Eurasian beaver (Castor fiber) health surveillance in Britain: Assessing a disjunctive reintroduced population.

BACKGROUND: Numerous translocations of Eurasian beavers have occurred with little implementation of standardised health screening. Pre-release health screening enables the selection of individuals with the best survival prospects and reduces potential health risks, but this is by-passed during unofficial releases. Beaver reintroduction to Britain has been haphazard and currently disjunctive populations of varying status exist. METHODS: This observational cross section study investigated the health status of three beaver populations, with 90 live beavers tested for a range of pathogens comprising 56 from Tayside (unofficially released Scotland), nine from Knapdale (officially released Scotland) and 25 from Devon (unofficially released England). In addition, a further 32 cadavers were screened (25 from Tayside and seven from Knapdale). RESULTS: All beavers were in good physical condition, did not harbour any non-native disease or parasites of concern and demonstrated remarkably low levels of any disease or parasite exposure. CONCLUSION: Beavers are establishing and adapting well to British landscapes and are not acting as reservoirs of significant zoonotic diseases. Official, licensed reintroduction programmes may appear overly convoluted; however, reputational damage of unofficial releases should be considered, along with the health and welfare of the animals involved and collateral damage to other wildlife, domestic animals and humans.

USE OF CLINDAMYCIN IN PALLAS' CATS [OTOCOLOBUS (FELIS) MANUL] TO REDUCE JUVENILE TOXOPLASMOSIS-ASSOCIATED MORTALITY RATES.

Pallas' cat [Otocolobus (Felis) manul] experiences a high mortality rate from toxoplasmosis. During the period 2006-2016, the overall mortality rate for this species from all causes during the first year of life was 71.59% in European Association of Zoos and Aquaria institutions, with the most significant infectious cause from systemic toxoplasmosis (20.6%) as confirmed by postmortem examination and histopathology. Clindamycin was used starting in 2014 in two collections that had previously experienced 100% mortality rates by toxoplasmosis in kittens less than one year of age, covering key Toxoplasma gondii exposure periods for kittens (n = 17) as a prophylactic measure. This protocol resulted in a 67.03% (95% confidence interval 41.76-78.61%) reduction in the first year mortality rate over a two-year period to 5.88% in those animals treated.

Transcript specific regulation of expression influences susceptibility to multiple sclerosis.

Genome-wide association studies (GWAS) have identified over 100 loci containing single nucleotide variants (SNVs) that influence the risk of developing multiple sclerosis (MS). Most of these loci lie in non-coding regulatory regions of the genome that are active in immune cells and are therefore thought to modify risk by altering the expression of key immune genes. To explore this hypothesis we screened genes flanking MS-associated variants for evidence of allele specific expression (ASE) by quantifying the transcription of coding variants in linkage disequilibrium with MS-associated SNVs. In total, we were able to identify and successfully analyse 200 such coding variants (from 112 genes) in both CD4+ and CD8+ T cells from 106 MS patients and 105 controls. Fifty-six of these coding variants (from 43 genes) showed statistically significant evidence of ASE in one or both cell types. In the Lck interacting transmembrane adaptor 1 gene (LIME1), for example, we were able to show that in both cell types, the MS-associated variant rs2256814 increased the expression of some transcripts while simultaneously reducing the expression of other transcripts. In CD4+ cells from an additional independent set of 96 cases and 93 controls we were able to replicate the effect of this SNV on the balance of alternate LIME1 transcripts using qPCR (p = 5 × 10-24). Our data thus indicate that some of the MS-associated SNVs identified by GWAS likely exert their effects on risk by distorting the balance of alternate transcripts rather than by changing the overall level of gene expression.

Evidence of Leptospira species and their significance during reintroduction of Eurasian beavers (Castorfiber) to Great Britain.

