Germline whole genome sequencing in pediatric oncology in Denmark:Practitioner perspectives

Background: With the implementation of a research project providing whole genome sequencing (WGS) to all pediatric cancer patients in Denmark (2016–2019), we sought to investigate healthcare professionals' views on WGS as it was actively being implemented in pediatric oncology. Methods: Semistructured interviews were carried out with pediatric oncologists, clinical geneticists, and research coordinating nurses (N = 17), followed by content analysis of transcribed interviews. Interviews were supplemented by ethnographic observations on Danish pediatric oncology wards. Additionally, questionnaires were distributed to healthcare professionals concerning when they found it appropriate to approach families regarding WGS. The response rate was 74%. Results: Healthcare professionals see imbalances in doctor–patient relationship, especially the double role doctors have as clinicians and researchers. Some were concerned that it might not be possible to obtain meaningful informed consent from all families following diagnosis. Still, 94% of respondents found it acceptable to approach families during the first 4 weeks from the child's diagnosis. Views on the utility of WGS, treatment adaptation, and surveillance differed among interviewees. Conclusion: Overall, healthcare professionals see dilemmas arising from WGS in the pediatric oncology clinic, and some advocate for further educational sessions with families and healthcare professionals. Despite concerns, healthcare professionals overwhelmingly supported early approach of families regarding WGS. Interviewees disagree on the benefits of surveillance based on genetic findings

Vocal behaviour of the Great Cormorant Phalacrocorax carbo sinensis during the breeding season

Capsule Great Cormorants Phalacrocorax carbo sinensis use vocal communication during the breeding season, with males being particularly vocal earlier in the breeding cycle and showing individual variation in some calls, which could be used for individual recognition. Aims To identify and describe vocal behaviour of Great Cormorants, to link calls with observed behaviours and to explore if the calls had potential for individual recognition. Methods We followed 21 nesting pairs of Great Cormorants by videoing and recording their vocal behaviour throughout the breeding season. We linked calls with observed behaviours, and measured the acoustic characteristics of the calls using signal analysis tools in Matlab. Results We identified and measured acoustic characteristics of six different call types: courtship, landing, nest building, nest relief, jumping, and chick begging calls. Five of these call types were linked to distinctive breeding behaviours. Vocal signalling occurred between the male and female, and between parents and offspring. Males showed higher vocal activity than females and used a larger repertoire of calls. The courtship call was the most common call type in both sexes. These calls also differed acoustically between the sexes; male calls were longer in duration than female calls (617 ms versus 323 ms) and had wider bandwidth (763 Hz versus 473 Hz). Conclusion Great Cormorants use vocal communication for social interactions. Males were vocally more active and had a larger repertoire of calls than females, and calls differed between the sexes. Calls of males also differed individually and could, therefore, function for individual recognition in this species.Peer reviewe

Causes of death among undocumented migrants in Sweden, 1997–2010

Background: Undocumented migrants are one of the most vulnerable groups in Swedish society, where they generally suffer from poor health and limited health care access. Due to their irregular status, such migrants are an under-researched group and are not included in the country's Cause of Death Register (CDR). Objective: To determine the causes of death among undocumented migrants in Sweden and to ascertain whether there are patterns in causes of death that differ between residents and undocumented migrants. Design: This is a cross-sectional study of death certificates issued from 1997 to 2010 but never included in the CDR from which we established our study sample of undocumented migrants. As age adjustments could not be performed due to lack of data, comparisons between residents and undocumented migrants were made at specific age intervals, based on the study sample's mean age at death±a half standard deviation. Results: Out of 7,925 individuals surveyed, 860 were classified as likely to have been undocumented migrants. External causes (49.8%) were the most frequent cause of death, followed by circulatory system diseases, and then neoplasms. Undocumented migrants had a statistically significant increased risk of dying from external causes (odds ratio [OR] 3.57, 95% confidence interval [CI]: 2.83–4.52) and circulatory system diseases (OR 2.20, 95% CI: 1.73–2.82) compared to residents, and a lower risk of dying from neoplasms (OR 0.07, 95% CI: 0.04–0.14). Conclusions: We believe our study is the first to determine national figures on causes of death of undocumented migrants. We found inequity in health as substantial differences in causes of death between undocumented migrants and residents were seen. Legal ambiguities regarding health care provision must be addressed if equity in health is to be achieved in a country otherwise known for its universal health coverage

Baseline data from a planned RCT on attitudes to female genital cutting after migration: when are interventions justified?

