Fire as an engineering tool of early modern humans.
The controlled use of fire was a breakthrough adaptation in human evolution. It first provided heat and light and later allowed the physical properties of materials to be manipulated for the production of ceramics and metals. The analysis of tools at multiple sites shows that the source stone materials were systematically manipulated with fire to improve their flaking properties. Heat treatment predominates among silcrete tools at approximately 72 thousand years ago (ka) and appears as early as 164 ka at Pinnacle Point, on the south coast of South Africa. Heat treatment demands a sophisticated knowledge of fire and an elevated cognitive ability and appears at roughly the same time as widespread evidence for symbolic behavior.


Associations of autozygosity with a broad range of human phenotypes.
In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.


Reciprocal interactions between the human thalamus and periaqueductal gray may be important for pain perception.
Pain perception can be altered by activity in the periaqueductal gray (PAG). The PAG can decrease the incoming nociceptive signals at the level of the spinal dorsal horn, but it is not clear whether the PAG can also affect the sensory thalamus, ventral posterolateral and ventral posteromedial thalamic nuclei, to modulate pain. However, the PAG and the thalamus have direct connections with each other; so we postulated that the PAG may also modulate pain by inhibiting the sensory nuclei in the thalamus, and that these may also reciprocally influence the PAG. Here, by analyzing the local field potentials recorded from the sensory thalamus and the PAG in chronic pain patients with deep brain stimulation electrodes, we show that PAG stimulation inhibited the sensory thalamus with decreasing thalamic delta, theta, alpha and beta power, and sensory thalamus stimulation excited the PAG with increasing PAG delta and theta power. We demonstrate that the PAG and the sensory thalamus interact reciprocally at short latency, which may be related to pain modulation.


Multiple measures of adiposity are associated with mean leukocyte telomere length in the northern Finland birth cohort 1966.
Studies of leukocyte telomere length (LTL) and adiposity have produced conflicting results, and the relationship between body mass index (BMI) and telomere length throughout life remains unclear. We therefore tested association of adult LTL measured in 5,598 participants with: i) childhood growth measures (BMI and age at adiposity rebound (AR)); ii) change in BMI from childhood to adulthood and iii) adult BMI, waist-to-hip ratio (WHR), body adiposity index (BAI). Childhood BMI at AR was positively associated with LTL at 31 years in women (P = 0.041). Adult BMI and WHR in both men (P = 0.025 and P = 0.049, respectively) and women (P = 0.029 and P = 0.008, respectively), and BAI in women (P = 0.021) were inversely associated with LTL at 31 years. An increase in standardised BMI between early childhood and adulthood was associated with shorter adult LTL in women (P = 0.008). We show that LTL is inversely associated with multiple measures of adiposity in both men and women. Additionally, BMI increase in women from childhood to adulthood is associated with shorter telomeres at age 31, potentially indicating accelerated biological ageing.


FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury.
The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury.


Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism.
The pedunculopontine nucleus, a component of the reticular formation, is topographically organized in animal models and implicated in locomotor control. In Parkinson's disease, pedunculopontine nucleus stimulation is an emerging treatment for gait freezing. Local field potentials recorded from pedunculopontine nucleus electrodes in such patients have demonstrated oscillations in the alpha and beta frequency bands, reactive to self-paced movement. Whether these oscillations are topographically organized or relevant to locomotion is unknown. Here, we recorded local field potentials from the pedunculopontine nucleus in parkinsonian patients during rest and unconstrained walking. Relative gait speed was assessed with trunk accelerometry. Peaks of alpha power were present at rest and during gait, when they correlated with gait speed. Gait freezing was associated with attenuation of alpha activity. Beta peaks were less consistently observed across rest and gait, and did not correlate with gait speed. Alpha power was maximal in the caudal pedunculopontine nucleus region and beta power was maximal rostrally. These results indicate a topographic distribution of neuronal activity in the pedunculopontine nucleus region and concur with animal data suggesting that the caudal subregion has particular relevance to gait. Alpha synchronization, proposed to suppress 'task irrelevant' distraction, has previously been demonstrated to correlate with performance of cognitive tasks. Here, we demonstrate a correlation between alpha oscillations and improved gait performance. The results raise the possibility that stimulation of caudal and rostral pedunculopontine nucleus regions may differ in their clinical effects.


Investigating white matter perfusion using optimal sampling strategy arterial spin labeling at 7 Tesla.
Cerebral blood flow (CBF) is an informative physiological marker for tissue health. Arterial spin labeling (ASL) is a noninvasive MRI method of measuring this parameter, but it has proven difficult to measure white matter (WM) CBF due to low intrinsic contrast-to-noise ratio compared with gray matter (GM). Here we combine ultra-high field and optimal sampling strategy (OSS) ASL to investigate WM CBF in reasonable scan times. A FAIR-based ASL sequence at 7T was combined with a real-time-feedback OSS technique, to iteratively improve post-label image acquisition times (TIs) on a tissue- and subject-specific basis to obtain WM CBF quantification. It was found 77% of WM voxels gave a reasonable CBF fit. Averaged WM CBF for these voxels was found to be 16.3 ± 1.5 mL/100 g/min (discarding partial-volumed voxels). The generated TI schedule was also significantly different when altering the OSS weighted-tissue-mask, favoring longer TIs in WM. WM CBF could be reasonably quantified in over 75% of identified voxels, from a total preparation and scan time of 15 min. OSS results suggest longer TIs should be used versus general GM ASL settings; this may become more important in WM disease studies.


The acceptability of repeat Internet-based hybrid diet assessment of previous 24-h dietary intake: administration of the Oxford WebQ in UK Biobank.
Although dietary intake over a single 24-h period may be atypical of an individual's habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ--a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53% of those invited) participants completed the online version of the Oxford WebQ at least once and 66% completed it more than once, although only 16% completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26%. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies.


Anatomical study of the thoracolumbar radiculomedullary arteries, including the Adamkiewicz artery and supporting radiculomedullary arteries.
The aim of this paper was to identify and characterize all the segmental radiculomedullary arteries (RMAs) that supply the thoracic and lumbar spinal cord. All RMAs from T4 to L5 were studied systematically in 25 cadaveric specimens. The RMA with the greatest diameter in each specimen was termed the artery of Adamkiewicz (AKA). Other supporting RMAs were also identified and characterized. A total of 27 AKAs were found in 25 specimens. Twenty-two AKAs (81%) originated from a left thoracic or a left lumbar radicular branch, and 5 (19%) arose from the right. Two specimens (8%) had two AKAs each: one specimen with two AKAs on the left side and the other specimen with one AKA on each side. Eight cadaveric specimens (32%) had 10 additional RMAs; among those, a single additional RMA was found in 6 specimens (75%), and 2 additional RMAs were found in each of the remaining 2 specimens (25%). Of those specimens with a single additional RMA, the supporting RMA was ipsilateral to the AKA in 5 specimens (83%) and contralateral in only 1 specimen (17%). The specimens containing 2 additional RMAs were all (100%) ipsilateral to their respective AKAs. The segmental RMAs supplying the thoracic and lumbar spinal cord can be unilateral, bilateral, or multiple. Multiple AKAs or additional RMAs supplying a single anterior spinal artery are common and should be considered when dealing with the spinal cord at the thoracolumbar level.


