaboration between different professions and between in- and outpatient services.

Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion.

OBJECTIVE: Transport of Ca2+ into pancreatic ß cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins allows modification of mitochondrial Ca2+ transport in intact cells. We examined the consequences of deficiency of the accessory protein MICU2 in rat and human insulin-secreting cells and mouse islets. METHODS: siRNA silencing of Micu2 in the INS-1 832/13 and EndoC-ßH1 cell lines was performed; Micu2-/- mice were also studied. Insulin secretion and mechanistic analyses utilizing live confocal imaging to assess mitochondrial function and intracellular Ca2+ dynamics were performed. RESULTS: Silencing of Micu2 abrogated GSIS in the INS-1 832/13 and EndoC-ßH1 cells. The Micu2-/- mice also displayed attenuated GSIS. Mitochondrial Ca2+ uptake declined in MICU2-deficient INS-1 832/13 and EndoC-ßH1 cells in response to high glucose and high K+. MICU2 silencing in INS-1 832/13 cells, presumably through its effects on mitochondrial Ca2+ uptake, perturbed mitochondrial function illustrated by absent mitochondrial membrane hyperpolarization and lowering of the ATP/ADP ratio in response to elevated glucose. Despite the loss of mitochondrial Ca2+ uptake, cytosolic Ca2+ was lower in siMICU2-treated INS-1 832/13 cells in response to high K+. It was hypothesized that Ca2+ accumulated in the submembrane compartment in MICU2-deficient cells, resulting in desensitization of voltage-dependent Ca2+ channels, lowering total cytosolic Ca2+. Upon high K+ stimulation, MICU2-silenced cells showed higher and prolonged increases in submembrane Ca2+ levels. CONCLUSIONS: MICU2 plays a critical role in ß cell mitochondrial Ca2+ uptake. ß cell mitochondria sequestered Ca2+ from the submembrane compartment, preventing desensitization of voltage-dependent Ca2+ channels and facilitating GSIS.

Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes.

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and ß-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key ß-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of ß-cell phenotype and function.

Somatic effects of AAS abuse: A 30-years follow-up study of male former power sports athletes.

OBJECTIVES: The aim of the present study was to investigate the association between somatic health and former abuse of AAS in former elite male athletes 30 years after the end of their active sports career. DESIGN: Retrospective follow-up study. METHODS: N=996 former elite male athletes were sent a questionnaire concerning sociodemographic variables, previous and past sport activity and lifetime prevalence of seeking professional help for health problems. N=683 (68.6%) answered the questionnaire. The lifetime prevalence of AAS-abuse was 21% (n=143), while 79% (n=540) did not admit having ever used AAS. RESULTS: Former AAS-abuse was associated with tendon ruptures (p=0.01), depression (p=0.001), anxiety (p=0.01) and lower prevalence of prostate hypertrophy (p=0.01) and decreased libido (p=0.01). Former advanced AAS-abusers had higher anxiety (p=0.004) compared to the former less advanced AAS-abusers. Moreover, former advanced AAS-abusers, compared to AAS-naïves, reported more psychiatric problems (p=0.002), depression (p=0.003) and anxiety (p=0.00). CONCLUSIONS: A former AAS-abuse seems to be associated with some somatic and mental health problem, although a former less advanced AAS-abuse is related to lower incidence of prostate hypertrophy. The results raise the question whether some of these associations might be dose- and frequency dependent. These findings should however be seen as hypothesis generating and further studies are needed.

Syntaxin-1a is a direct target of miR-29a in insulin-producing ß-cells.

