Search

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated toward COVID-19 elimination (Zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases toward advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided.

Purpose To compare radiological outcome, complications and reoperations in individuals with cerebral palsy and scoliosis fused to the fifth lumbar vertebra (L5), the sacrum, or the ilia. Methods 208 individuals were identified in the national quality registry Swespine. Lowest level of fusion was L5 in 58, the sacrum in 92, and the ilia in 58 individuals. A subanalysis on 58 matched pairs operated to L5 or the pelvis (sacrum = 42, ilia = 16) with similar pelvic obliquity (± 5°) was performed. Results The median (interquartile range) follow-up for the last radiograph was 1.7 (1.7) years and for reoperations 6.0 (5.9) years. Preoperatively, median Cobb angle of the major curve was 65° (23°) in the L5 group, 68° (28°) in the sacrum group, and 78° (25°) in the ilia group (p = 0.006). Preoperative median pelvic obliquity according to Maloney was 16° (19°), 21° (13°), and 27° (28°), respectively (p = 0.004). Immediate postoperative Cobb angles were 28° (18°), 28° (16°), and 32° (25°), respectively (p = 0.11). Immediate postoperative pelvic obliquity was 7° (10°), 7° (8°), and 8° (10°), respectively (p = 0.28). The median change in pelvic obliquity from the first to the last postoperative radiograph was − 5° (7°), − 3° (6°), − 3° (6°), respectively (p = 0.55). 7 (12%), 11 (12%), and 7 (12%) patients required at least one reoperation (p = 1.0), respectively. In the matched analysis, no significant differences in the radiological outcomes were found (all p ≥ 0.38). Conclusions Maintained curve and pelvic obliquity correction with no significant difference in complication and reoperation rates were found irrespective of distal fusion level.

Purpose To compare radiological outcome, complications and reoperations in individuals with cerebral palsy and scoliosis fused to the fifth lumbar vertebra (L5), the sacrum, or the ilia. Methods 208 individuals were identified in the national quality registry Swespine. Lowest level of fusion was L5 in 58, the sacrum in 92, and the ilia in 58 individuals. A subanalysis on 58 matched pairs operated to L5 or the pelvis (sacrum = 42, ilia = 16) with similar pelvic obliquity (± 5°) was performed. Results The median (interquartile range) follow-up for the last radiograph was 1.7 (1.7) years and for reoperations 6.0 (5.9) years. Preoperatively, median Cobb angle of the major curve was 65° (23°) in the L5 group, 68° (28°) in the sacrum group, and 78° (25°) in the ilia group (p = 0.006). Preoperative median pelvic obliquity according to Maloney was 16° (19°), 21° (13°), and 27° (28°), respectively (p = 0.004). Immediate postoperative Cobb angles were 28° (18°), 28° (16°), and 32° (25°), respectively (p = 0.11). Immediate postoperative pelvic obliquity was 7° (10°), 7° (8°), and 8° (10°), respectively (p = 0.28). The median change in pelvic obliquity from the first to the last postoperative radiograph was − 5° (7°), − 3° (6°), − 3° (6°), respectively (p = 0.55). 7 (12%), 11 (12%), and 7 (12%) patients required at least one reoperation (p = 1.0), respectively. In the matched analysis, no significant differences in the radiological outcomes were found (all p ≥ 0.38). Conclusions Maintained curve and pelvic obliquity correction with no significant difference in complication and reoperation rates were found irrespective of distal fusion level.

Purpose To compare radiological outcome, complications and reoperations in individuals with cerebral palsy and scoliosis fused to the fifth lumbar vertebra (L5), the sacrum, or the ilia. Methods 208 individuals were identified in the national quality registry Swespine. Lowest level of fusion was L5 in 58, the sacrum in 92, and the ilia in 58 individuals. A subanalysis on 58 matched pairs operated to L5 or the pelvis (sacrum = 42, ilia = 16) with similar pelvic obliquity (± 5°) was performed. Results The median (interquartile range) follow-up for the last radiograph was 1.7 (1.7) years and for reoperations 6.0 (5.9) years. Preoperatively, median Cobb angle of the major curve was 65° (23°) in the L5 group, 68° (28°) in the sacrum group, and 78° (25°) in the ilia group (p = 0.006). Preoperative median pelvic obliquity according to Maloney was 16° (19°), 21° (13°), and 27° (28°), respectively (p = 0.004). Immediate postoperative Cobb angles were 28° (18°), 28° (16°), and 32° (25°), respectively (p = 0.11). Immediate postoperative pelvic obliquity was 7° (10°), 7° (8°), and 8° (10°), respectively (p = 0.28). The median change in pelvic obliquity from the first to the last postoperative radiograph was − 5° (7°), − 3° (6°), − 3° (6°), respectively (p = 0.55). 7 (12%), 11 (12%), and 7 (12%) patients required at least one reoperation (p = 1.0), respectively. In the matched analysis, no significant differences in the radiological outcomes were found (all p ≥ 0.38). Conclusions Maintained curve and pelvic obliquity correction with no significant difference in complication and reoperation rates were found irrespective of distal fusion level.

Purpose To compare radiological outcome, complications and reoperations in individuals with cerebral palsy and scoliosis fused to the fifth lumbar vertebra (L5), the sacrum, or the ilia. Methods 208 individuals were identified in the national quality registry Swespine. Lowest level of fusion was L5 in 58, the sacrum in 92, and the ilia in 58 individuals. A subanalysis on 58 matched pairs operated to L5 or the pelvis (sacrum = 42, ilia = 16) with similar pelvic obliquity (± 5°) was performed. Results The median (interquartile range) follow-up for the last radiograph was 1.7 (1.7) years and for reoperations 6.0 (5.9) years. Preoperatively, median Cobb angle of the major curve was 65° (23°) in the L5 group, 68° (28°) in the sacrum group, and 78° (25°) in the ilia group (p = 0.006). Preoperative median pelvic obliquity according to Maloney was 16° (19°), 21° (13°), and 27° (28°), respectively (p = 0.004). Immediate postoperative Cobb angles were 28° (18°), 28° (16°), and 32° (25°), respectively (p = 0.11). Immediate postoperative pelvic obliquity was 7° (10°), 7° (8°), and 8° (10°), respectively (p = 0.28). The median change in pelvic obliquity from the first to the last postoperative radiograph was − 5° (7°), − 3° (6°), − 3° (6°), respectively (p = 0.55). 7 (12%), 11 (12%), and 7 (12%) patients required at least one reoperation (p = 1.0), respectively. In the matched analysis, no significant differences in the radiological outcomes were found (all p ≥ 0.38). Conclusions Maintained curve and pelvic obliquity correction with no significant difference in complication and reoperation rates were found irrespective of distal fusion level.