Efficient attentional selection predicts distractor devaluation: event-related potential evidence for a direct link between attention and emotion.
Links between attention and emotion were investigated by obtaining electrophysiological measures of attentional selectivity together with behavioral measures of affective evaluation. Participants were asked to rate faces that had just been presented as targets or distractors in a visual search task. Distractors were rated as less trustworthy than targets. To study the association between the efficiency of selective attention during visual search and subsequent emotional responses, the N2pc component was quantified as a function of evaluative judgments. Evaluation of distractor faces (but not target faces) covaried with selective attention. On trials where distractors were later judged negatively, the N2pc emerged earlier, demonstrating that attention was strongly biased toward target events, and distractors were effectively inhibited. When previous distractors were judged positively, the N2pc was delayed, indicating unfocused attention to the target and less distractor suppression. Variations in attentional selectivity across trials can predict subsequent emotional responses, strongly suggesting that attention is closely associated with subsequent affective evaluation.


Novel computational method for predicting polytherapy switching strategies to overcome tumor heterogeneity and evolution.
The success of targeted cancer therapy is limited by drug resistance that can result from tumor genetic heterogeneity. The current approach to address resistance typically involves initiating a new treatment after clinical/radiographic disease progression, ultimately resulting in futility in most patients. Towards a potential alternative solution, we developed a novel computational framework that uses human cancer profiling data to systematically identify dynamic, pre-emptive, and sometimes non-intuitive treatment strategies that can better control tumors in real-time. By studying lung adenocarcinoma clinical specimens and preclinical models, our computational analyses revealed that the best anti-cancer strategies addressed existing resistant subpopulations as they emerged dynamically during treatment. In some cases, the best computed treatment strategy used unconventional therapy switching while the bulk tumor was responding, a prediction we confirmed in vitro. The new framework presented here could guide the principled implementation of dynamic molecular monitoring and treatment strategies to improve cancer control.


Elliptic Cylinder Airborne Sampling and Geostatistical Mass Balance Approach for Quantifying Local Greenhouse Gas Emissions.
In this study, we explore observational, experimental, methodological, and practical aspects of the flux quantification of greenhouse gases from local point sources by using in situ airborne observations, and suggest a series of conceptual changes to improve flux estimates. We address the major sources of uncertainty reported in previous studies by modifying (1) the shape of the typical flight path, (2) the modeling of covariance and anisotropy, and (3) the type of interpolation tools used. We show that a cylindrical flight profile offers considerable advantages compared to traditional profiles collected as curtains, although this new approach brings with it the need for a more comprehensive subsequent analysis. The proposed flight pattern design does not require prior knowledge of wind direction and allows for the derivation of an ad hoc empirical correction factor to partially alleviate errors resulting from interpolation and measurement inaccuracies. The modified approach is applied to a use-case for quantifying CH4 emission from an oil field south of San Ardo, CA, and compared to a bottom-up CH4 emission estimate.


Determining the "Health Benefit Basket" of the Statutory Health Insurance scheme in Germany: methodologies and criteria.
The issue of defining health benefit catalogues has recently gained new importance in Germany as a result of the creation of the new Institute for Quality and Efficiency. The Institute was designed to support the Federal Joint Committee conducting effectiveness studies for benefit coverage decisions. The Committee and the contractual partners (sickness funds and providers) define the benefit catalogues for the Statutory Health Insurance in the framework of Social Code Book V, Germany's most relevant health care scheme. Unlike other countries, the German federal government limits its regulatory role to defining procedures that determine the scope of Statutory Health Insurance services. The explicitness of the benefit catalogues varies greatly between different sectors. While benefits in outpatient care are rather explicitly defined, benefit definitions for inpatient care are vague. It is argued that the establishment of the new Institute and the development of the DRG system are initial steps towards a more effective and explicit benefit catalogue.


Accelerating scientific publication in biology.
Scientific publications enable results and ideas to be transmitted throughout the scientific community. The number and type of journal publications also have become the primary criteria used in evaluating career advancement. Our analysis suggests that publication practices have changed considerably in the life sciences over the past 30 years. More experimental data are now required for publication, and the average time required for graduate students to publish their first paper has increased and is approaching the desirable duration of PhD training. Because publication is generally a requirement for career progression, schemes to reduce the time of graduate student and postdoctoral training may be difficult to implement without also considering new mechanisms for accelerating communication of their work. The increasing time to publication also delays potential catalytic effects that ensue when many scientists have access to new information. The time has come for life scientists, funding agencies, and publishers to discuss how to communicate new findings in a way that best serves the interests of the public and the scientific community.


YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation.
Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases.


Joint depth and color camera calibration with distortion correction.
We present an algorithm that simultaneously calibrates two color cameras, a depth camera, and the relative pose between them. The method is designed to have three key features: accurate, practical, and applicable to a wide range of sensors. The method requires only a planar surface to be imaged from various poses. The calibration does not use depth discontinuities in the depth image, which makes it flexible and robust to noise. We apply this calibration to a Kinect device and present a new depth distortion model for the depth sensor. We perform experiments that show an improved accuracy with respect to the manufacturer's calibration.


Green politics in Germany: what is Green health care policy?
For the first time ever, a Green party has governed in Germany. From September 1998 to January 2001 the German Green party, Bündnis 90/Die Grünen, held the Federal Ministry of Health. Little has been said so far about Bündnis 90/Die Grünen and its relation to health policy. This article is intended to fill that void. An analysis of the health policy program of the Greens reveals that it centers around moving the health sector toward more comprehensiveness and decentralization, strengthened patients' rights, increased use of preventive and alternative medicine, and a critique of the German cost-containment debate and policy. The current health policy program of the Greens is closest to that of the Party of Democratic Socialism, and to a lesser extent it has affinities to the program of the Social Democratic Party. The health policy program of Bündnis 90/Die Grünen is furthest from those of the Christian Democratic Union and the Free Democratic Party. The health care reforms passed in 1998 and 1999 were not a shift toward a "Green paradigm" of health care policy, because they included no fundamental changes. In addition, cost-containment is still a major political goal in German health care policy.


Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.
Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD. To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B12. Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects. Referral population to a hospital clinic between July 1988 and April 1996. Serum tHcy, folate, and vitamin B12 levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry. Serum tHcy levels were significantly higher and serum folate and vitamin B12 levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (> or = 14 micromol/L) compared with the bottom third (< or = 11 micromol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E epsilon4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B12 distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry. Low blood levels of folate and vitamin B12, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.


In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma.
CXCR4 is a G-protein-coupled receptor that mediates recruitment of blood cells toward its ligand SDF-1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [(68)Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4-positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [(68)Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [(68)Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [(18)F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34(+) flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [(68)Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4-directed therapeutic approaches in MM and other diseases.