Downregulation of proteins involved in the -exocytotic machinery has been implicated in the impairment of normal ß-cell function in response to high glucose levels. Syntaxin-1a -(Stx-1a) is one of two t-SNAREs involved in insulin exocytosis and decreased expression of Stx-1a protein impairs glucose-stimulated insulin secretion (GSIS) in isolated rat pancreatic islets. In diabetic patients Stx-1a protein levels are reduced, but the mechanism of this suppression is unknown.MicroRNAs are small noncoding RNAs, which are important regulators of gene-expression at the post transcriptional level, partially binding to the 3'UTRs of their target gene transcripts either mediating transcript degradation or inhibiting translation. We have recently shown that miR-29a is upregulated in response to elevated glucose levels in ß-cells and is involved in mediating the negative effect of high glucose levels on GSIS. Stx-1a has a predicted target site of miR-29a present in its 3' untranslated region. The objective of this study was to evaluate whether miR-29a targets Stx-1a directly to decrease mRNA and/or protein levels in response to glucose. Stx-1a mRNA and protein levels decreased in ß-cells treated with increased glucose levels. Overexpression of miR-29a decreased Stx-1a mRNA and protein levels. Furthermore, miR-29a decreases the response of a luciferase reporter construct containing the predicted target site normally present in the Stx-1a gene. When 2 nucleotides are mutated in this target site, responsiveness to miR-29a disappears, confirming miR-29a binding to this sequence. Collectively, these data implicate miR-29a as a mediator of glucose-induced downregulation of Stx-1a in ß-cells.

Monogenean assemblages and the apparent transmission capability of monogeneans between related fish species: an experimental study.

Gyrodactylid monogeneans are considered to be the most invasive fish parasites. They are omnipresent on teleost fishes and host change might play a crucial role in their biology. In the present study, related fish species were kept in single- or mixed-species groups to test the ability of Gyrodactylus species to change their host fish under experimental conditions. The first group included two percid fish species, perch Perca fluviatilis L. and ruffe Gymnocephalus cernuus (L.), and the second group two cyprinid species, roach Rutilus rutilus (L.) and minnow Phoxinus phoxinus (L.). A total of 4,182 specimens of 19 monogenean species belonging to five genera were observed, and eight species of Gyrodactylus were identified. There were three species of Gyrodactylus found on roach and six species on minnow. Gyrodactylus vimbi parasitized both cyprinid fish species and was the only species that increased in intensity during the experiments and also assumed to transmit from minnow to roach, while the other recorded host change case, Gyrodactylus macronychus, was represented by a single individual that transmitted from minnow to roach. Gyrodactylus rutilensis and Gyrodactylus pannonicus remained on their original hosts (roach and minnow, respectively). Gyrodactylus cernuae was the only species observed on both ruffe and perch, but ruffe appeared more susceptible to this parasite. Most of the gyrodactylids observed on roach and minnow were situated on the fins, while gyrodactylids of perch and ruffe parasitized mainly the gill chamber and head.

Interspecific and intraspecific interactions in the monogenean communities of fish: a question of study scale?

Monogenean communities of fish have generally been considered non-interactive as negative interspecific interactions have rarely been reported. Most of the earlier studies on monogenean communities, however, have been conducted not only in systems with relatively low parasite abundances but, more importantly, at study scales where microhabitat-level interactions between the parasites are easily overlooked. We examined the communities of 3 abundant Dactylogyrus (Monogenea) species on the gills of crucian carp (Carassius carassius) by analysing the interactions at the scale of individual gill filaments, where interactions between the species, if any, should most likely take place. Contrary to our expectations, we did not find evidence for competitive exclusion between the species, which suggests that monogenean communities are non-interactive even in high parasite abundances. At the species level, individual parasites were highly aggregated within the filaments, essentially showing a strong tendency to occur at either end of a filament. This, together with the result of differences in the distribution of juvenile parasites within the filaments compared to adults, suggests that these parasites are able to actively seek out their conspecifics in small-scale microhabitats during maturation, which again could enhance their mate-finding.

Infracommunity level aggregation in the monogenean communities of crucian carp (Carassius carassius).

Aggregation is one of the distinctive features in parasite-host relationships, which has generally been studied at the level of host communities. Parasite aggregation at the infracommunity level may nevertheless be important for intraspecific interactions such as parasite mating success and opportunities for cross-fertilization. In the present paper, we studied the infracommunity aggregation of 3 highly abundant Dactylogyrus (Monogenea) species occurring on the gills of crucian carp (Carassius carassius). In line with the previous work on monogenean communities, we observed no competition between the species. At the species level, parasites were distributed unevenly on the gills showing aggregation in the majority of infracommunities. However, aggregation decreased with increasing parasite abundance, which supports the hypothesis that less aggregation may be needed to ensure successful mating when the distance to a potential mate decreases with increasing number of conspecifics. Lack of interspecific interactions, species specific site selection and the importance of study scale for aggregation patterns in dactylogyrids are discussed.