The Scottish Beaver Trial (SBT) reintroduced the Eurasian beaver (Castor fiber) in 2009 using wild-caught Norwegian beavers. This included a six-month prerelease quarantine in Devon, England. The International Union for Conservation of Nature (IUCN) and government guidelines for health screening were followed, including testing for Leptospira species. Unlicensed beavers, from Germany, were also identified in Scotland (Tayside) and Devon (later forming the River Otter Beaver Trial (ROBT)) and were health-screened under licence. Due to positive Leptospira species results and lack of prerelease screening in ROBT and Tayside, beavers from Germany and Norway (range sources) were screened. One hundred and fifty-six samples from 151 beavers were analysed by Leptospira species quantitative PCR (qPCR) (n=73 kidney (postmortem)/urine samples (antemortem)) or microscopic agglutination test (MAT, Leptospira pools 1-6) (n=83 serum samples). No beavers from Norway (95 per cent confidence interval (CI) 0-5.6 per cent, n=52), Tayside or SBT postrelease (95 per cent CI 0-4.6 per cent, n=63) tested positive. Seven beavers from Germany and Devon were positive. This gives an overall 9.3 per cent (95 per cent CI 5.2-15.1 per cent) exposure level, of which 4.6 per cent (95 per cent CI 1.9-9.3 per cent) suggested infection on a positive qPCR (n=1) or MAT titre of at least 1/400 (n=6), although none had abnormal physical, biochemical or haematological changes. This study suggests that Leptospira species infection in wild Eurasian beavers occurs at a low level, has no sex bias and does not appear to cause significant morbidity or mortality.

Absence of hantavirus in water voles and Eurasian beavers in Britain.

Hantaviruses are RNA viruses (order Bunyavirales, family Hantaviridae) found in rodent, bat and insectivore reservoir-hosts and have been reported as an emerging significant zoonotic risk in Europe. As part of two native semiaquatic rodent restoration projects, tissue and urine samples were tested for hantavirus from water voles (Arvicola amphibius) (n=26, in 2015) and Eurasian beavers (Castor fiber) (n=20, covering 2010-2015) using a pan-hantavirus nested real-time PCR test. Kidney and lung samples were also analysed by light microscopy after haematoxylin and eosin staining of formalin-fixed paraffin wax sections. Individuals selected included those forming the source of release animals and from those already free-living in Britain in areas targeted for release, to identify existing reservoirs. For water voles all tested individuals were from Britain (n=26); for beavers some were from Britain (Scotland) (n=9) and some were samples from wild Norwegian (Telemark region) (n=6) and German (Bavaria region) animals (n=5) that formed the source of accepted wild populations currently present in Scotland. All samples tested from both species were negative for hantavirus RNA and showed no significant histopathological changes suggesting that reservoir infection with hantavirus in water voles in Britain and Eurasian beavers present in Britain, Norway and Bavaria, Germany, is unlikely.

Pediatric melanoma in melanoma-prone families.

BACKGROUND: In the United States, only approximately 0.4% of all melanomas are diagnosed in patients aged <20 years. To the authors' knowledge, melanoma in pediatric members of melanoma-prone families has not been fully investigated to date. The objective of the current study was to evaluate pediatric patients with melanoma with extensive follow-up in melanoma-prone families with and without cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations. METHODS: For this non-population-based study, families were followed prospectively for up to 40 years. A total of 60 families with ≥ 3 patients with melanoma were included for analysis: 30 CDKN2A mutation-positive (CDKN2A+) and 30 CDKN2A mutation-negative (CDKN2A-) families. Age at the time of first melanoma and number of melanomas were obtained for each patient and summarized by family or sets (CDKN2A + vs CDKN2A-). For set comparisons and categorical variables (occurrence of melanoma in pediatric patients, number of melanomas, number of patients with single or multiple melanomas), the Pearson chi-square or Fisher exact test was used. RESULTS: Regardless of CDKN2A status, melanoma-prone families were found to have 6-fold to 28-fold higher percentages of patients with pediatric melanoma compared with the general population of patients with melanoma in the United States. Within CDKN2A + families, pediatric patients with melanoma were significantly more likely to have multiple melanomas compared with their relatives who were diagnosed at age >20 years (71% vs 38%, respectively; P = .004). CDKN2A + families had significantly higher percentages of pediatric patients with melanoma compared with CDKN2A- families (11.1% vs 2.5%; P = .004). CONCLUSIONS: These observations have implications for the prevention of melanoma as well as clinical care for its early detection. Children in melanoma-prone families should have careful sun protection from an early age and skin surveillance to reduce their risk of melanoma.

Risks of Melanoma and Other Cancers in Melanoma-Prone Families over 4 Decades.

Since 1976, melanoma-prone families have been followed at the National Cancer Institute to identify etiologic factors for melanoma. We compared risks of melanoma and other cancers in 1,226 members of 56 families followed for up to 4 decades with population rates in the Surveillance, Epidemiology, and End Results program. All families were tested for mutations in CDKN2A and CDK4; 29 were mutation-positive and 27 mutation-negative. We compared rates of invasive melanomas, both first and second, by family mutation status, with Surveillance, Epidemiology, and End Results program. Comparing three calendar periods of the study, risk of first primary melanoma decreased slightly. Risks of melanoma after first examination, however, were approximately one-third the risks prior to the first examination in both mutation-positive and mutation-negative families. Among patients with melanoma, risk of a second melanoma was increased 10-fold in all families; risk was somewhat higher in mutation-positive families. Risks of other second cancers were increased only for pancreatic cancer after melanoma in mutation-positive families. Over 4 decades, prospective risk of melanoma has decreased substantially in both mutation-positive and mutation-negative families, when melanoma has greatly increased in the general population. TRIAL REGISTRATION: NCI 02-C-0211, ClinicalTrials.gov ID NCT00040352.