Severe diabetic ketoacidosis complicated by hypocapnic seizure.
In clinical practice, seizures independent of hypoglycemia are observed in patients with type 1 diabetes mellitus (T1DM) more frequently than expected by chance, suggesting a link. However, seizures during management of diabetic ketoacidosis (DKA) have generally been considered a bad prognostic factor, and usually associated with well-known biochemical or neurological complications. We present the case of a 17-year-old girl with known T1DM managed for severe DKA complicated by hypocapnic seizure. We review the literature on this rare occurrence as well as outline other possible differentials to consider when faced with the alarming combination of DKA and seizure. Seizures during DKA treatment require immediate management as well as evaluation to determine their underlying cause.Their etiology is varied, but a lowered seizure threshold, electrolyte disturbances and serious neurological complications of DKA such as cerebral edema must all be considered.Sudden severe hypocapnia may represent a rare contributor to seizure during the treatment of DKA.


Effects of adrenocorticotropin on 17 alpha-hydroxylase activity and cytochrome P-450(17 alpha) synthesis in bovine adrenocortical cells.
The effects of adrenocorticotropin (ACTH) on 17 alpha-hydroxylase activity and cytochrome P-450(17 alpha) synthesis have been studied utilizing bovine adrenocortical cells in primary monolayer culture. A 20-fold stimulation of the conversion of pregnenolone to 17 alpha-hydroxypregnenolone was observed in postmitochondrial supernatant fractions from cells treated with ACTH as compared to controls. This increase in 17 alpha-hydroxylase activity was found to be due to a change in the Vmax and not a change in the Km(app). By immunoisolation of newly synthesized protein from an RNA-directed cell-free translation system we found that the level of P-450(17 alpha) was many-fold greater when RNA from ACTH-stimulated cells was used, as compared to RNA from control cells. A similar pattern was obtained when the rate of P-450(17 alpha) synthesis was analyzed by immunoisolation from radiolabeled cellular protein from ACTH-stimulated cells. When the total amount of P-450(17 alpha) was measured by immunoblotting we found that the levels of enzyme present correlated with the 17 alpha-hydroxylase activity. In addition, we found that these ACTH-mediated effects could be mimicked by treatment of cells with analogs of cyclic AMP. These results indicate that the activity of P-450(17 alpha) is regulated primarily by cyclic AMP-mediated changes in synthesis, probably at the transcriptional level, which in turn has a profound effect on the pattern of steroid secretion. Thus, we believe cytochrome P-450(17 alpha) to be a key regulatory enzyme in the steroidogenic pathway.


Developing treatments of persistent persecutory delusions: the impact of an emotional processing and metacognitive awareness intervention.
Worry has been implicated in increasing the levels of distress associated with persecutory delusions. It may partly cause this distress via the impediment of emotional processing of upsetting experiences. The clinical implication is that enhancing emotional processing of paranoid experiences will reduce distress. We therefore piloted a new brief intervention-the Emotional Processing and Metacognitive Awareness (EPMA)-on 12 patients with persistent persecutory delusions. The intervention was predominately influenced by written emotional disclosure and lasted for three sessions. The delusions were assessed at baseline, preintervention and postintervention and during a one-month follow-up. It was found that EPMA particularly reduced levels of delusion distress, and this was maintained at follow-up. The effect sizes were large but were likely overestimated given the absence of a control group and assessments that were not blind. These preliminary findings suggest that simply encouraging patients to talk, in the right way, about their delusions can be beneficial.


Childhood and adult cancers: contrasts and commonalities.
Tumours occurring in children differ considerably from those occurring at older ages but exhibit common features. Those occurring in the teenage/young adult (TYA) years represent a transitional mixture of child and adult tumours and pose a considerable challenge for optimal clinical management and service provision. Nevertheless the fundamental processes of malignant change, arising from genetic/epigenetic interaction with environmental exposures, seem to operate across all ages and the entire tumour spectrum. We focus here on the ways in which genotype (and epigenetic modification), growth processes (particularly in utero), and exposure to ionising radiation (in conjunction with genetic susceptibility) affect cancer risk from childhood to adulthood, whether as a primary occurrence, or a second primary tumour following earlier primary occurrence and treatment.


Pan-cancer analysis of whole genomes.
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1-3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10-18.


HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.
HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Rheumatoid arthritis association at 6q23.
The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-5) - 5 x 10(-7) in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 x 10(-8)) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-alpha-induced protein 3 (TNFAIP3).


Cell-to-cell variation and specialization in sugar metabolism in clonal bacterial populations.
While we have good understanding of bacterial metabolism at the population level, we know little about the metabolic behavior of individual cells: do single cells in clonal populations sometimes specialize on different metabolic pathways? Such metabolic specialization could be driven by stochastic gene expression and could provide individual cells with growth benefits of specialization. We measured the degree of phenotypic specialization in two parallel metabolic pathways, the assimilation of glucose and arabinose. We grew Escherichia coli in chemostats, and used isotope-labeled sugars in combination with nanometer-scale secondary ion mass spectrometry and mathematical modeling to quantify sugar assimilation at the single-cell level. We found large variation in metabolic activities between single cells, both in absolute assimilation and in the degree to which individual cells specialize in the assimilation of different sugars. Analysis of transcriptional reporters indicated that this variation was at least partially based on cell-to-cell variation in gene expression. Metabolic differences between cells in clonal populations could potentially reduce metabolic incompatibilities between different pathways, and increase the rate at which parallel reactions can be performed.


Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.
Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5×10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60·3% (95% CI 43·7-69·3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2·51 (95% CI 2·23-2·83) compared with 1·00 in the lowest quintile of disease risk. These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. Wellcome Trust, National Institute on Aging, and US Department of Defense.


Relationship between estimated cardiovascular disease risk and insulin resistance in a black African population living with HIV: a cross-sectional study from Cameroon.
Cardiovascular disease (CVD) and metabolic diseases are growing concerns among patients with HIV infection as a consequence of the improving survival of this population. We aimed to assess the relationship between CVD risk and insulin resistance in a group of black African individuals with HIV infection. This cross-sectional study involved patients with HIV infection aged 30-74 years and followed up at the Yaoundé Central Hospital, Cameroon. Absolute CVD risk was calculated using the Framingham and the DAD CVD risk equations while the HOMA-IR index was used to assess insulin resistance (index ≥2.1). A total of 452 patients (361 women; 80%) were screened. The mean age was 44.4 years and most of the respondents were on antiretroviral therapy (88.5%). The median 5-year cardiovascular risk was 0.7% (25th-75th percentiles: 0.2-2.0) and 0.6% (0.3-1.3) according to the Framingham and DAD equations respectively. Of all participants, 47.3% were insulin resistant. The Framingham equation derived absolute CVD risk was significantly associated with insulin resistance; while no linear association was found using the DAD equation. The relationship between cardiovascular risk and insulin resistance in black African patients with HIV infection seems to depend on the cardiovascular risk equation used.