Purpose To compare radiological outcome, complications and reoperations in individuals with cerebral palsy and scoliosis fused to the fifth lumbar vertebra (L5), the sacrum, or the ilia. Methods 208 individuals were identified in the national quality registry Swespine. Lowest level of fusion was L5 in 58, the sacrum in 92, and the ilia in 58 individuals. A subanalysis on 58 matched pairs operated to L5 or the pelvis (sacrum = 42, ilia = 16) with similar pelvic obliquity (± 5°) was performed. Results The median (interquartile range) follow-up for the last radiograph was 1.7 (1.7) years and for reoperations 6.0 (5.9) years. Preoperatively, median Cobb angle of the major curve was 65° (23°) in the L5 group, 68° (28°) in the sacrum group, and 78° (25°) in the ilia group (p = 0.006). Preoperative median pelvic obliquity according to Maloney was 16° (19°), 21° (13°), and 27° (28°), respectively (p = 0.004). Immediate postoperative Cobb angles were 28° (18°), 28° (16°), and 32° (25°), respectively (p = 0.11). Immediate postoperative pelvic obliquity was 7° (10°), 7° (8°), and 8° (10°), respectively (p = 0.28). The median change in pelvic obliquity from the first to the last postoperative radiograph was − 5° (7°), − 3° (6°), − 3° (6°), respectively (p = 0.55). 7 (12%), 11 (12%), and 7 (12%) patients required at least one reoperation (p = 1.0), respectively. In the matched analysis, no significant differences in the radiological outcomes were found (all p ≥ 0.38). Conclusions Maintained curve and pelvic obliquity correction with no significant difference in complication and reoperation rates were found irrespective of distal fusion level.

Background: The available care for people with psychosis in South Africa is inadequate to support personal recovery. Group peer support interventions are a promising approach to foster recovery, but little is known about the preferences of service users, or the practical application of this care model, in low- and middle-income countries (LMIC). This study aims to assess the acceptability and feasibility of integrating peer-led recovery groups for people with psychosis and their caregivers in South Africa into existing systems of care, and to determine key parameters in preparation for a definitive trial. Methods: The study is set in Nelson Mandela Bay Metropolitan district of the Eastern Cape Province, South Africa. The design is an individually randomised parallel group feasibility trial comparing recovery groups in addition to treatment as usual (TAU) with TAU alone in a 1:1 allocation ratio. We aim to recruit 100 isiXhosa-speaking people with psychosis and 100 linked caregivers. TAU comprises anti-psychotic medication-focused outpatient care. The intervention arm will comprise seven recovery groups, including service users and caregiver participants. Recovery groups will be delivered in two phases: a 2-month phase facilitated by an auxiliary social worker, then a 3-month peer-led phase. We will use mixed methods to evaluate the process and outcomes of the study. Intervention acceptability and feasibility (primary outcomes) will be assessed at 5 months post-intervention start using qualitative data collected from service users, caregivers, and auxiliary social workers, along with quantitative process indicators. Facilitator competence will be assessed with the GroupACT observational rating tool. Trial procedures will be assessed, including recruitment and retention rates, contamination, and validity of quantitative outcome measures. To explore potential effectiveness, quantitative outcome data (functioning, unmet needs, personal recovery, internalised stigma, hea

Among first order optimization methods, Polyak's heavy ball method has long been known to guarantee the asymptotic rate of convergence matching Nesterov's lower bound for functions defined in an infinite-dimensional space. In this paper, we use results on the robust gain margin of linear uncertain feedback control systems to show that the heavy ball method is provably worst-case asymptotically optimal when applied to quadratic functions in a finite dimensional space., Comment: Accepted for publication in Automatica

ObjectiveTo analyze the clinicopathological features and outcomes in patients with endometrial cancer with isolated lymphatic recurrence after lymphadenectomy, stratified by different isolated lymphatic recurrence sites and treatment approaches. MethodsWe retrospectively reviewed all surgically treated patients with endometrial cancer, identifying those with recurrence. We defined primary isolated lymphatic recurrence as the first and unique evidence of recurrence in lymph node-bearing areas, without concomitant vaginal, hematogenous, or peritoneal recurrence. Isolated lymphatic recurrences were classified as pelvic, para-aortic, distant, or multiple sites. Our primary outcome was cause-specific survival after diagnosis of the recurrence. ResultsAmong 4216 patients with surgically staged endometrial cancer, we identified 66 (1.6%) women with isolated lymphatic recurrence. The overall median cause-specific survival for patients with isolated lymphatic recurrence was 24 months. Although cause-specific survival was not significantly different between the four isolated lymphatic recurrence groups (p=0.21), 7 of 15 (47%) patients with isolated lymphatic recurrence in the para-aortic area were long-term survivors. At multivariate Cox regression, the absence of lymphovascular space invasion and grade 1 histology in the primary tumor were significantly associated with improved cause-specific survival. In addition, patients with isolated lymphatic recurrence who underwent surgery for recurrence (with/without other associated therapies) had improved cause-specific survival compared with patients who did not undergo surgery, also after adjusting for age. ConclusionsLow-grade histology and absence of lymphovascular space invasion in the primary tumor were predictors of improved prognosis in patients with endometrial cancer with isolated lymphatic recurrence. In addition, in this retrospective cohort, patients with isolated lymphatic recurrence who were selected for eradicative

To achieve universal health coverage, health system strengthening (HSS) is required to support the of delivery of high-quality care. The aim of the National Institute for Health Research Global Research Unit on HeAlth System StrEngThening in Sub-Saharan Africa (ASSET) is to address this need in a four-year programme, with three healthcare platforms involving eight work-packages. Key to effective health system strengthening (HSS) is the pre-implementation phase of research where efforts focus on applying participatory methods to embed the research programme within the existing health system. To conceptualise the approach, we provide an overview of the key methods applied across work-package to address this important phase of research conducted between 2017 and 2021.Work-packages are being undertaken in publicly funded health systems in rural and urban areas in Ethiopia, Sierra Leone, South Africa, and Zimbabwe. Stakeholders including patients and their caregivers, community representatives, clinicians, managers, administrators, and policymakers are the main research participants.In each work-package, initial activities engage stakeholders and build relationships to ensure co-production and ownership of HSSIs. A mixed-methods approach is then applied to understand and address determinants of high-quality care delivery. Methods such as situation analysis, cross-sectional surveys, interviews and focus group discussions are adopted to each work-package aim and context. At the end of the pre-implementation phase, findings are disseminated using focus group discussions and participatory Theory of Change workshops where stakeholders from each work package use findings to select HSSIs and develop a programme theory.ASSET places a strong emphasis of the pre-implementation phase in order to provide an in-depth and systematic diagnosis of the existing heath system functioning, needs for strengthening and stakeholder engagement. This common approach will inform the design and ev

