Molecular profiling of lung adenosquamous carcinoma: hybrid or genuine type?

Lung adenosquamous carcinoma is a particular subtype of non-small cell lung carcinoma that is defined by the coexistence of adenocarcinoma and squamous cell carcinoma components. The aim of this study was to assess the mutational profile in each component of 16 adenosquamous carcinoma samples from a Caucasian population by a combination of next generation sequencing using the cancer hotspot panel as well as the colon and lung cancer panel and FISH. Identified mutations were confirmed by Sanger sequencing of DNA from cancer cells of each component collected by Laser Capture microdissection. Mutations typical for adenocarcinoma as well as squamous cell carcinoma were identified. Driver mutations were predominantly in the trunk suggesting a monoclonal origin of adenosquamous carcinoma. Most remarkably, EGFR mutations and mutations in the PI3K signaling pathway, which accounted for 30% and 25% of tumors respectively, were more prevalent while KRAS mutations were less prevalent than expected for a Caucasian population. Surprisingly, expression of classifier miR-205 was intermediate between that of classical adenocarcinoma and squamous cell carcinoma suggesting that adenosquamous carcinoma is a transitional stage between these tumor types. The high prevalence of therapy-relevant targets opens new options of therapeutic intervention for adenosquamous carcinoma patients.

Influence of noninjecting and injecting drug use on mortality, retention in the cohort, and antiretroviral therapy, in participants in the Swiss HIV Cohort Study.

OBJECTIVES We studied the influence of noninjecting and injecting drug use on mortality, dropout rate, and the course of antiretroviral therapy (ART), in the Swiss HIV Cohort Study (SHCS). METHODS Cohort participants, registered prior to April 2007 and with at least one drug use questionnaire completed until May 2013, were categorized according to their self-reported drug use behaviour. The probabilities of death and dropout were separately analysed using multivariable competing risks proportional hazards regression models with mutual correction for the other endpoint. Furthermore, we describe the influence of drug use on the course of ART. RESULTS A total of 6529 participants (including 31% women) were followed during 31 215 person-years; 5.1% participants died; 10.5% were lost to follow-up. Among persons with homosexual or heterosexual HIV transmission, noninjecting drug use was associated with higher all-cause mortality [subhazard rate (SHR) 1.73; 95% confidence interval (CI) 1.07-2.83], compared with no drug use. Also, mortality was increased among former injecting drug users (IDUs) who reported noninjecting drug use (SHR 2.34; 95% CI 1.49-3.69). Noninjecting drug use was associated with higher dropout rates. The mean proportion of time with suppressed viral replication was 82.2% in all participants, irrespective of ART status, and 91.2% in those on ART. Drug use lowered adherence, and increased rates of ART change and ART interruptions. Virological failure on ART was more frequent in participants who reported concomitant drug injections while on opiate substitution, and in current IDUs, but not among noninjecting drug users. CONCLUSIONS Noninjecting drug use and injecting drug use are modifiable risks for death, and they lower retention in a cohort and complicate ART.

Beyond deforestation monitoring in conservation hotspots: Analysing landscape mosaic dynamics in north-eastern Madagascar

Due to its extraordinary biodiversity and rapid deforestation, north-eastern Madagascar is a conservation hotspot of global importance. Reducing shifting cultivation is a high priority for policy-makers and conservationists; however, spatially explicit evidence of shifting cultivation is lacking due to the difficulty of mapping it with common remote sensing methods. To overcome this challenge, we adopted a landscape mosaic approach to assess the changes between natural forests, shifting cultivation and permanent cultivation systems at the regional level from 1995 to 2011. Our study confirmed that shifting cultivation is still being used to produce subsistence rice throughout the region, but there is a trend of intensification away from shifting cultivation towards permanent rice production, especially near protected areas. While large continuous forest exists today only in the core zones of protected areas, the agricultural matrix is still dominated by a dense cover of tree crops and smaller forest fragments. We believe that this evidence makes a crucial contribution to the development of interventions to prevent further conversion of forest to agricultural land while improving local land users' well-being.

Development of an Interleukin-1β Vaccine in Patients with Type 2 Diabetes

Interleukin-1β (IL-1β) is a key cytokine involved in inflammatory illnesses including rare hereditary diseases and common chronic inflammatory conditions as gout, rheumatoid arthritis, and type 2 diabetes mellitus, suggesting reduction of IL-1β activity as new treatment strategy. The objective of our study was to assess safety, antibody response, and preliminary efficacy of a novel vaccine against IL-1β. The vaccine hIL1bQb consisting of full-length, recombinant IL-1β coupled to virus-like particles was tested in a preclinical and clinical, randomized, placebo-controlled, double-blind study in patients with type 2 diabetes. The preclinical simian study showed prompt induction of IL-1β-specific antibodies upon vaccination, while neutralizing antibodies appeared with delay. In the clinical study with 48 type 2 diabetic patients, neutralizing IL-1β-specific antibody responses were detectable after six injections with doses of 900 µg. The development of neutralizing antibodies was associated with higher number of study drug injections, lower baseline body mass index, improvement of glycemia, and C-reactive protein (CRP). The vaccine hIL1bQb was safe and well-tolerated with no differences regarding adverse events between patients receiving hIL1bQb compared to placebo. This is the first description of a vaccine against IL-1β and represents a new treatment option for IL-1β-dependent diseases such as type 2 diabetes mellitus (ClinicalTrials.gov NCT00924105).Molecular Therapy (2016); doi:10.1038/mt.2015.227.

Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair).

BACKGROUND Preterm infants suffering from intraventricular hemorrhage (IVH) are at increased risk for neurodevelopmental impairment. Observational data suggest that recombinant human erythropoietin (rEPO) improves long-term cognitive outcome in infants with IVH. Recent studies revealed a beneficial effect of early high-dose rEPO on white matter development in preterm infants determined by magnetic resonance imaging (MRI). OBJECTIVES To summarize the current evidence and to delineate the study protocol of the EpoRepair trial (Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants). METHODS The study involves a review of the literature and the design of a double-blind, placebo-controlled, multicenter trial of repetitive high-dose rEPO administration, enrolling 120 very preterm infants with moderate-to-severe IVH diagnosed by cranial ultrasound in the first days of life, qualitative and quantitative MRI at term-equivalent age and long-term neurodevelopmental follow-up until 5 years of age. RESULTS AND CONCLUSIONS The hypothesis generated by observational data that rEPO may improve long-term cognitive outcomes of preterm infants suffering from IVH are to be confirmed or refuted by the randomized controlled trial, EpoRepair.

PP080. First trimester umbilical artery end-diastolic flow and pulsatility index: Comparison between preeclampsia and control.

INTRODUCTION The appearance of end-diastolic flow velocities (EDF) in the umbilical artery (UA), usually between 10 and 14 weeks of gestation, has been associated with the opening of the spiral arteries and consequently of the intervillous space. OBJECTIVES The aim of our study was to compare first trimester UA pulsatility index (PI) and EDF between women who developed preeclampsia (cases) and controls. METHODS Our database was searched for cases who had UA Doppler between 10-14 weeks. UA PI and EDF were compared between cases and two gestational age (GA) matched controls. RESULTS 15 cases with severe preeclampsia (PE) were matched to 30 controls. GA with negative EDF was lower than with positive EDF (12.1±0.79 vs. 12.8±0.34; p=0.001). UA PI in cases was higher than in controls, although not significant (cases: 2.18±0.6 vs. CONTROLS 1.92±0.48; p=0.12). However, comparing groups with negative EDF, the difference became significant (PI cases: 2.45±0.57 vs. PI controls: 1.94±0.56; p=0.038), while no difference was found comparing groups with positive EDF. CONCLUSION First trimester UA PI is significantly higher in women which will develop PE than in controls. Interestingly, the timing of screening for PE by UA Doppler seems to play an important issue.

The impact of a register on the management of neonatal cooling in Switzerland.

BACKGROUND Therapeutic hypothermia following hypoxic ischaemic encephalopathy in term infants was introduced into Switzerland in 2005. Initial documentation of perinatal and resuscitation details was poor and neuromonitoring insufficient. In 2011, a National Asphyxia and Cooling Register was introduced. AIMS To compare management of cooled infants before and after introduction of the register concerning documentation, neuromonitoring, cooling methods and evaluation of temperature variability between cooling methods. STUDY DESIGN Data of cooled infants before the register was in place (first time period: 2005-2010) and afterwards (second time period: 2011-2012) was collected with a case report form. RESULTS 150 infants were cooled during the first time period and 97 during the second time period. Most infants were cooled passively or passively with gel packs during both time periods (82% in 2005-2010 vs 70% in 2011-2012), however more infants were cooled actively during the second time period (18% versus 30%). Overall there was a significant reduction in temperature variability (p < 0.001) comparing the two time periods. A significantly higher proportion of temperature measurements within target temperature range (72% versus 77%, p < 0.001), fewer temperature measurements above (24% versus 7%, p < 0.001) and more temperatures below target range (4% versus 16%, p < 0.001) were recorded during the second time period. Neuromonitoring improved after introduction of the cooling register. CONCLUSION Management of infants with HIE improved since introducing the register. Temperature variability was reduced, more temperature measurements in the target range and fewer temperature measurements above target range were observed. Neuromonitoring has improved, however imaging should be performed more often.