A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis.
Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard-Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V.


Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials.
Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4-8·6]; rate ratio 1·37 [95% CI 1·17-1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92-1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95-1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94-1·15]; p=0·45). Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. Cancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health.


Connectivity-based parcellation of human cortex using diffusion MRI: Establishing reproducibility, validity and observer independence in BA 44/45 and SMA/pre-SMA.
The identification of specialized, functional regions of the human cortex is a vital precondition for neuroscience and clinical neurosurgery. Functional imaging modalities are used for their delineation in living subjects, but these methods rely on subject cooperation, and many regions of the human brain cannot be activated specifically. Diffusion tractography is a novel tool to identify such areas in the human brain, utilizing underlying white matter pathways to separate regions of differing specialization. We explore the reproducibility, generalizability and validity of diffusion tractography-based localization in four functional areas across subjects, timepoints and scanners, and validate findings against fMRI and post-mortem cytoarchitectonic data. With reproducibility across modalities, clustering methods, scanners, timepoints, and subjects in the order of 80-90%, we conclude that diffusion tractography represents a useful and objective tool for parcellation of the human cortex into functional regions, enabling studies into individual functional anatomy even when there are no specific activation paradigms available.


Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials.
Most randomised trials of anticoagulant therapy for suspected acute myocardial infarction have been small and, in some, aspirin and fibrinolytic therapy were not used routinely. A systematic overview (meta-analysis) of their results is needed, in particular to assess the clinical effects of adding heparin to aspirin. Computer aided searches, scrutiny of reference lists, and inquiry of investigators and companies were used to identify potentially eligible studies. On central review, 26 studies were found to involve unconfounded randomised comparisons of anticoagulant therapy versus control in suspected acute myocardial infarction. Additional information on study design and outcome was sought by correspondence with study investigators. Patients with suspected acute myocardial infarction. No routine aspirin was used among about 5000 patients in 21 trials (including half of one small trial) that assessed heparin alone or heparin plus oral anticoagulants, and aspirin was used routinely among 68,000 patients in six trials (including the other half of one small trial) that assessed the addition of intravenous or high dose subcutaneous heparin. Death, reinfarction, stroke, pulmonary embolism, and major bleeds (average follow up of about 10 days). In the absence of aspirin, anticoagulant therapy reduced mortality by 25% (SD 8%; 95% confidence interval 10% to 38%; 2P = 0.002), representing 35 (11) fewer deaths per 1000. There were also 10 (4) fewer strokes per 1000 (2P = 0.01), 19 (5) fewer pulmonary emboli per 1000 (2P < 0.001), and non-significantly fewer reinfarctions, with about 13 (5) extra major bleeds per 1000 (2P = 0.01). Similar sized effects were seen with the different anticoagulant regimens studied. In the presence of aspirin, however, heparin reduced mortality by only 6% (SD 3%; 0% to 10%; 2P = 0.03), representing just 5 (2) fewer deaths per 1000. There were 3 (1.3) fewer reinfarctions per 1000 (2P = 0.04) and 1 (0.5) fewer pulmonary emboli per 1000 (2P = 0.01), but there was a small non-significant excess of stroke and a definite excess of 3 (1) major bleeds per 1000 (2P < 0.0001). The clinical evidence from randomised trials dose not justify the routine addition of either intravenous or subcutaneous heparin to aspirin in the treatment of acute myocardial infarction (irrespective of whether any type of fibrinolytic therapy is used).


WikiPathways for plants: a community pathway curation portal and a case study in rice and arabidopsis seed development networks.
Next-generation sequencing and 'omics' platforms are used extensively in plant biology research to unravel new genomes and study their interactions with abiotic and biotic agents in the growth environment. Despite the availability of a large and growing number of genomic data sets, there are only limited resources providing highly-curated and up-to-date metabolic and regulatory networks for plant pathways. Using PathVisio, a pathway editor tool associated with WikiPathways, we created a gene interaction network of 430 rice (Oryza sativa) genes involved in the seed development process by curating interactions reported in the published literature. We then applied an InParanoid-based homology search to these genes and used the resulting gene clusters to identify 351 Arabidopsis thaliana genes. Using this list of homologous genes, we constructed a seed development network in Arabidopsis by processing the gene list and the rice network through a Perl utility software called Pathway GeneSWAPPER developed by us. In order to demonstrate the utility of these networks in generating testable hypotheses and preliminary analysis prior to more in-depth downstream analysis, we used the expression viewer and statistical analysis features of PathVisio to analyze publicly-available and published microarray gene expression data sets on diurnal photoperiod response and the seed development time course to discover patterns of coexpressed genes found in the rice and Arabidopsis seed development networks. These seed development networks described herein, along with other plant pathways and networks, are freely available on the plant pathways portal at WikiPathways (http://plants.wikipathways.org). In collaboration with the WikiPathways project we present a community curation and analysis platform for plant biologists where registered users can freely create, edit, share and monitor pathways supported by published literature. We describe the curation and annotation of a seed development network in rice, and the projection of a similar, gene homology-based network in Arabidopsis. We also demonstrate the utility of the Pathway GeneSWAPPER (PGS) application in saving valuable time and labor when a reference network in one species compiled in GPML format is used to project a similar network in another species based on gene homology.


A pilot validation of a modified Illness Perceptions Questionnaire designed to predict response to cognitive therapy for psychosis.
Clinical responsiveness to cognitive behavioural therapy for psychosis (CBTp) varies. Recent research has demonstrated that illness perceptions predict active engagement in therapy, and, thereby, better outcomes. In this study, we aimed to investigate the psychometric properties of a modification of the Illness Perceptions Questionnaire (M-IPQ) designed to predict response following CBTp. Fifty-six participants with persistent, distressing delusions completed the M-IPQ; forty before a brief CBT intervention targeting persecutory ideation and sixteen before and after a control condition. Additional predictors of outcome (delusional conviction, symptom severity and belief inflexibility) were assessed at baseline. Outcomes were assessed at baseline and at follow-up four to eight weeks later. The M-IPQ comprised two factors measuring problem duration and therapy-specific perceptions of Cure/Control. Associated subscales, formed by summing the relevant items for each factor, were reliable in their structure. The Cure/Control subscale was also reliable over time; showed convergent validity with other predictors of outcome; predicted therapy outcomes; and differentially predicted treatment effects. We measured outcome without an associated measure of engagement, in a small sample. Findings are consistent with hypothesis and existing research, but require replication in a larger, purposively recruited sample. The Cure/Control subscale of the M-IPQ shows promise as a predictor of response to therapy. Specifically targeting these illness perceptions in the early stages of cognitive behavioural therapy may improve engagement and, consequently, outcomes.


Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016.
The UN's Sustainable Development Goals (SDGs) are grounded in the global ambition of "leaving no one behind". Understanding today's gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990-2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030. We used standardised GBD 2016 methods to measure 37 health-related indicators from 1990 to 2016, an increase of four indicators since GBD 2015. We substantially revised the universal health coverage (UHC) measure, which focuses on coverage of essential health services, to also represent personal health-care access and quality for several non-communicable diseases. We transformed each indicator on a scale of 0-100, with 0 as the 2·5th percentile estimated between 1990 and 2030, and 100 as the 97·5th percentile during that time. An index representing all 37 health-related SDG indicators was constructed by taking the geometric mean of scaled indicators by target. On the basis of past trends, we produced projections of indicator values, using a weighted average of the indicator and country-specific annualised rates of change from 1990 to 2016 with weights for each annual rate of change based on out-of-sample validity. 24 of the currently measured health-related SDG indicators have defined SDG targets, against which we assessed attainment. Globally, the median health-related SDG index was 56·7 (IQR 31·9-66·8) in 2016 and country-level performance markedly varied, with Singapore (86·8, 95% uncertainty interval 84·6-88·9), Iceland (86·0, 84·1-87·6), and Sweden (85·6, 81·8-87·8) having the highest levels in 2016 and Afghanistan (10·9, 9·6-11·9), the Central African Republic (11·0, 8·8-13·8), and Somalia (11·3, 9·5-13·1) recording the lowest. Between 2000 and 2016, notable improvements in the UHC index were achieved by several countries, including Cambodia, Rwanda, Equatorial Guinea, Laos, Turkey, and China; however, a number of countries, such as Lesotho and the Central African Republic, but also high-income countries, such as the USA, showed minimal gains. Based on projections of past trends, the median number of SDG targets attained in 2030 was five (IQR 2-8) of the 24 defined targets currently measured. Globally, projected target attainment considerably varied by SDG indicator, ranging from more than 60% of countries projected to reach targets for under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria, to less than 5% of countries projected to achieve targets linked to 11 indicator targets, including those for childhood overweight, tuberculosis, and road injury mortality. For several of the health-related SDGs, meeting defined targets hinges upon substantially faster progress than what most countries have achieved in the past. GBD 2016 provides an updated and expanded evidence base on where the world currently stands in terms of the health-related SDGs. Our improved measure of UHC offers a basis to monitor the expansion of health services necessary to meet the SDGs. Based on past rates of progress, many places are facing challenges in meeting defined health-related SDG targets, particularly among countries that are the worst off. In view of the early stages of SDG implementation, however, opportunity remains to take actions to accelerate progress, as shown by the catalytic effects of adopting the Millennium Development Goals after 2000. With the SDGs' broader, bolder development agenda, multisectoral commitments and investments are vital to make the health-related SDGs within reach of all populations. Bill & Melinda Gates Foundation.


Dependence of aptamer activity on opposed terminal extensions: improvement of light-regulation efficiency.
Aptamers that can be regulated with light allow precise control of protein activity in space and time and hence of biological function in general. In a previous study, we showed that the activity of the thrombin-binding aptamer HD1 can be turned off by irradiation using a light activatable 'caged' intramolecular antisense-domain. However, the activity of the presented aptamer in its ON state was only mediocre. Here we studied the nature of this loss in activity in detail and found that switching from 5'- to 3'-extensions affords aptamers that are even more potent than the unmodified HD1. In particular we arrived at derivatives that are now more active than the aptamer NU172 that is currently in phase 2 clinical trials as an anticoagulant. As a result, we present light-regulatable aptamers with a superior activity in their ON state and an almost digital ON/OFF behavior upon irradiation.


Can we systematically review studies that evaluate complex interventions?
The UK Medical Research Council defines complex interventions as those comprising "a number of separate elements which seem essential to the proper functioning of the interventions although the 'active ingredient' of the intervention that is effective is difficult to specify." A typical example is specialist care on a stroke unit, which involves a wide range of health professionals delivering a variety of treatments. Michelle Campbell and colleagues have argued that there are "specific difficulties in defining, developing, documenting, and reproducing complex interventions that are subject to more variation than a drug". These difficulties are one of the reasons why it is challenging for researchers to systematically review complex interventions and synthesize data from separate studies. This PLoS Medicine Debate considers the challenges facing systematic reviewers and suggests several ways of addressing them.


A comprehensive review and model of putative prodromal features of bipolar affective disorder.
Identifying prodromal features that predate the onset of bipolar disorder (BD) may enable the prevention of BD and aid early intervention. This review addresses two key questions: Is there a bipolar prodrome? And, if there is, what are its characteristic features? A comprehensive search of databases (PubMed, Medline, EMBASE and PsycINFO) supplemented by hand searches was used to identify studies of symptoms preceding the onset of BD. Fifty-nine studies were identified, of which 14 met inclusion criteria. Symptoms can predate the onset of BD by months to years and can be categorized as attenuated forms of BD symptoms, general symptoms common to a range of mental disorders, and personality traits, particularly cyclothymia. Two studies provided sufficient data to enable sensitivity and specificity to be calculated. Specificity of several of the features was high (>90%) but sensitivity was generally low (all <60%). We propose a model based on the findings in the studies reviewed to illustrate the potential trajectory to BD and the points at which it may be possible to intervene. Clinical features preceding the onset of BD can be identified. However, conclusions about whether there is a distinct prodrome to BD are restricted by the limitations of current evidence. The high specificity of some features suggests they may be useful in clinical practice. Large-scale longitudinal studies are needed to validate these features and characterize their specificity and sensitivity in independent samples.


[Evaluation of cognitive-behavioral therapy for drinking. Outcome of Japanese alcoholic patients].
This study examined the efficacy of a group-based cognitive-behavioral treatment (CBT) for Japanese alcoholic outpatients. Participants (N = 169) were assigned either to a CBT-based relapse prevention group or a TAU (treatment as usual) group. The CBT group received 12-session CBT treatment with a structured treatment workbook once a week. The TAU group received usual daycare treatment including 12-step meeting, vocational training and leisure activities. Participants in the CBT group demonstrated a significantly low relapse rate at the end of treatment. Moreover, coping skills of the CBT group participants were significantly improved than those of the TAU group at the 6-month follow-up period. However, at the 6-month follow-up, the difference in relapse rates diminished. The effectiveness of CBT for alcoholics was well documented in Western countries but few studies were conducted outside of the West. The results provide support for the use of CBT for Japanese alcoholics.


Functional Heterogeneity within the Developing Zebrafish Epicardium.
The epicardium is essential during cardiac development, homeostasis, and repair, and yet fundamental insights into its underlying cell biology, notably epicardium formation, lineage heterogeneity, and functional cross-talk with other cell types in the heart, are currently lacking. In this study, we investigated epicardial heterogeneity and the functional diversity of discrete epicardial subpopulations in the developing zebrafish heart. Single-cell RNA sequencing uncovered three epicardial subpopulations with specific genetic programs and distinctive spatial distribution. Perturbation of unique gene signatures uncovered specific functions associated with each subpopulation and established epicardial roles in cell adhesion, migration, and chemotaxis as a mechanism for recruitment of leukocytes into the heart. Understanding which mechanisms epicardial cells employ to establish a functional epicardium and how they communicate with other cardiovascular cell types during development will bring us closer to repairing cellular relationships that are disrupted during cardiovascular disease.


Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration.
Parkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD. Now we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of alpha-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons. Thus, aging Pink1(-/-) mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.


Hypoxia response elements.
Hypoxia-inducible factor-1 (HIF-1) has been shown to mediate the transcriptional activation of its target genes in response to oxygen concentration, most likely via a pathway involving a specific oxygen sensor. Molecular cloning of HIF-1 has shown that this widely expressed, DNA binding transcription factor is a heterodimer of two proteins, HIF-1 alpha and HIF-1 beta. A major control of HIF-1 activity by oxygen tension is achieved by changes in the level of the HIF-1 alpha subunit, which complexes with the constitutively expressed HIF-1 beta subunit. Such changes in HIF-1 alpha abundance occur via regulated stability, probably involving proteolysis, rather than at the level of transcription or translation. Further analysis has shown the existence of two separate regulatory domains in the C-terminus of the alpha subunit. Thus, a mechanism of oxygen-regulated HIF-1 activation is proposed, which involves the operation of one inducible domain being amplified by changes in protein level conferred by a second regulatory domain. Evidence for a critical role of HIF-1 in the response of diverse target genes involved in cellular growth and metabolism comes from studies on cultured, mutant mouse cells that lack a functional HIF-1 beta subunit. Furthermore, studies on tumor xenografts derived from the mutant and wild-type cells show that HIF-1 is activated in vivo, and has major effects on gene expression in response to tumor hypoxia. Thus, HIF-1 is a critical component of the oxygen-signaling pathway, and is a prime candidate regulator molecule for the role of coordinating vascular oxygen supply with cellular growth and energy metabolism.


Acupuncture for the treatment of dry eye: a multicenter randomised controlled trial with active comparison intervention (artificial teardrops).
To evaluate the effects of acupuncture compared to a control group using artificial tears. multicenter randomised controlled trial (three local research hospitals of South Korea). 150 patients with moderate to severe dry eye. Participants were randomly allocated into four weeks of acupuncture treatment (bilateral BL2, GB14, TE 23, Ex1, ST1, GB20, LI4, LI11 and single GV23) or to the artificial tears group (sodium carboxymethylcellulose). The ocular surface disease index (OSDI), tear film break-up time (TFBUT), Schirmer Ι test, visual analogue scale (VAS) for self-assessment of ocular discomfort, general assessment (by both acupuncture practitioners and participants) and quality of life (QOL) through the Measure Yourself Medical Outcome Profile-2 (MYMOP-2). There was no statistically significant difference between two groups for the improvement of dry eye symptoms as measured by OSDI (MD -16.11, 95% CI [-20.91, -11.32] with acupuncture and -15.37, 95% CI [-19.57, -11.16] with artificial tears; P = 0.419), VAS (acupuncture: -23.84 [-29.59, -18.09]; artificial tears: -22.2 [-27.24, -17.16], P = 0.530) or quality of life (acupuncture: -1.32 [-1.65, -0.99]; artificial tears: -0.96 [-1.32, -0.6], P = 0.42) immediately after treatment. However, compared with artificial tears group, the OSDI (acupuncture: -16.15 [-21.38, -10.92]; artificial tears: -10.76 [-15.25, -6.27], P = 0.030) and VAS (acupuncture: -23.88 [-30.9, -16.86]; artificial tears: -14.71 [-20.86, -8.55], P = 0.018) were significantly improved in the acupuncture group at 8 weeks after the end of acupuncture treatment. TFBUT measurements increased significantly in the acupuncture group after treatment. Acupuncture may have benefits on the mid-term outcomes related to dry eye syndrome compared with artificial tears. ClinicalTrials.gov NCT01105221.


Experiencing everyday ethics in context: frontline data collectors perspectives and practices of bioethics.
Data collectors play a vital role in producing scientific knowledge. They are also an important component in understanding the practice of bioethics. Yet, very little attention has been given to their everyday experiences or the context in which they are expected to undertake these tasks. This paper argues that while there has been extensive philosophical attention given to 'the what' and 'the why' in bioethics - what action is taken place and why - these should be considered along 'the who' - who are the individuals tasked with bioethics and what can their insights bring to macro-level and abstract discussions of bioethics. This paper will draw on the philosophical theories of Paul Ricoeur which compliments a sociological examination of data collectors experiences and use of their agency coupled with a concern for contextual and institutional factors in which they worked. In emphasising everyday experiences and contexts, I will argue that data collectors' practice of bioethics was shaped by their position at the frontline of face-to-face interactions with medical research participants and community members, alongside their own personal ethical values and motivations. Institutional interpretations of bioethics also imposed certain parameters on their bioethical practice but these were generally peripheral to their sense of obligation and the expectations conferred in witnessing the needs and suffering of those they encountered during their quotidian research duties. This paper will demonstrate that although the principle of autonomy has dominated discussions of bioethics and gaining informed consent seen as a central facet of ethical research by many research institutions, for data collectors this principle was seldom the most important marker of their ethical practice. Instead, data collectors were concerned with remedying the dilemmas they encountered through enacting their own interpretations of justice and beneficence and imposing their own agency on the circumstances they experienced. Their practice of bioethics demonstrates their contribution to the conduct of research and the shortcomings of an over-emphasis on autonomy.


Perinatal risk factors in offenders with severe personality disorder: a population-based investigation.
Although perinatal factors are associated with the development of several psychiatric disorders, it is unknown whether these factors are linked with personality disorder. Cases of personality disorder were drawn from a national registry of all forensic psychiatric evaluations (n = 150). Two control groups were used: (1) A sample of forensic evaluations without any psychiatric disorder (n = 97) allowing for a nested case-control investigation; and (2) A population-based sample matched by age and gender with no history of psychiatric hospitalization (n = 1498). Prematurity (<37 weeks of completed gestation) was significantly associated with a diagnosis of personality disorder, both in the nested and the population-based case-control comparisons with adjusted odds ratios (OR) for this risk factor ranging from 2 to 4. Asphyxia (adjusted OR = 2.4, 95% CI: 1.4-4.1) and complicated delivery (adjusted OR = 1.5, 1.0-2.1) were associated with personality disorder in the population-based study, and the former remained significant in multivariate models. Overall, perinatal complications were found to be associated with a later diagnosis of personality disorder in this selected sample. As with other psychiatric disorders where such associations have been demonstrated, changes during the perinatal period may lead to abnormal brain development and function.


Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016.
Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends. We estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016. The quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72·3% (95% uncertainty interval [UI] 71·2-73·2) of deaths in 2016 with 19·3% (18·5-20·4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8·43% (8·00-8·67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006-16-age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1·80 million deaths (95% UI 1·59 million to 1·89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176-181) increase in deaths in ages 90-94 years and a 210% (208-212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2·89%); the median annualised rate of change for all other causes was lower (a decrease of 1·59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe. The past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs might reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems. Bill & Melinda Gates Foundation.


Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801.
It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.