To achieve universal health coverage, health system strengthening (HSS) is required to support the of delivery of high-quality care. The aim of the National Institute for Health Research Global Research Unit on HeAlth System StrEngThening in Sub-Saharan Africa (ASSET) is to address this need in a four-year programme, with three healthcare platforms involving eight work-packages. Key to effective health system strengthening (HSS) is the pre-implementation phase of research where efforts focus on applying participatory methods to embed the research programme within the existing health system. To conceptualise the approach, we provide an overview of the key methods applied across work-package to address this important phase of research conducted between 2017 and 2021.Work-packages are being undertaken in publicly funded health systems in rural and urban areas in Ethiopia, Sierra Leone, South Africa, and Zimbabwe. Stakeholders including patients and their caregivers, community representatives, clinicians, managers, administrators, and policymakers are the main research participants.In each work-package, initial activities engage stakeholders and build relationships to ensure co-production and ownership of HSSIs. A mixed-methods approach is then applied to understand and address determinants of high-quality care delivery. Methods such as situation analysis, cross-sectional surveys, interviews and focus group discussions are adopted to each work-package aim and context. At the end of the pre-implementation phase, findings are disseminated using focus group discussions and participatory Theory of Change workshops where stakeholders from each work package use findings to select HSSIs and develop a programme theory.ASSET places a strong emphasis of the pre-implementation phase in order to provide an in-depth and systematic diagnosis of the existing heath system functioning, needs for strengthening and stakeholder engagement. This common approach will inform the design and ev

Background: To prevent transmission of, and infection with, meticillin-resistant Staphylococcus aureus (MRSA), eradication treatment of colonized individuals is recommended. Throat colonization is a well-known risk factor for eradication failure. Staphylococcus aureus throat colonization is associated with colonization of the rhinopharynx, but in the currently recommended Danish MRSA eradication strategies, rhinopharynx colonization is not directly targeted. Rhinopharynx colonization could therefore be an important risk factor for prolonged MRSA throat carriage. Aim: To determine whether irrigation and wash of the rhinopharynx and mouth with dissolved mupirocin is a feasible and potentially efficacious supplementary strategy against treatment-resistant MRSA throat carriage. Methods: The patient study was an open, non-blinded, trial including 20 treatment-resistant MRSA throat carriers. In the study, the patients received a supplementary treatment besides the standard treatment according to the Danish MRSA eradication strategy. The supplementary treatment consisted of rhinopharyngeal irrigation and mouth-gurgling twice a day for 14 days with a mupirocin ointment (22 g 2% ointment per litre of isotonic sterile saline solution) in a 37°C solution. Findings: Eighteen patients (90%) complied with the treatment protocol and none ex-perienced any major adverse events. Out of the 18 patients who finished the study per protocol, 15 (83%) and seven (39%) patients had negative MRSA sampling results one and six months after end of treatment, respectively. Conclusion: This study demonstrates the feasibility and clinical potential of also targeting the rhinopharynx and oropharynx in non-systemic throat MRSA eradication strategies.

BACKGROUND: The diagnostic assessment of abdominal symptoms in primary care presents a challenge. Evidence is needed about the positive predictive values (PPVs) of abdominal symptoms for different cancers and inflammatory bowel disease (IBD). METHODS AND FINDINGS: Using data from The Health Improvement Network (THIN) in the United Kingdom (2000-2017), we estimated the PPVs for diagnosis of (i) cancer (overall and for different cancer sites); (ii) IBD; and (iii) either cancer or IBD in the year post-consultation with each of 6 abdominal symptoms: dysphagia (n = 86,193 patients), abdominal bloating/distension (n = 100,856), change in bowel habit (n = 106,715), rectal bleeding (n = 235,094), dyspepsia (n = 517,326), and abdominal pain (n = 890,490). The median age ranged from 54 (abdominal pain) to 63 years (dysphagia and change in bowel habit); the ratio of women/men ranged from 50%:50% (rectal bleeding) to 73%:27% (abdominal bloating/distension). Across all studied symptoms, the risk of diagnosis of cancer and the risk of diagnosis of IBD were of similar magnitude, particularly in women, and younger men. Estimated PPVs were greatest for change in bowel habit in men (4.64% cancer and 2.82% IBD) and for rectal bleeding in women (2.39% cancer and 2.57% IBD) and lowest for dyspepsia (for cancer: 1.41% men and 1.03% women; for IBD: 0.89% men and 1.00% women). Considering PPVs for specific cancers, change in bowel habit and rectal bleeding had the highest PPVs for colon and rectal cancer; dysphagia for esophageal cancer; and abdominal bloating/distension (in women) for ovarian cancer. The highest PPVs of abdominal pain (either sex) and abdominal bloating/distension (men only) were for non-abdominal cancer sites. For the composite outcome of diagnosis of either cancer or IBD, PPVs of rectal bleeding exceeded the National Institute of Health and Care Excellence (NICE)-recommended specialist referral threshold of 3% in all age-sex strata, as did PPVs of abdominal pain, change

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

Background: Many people with refugee backgrounds suffer from trauma-related complex social and psychological problems, and compliance with standard psychological treatment tends to be low. More culturally adaptable treatment options seem to be needed. Objective: We aimed to investigate whether the music therapy method: ‘trauma-focused music and imagery’ (tr-MI), characterized by a particular focus on arousal and affect regulation, would be equally effective as the standard psychological talk therapies for ameliorating trauma symptoms in Danish refugees. Methods: A pragmatic, noninferiority, parallel, randomized controlled trial with six-month follow-up was carried out at three clinics for refugees in the public mental health services of the Psychiatry (DK). Seventy-four adults diagnosed with posttraumatic stress disorder (PTSD) were allocated to either music therapy sessions (tr-MI, N = 39) or psychological treatment as usual (TAU, N = 35). Western classical music, new age music, and music from the participants’ own national culture were used to generate inner imagery, following a phased treatment protocol. Homework entailed listening to music. The primary outcome was the measurement of trauma symptoms by the Harvard Trauma Questionnaire, section IV (HTQ-IV); secondary measures were somatoform and psychoform dissociation (DSS-20), SDQ-20), attachment (RAAS), and well-being (WHO-5). Treatment effects reflected by primary and secondary measures were estimated using linear mixed models. Results: Tr-MI was noninferior to TAU (mean difference at follow-up HTQ-IV: 0.14, CI (−0.10; 0.38), with a − 0.3 noninferiority margin). A high dropout rate of 40% occurred in the TAU group, compared to 5% in the music therapy group. Secondary measures generated small to medium effect sizes in both groups, with significant medium effect sizes for well-being and psychoform dissociation at follow-up in tr-MI. Conclusions: Tr-MI is an innovative form of psychological treatment in refuge