Haematology and Serum Biochemistry Parameters and Variations in the Eurasian Beaver (Castor fiber).

Haematology parameters (N = 24) and serum biochemistry parameters (N = 35) were determined for wild Eurasian beavers (Castor fiber), between 6 months - 12 years old. Of the population tested in this study, N = 18 Eurasian beavers were from Norway and N = 17 originating from Bavaria but now living extensively in a reserve in England. All blood samples were collected from beavers via the ventral tail vein. All beavers were chemically restrained using inhalant isoflurane in 100% oxygen prior to blood sampling. Results were determined for haematological and serum biochemical parameters for the species and were compared between the two different populations with differences in means estimated and significant differences being noted. Standard blood parameters for the Eurasian beaver were determined and their ranges characterised using percentiles. Whilst the majority of blood parameters between the two populations showed no significant variation, haemoglobin, packed cell volume, mean cell haemoglobin and white blood cell counts showed significantly greater values (p<0.01) in the Bavarian origin population than the Norwegian; neutrophil counts, alpha 2 globulins, cholesterol, sodium: potassium ratios and phosphorus levels showed significantly (p<0.05) greater values in Bavarian versus Norwegian; and potassium, bile acids, gamma globulins, urea, creatinine and total calcium values levels showed significantly (p<0.05) greater values in Norwegian versus Bavarian relict populations. No significant differences were noted between male and female beavers or between sexually immature (<3 years old) and sexually mature (≥3 years old) beavers in the animals sampled. With Eurasian beaver reintroduction encouraged by legislation throughout Europe, knowledge of baseline blood values for the species and any variations therein is essential when assessing their health and welfare and the success or failure of any reintroduction program. This is the first study to produce base-line blood values and their variations for the Eurasian beaver.

The frequency, longitudinal course, clinical associations, and causes of emotional distress during primary treatment of cerebral glioma.

BACKGROUND: Relatively little is known about the frequency, longitudinal course, independent associations, and reported causes of emotional distress in adults with primary cerebral glioma. We aimed to describe these features in an observational study. METHODS: This was a twin-center prospective cohort study. Eligible adults were those with a new histological diagnosis of glioma who were receiving active management. Distress was measured using the National Comprehensive Cancer Network Distress Thermometer and problem checklist. Subjects were sampled at 3 timepoints: T1 (shortly after starting chemo/radiotherapy), T2 (3 months later), and T3 (6 months later). RESULTS: T1 n = 154; T2 n = 103; T3 n = 83. Significant distress was present in 36.4 ± 7.6% at T1, 35.9 ± 9.3% at T2, and 33.7 ± 10.2% at T3. Longitudinally, subjects with high distress at T1 (median Distress Thermometer score = 8; interquartile range [IQR] 7-9) remained highly distressed on follow-up (T2 median = 8, IQR 6-8; T3 median = 7, IQR 5-8) (Friedman test P = .304). Younger age, functional impairment, and concurrent major depressive disorder were independently associated with high distress (logistic regression χ(2) for model = 39.882, P < .001, R(2) = 0.312). The most frequently reported causes of distress were worry, fatigue, sleep difficulties, and sadness. Emotional difficulties were among the most common causes of distress at all 3 timepoints. CONCLUSIONS: At each timepoint, one-third of patients reported significant emotional distress, which persisted during follow-up among those initially highly distressed. Young, functionally impaired, and depressed glioma patients may particularly benefit from increased support.

Screening for major depressive disorder in adults with glioma using the PHQ-9: a comparison of patient versus proxy reports.