A micro-costing approach to estimating hospital costs for appendectomy in a cross-European context.
This paper aims (a) to determine whether variations in the hospital costs of appendectomy in EU member states are larger within individual countries or between different countries and (b) to explore causes for variations in costs between hospitals and countries. To do so, hospitalisation costs and reimbursement rates for appendectomy were obtained from 54 hospitals in nine European member states based on 1786 cases using a standardised methodology. Regression analysis was performed using hospital characteristics, treatment characteristics, and purchasing power parities (PPP) as explanatory variables in a multilevel framework. The within-country standard error was estimated to 294 euros (27%), whereas the between-country standard error was 796 euros (73%). Excluding hospitals in Spain, Hungary, and Poland, which had significantly lower costs than hospitals in the other countries in our analysis, the within-country standard error was 331 euros (57%) and the between-country standard error dropped to 248 euros (43%). Regression results show that the treatment decision for open surgery was associated with significantly lower costs, whereas a greater number of beds and a higher staff per bed ratio were associated with significantly higher costs. PPP explained a major part of the between-country variance.


Factorial structure and long-term stability of the Autonomy Preference Index.
The autonomy preference index scale (API) has been designed to measure patient preference for 2 dimensions of autonomy: Their desire to take part in making medical decisions (decision making, [DM]) and their desire to be informed about their illness and the treatment (information seeking; [IS]). The DM dimension is measured by 6 general items together with 9 items related to 3 clinical vignettes (3 × 3 items). The IS dimension is measured by 8 items. While the API is widely used, a review of literature has identified several inconsistencies in the way it is scored. The first aim of this study was to determine the best scoring structure of the API on the basis of validity and reliability evidence. The second aim was to investigate the long-term stability of API scores. Two-hundred and 85 patients with a diagnosis of psychosis were assessed as they were about to be discharged from involuntary psychiatric hospitalization and they were reassessed after 6 and 12 months. Confirmatory factor analysis (CFA) revealed that a 3-factor solution was most adequate and that 2 distinct DM subscales should be preferred to 1 total DM score. While internal consistency estimates of the 3 subscales were good, the long-term stability of API scores was only modest. Multigroup-CFA revealed scalar invariance indicating API scores kept the same meaning longitudinally. In conclusion, a 3-factor structure seemed to be most adequate for the API scale. Long-term stability estimates suggested that clinicians should regularly assess patients' preferences for autonomy because API scores fluctuate over time. (PsycINFO Database Record


Control of spread of Methicillin Resistant Staphylococcus aureus (MRSA) in Burns Units.
Results of four years' studies from a number of hospitals in Kenya have shown that nosocomial infections in burns units are due to Methicillin Resistant Staphylococcus aureus (MRSA). Through chromosomal DNA and plasmid DNA, the stain is highly resistant to sulphonamide ointment and other antibiotics. 90% of patients admitted in burns units get colonized or infected with MRSA. The strain prolongs the duration of patients in hospitals. The burns degenerate to second and third degree burns, thereby necessitating skin grafting. The environment has been found to be contaminated with this strain with some staff members having chronic throat infections. Minocycline was found to be effective in treating the infected staff members. Cleaning this environment with Sodium dichloroisocyanurate (precepts)/Sodium hypochlorite (JIK) reduced drastically the mechanical transmission of bacteria in the units. The duration of stay of the patient was reduced. This shows that MRSA which is spread in government and private hospitals can cheaply be controlled by the proper use of disinfectants, antiseptics, and use of effective antibiotics when necessary.


Epidermal growth factor receptor in human bladder cancer: a comparison of immunohistochemistry and ligand binding.
Epidermal growth factor receptors were measured in biopsies from patients with newly diagnosed bladder cancer. Two methods to detect these receptors were compared: immunohistochemical staining of frozen sections, and a ligand binding study using radiolabeled epidermal growth factor and tumor cell membranes. We studied 101 patients by immunohistochemistry and 47 patients by both methods. An association was found between immunohistochemical positivity for epidermal growth factor receptors and high tumor stage (p less than 0.001). Thus, most of the muscle invasive tumors were positive (35 of 49, 71 per cent) and more stage pT1 tumors were positive (8 of 18, 44 per cent) than were stage pTa tumors (5 of 34, 15 per cent, p less than 0.05). The ligand binding study was slightly more sensitive in detecting receptors than immunohistochemistry (30 of 47, 64 per cent and 25 of 47, 53 per cent, respectively). Greater amounts of receptors were found in muscle invasive tumors compared to tumors not invading muscle (p less than 0.05). A significant association was found between the 2 methods in the detection of receptors (p less than 0.001) and no discrepancies were found between the 2 methods in tumors containing high levels of receptors. Immunohistochemistry provides a satisfactory method to detect receptors in tumors with high levels of receptors, although ligand binding is more sensitive in tumors with low levels of receptors.


Is there a difference between the effects of one-point and three-point indirect moxibustion stimulation on skin temperature changes of the posterior trunk surface?
To determine whether any difference exists in responses to indirect moxibustion relative to thermal stimulation sites. Twenty one healthy men of mean±SD age 22.5±6.1 years were randomly divided into two groups, one receiving a single moxibustion stimulation in three locations (the three-point stimulation group, n=10 participants) and the other receiving three stimulations in one location (the one-point stimulation group, n=11 participants). The thermal stimulation sites were GV14, GV9 and GV4 acupuncture points. A thermograph was used to obtain the skin temperature on the posterior trunks of the participants. To analyse skin temperature, four arbitrary frames (the scapular, interscapular, lumbar and vertebral regions) were made on the posterior trunk. An increase in skin temperature on the posterior trunk was observed following both one- and three-point moxibustion administrations. The skin temperature of the lumbar region showed a significant increase after three-point stimulation compared with single-point stimulation (p=0.011). There was also a significant increase in skin temperature of the spinal region after three-point stimulation compared with one-point stimulation (p=0.046). Administration of single moxibustion doses on the GV14, GV9 and GV4 points produces greater changes in skin temperature than three applications of moxibustion to the GV14 point only.


Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation.
Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses. The T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations. Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.


Health technology assessment in Germany. Status, challenges, and development.
The objectives of this paper are to describe the status and development of health technology regulation with regard to coverage decisions and utilization, and to analyze the current situation of health technology assessment (HTA) in Germany. The relevant literature for controlling health technologies was identified by searching the literature and databases and through personal contacts. The literature was analyzed with regard to the different sectors in the healthcare system. For the analysis of the current state of HTA in Germany, a national survey was carried out. In addition, the names of topics under assessment were collected. The results show that coverage decisions in the ambulatory sector appear to be much more regulated than those in the inpatient sector. The same is true for diffusion and usage of technologies. The strict separation of the hospital and the ambulatory care sector in Germany constitutes a barrier to regulation and to making HTA an effective instrument in Germany. Until recently, HTA in Germany focused on biotechnology, such as gene technology. Recently the German Scientific Working Group of Technology Assessment in Health Care has adopted a systematic methodology to undertake HTAs. It can be concluded that regulation of health technologies in Germany is characterized by inconsistencies ranging from strict regulation in the ambulatory sector to almost no regulation in the rehabilitation sector. Increasing interest in HTA, in conjunction with a high priority assigned to evaluation of health technologies by the newly elected government, is likely to improve this situation in the future.