Background: Many people with refugee backgrounds suffer from trauma-related complex social and psychological problems, and compliance with standard psychological treatment tends to be low. More culturally adaptable treatment options seem to be needed. Objective: We aimed to investigate whether the music therapy method: ‘trauma-focused music and imagery’ (tr-MI), characterized by a particular focus on arousal and affect regulation, would be equally effective as the standard psychological talk therapies for ameliorating trauma symptoms in Danish refugees. Methods: A pragmatic, noninferiority, parallel, randomized controlled trial with six-month follow-up was carried out at three clinics for refugees in the public mental health services of the Psychiatry (DK). Seventy-four adults diagnosed with posttraumatic stress disorder (PTSD) were allocated to either music therapy sessions (tr-MI, N = 39) or psychological treatment as usual (TAU, N = 35). Western classical music, new age music, and music from the participants’ own national culture were used to generate inner imagery, following a phased treatment protocol. Homework entailed listening to music. The primary outcome was the measurement of trauma symptoms by the Harvard Trauma Questionnaire, section IV (HTQ-IV); secondary measures were somatoform and psychoform dissociation (DSS-20), SDQ-20), attachment (RAAS), and well-being (WHO-5). Treatment effects reflected by primary and secondary measures were estimated using linear mixed models. Results: Tr-MI was noninferior to TAU (mean difference at follow-up HTQ-IV: 0.14, CI (−0.10; 0.38), with a − 0.3 noninferiority margin). A high dropout rate of 40% occurred in the TAU group, compared to 5% in the music therapy group. Secondary measures generated small to medium effect sizes in both groups, with significant medium effect sizes for well-being and psychoform dissociation at follow-up in tr-MI. Conclusions: Tr-MI is an innovative form of psychological treatment in refuge

Robustness in the face of uncertainties is an important aspect in designing high performance control systems. This paper addresses the problem of accurate trajectory tracking of a small quadcopter unmanned aerial vehicle in the face of uncertainties. Accommodating the worst-case scenario, we propose a hybrid feedback and feedforward autopilot that has the capability to eliminate the cross-coupling disturbance between the lateral and the longitudinal loops with respect to the vertical loop as well as external disturbances (e.g., wind gusts). The proposed control system leverages on the technical benefits of both the nonlinear model predictive control and the fuzzy feedforward compensator. We highlight the efficacy of our hybrid autopilot system with respect to the performance of the conventional PD control systems through rigorous comparative studies. We also present stability analysis of our hybrid control system.

OBJECTIVES: Depression symptom questionnaires are not for diagnostic classification. Patient Health Questionnaire-9 (PHQ-9) scores ≥10 are nonetheless often used to estimate depression prevalence. We compared PHQ-9 ≥10 prevalence to Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID) major depression prevalence and assessed whether an alternative PHQ-9 cutoff could more accurately estimate prevalence. STUDY DESIGN AND SETTING: Individual participant data meta-analysis of datasets comparing PHQ-9 scores to SCID major depression status. RESULTS: A total of 9,242 participants (1,389 SCID major depression cases) from 44 primary studies were included. Pooled PHQ-9 ≥10 prevalence was 24.6% (95% confidence interval [CI]: 20.8%, 28.9%); pooled SCID major depression prevalence was 12.1% (95% CI: 9.6%, 15.2%); and pooled difference was 11.9% (95% CI: 9.3%, 14.6%). The mean study-level PHQ-9 ≥10 to SCID-based prevalence ratio was 2.5 times. PHQ-9 ≥14 and the PHQ-9 diagnostic algorithm provided prevalence closest to SCID major depression prevalence, but study-level prevalence differed from SCID-based prevalence by an average absolute difference of 4.8% for PHQ-9 ≥14 (95% prediction interval: -13.6%, 14.5%) and 5.6% for the PHQ-9 diagnostic algorithm (95% prediction interval: -16.4%, 15.0%). CONCLUSION: PHQ-9 ≥10 substantially overestimates depression prevalence. There is too much heterogeneity to correct statistically in individual studies.

OBJECTIVES:Depression symptom questionnaires are not for diagnostic classification. Patient Health Questionnaire-9 (PHQ-9) scores ≥10 are nonetheless often used to estimate depression prevalence. We compared PHQ-9 ≥10 prevalence to Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID) major depression prevalence and assessed whether an alternative PHQ-9 cutoff could more accurately estimate prevalence. STUDY DESIGN AND SETTING:Individual participant data meta-analysis of datasets comparing PHQ-9 scores to SCID major depression status. RESULTS:A total of 9,242 participants (1,389 SCID major depression cases) from 44 primary studies were included. Pooled PHQ-9 ≥10 prevalence was 24.6% (95% confidence interval [CI]: 20.8%, 28.9%); pooled SCID major depression prevalence was 12.1% (95% CI: 9.6%, 15.2%); and pooled difference was 11.9% (95% CI: 9.3%, 14.6%). The mean study-level PHQ-9 ≥10 to SCID-based prevalence ratio was 2.5 times. PHQ-9 ≥14 and the PHQ-9 diagnostic algorithm provided prevalence closest to SCID major depression prevalence, but study-level prevalence differed from SCID-based prevalence by an average absolute difference of 4.8% for PHQ-9 ≥14 (95% prediction interval: -13.6%, 14.5%) and 5.6% for the PHQ-9 diagnostic algorithm (95% prediction interval: -16.4%, 15.0%). CONCLUSION:PHQ-9 ≥10 substantially overestimates depression prevalence. There is too much heterogeneity to correct statistically in individual studies.