When screening for depression in glioma patients, the utility of proxy carer report is unknown. We studied how patients and proxies differed in the frequency, severity and agreement of reported depressive symptoms, the external validity of these reports, and whether patient-proxy agreement was associated with cognitive function. This was a cross-sectional study within a prospective cohort study of depression in glioma. Eligible patients were adults with a new diagnosis of cerebral glioma whose cohabiting partners chose to attend study interviews. Patients completed the Patient Health Questionnaire-9 (PHQ-9, maximum score 27) to screen for major depressive disorder. Proxies independently completed the PHQ-9 'for the patient'. A structured clinical interview for MDD was then given. From 55 couples attending, 41 participated (74 %). Patient-proxy total PHQ-9 score differed by 3 or more points in 26/41 cases (63.4 %). Disagreement within dyads ranged from -7 to +10 points. Proxies observed more individual depressive symptoms than patients reported (mean 2.7 vs 1.8 symptoms respectively, p = 0.013, Wilcoxon Rank Sum Test), and a greater severity of symptom burden (mean PHQ-9 score 8.4 vs 6.8 respectively, p = 0.016, Wilcoxon Rank Sum Test). Proxies were more reliable than patients on objective behavioural symptoms of depression. Dyadic agreement was not associated with severity of patient cognitive impairment. There was frequent disagreement between glioma patients and proxies reports of depressive symptoms. Proxies reported more depressive symptoms than patients, and were more reliable when reporting observable behavioural symptoms. When diagnosing depression in glioma, collateral history should be obtained.

Screening for major depressive disorder in adults with cerebral glioma: an initial validation of 3 self-report instruments.

No depression screening tool is validated for use in cases of cerebral glioma. To address this, we studied the operating characteristics of the Hospital Anxiety and Depression Scale (Depression subscale) (HAD-D), the Patient Health Questionnaire-9 (PHQ-9), and the Distress Thermometer (DT) in glioma patients.We conducted a twin-center prospective observational cohort study of major depressive disorder (MDD), according to the Diagnostic and Statistical Manual, 4th edition, in adults with a new diagnosis of cerebral glioma receiving active management or "watchful waiting." At each of 3 interviews over a 6-month period, patients completed the screening questionnaires and received a structured clinical interview to diagnose MDD. Internal consistency, area under the receiver operating characteristics curve (AUC), sensitivity, specificity, positive predictive value, and positive likelihood ratio were calculated. A maximum of 154 patients completed the DT, 133 completed the HAD-D, and 129 completed the PHQ-9. The HAD-D and PHQ-9 showed good internal consistency (α ≥ 0.77 at all timepoints). Median AUCs were 0.931 ± 0.074 for the HAD-D and 0.915 ± 0.055 for the PHQ-9. The optimal threshold was 7+ for the HAD-D, but 8+ had similar operating characteristics. There was no consistently optimal PHQ-9 threshold, but 10+ was optimal in the largest sample. The DT was inferior to the multi-item instruments. Clinicians can screen for depression in well-functioning glioma patients using the HAD-D at the existing recommended lower threshold of 8+, or the PHQ-9 at a threshold of 10+. Due to a modest positive predictive value of either instrument, patients scoring above these thresholds need a clinical assessment to diagnose or exclude depression.

Frequency, clinical associations, and longitudinal course of major depressive disorder in adults with cerebral glioma.

PURPOSE: There is a need for high-quality evidence regarding the frequency, independent clinical associations, and longitudinal course of depression in patients with cerebral glioma. PATIENTS AND METHODS: This was a twin-center, prospective, observational cohort study with 6-month follow-up. Consenting adults with a new diagnosis of cerebral glioma received the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition to diagnose major depressive disorder (MDD). Interviews occurred shortly after the start of radiotherapy (T1), with follow-up interviews 3 months later (T2) and 6 months later (T3). Independent associations between MDD and clinical variables were analyzed using logistic regression. RESULTS: One hundred fifty-five patients participated. The frequency of MDD was 13.5% ± 5.4% at T1 (n = 155); 14.8% ± 6.7% at T2 (n = 108); and 6.8% ± 5.3% at T3 (n = 88). Overall, 32 individuals were diagnosed with MDD during the study period (20.6% ± 6.4%). Inter-rater diagnostic agreement for MDD was good (κ = 0.81; 95% CI, 0.60 to 1.00). Independent predictors of MDD were functional impairment (odds ratio, 3.9; 95% CI, 1.5 to 10.8) and a previous history of depression (odds ratio, 2.7; 95% CI, 0.99 to 7.3). MDD persisted for at least 3 months in half of the patients with adequate follow-up, but many depressed patients also dropped out of the study as a result of clinical deterioration. CONCLUSION: In this longitudinal study, one in five patients with glioma developed clinical depression in the 6 months after starting radiotherapy. Patients with functional impairment or previous depression were at higher risk. MDD often persisted for at least 3 months. Clinicians should seek and treat depression in adults with glioma.