Review of overlap between thermoregulation and pain modulation in fibromyalgia.
Fibromyalgia (FM) syndrome is characterized by widespread pain that is exacerbated by cold and stress but relieved by warmth. We review the points along thermal and pain pathways where temperature may influence pain. We also present evidence addressing the possibility that brown adipose tissue activity is linked to the pain of FM given that cold initiates thermogenesis in brown adipose tissue through adrenergic activity, whereas warmth suspends thermogenesis. Although females have a higher incidence of FM and more resting thermogenesis, they are less able to recruit brown adipose tissue in response to chronic stress than males. In addition, conditions that are frequently comorbid with FM compromise brown adipose activity making it less responsive to sympathetic stimulation. This results in lower body temperatures, lower metabolic rates, and lower circulating cortisol/corticosterone in response to stress--characteristics of FM. In the periphery, sympathetic nerves to brown adipose also project to surrounding tissues, including tender points characterizing FM. As a result, the musculoskeletal hyperalgesia associated with conditions such as FM may result from referred pain in the adjacent muscle and skin.


Impact of 68Ga-PSMA PET/CT on salvage radiotherapy planning in patients with prostate cancer and persisting PSA values or biochemical relapse after prostatectomy.
Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced 68Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning. Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent 68Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of 68Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity. Suspicious lesions were detected in 24/45 (53.3 %) patients. In 62.5 % of patients, lesions were only detected by 68Ga-PSMA PET. Treatment was changed in 19/45 (42.2 %) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 %) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 %) within a mean follow-up of 8.12 ± 5.23 months. 68Ga-PSMA PET/CT impacts treatment planning in more than 40 % of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.


Drug prescription patterns in schizophrenia outpatients: analysis of data from a German health insurance fund.
The aim of this study was to investigate routine administrative data from a major German health insurance fund, Techniker Krankenkasse, which covers 5.4 million insured individuals. Using a retrospective cohort design, this study analysed data collected from patients with a hospital diagnosis of schizophrenia in 2003 (index hospitalisation) in order to evaluate prescription patterns of antipsychotic drugs. Patients with an ICD-10 diagnosis of schizophrenia, at least one year prior membership with the insurance fund and a follow-up period of one year were identified. Results were standardised by age and stratified by the severity of their illness, defined by the number of hospital bed days during the three years preceding the index hospitalisation. A total of 3,121 patients with schizophrenia (male 56.4%, female 43.6%) received 56 692 single prescriptions of antipsychotics. Of these, 35.4% of the prescriptions were for typical and 64.6% for atypical antipsychotics; 55% were for high-potency, 45% for low-potency typical antipsychotics. The most frequently prescribed drugs were olanzapine (26.6%), clozapine (21.3%) and risperidone (19%). There were no relevant gender differences concerning prescription patterns. During a 12-month follow-up period after the first hospitalisation, 1 372 patients (43.9%) were treated exclusively with an atypical antipsychotic, another 499 patients (16%) had a combination of an atypical plus a low-potency typical antipsychotic. Thus, basal therapy with an atypical was observed in 59.9% of our study population. Only 327 patients (10.5%) were treated exclusively with a typical antipsychotic. A total of 645 patients (20.7%) were treated with a combination of atypical plus typical antipsychotic. Changes of medication within one substance group occurred more often with typical antipsychotics (50%) as compared to atypical antipsychotics (25%). At 60%, the proportion of patients in this study treated with atypical antipsychotics was surprisingly high. Of significant interest is the frequent prescription of clozapine (14%). The results are discussed in comparison to comparable studies from other countries.


Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro.
The biologic relevance of human connective tissue growth factor (hCTGF) for primary human tenon fibroblasts (HTFs) was investigated by RNA expression profiling using affymetrix(TM) oligonucleotide array technology to identify genes that are regulated by hCTGF. Recombinant hCTGF was expressed in HEK293T cells and purified by affinity and gel chromatography. Specificity and biologic activity of hCTGF was confirmed by biosensor interaction analysis and proliferation assays. For RNA expression profiling HTFs were stimulated with hCTGF for 48h and analyzed using affymetrix(TM) oligonucleotide array technology. Results were validated by real time RT-PCR. hCTGF induces various groups of genes responsible for a wound healing and inflammatory response in HTFs. A new subset of CTGF inducible inflammatory genes was discovered (e.g., chemokine [C-X-C motif] ligand 1 [CXCL1], chemokine [C-X-C motif] ligand 6 [CXCL6], interleukin 6 [IL6], and interleukin 8 [IL8]). We also identified genes that can transmit the known biologic functions initiated by CTGF such as proliferation and extracellular matrix remodelling. Of special interest is a group of genes, e.g., osteoglycin (OGN) and osteomodulin (OMD), which are known to play a key role in osteoblast biology. This study specifies the important role of hCTGF for primary tenon fibroblast function. The RNA expression profile yields new insights into the relevance of hCTGF in influencing biologic processes like wound healing, inflammation, proliferation, and extracellular matrix remodelling in vitro via transcriptional regulation of specific genes. The results suggest that CTGF potentially acts as a modulating factor in inflammatory and wound healing response in fibroblasts of the human eye.


Acute neurological complications following gamma knife surgery for vestibular schwannoma. Case report.
The authors describe an acute facial and acoustic neuropathy following gamma knife surgery (GKS) for vestibular schwannoma (VS). This 39-year-old woman presenting with tinnitus underwent GKS for a small right-sided intracanalicular VS, receiving a maximal dose of 26 Gy and a tumor margin dose of 13 Gy to the 50% isodose line. Thirty-six hours following treatment she presented with nausea, vomiting, vertigo, diminished hearing, and a House-Brackmann Grade III facial palsy. She was started on intravenous glucocorticosteroid agents, and over the course of 2 weeks her facial function returned to House-Brackmann Grade I. Unfortunately, her hearing loss persisted. A magnetic resonance (MR) image obtained at the time of initial deterioration demonstrated a significant decrease in tumor enhancement but no change in tumor size or peritumoral edema. Subsequently, the patient experienced severe hemifacial spasms, which persisted for a period of 3 weeks and then progressed to a House-Brackmann Grade V facial palsy. During the next 3 months, the patient was treated with steroids and in time her facial function and hearing returned to baseline levels. Results of MR imaging revealed transient enlargement (3 mm) of the tumor, which subsequently returned to its baseline size. This change corresponded to the tumor volume increase from 270 to 336 mm3. The patient remains radiologically and neurologically stable at 10 months posttreatment. This is the first detailed report of acute facial and vestibulocochlear neurotoxicity following GKS for VS that improved with time. In addition, MR imaging findings were indicative of early neurotoxic changes. A review of possible risk factors and explanations of causative mechanisms is provided.