Importance:The Patient Health Questionnaire depression module (PHQ-9) is a 9-item self-administered instrument used for detecting depression and assessing severity of depression. The Patient Health Questionnaire-2 (PHQ-2) consists of the first 2 items of the PHQ-9 (which assess the frequency of depressed mood and anhedonia) and can be used as a first step to identify patients for evaluation with the full PHQ-9. Objective:To estimate PHQ-2 accuracy alone and combined with the PHQ-9 for detecting major depression. Data Sources:MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-May 2018). Study Selection:Eligible data sets compared PHQ-2 scores with major depression diagnoses from a validated diagnostic interview. Data Extraction and Synthesis:Individual participant data were synthesized with bivariate random-effects meta-analysis to estimate pooled sensitivity and specificity of the PHQ-2 alone among studies using semistructured, fully structured, or Mini International Neuropsychiatric Interview (MINI) diagnostic interviews separately and in combination with the PHQ-9 vs the PHQ-9 alone for studies that used semistructured interviews. The PHQ-2 score ranges from 0 to 6, and the PHQ-9 score ranges from 0 to 27. Results:Individual participant data were obtained from 100 of 136 eligible studies (44 318 participants; 4572 with major depression [10%]; mean [SD] age, 49 [17] years; 59% female). Among studies that used semistructured interviews, PHQ-2 sensitivity and specificity (95% CI) were 0.91 (0.88-0.94) and 0.67 (0.64-0.71) for cutoff scores of 2 or greater and 0.72 (0.67-0.77) and 0.85 (0.83-0.87) for cutoff scores of 3 or greater. Sensitivity was significantly greater for semistructured vs fully structured interviews. Specificity was not significantly different across the types of interviews. The area under the receiver operating characteristic curve was 0.88 (0.86-0.89) for semistructured interviews, 0.82 (0.81-0.84

Importance:The Patient Health Questionnaire depression module (PHQ-9) is a 9-item self-administered instrument used for detecting depression and assessing severity of depression. The Patient Health Questionnaire-2 (PHQ-2) consists of the first 2 items of the PHQ-9 (which assess the frequency of depressed mood and anhedonia) and can be used as a first step to identify patients for evaluation with the full PHQ-9. Objective:To estimate PHQ-2 accuracy alone and combined with the PHQ-9 for detecting major depression. Data Sources:MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO, and Web of Science (January 2000-May 2018). Study Selection:Eligible data sets compared PHQ-2 scores with major depression diagnoses from a validated diagnostic interview. Data Extraction and Synthesis:Individual participant data were synthesized with bivariate random-effects meta-analysis to estimate pooled sensitivity and specificity of the PHQ-2 alone among studies using semistructured, fully structured, or Mini International Neuropsychiatric Interview (MINI) diagnostic interviews separately and in combination with the PHQ-9 vs the PHQ-9 alone for studies that used semistructured interviews. The PHQ-2 score ranges from 0 to 6, and the PHQ-9 score ranges from 0 to 27. Results:Individual participant data were obtained from 100 of 136 eligible studies (44 318 participants; 4572 with major depression [10%]; mean [SD] age, 49 [17] years; 59% female). Among studies that used semistructured interviews, PHQ-2 sensitivity and specificity (95% CI) were 0.91 (0.88-0.94) and 0.67 (0.64-0.71) for cutoff scores of 2 or greater and 0.72 (0.67-0.77) and 0.85 (0.83-0.87) for cutoff scores of 3 or greater. Sensitivity was significantly greater for semistructured vs fully structured interviews. Specificity was not significantly different across the types of interviews. The area under the receiver operating characteristic curve was 0.88 (0.86-0.89) for semistructured interviews, 0.82 (0.81-0.84

OBJECTIVES:Depression symptom questionnaires are not for diagnostic classification. Patient Health Questionnaire-9 (PHQ-9) scores ≥10 are nonetheless often used to estimate depression prevalence. We compared PHQ-9 ≥10 prevalence to Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID) major depression prevalence and assessed whether an alternative PHQ-9 cutoff could more accurately estimate prevalence. STUDY DESIGN AND SETTING:Individual participant data meta-analysis of datasets comparing PHQ-9 scores to SCID major depression status. RESULTS:A total of 9,242 participants (1,389 SCID major depression cases) from 44 primary studies were included. Pooled PHQ-9 ≥10 prevalence was 24.6% (95% confidence interval [CI]: 20.8%, 28.9%); pooled SCID major depression prevalence was 12.1% (95% CI: 9.6%, 15.2%); and pooled difference was 11.9% (95% CI: 9.3%, 14.6%). The mean study-level PHQ-9 ≥10 to SCID-based prevalence ratio was 2.5 times. PHQ-9 ≥14 and the PHQ-9 diagnostic algorithm provided prevalence closest to SCID major depression prevalence, but study-level prevalence differed from SCID-based prevalence by an average absolute difference of 4.8% for PHQ-9 ≥14 (95% prediction interval: -13.6%, 14.5%) and 5.6% for the PHQ-9 diagnostic algorithm (95% prediction interval: -16.4%, 15.0%). CONCLUSION:PHQ-9 ≥10 substantially overestimates depression prevalence. There is too much heterogeneity to correct statistically in individual studies.

Contains fulltext : 203163.pdf (publisher's version ) (Open Access), Background: Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are lesions of the skin with overlapping histologic features and unspecific molecular traits. PDS behaves aggressive compared to AFX. Thus, a precise delineation, although challenging in some instances, is relevant. Methods: We examined the value of DNA-methylation profiling and copy number analysis for separating these tumors. DNA-methylation data were generated from 17 AFX and 15 PDS using the Illumina EPIC array. These were compared with DNA-methylation data generated from 196 tumors encompassing potential histologic mimics like cutaneous squamous carcinomas (cSCC; n = 19), basal cell carcinomas (n = 10), melanoma metastases originating from the skin (n = 11), leiomyosarcomas (n = 11), angiosarcomas of the skin and soft tissue (n = 11), malignant peripheral nerve sheath tumors (n = 19), dermatofibrosarcomas protuberans (n = 13), extraskeletal myxoid chondrosarcomas (n = 9), myxoid liposarcomas (n = 14), schwannomas (n = 10), neurofibromas (n = 21), alveolar (n = 19) and embryonal (n = 17) rhabdomyosarcomas as well as undifferentiated pleomorphic sarcomas (n = 12). Results: DNA-methylation profiling did not separate AFX from PDS. The DNA-methylation profiles of the other cases, however, were distinct from AFX/PDS. They reliably assigned to subtype-specific DNA-methylation clusters, although overlap occurred between some AFX/PDS and cSCC. Copy number profiling revealed alterations in a similar frequency and distribution between AFX and PDS. They involved losses of 9p (22/32) and 13q (25/32). Gains frequently involved 8q (8/32). Notably, a homozygous deletion of CDKN2A was more frequent in PDS (6/15) than in AFX (2/17), whereas amplifications were non-recurrent and overall rare (5/32). Conclusions: Our findings support the concept that AFX and PDS belong to a common tumor spectrum. We could demonstrate the diagnostic value of DNA-methylation profiling to delineating AFX/PDS from potentia

