The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited ...statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
The Internet is now all-pervasive across much of the globe. While it has positive uses (e.g. prompt access to information, rapid news dissemination), many individuals develop Problematic Use of the ...Internet (PUI), an umbrella term incorporating a range of repetitive impairing behaviours. The Internet can act as a conduit for, and may contribute to, functionally impairing behaviours including excessive and compulsive video gaming, compulsive sexual behaviour, buying, gambling, streaming or social networks use. There is growing public and National health authority concern about the health and societal costs of PUI across the lifespan. Gaming Disorder is being considered for inclusion as a mental disorder in diagnostic classification systems, and was listed in the ICD-11 version released for consideration by Member States (http://www.who.int/classifications/icd/revision/timeline/en/). More research is needed into disorder definitions, validation of clinical tools, prevalence, clinical parameters, brain-based biology, socio-health-economic impact, and empirically validated intervention and policy approaches. Potential cultural differences in the magnitudes and natures of types and patterns of PUI need to be better understood, to inform optimal health policy and service development. To this end, the EU under Horizon 2020 has launched a new four-year European Cooperation in Science and Technology (COST) Action Programme (CA 16207), bringing together scientists and clinicians from across the fields of impulsive, compulsive, and addictive disorders, to advance networked interdisciplinary research into PUI across Europe and beyond, ultimately seeking to inform regulatory policies and clinical practice. This paper describes nine critical and achievable research priorities identified by the Network, needed in order to advance understanding of PUI, with a view towards identifying vulnerable individuals for early intervention. The network shall enable collaborative research networks, shared multinational databases, multicentre studies and joint publications.
Greenland ice sheet mass loss has accelerated in the past decade responding to combined glacier discharge and surface melt water runoff increases. During summer, absorbed solar energy, modulated at ...the surface primarily by albedo, is the dominant factor governing surface melt variability in the ablation area. Using satellite-derived surface albedo with calibrated regional climate modeled surface air temperature and surface downward solar irradiance, we determine the spatial dependence and quantitative impact of the ice sheet albedo feedback over 12 summer periods beginning in 2000. We find that, while albedo feedback defined by the change in net solar shortwave flux and temperature over time is positive over 97% of the ice sheet, when defined using paired annual anomalies, a second-order negative feedback is evident over 63% of the accumulation area. This negative feedback damps the accumulation area response to warming due to a positive correlation between snowfall and surface air temperature anomalies. Positive anomaly-gauged feedback concentrated in the ablation area accounts for more than half of the overall increase in melting when satellite-derived melt duration is used to define the timing when net shortwave flux is sunk into melting. Abnormally strong anticyclonic circulation, associated with a persistent summer North Atlantic Oscillation extreme since 2007, enabled three amplifying mechanisms to maximize the albedo feedback: (1) increased warm (south) air advection along the western ice sheet increased surface sensible heating that in turn enhanced snow grain metamorphic rates, further reducing albedo; (2) increased surface downward shortwave flux, leading to more surface heating and further albedo reduction; and (3) reduced snowfall rates sustained low albedo, maximizing surface solar heating, progressively lowering albedo over multiple years. The summer net infrared and solar radiation for the high elevation accumulation area approached positive values during this period. Thus, it is reasonable to expect 100% melt area over the ice sheet within another similar decade of warming.
Interparticle forces in granular materials are intimately linked to mechanical properties and are known to self-organize into heterogeneous structures, or force chains, under external load. Despite ...progress in understanding the statistics and spatial distribution of interparticle forces in recent decades, a systematic method for measuring forces in opaque, three-dimensional (3D), frictional, stiff granular media has yet to emerge. In this Letter, we present results from an experiment that combines 3D x-ray diffraction, x-ray tomography, and a numerical force inference technique to quantify interparticle forces and their heterogeneity in an assembly of quartz grains undergoing a one-dimensional compression cycle. Forces exhibit an exponential decay above the mean and partition into strong and weak networks. We find a surprising inverse relationship between macroscopic load and the heterogeneity of interparticle forces, despite the clear emergence of two force chains that span the system.
Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed ...size.
Women with PPH 1000–1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused.
Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3–1.7), P=0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th–75th centile) of 1 (0–4.5) unit of allogeneic blood products and had an additional 300 (100–350) ml blood loss whereas those who received placebo also received 3 (0–6) units of allogeneic blood products and had 700 (200–1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group.
Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre−1, but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis.
ISRCTN46295339 (http://www.isrctn.com/ISRCTN46295339, last accessed 5 July 2017), EudraCT 2012-005511-11 (https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-005511-11, last accessed 5 July 2017).
In recent years, there has been a rapid increase in the number of CT scans performed, both in the US and the UK, which has fuelled concern about the long-term consequences of these exposures, ...particularly in terms of cancer induction. Statistics from the US and the UK indicate a 20-fold and 12-fold increase, respectively, in CT usage over the past two decades, with per caput CT usage in the US being about five times that in the UK. In both countries, most of the collective dose from diagnostic radiology comes from high-dose (in the radiological context) procedures such as CT, interventional radiology and barium enemas; for these procedures, the relevant organ doses are in the range for which there is now direct credible epidemiological evidence of an excess risk of cancer, without the need to extrapolate risks from higher doses. Even for high-dose radiological procedures, the risk to the individual patient is small, so that the benefit/risk balance is generally in the patients' favour. Concerns arise when CT examinations are used without a proven clinical rationale, when alternative modalities could be used with equal efficacy, or when CT scans are repeated unnecessarily. It has been estimated, at least in the US, that these scenarios account for up to one-third of all CT scans. A further issue is the increasing use of CT scans as a screening procedure in asymptomatic patients; at this time, the benefit/risk balance for any of the commonly suggested CT screening techniques has yet to be established.
Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV ...to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus‐induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine‐activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus‐loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand‐off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL‐12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune‐mediated tumor cell killing.
What's new?
Oncolytic viruses (OVs) specifically infect and kill tumor cells. In this study, the authors began to examine whether intraperitoneal delivery of an OV could be effective against ovarian cancer. They found that, while the virus does kill ovarian‐cancer cells in vitro, this effect is blocked when ascites fluid is added. Cytotoxicity can be restored, however, by using a combination of lymphokine‐activated killer and dendritic cells (LAKDC) as carriers, which protect the virus from neutralizing antibodies in the ascites. The LAKDC combination may also support subsequent adaptive immune priming.
Balanced fishing across a range of species, stocks, and sizes could mitigate adverse effects and address food security better than increased selectivity.
Concern about the impact of fishing on ...ecosystems and fisheries production is increasing (
1
,
2
). Strategies to reduce these impacts while addressing the growing need for food security (
3
) include increasing selectivity (
1
,
2
): capturing species, sexes, and sizes in proportions that differ from their occurrence in the ecosystem. Increasing evidence suggests that more selective fishing neither maximizes production nor minimizes impacts (
4
–
7
). Balanced harvesting would more effectively mitigate adverse ecological effects of fishing while supporting sustainable fisheries. This strategy, which challenges present management paradigms, distributes a moderate mortality from fishing across the widest possible range of species, stocks, and sizes in an ecosystem, in proportion to their natural productivity (
8
), so that the relative size and species composition is maintained.
Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and ...diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T(1)-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.
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