How does a standardized care plan facilitate the practice of pharmaceutical care planning in mental health settings across Scotland?

OBJECTIVES: The aim of the project was to understand how a standardized generic pharmaceutical care plan could facilitate the practice of mental health pharmacy care planning across Scotland. Specifically, the objectives were to examine whether the plan was easy to use, collected appropriate information and enabled communication on discharge; when the plan was used in relation to multidisciplinary meetings; how useful it was to other team members; whether it changed the way pharmacists worked; and who wrote in the plan. A further objective was to examine whether there were barriers to implementing the plan and how these may be overcome. METHODS: A piloted questionnaire and diary were completed by practising pharmacists, asking them to describe their use of the generic care plan. Mental health pharmacists throughout Scotland used the care plans with adult, elderly and forensic mental health inpatients over the 2 month period. KEY FINDINGS: Forty-four mental health pharmacists participated (69.84% of practising mental health pharmacists across Scotland). They used the plan with 241 adult, 70 elderly and 16 forensic mental health patients. Many sections of the plan received positive appraisal, but changes were also widely recommended. Changes were on three levels: (1) additions or deletions to individual sections of the care plan, some of which may reflect local circumstances, (2) more radical deletions or changes to entire sections or pages and (3) to take into account the wider social and political context in which pharmacists work, with the potential for local rates of progress towards national imperatives, such as multidisciplinary working. CONCLUSIONS: The development of a standardized care plan for mental health pharmacists should address policy issues and could enhance the role of the pharmacist within multidisciplinary teams.

Genetic testing for melanoma predisposition: current challenges.

A complex interaction of genetic, host, and environmental factors results in cutaneous malignant melanoma, the fifth most common cancer among men and the sixth among women in the United States. Mortality rates for cutaneous malignant melanoma depend on stage at diagnosis; thus, efforts are aimed at early detection and identification of risk factors for melanoma to distinguish those individuals requiring close surveillance. Melanoma susceptibility genes CDKN2A and CDK4 play a role in the development of melanoma, especially among some familial melanoma kindreds. The functions of CDKN2A and CDK4 in melanoma development, however, are currently incompletely understood. Therefore, at this time, predictive genetic testing for CDKN2A mutations outside of defined research protocols is not recommended because of the low likelihood of detecting mutations even in high-risk groups, the present inadequacy of interpreting a test result due to variations in penetrance and unclear associations with other cancers, and the minimal influence knowledge of mutation status currently has on medical management. Oncology nurses have an important role in identifying individuals at high risk for melanoma regardless of CDKN2A mutation status, encouraging enrollment in skin surveillance programs, and providing patient education regarding sun protection, prevention and early detection of melanoma.

Recent tanning bed use: a risk factor for melanoma.

BACKGROUND: Individuals at increased risk of melanoma should use sun-protective measures to decrease their risk of developing melanoma. OBSERVATION: We report a case of a 39-year-old patient with a CDKN2A mutation who developed 3 primary melanomas within a few years of initiating tanning bed use. CONCLUSION: Intense UV exposure as an adult likely contributed to the development of additional primary melanomas in this individual.

Association of MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A mutations.

Major risk factors for melanoma include many nevi, especially dysplastic nevi, fair pigmentation, freckling, poor tanning ability, and germ line mutations in the CDKN2A, CDK4, or MC1R genes. We evaluated the relationship between MC1R and melanoma risk in CDKN2A melanoma-prone families with extensive clinical and epidemiologic data. We studied 395 subjects from 16 American CDKN2A families. Major melanoma risk factors were assessed by clinical examination or questionnaire; MC1R was sequenced. Odds ratios were estimated by unconditional and conditional logistic regression models. We examined the distribution of MC1R variants and median ages at melanoma diagnosis in multiple primary melanoma (MPM) and single primary melanoma (SPM) patients. Presence of multiple MC1R variants was significantly associated with melanoma, even after adjustment for major melanoma risk factors. All 40 MPM patients had at least one MC1R variant; 65% of MPM patients versus only 17% of SPM patients had at least two MC1R variants (P < 0.0001). For all 69 melanoma patients combined, as well as the 40 MPM patients, there was a statistically significant decrease in median age at diagnosis as numbers of MC1R variants increased (P = 0.010 and P = 0.008, respectively). In contrast, no significant reduction in age at melanoma diagnosis was observed for SPM patients (P = 0.91). The current study suggests that the presence of multiple MC1R variants is associated with the development of multiple melanoma tumors in patients with CDKN2A mutations. Additional studies are needed to confirm these findings and to explore the mechanisms that may contribute to this relationship.