Contains fulltext : 208464.pdf (publisher's version ) (Open Access), Based on histological findings, calcifying fibrous tumor (CFT) may be a late (burned out) stage of inflammatory myofibroblastic tumor (IMT). This concept, however, has not been proven by molecular means. Five CFTs were analyzed for IMT-related rearrangements in ALK, ROS1 and RET using fluorescence in situ hybridization (FISH). Additionally, genome-wide methylation patterns were investigated and compared with IMT (n=7), leiomyoma (n=7), angioleiomyoma (n=9), myopericytoma (n=7) and reactive soft tissue lesions (n=10) using unsupervised hierarchical cluster analysis and t distributed stochastic neighbor embedding. CFT patients, 4 females and 1 male, had a median age of 20years ranging from 7 to 43years. Two patients were younger than 18years old. The tumors originated in the abdomen (n=4) and axilla (n=1). Histologically, all lesions were (multi) nodular and hypocellular consisting of bland looking (myo)fibroblasts embedded in a collagenous matrix with calcifications. FISH analysis brought up negative results for ALK, RET and ROS1 rearrangements. However, genome-wide methylation analysis revealed overlapping methylation patterns of CFT and IMT forming a distinct homogeneous methylation cluster with exception of one case clustering with myopericytoma/angioleiomyoma. In conclusion, DNA methylation profiling supports the concept that CFT and IMT represent both ends of a spectrum of one entity with CFT being the burn out stage of IMT.

Contains fulltext : 203163.pdf (publisher's version ) (Open Access), Background: Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are lesions of the skin with overlapping histologic features and unspecific molecular traits. PDS behaves aggressive compared to AFX. Thus, a precise delineation, although challenging in some instances, is relevant. Methods: We examined the value of DNA-methylation profiling and copy number analysis for separating these tumors. DNA-methylation data were generated from 17 AFX and 15 PDS using the Illumina EPIC array. These were compared with DNA-methylation data generated from 196 tumors encompassing potential histologic mimics like cutaneous squamous carcinomas (cSCC; n = 19), basal cell carcinomas (n = 10), melanoma metastases originating from the skin (n = 11), leiomyosarcomas (n = 11), angiosarcomas of the skin and soft tissue (n = 11), malignant peripheral nerve sheath tumors (n = 19), dermatofibrosarcomas protuberans (n = 13), extraskeletal myxoid chondrosarcomas (n = 9), myxoid liposarcomas (n = 14), schwannomas (n = 10), neurofibromas (n = 21), alveolar (n = 19) and embryonal (n = 17) rhabdomyosarcomas as well as undifferentiated pleomorphic sarcomas (n = 12). Results: DNA-methylation profiling did not separate AFX from PDS. The DNA-methylation profiles of the other cases, however, were distinct from AFX/PDS. They reliably assigned to subtype-specific DNA-methylation clusters, although overlap occurred between some AFX/PDS and cSCC. Copy number profiling revealed alterations in a similar frequency and distribution between AFX and PDS. They involved losses of 9p (22/32) and 13q (25/32). Gains frequently involved 8q (8/32). Notably, a homozygous deletion of CDKN2A was more frequent in PDS (6/15) than in AFX (2/17), whereas amplifications were non-recurrent and overall rare (5/32). Conclusions: Our findings support the concept that AFX and PDS belong to a common tumor spectrum. We could demonstrate the diagnostic value of DNA-methylation profiling to delineating AFX/PDS from potentia

Contains fulltext : 208464.pdf (publisher's version ) (Open Access), Based on histological findings, calcifying fibrous tumor (CFT) may be a late (burned out) stage of inflammatory myofibroblastic tumor (IMT). This concept, however, has not been proven by molecular means. Five CFTs were analyzed for IMT-related rearrangements in ALK, ROS1 and RET using fluorescence in situ hybridization (FISH). Additionally, genome-wide methylation patterns were investigated and compared with IMT (n=7), leiomyoma (n=7), angioleiomyoma (n=9), myopericytoma (n=7) and reactive soft tissue lesions (n=10) using unsupervised hierarchical cluster analysis and t distributed stochastic neighbor embedding. CFT patients, 4 females and 1 male, had a median age of 20years ranging from 7 to 43years. Two patients were younger than 18years old. The tumors originated in the abdomen (n=4) and axilla (n=1). Histologically, all lesions were (multi) nodular and hypocellular consisting of bland looking (myo)fibroblasts embedded in a collagenous matrix with calcifications. FISH analysis brought up negative results for ALK, RET and ROS1 rearrangements. However, genome-wide methylation analysis revealed overlapping methylation patterns of CFT and IMT forming a distinct homogeneous methylation cluster with exception of one case clustering with myopericytoma/angioleiomyoma. In conclusion, DNA methylation profiling supports the concept that CFT and IMT represent both ends of a spectrum of one entity with CFT being the burn out stage of IMT.

Contains fulltext : 208464.pdf (publisher's version ) (Open Access), Based on histological findings, calcifying fibrous tumor (CFT) may be a late (burned out) stage of inflammatory myofibroblastic tumor (IMT). This concept, however, has not been proven by molecular means. Five CFTs were analyzed for IMT-related rearrangements in ALK, ROS1 and RET using fluorescence in situ hybridization (FISH). Additionally, genome-wide methylation patterns were investigated and compared with IMT (n=7), leiomyoma (n=7), angioleiomyoma (n=9), myopericytoma (n=7) and reactive soft tissue lesions (n=10) using unsupervised hierarchical cluster analysis and t distributed stochastic neighbor embedding. CFT patients, 4 females and 1 male, had a median age of 20years ranging from 7 to 43years. Two patients were younger than 18years old. The tumors originated in the abdomen (n=4) and axilla (n=1). Histologically, all lesions were (multi) nodular and hypocellular consisting of bland looking (myo)fibroblasts embedded in a collagenous matrix with calcifications. FISH analysis brought up negative results for ALK, RET and ROS1 rearrangements. However, genome-wide methylation analysis revealed overlapping methylation patterns of CFT and IMT forming a distinct homogeneous methylation cluster with exception of one case clustering with myopericytoma/angioleiomyoma. In conclusion, DNA methylation profiling supports the concept that CFT and IMT represent both ends of a spectrum of one entity with CFT being the burn out stage of IMT.