Variation in Current Management of Term and Late-Preterm Neonates at Risk for Early-Onset Sepsis "An International Survey and Review of Guidelines"

BACKGROUND Uncertainty about the presence of infection results in unnecessary and prolonged empiric antibiotic treatment of newborns at risk for early-onset sepsis (EOS). This study evaluates the impact of this uncertainty on the diversity in management. METHODS A web-based survey with questions addressing management of infection risk-adjusted scenarios was performed in Europe, North America, and Australia. Published national guidelines (n=5) were reviewed and compared to the results of the survey. RESULTS 439 Clinicians (68% were neonatologists) from 16 countries completed the survey. In the low-risk scenario, 29% would start antibiotic therapy and 26% would not, both groups without laboratory investigations; 45% would start if laboratory markers were abnormal. In the high-risk scenario, 99% would start antibiotic therapy. In the low-risk scenario, 89% would discontinue antibiotic therapy before 72 hours. In the high-risk scenario, 35% would discontinue therapy before 72 hours, 56% would continue therapy for five to seven days, and 9% for more than 7 days. Laboratory investigations were used in 31% of scenarios for the decision to start, and in 72% for the decision to discontinue antibiotic treatment. National guidelines differ considerably regarding the decision to start in low-risk and regarding the decision to continue therapy in higher risk situations. CONCLUSIONS There is a broad diversity of clinical practice in management of EOS and a lack of agreement between current guidelines. The results of the survey reflect the diversity of national guidelines. Prospective studies regarding management of neonates at risk of EOS with safety endpoints are needed.

Anwendung einer Liste von Qualitätsmerkmale des Rollenspiels von SPs im Rahmen von OSCE

Fragestellung / Zielsetzung Rollenspiel von standardisierten Patienten (SPs) bei hochstehenden Prüfungen unterliegt hohen Qualitätsansprüchen, um die Reliabilität und Validität der Prüfung zu gewährleisten. Die Literatur über die Qualitätskontrolle bei SPs konzentriert sich vor allen Dingen auf das Feedback (1,2) oder das Ausfüllen der Checklisten (3,4). Bei Qualitätskontrollen bezüglich des Rollenspiels sind Instrumente mit Bezug auf spezifische Rollen publiziert(5). In den meisten Fakultäten beobachten die SP Trainer die von ihnen trainierten SPs während der OSCEs und bilden sich so ein Urteil über die Qualität der Performance. Die Machbarkeit / Notwendigkeit einer systematischen Qualitätskontrolle des Rollenspiels von SPs in OSCEs über diese Praxis hinaus ist unter SP Trainern umstritten. Das Ziel des hier beschriebenen Projektes ist es, die Anwendungen einer Liste von rollenunabhängigen Qualitätsmerkmalen der Spiels von SPs im Rahmen von OSCEs in der Praxis zu testen. Materialien und Methoden Im Rahmen einer Konsensbildung von Experten auf nationaler Ebene wurde eine Liste von Qualitätsmerkmalen zum Rollenspiel von SPs bei OSCEs erstellt. Diese Liste wurde seitdem systematisch zur Vorbereitung, Durchführung und zum Debriefing von OSCEs eingesetzt. Ergebnisse 1. Bei der Erarbeitung der Liste wurde klar, dass verschiedene SP Trainer unterschiedliche Vorstellungen bezüglich von Qualitätsmerkmalen des Rollenspiels beim OSCE hatten. Diese Vorstellungen konnten im Rahmen Erarbeitung der Liste vereinheitlicht werden. 2. Die Liste wird eingesetzt, um den SPs die in sie gesetzten Erwartungen bezüglich eines guten Rollenspiels beim OSCE gezielt zu vermitteln. 3. Die Liste wird zur Qualitätssicherung des Schauspiels in OSCE Prüfungen eingesetzt. Dabei zeigte sich, dass die SPs in der Qualität ihres Spiels in über 90% der Beobachtungen den in sie gesetzten Erwartungen der SP Trainer entsprechen. 4. Anhand der Liste wird den SPs ein formatives Feedbacks zu ihrer Leistung gegeben. Die SPs in unserem Programm haben uns immer wieder zurückgemeldet, dass sie diese Rückmeldungen zu ihrer Performance sehr schätzen. 5. Die Dokumentation der Performance in den vergangenen Prüfungen kann im Training zur nächsten Rolle benutzt werden, um gezielt etwaige Schwächen zu trainieren und die Performance dadurch zu verbessern. 6. In seltenen Fällen, in denen ein SP nicht mehr im Programm behalten werden kann, liefert die Dokumentation der Performance eine gute Gesprächsgrundlage zur Begründung der Differenzen bezüglich der Erwartung und der aktuellen Leistung. Diskussion In unseren Händen ist der Einsatz der Liste von Qualitätsmerkmalen zur Beurteilung der Leistung von Schauspielpatienten mit hoher Konzentration verbunden. Die gewonnene Klarheit in Bezug auf die Erwartungen und die gebrachten Leistungen bringt eine Struktur und Transparenz in unser Programm, die wir und entsprechend ihrer Rückmeldungen auch unsere SPs sehr schätzen.