OBJECTIVES: To present the primary outcomes from a baseline study on attitudes towards female genital cutting (FGC) after migration. DESIGN: Baseline data from a planned cluster randomised, controlled trial. Face-to-face interviews were used to collect questionnaire data in 2015. Based on our hypothesis that established Somalis could be used as facilitators of change among those newly arrived, data were stratified into years of residency in Sweden. SETTING: Sweden. PARTICIPANTS: 372 Somali men and women, 206 newly arrived (0-4 years), 166 established (>4 years). PRIMARY OUTCOME MEASURES: Whether FGC is acceptable, preferred for daughter and should continue, specified on anatomical extent. RESULTS: The support for anatomical change of girls and women's genitals ranged from 0% to 2% among established and from 4% to 8% among newly arrived. Among those supporting no anatomical change, 75%-83% among established and 53%-67% among newly arrived opposed all forms of FGC, with the remaining supporting pricking of the skin with no removal of tissue. Among newly arrived, 37% stated that pricking was acceptable, 39% said they wanted their daughter to be pricked and 26% reported they wanted pricking to continue being practised. Those who had lived in Sweden ≤ 2 years had highest odds of supporting FGC; thereafter, the opposition towards FGC increased over time after migration. CONCLUSION: A majority of Somali immigrants, including those newly arrived, opposed all forms of FGC with increased opposition over time after migration. The majority of proponents of FGC supported pricking. We argue that it would have been unethical to proceed with the intervention as it, with this baseline, would have been difficult to detect a change in attitudes given that a majority opposed all forms of FGC together with the evidence that a strong attitude change is already happening. Therefore, we decided not to implement the planned intervention. TRIAL REGISTRATION NUMBER: Trial registration number NCT02335697;Pre-results

Deaths Among Adult Patients with Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality.

Context:Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified.Objective:To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up.Design and Methods:All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed.Main Outcome Measures:Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up.Results:An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy.Conclusion:Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease

Plasma-Metanephrines in Patients with Autoimmune Addison’s Disease with and without Residual Adrenocortical Function

Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison’s disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD

Residual Corticosteroid Production in Autoimmune Addison Disease

Context - Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective - To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Design - Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results - Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P P P P P P P  Conclusion - In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life

Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study

Objective - Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. Methods - We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. Results - Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = −0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (−0.15 normalized protein expression [NPX], P = .0001, and −0.25 NPX, P = .0003, respectively). Conclusions - We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small

Conserved ancestral tropical niche but different continental histories explain the latitudinal diversity gradient in brush-footed butterflies.

The global increase in species richness toward the tropics across continents and taxonomic groups, referred to as the latitudinal diversity gradient, stimulated the formulation of many hypotheses to explain the underlying mechanisms of this pattern. We evaluate several of these hypotheses to explain spatial diversity patterns in a butterfly family, the Nymphalidae, by assessing the contributions of speciation, extinction, and dispersal, and also the extent to which these processes differ among regions at the same latitude. We generate a time-calibrated phylogeny containing 2,866 nymphalid species (~45% of extant diversity). Neither speciation nor extinction rate variations consistently explain the latitudinal diversity gradient among regions because temporal diversification dynamics differ greatly across longitude. The Neotropical diversity results from low extinction rates, not high speciation rates, and biotic interchanges with other regions are rare. Southeast Asia is also characterized by a low speciation rate but, unlike the Neotropics, is the main source of dispersal events through time. Our results suggest that global climate change throughout the Cenozoic, combined with tropical niche conservatism, played a major role in generating the modern latitudinal diversity gradient of nymphalid butterflies