Contains fulltext : 203163.pdf (publisher's version ) (Open Access), Background: Atypical fibroxanthomas (AFX) and pleomorphic dermal sarcomas (PDS) are lesions of the skin with overlapping histologic features and unspecific molecular traits. PDS behaves aggressive compared to AFX. Thus, a precise delineation, although challenging in some instances, is relevant. Methods: We examined the value of DNA-methylation profiling and copy number analysis for separating these tumors. DNA-methylation data were generated from 17 AFX and 15 PDS using the Illumina EPIC array. These were compared with DNA-methylation data generated from 196 tumors encompassing potential histologic mimics like cutaneous squamous carcinomas (cSCC; n = 19), basal cell carcinomas (n = 10), melanoma metastases originating from the skin (n = 11), leiomyosarcomas (n = 11), angiosarcomas of the skin and soft tissue (n = 11), malignant peripheral nerve sheath tumors (n = 19), dermatofibrosarcomas protuberans (n = 13), extraskeletal myxoid chondrosarcomas (n = 9), myxoid liposarcomas (n = 14), schwannomas (n = 10), neurofibromas (n = 21), alveolar (n = 19) and embryonal (n = 17) rhabdomyosarcomas as well as undifferentiated pleomorphic sarcomas (n = 12). Results: DNA-methylation profiling did not separate AFX from PDS. The DNA-methylation profiles of the other cases, however, were distinct from AFX/PDS. They reliably assigned to subtype-specific DNA-methylation clusters, although overlap occurred between some AFX/PDS and cSCC. Copy number profiling revealed alterations in a similar frequency and distribution between AFX and PDS. They involved losses of 9p (22/32) and 13q (25/32). Gains frequently involved 8q (8/32). Notably, a homozygous deletion of CDKN2A was more frequent in PDS (6/15) than in AFX (2/17), whereas amplifications were non-recurrent and overall rare (5/32). Conclusions: Our findings support the concept that AFX and PDS belong to a common tumor spectrum. We could demonstrate the diagnostic value of DNA-methylation profiling to delineating AFX/PDS from potentia

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1high/DLL3high/NOTCHlow, type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1low/DLL3low/NOTCHhigh, and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

Ocean acidification (OA), the dissolution of excess anthropogenic carbon dioxide in ocean waters, is a potential stressor to many marine fish species. Whether species have the potential to acclimate and adapt to changes in the seawater carbonate chemistry is still largely unanswered. Simulation experiments across several generations are challenging for large commercially exploited species because of their long generation times. For Atlantic cod (Gadus morhua), we present first data on the effects of parental acclimation to elevated aquatic CO2 on larval survival, a fundamental parameter determining population recruitment. The parental generation in this study was exposed to either ambient or elevated aquatic CO2 levels simulating end-of-century OA levels (~1100 µatm CO2) for six weeks prior to spawning. Upon fully reciprocal exposure of the F1 generation, we quantified larval survival, combined with two larval feeding regimes in order to investigate the potential effect of energy limitation. We found a significant reduction in larval survival at elevated CO2 that was partly compensated by parental acclimation to the same CO2 exposure. Such compensation was only observed in the treatment with high food availability. This complex 3-way interaction indicates that surplus metabolic resources need to be available to allow a transgenerational alleviation response to ocean acidification.

[EN] Diploid and triploid Atlantic salmon, Salmo salarwere fed high-protein, phosphorus-rich diets (56-60% protein; ca 18g phosphorus kg(-1) diet) whilst being reared at low temperature from start-feeding until parr-smolt transformation. Performances of salmon fed diets based on fish meal (STD) or a mix of fishmeal and hydrolysed fish proteins (HFM) as the major protein sources were compared in terms of mortality, diet digestibility, growth and skeletal deformities. Separate groups of diploids and triploids were reared in triplicate tanks (initially 3000 fish per tank; tank biomass ca. 620 g) from 0-2745 degree-days post-start feeding (ddPSF). Growth metrics (weight, length, condition factor) were recorded at ca. 4 week intervals, external signs of deformities to the operculum, jaws and spinal column were examined in parr sampled at 1390 ddPSF, and external signs of deformity and vertebral anomalies (by radiography) were examined in fish sampled at the end of the trial (2745 ddPSF). The triploid salmon generally had a lower mass per unit length, i.e. lower condition factor, throughout the trial, but this did not seem to reflect any consistent dietary or ploidy effects on either dietary digestibility or the growth of the fish. By the end of the trial fish in all treatment groups had achieved a weight of 50+ g, and had completed the parr-smolt transformation. The triploids had slightly, but significantly, fewer vertebrae (Triploids STD 58.74 0.10; HFM 58.68 0.05) than the diploids (Diploids STD 58.97 0.14; HFM 58.89 0.01), and the incidence of skeletal (vertebral) abnormalities was higher in triploids (Triploids STD 31 0.90%; HFM 15 1.44%) than in diploids (Diploids STD 4 0.80%; HFM 4 0.83%). The HFM diet gave a significant reduction in the numbers of triploid salmon with vertebral anomalies in comparison with the triploids fed the STD diet possibly as a result of differences in phosphorus bioavailability between the two diets. Overall, the incidence of skeletal defor

[EN] Diploid and triploid Atlantic salmon, Salmo salarwere fed high-protein, phosphorus-rich diets (56-60% protein; ca 18g phosphorus kg(-1) diet) whilst being reared at low temperature from start-feeding until parr-smolt transformation. Performances of salmon fed diets based on fish meal (STD) or a mix of fishmeal and hydrolysed fish proteins (HFM) as the major protein sources were compared in terms of mortality, diet digestibility, growth and skeletal deformities. Separate groups of diploids and triploids were reared in triplicate tanks (initially 3000 fish per tank; tank biomass ca. 620 g) from 0-2745 degree-days post-start feeding (ddPSF). Growth metrics (weight, length, condition factor) were recorded at ca. 4 week intervals, external signs of deformities to the operculum, jaws and spinal column were examined in parr sampled at 1390 ddPSF, and external signs of deformity and vertebral anomalies (by radiography) were examined in fish sampled at the end of the trial (2745 ddPSF). The triploid salmon generally had a lower mass per unit length, i.e. lower condition factor, throughout the trial, but this did not seem to reflect any consistent dietary or ploidy effects on either dietary digestibility or the growth of the fish. By the end of the trial fish in all treatment groups had achieved a weight of 50+ g, and had completed the parr-smolt transformation. The triploids had slightly, but significantly, fewer vertebrae (Triploids STD 58.74 0.10; HFM 58.68 0.05) than the diploids (Diploids STD 58.97 0.14; HFM 58.89 0.01), and the incidence of skeletal (vertebral) abnormalities was higher in triploids (Triploids STD 31 0.90%; HFM 15 1.44%) than in diploids (Diploids STD 4 0.80%; HFM 4 0.83%). The HFM diet gave a significant reduction in the numbers of triploid salmon with vertebral anomalies in comparison with the triploids fed the STD diet possibly as a result of differences in phosphorus bioavailability between the two diets. Overall, the incidence of skeletal defor