Parasite assemblages of crucian carp (Carassius carassius)--is depauperate composition explained by lack of parasite exchange, extreme environmental conditions or host unsuitability?

Recent studies on parasite communities have considered the factors which contribute to variability in parasite infections among populations of one host species. This paper examined parasite assemblages of crucian carp (Carassius carassius) in a natural set-up of two distinctive environments inhabited by the same host species and differing in respect to composition of other fish species: ponds, where extreme conditions prevent other fish species from occurring and lakes, where crucian carp coexist with other fish species. Our aim was to evaluate the significance of parasite exchange, environmental conditions and host suitability for the depauperate parasite assemblages observed in pond crucian carp. As predicted, crucian carp had more diverse parasite species composition in lakes, which supports the hypotheses of increased opportunities for parasite exchange with other fish species and better environmental conditions for the parasites. However, for instance, diplostomids were found only from few fish individuals in very low numbers. Experimental exposure trials with the eye fluke Diplostomum spathaceum in the laboratory indicated that crucian carp were totally resistant to infection, which is exceptional and suggests that the low number of these parasites in crucian carp was due to physiological unsuitability of the host. To obtain a better understanding on the mechanisms underlying the formation of parasite assemblages in these fish, further studies on the relationships between the unique physiology of crucian carp and infection success by other parasite species are needed.

Fish population size, and not density, as the determining factor of parasite infection: a case study.

The diversity and abundance of parasites vary widely among populations of the same host species. These infection parameters are, to some extent, determined by characteristics of the host population or of its habitat. Recent studies have supported predictions derived from epidemiological models regarding the influence of host population density: parasite abundance and parasite species richness are expected to increase with increasing host population density, at least for directly transmitted parasites. Here, we test this prediction using a natural system in which populations of the crucian carp, Carassius carassius (L.), occur alone, with no other fish species, in a series of 9 isolated ponds in Finland. The ectoparasite communities in these fish populations consist of only 4 species of monogeneans (Dactylogyrus formosus, D. wegeneri, D. intermedius and Gyrodactylus carassii); the total and relative abundance of these 4 species varies among ponds, with one or two of the species missing from certain ponds. Across ponds, only one factor, total fish population size, explained a significant portion of the variance in both the mean number of monogenean species per fish and the mean total abundance of monogenean individual per fish. In contrast, fish population density did not influence either monogenean abundance or species richness, and neither did any of the other variables investigated (mean fish length per pond, number (of fish examined per pond, distance to the nearest lake, and several water quality measures). In our system, proximity among fish individuals (i.e. host population density) may not be relevant to the proliferation of monogeneans; instead, the overall availability of host individuals in the host population appeared to be the main constraint limiting parasite population growth.

Development of monogenean communities on the gills of roach fry (Rutilus rutilus).

The formation and development of monogenean communities on the gills of roach fry was followed in 1992 from early June to October (size range 9 to 47 mm). Roach fry (n = 291) were sampled weekly from the small, humic River Rutajoki in central Finland. A further 209 roach fry were reared in a fish farm supplied by water from the river. Four Dactylogyrus species were found: D. nanus, D. crucifer, D. micracanthus and D. suecicus. Other species found on the gills were Gyrodactylus sp. and Paradiplozoon homoion. The first Dactylogyrus juvenile occurred on a 12 mm long fish fry in late June and the first adult (D. nanus) 1 week later in Tank 1. D. nanus was also the most common parasite in the river. Young fry had high numbers of Gyrodactylus sp. on the gills compared with adult roach in previous studies. Signs of site preference were found; D. nanus and D. micracanthus preferred the 2nd gill-arch and Dactylogyrus juveniles the outmost one. Abundances of monogenean infracommunities increased until the middle of August when, on average, 1.9 species and 3.7 worms per fry were noted and decreased then as the water temperatures fell. A lack of competition between species is suggested; for example, D. crucifer appeared on the gills at that time when abundance of D. nanus was at its highest. The roach fry hatched and reared in the fish farm revealed that larvae of the most common dactylogyrid species were able to disseminate and colonize over 120 m from the river to the farm. Influence of change colonization events was shown by the appearance and development of Gyrodactylus sp. population on roach fry in only 1 of the 2 tanks at the farm.