Ocean acidification (OA), the dissolution of excess anthropogenic carbon dioxide in ocean waters, is a potential stressor to many marine fish species. Whether species have the potential to acclimate and adapt to changes in the seawater carbonate chemistry is still largely unanswered. Simulation experiments across several generations are challenging for large commercially exploited species because of their long generation times. For Atlantic cod (Gadus morhua), we present first data on the effects of parental acclimation to elevated aquatic CO2 on larval survival, a fundamental parameter determining population recruitment. The parental generation in this study was exposed to either ambient or elevated aquatic CO2 levels simulating end-of-century OA levels (~1100 µatm CO2) for six weeks prior to spawning. Upon fully reciprocal exposure of the F1 generation, we quantified larval survival, combined with two larval feeding regimes in order to investigate the potential effect of energy limitation. We found a significant reduction in larval survival at elevated CO2 that was partly compensated by parental acclimation to the same CO2 exposure. Such compensation was only observed in the treatment with high food availability. This complex 3-way interaction indicates that surplus metabolic resources need to be available to allow a transgenerational alleviation response to ocean acidification.

Ocean acidification (OA), the dissolution of excess anthropogenic carbon dioxide in ocean waters, is a potential stressor to many marine fish species. Whether species have the potential to acclimate and adapt to changes in the seawater carbonate chemistry is still largely unanswered. Simulation experiments across several generations are challenging for large commercially exploited species because of their long generation times. For Atlantic cod (Gadus morhua), we present first data on the effects of parental acclimation to elevated aquatic CO2 on larval survival, a fundamental parameter determining population recruitment. The parental generation in this study was exposed to either ambient or elevated aquatic CO2 levels simulating end-of-century OA levels (~1100 µatm CO2) for six weeks prior to spawning. Upon fully reciprocal exposure of the F1 generation, we quantified larval survival, combined with two larval feeding regimes in order to investigate the potential effect of energy limitation. We found a significant reduction in larval survival at elevated CO2 that was partly compensated by parental acclimation to the same CO2 exposure. Such compensation was only observed in the treatment with high food availability. This complex 3-way interaction indicates that surplus metabolic resources need to be available to allow a transgenerational alleviation response to ocean acidification.

Contains fulltext : 173988.pdf (publisher's version ) (Open Access), BACKGROUND: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown. METHODS: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs. RESULTS: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005). CONCLUSIONS: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.

Contains fulltext : 173988.pdf (publisher's version ) (Open Access), BACKGROUND: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown. METHODS: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs. RESULTS: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005). CONCLUSIONS: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB.

L Fardet,1–3 I Nazareth,1 I Petersen1 1Department of Primary Care and Population Health, University College London, UK; 2Department of Dermatology, Henri Mondor Hospital AP-HP, Créteil, France; 3Equipe d’Accueil 7379 EpiDermE, Université Paris Est Créteil, Créteil, France Background: Hydroxychloroquine and chloroquine may reduce the risk of cancer as they inhibit autophagy, in particular, in people with connective tissue diseases.Methods: The hazard ratios of cancers, metastases, and death were assessed in adults with connective tissue diseases prescribed hydroxychloroquine/chloroquine for at least 1 year in comparison with unexposed individuals with the same underlying conditions. A competing risk survival regression analysis was performed. Data were extracted from the Health Improvement Network UK primary care database.Results: Eight thousand nine hundred and ninety-nine individuals exposed to hydroxychloroquine (98.6%) or chloroquine (1.4%) and 24,118 unexposed individuals were included in the study (median age: 56 [45–66] years, women: 76.8%). When compared to the unexposed group, individuals exposed to hydroxychloroquine/chloroquine were not at lower risk of non-skin cancers (adjusted sub-distribution hazard ratio [sHR]: 1.04 [0.92–1.18], p=0.54), hematological malignancies (adjusted sHR: 1.00 [0.73–1.38], p=0.99), or skin cancers (adjusted sHR: 0.92 [0.78–1.07], p=0.26). The risk of metastasis was not significantly different between the two groups. However, it was significantly lower during the exposure period when compared with the unexposed (adjusted sHR: 0.64 [0.44–0.95] for the overall population and 0.61 [0.38–1.00] for those diagnosed with incident cancers). The risk of death was also significantly lower in those exposed to hydroxychloroquine/chloroquine (adjusted HR: 0.90 [0.81–1.00] in the overall population and 0.78 [0.

(18)F-Labelling of aromatic moieties was limited to electron deficient aromatic systems for many years but recent developments have provided access to the direct labelling of electron rich aromatic systems. Herein we report the synthesis and (18)F-labelling of iodonium ylide precursors in the pursuit of (18)F-labelled 5-HT2A receptor agonist PET-ligands. Subsequent evaluation in pigs showed high brain uptake of the PET ligands but a blocking dose of ketanserin did not significantly reduce the signal in relevant brain regions - indicating that the ligands do not interact specifically with the 5-HT2A receptor in vivo.

BACKGROUND: Evidence links the lectin pathway of complement activation to diabetic kidney disease. Upon carbohydrate-recognition by pattern-recognition molecules, e.g., mannan-binding lectin (MBL), the MBL-associated serine protease (MASP-2) is activated and initiates the complement cascade. The MASP2 gene encodes MASP-2 and the alternative splice product MBL-associated protein 19 (MAp19). Both MAp19 and MASP-2 circulate in complex with MBL. We tested the hypothesis that MAp19 and MASP-2 concentrations predict the risk of incident microalbuminuria.METHODS: Baseline MAp19 and MASP-2 were measured in 270 persons with newly diagnosed type 1 diabetes tracked for incidence of persistent microalbuminuria in a prospective observational 18-year-follow-up study.RESULTS: Seventy-five participants (28%) developed microalbuminuria during follow-up. MAp19 concentrations were higher in participants that later progressed to microalbuminuria as compared with those with persistent normoalbuminuria (268 ng/ml (CI 95% 243 - 293) vs 236 ng/ml (CI95% 223 - 250), P = 0.02). Participants with MAp19 concentration within the highest quartile of the cohort had an increased risk of microalbuminuria as compared with participants with MAp19 concentration within the combined lower three quartiles in unadjusted Cox analysis, hazard ratio 1.86 (CI95% 1.17 - 2.96), P = 0.009). This remained significant in adjusted models, e.g., adjusting for age, sex, HbA1c , systolic blood pressure, urinary albumin excretion, smoking, serum creatinine, and serum cholesterol. MASP-2 concentration was not associated with incidence of microalbuminuria.CONCLUSIONS: In conclusion, the results show an association between baseline MAp19 concentration and the incidence of microalbuminuria in an 18-year-follow-up study on persons with newly diagnosed type 1 diabetes.