Prenatal and Perinatal Risk Factors for Autism in China

We conducted a case–control study using 190 Han children with and without autism to investigate prenatal and perinatal risk factors for autism in China. Cases were recruited through public special education schools and controls from regular public schools in the same region (Tianjin), with frequency matching on sex and birth year. Unadjusted analyses identified seven prenatal and seven perinatal risk factors significantly associated with autism. In the adjusted analysis, nine risk factors showed significant association with autism: maternal second-hand smoke exposure, maternal chronic or acute medical conditions unrelated to pregnancy, maternal unhappy emotional state, gestational complications, edema, abnormal gestational age (<35 or >42 weeks), nuchal cord, gravidity >1, and advanced paternal age at delivery (>30 year-old)

Planck 2018 results. IX. Constraints on primordial non-Gaussianity

We analyse the Planck full-mission cosmic microwave background (CMB) temperature and E-mode polarization maps to obtain constraints on primordial non-Gaussianity (NG). We compare estimates obtained from separable template-fitting, binned, and modal bispectrum estimators, finding consistent values for the local, equilateral, and orthogonal bispectrum amplitudes. Our combined temperature and polarization analysis produces the following results: f_NL^local = -0.9 +\- 5.1; f_NL^equil = -26 +\- 47; and f_NL^ortho = - 38 +\- 24 (68%CL, statistical). These results include the low-multipole (4 <= l < 40) polarization data, not included in our previous analysis, pass an extensive battery of tests, and are stable with respect to our 2015 measurements. Polarization bispectra display a significant improvement in robustness; they can now be used independently to set NG constraints. We consider a large number of additional cases, e.g. scale-dependent feature and resonance bispectra, isocurvature primordial NG, and parity-breaking models, where we also place tight constraints but do not detect any signal. The non-primordial lensing bispectrum is detected with an improved significance compared to 2015, excluding the null hypothesis at 3.5 sigma. We present model-independent reconstructions and analyses of the CMB bispectrum. Our final constraint on the local trispectrum shape is g_NLl^local = (-5.8 +\-6.5) x 10^4 (68%CL, statistical), while constraints for other trispectra are also determined. We constrain the parameter space of different early-Universe scenarios, including general single-field models of inflation, multi-field and axion field parity-breaking models. Our results provide a high-precision test for structure-formation scenarios, in complete agreement with the basic picture of the LambdaCDM cosmology regarding the statistics of the initial conditions (abridged)

Planck 2018 results. VII. Isotropy and statistics of the CMB

Analysis of the Planck 2018 data set indicates that the statistical properties of the cosmic microwave background (CMB) temperature anisotropies are in excellent agreement with previous studies using the 2013 and 2015 data releases. In particular, they are consistent with the Gaussian predictions of the $\Lambda$CDM cosmological model, yet also confirm the presence of several so-called "anomalies" on large angular scales. The novelty of the current study, however, lies in being a first attempt at a comprehensive analysis of the statistics of the polarization signal over all angular scales, using either maps of the Stokes parameters, $Q$ and $U$, or the $E$-mode signal derived from these using a new methodology (which we describe in an appendix). Although remarkable progress has been made in reducing the systematic effects that contaminated the 2015 polarization maps on large angular scales, it is still the case that residual systematics (and our ability to simulate them) can limit some tests of non-Gaussianity and isotropy. However, a detailed set of null tests applied to the maps indicates that these issues do not dominate the analysis on intermediate and large angular scales (i.e., $\ell \lesssim 400$). In this regime, no unambiguous detections of cosmological non-Gaussianity, or of anomalies corresponding to those seen in temperature, are claimed. Notably, the stacking of CMB polarization signals centred on the positions of temperature hot and cold spots exhibits excellent agreement with the $\Lambda$CDM cosmological model, and also gives a clear indication of how Planck provides state-of-the-art measurements of CMB temperature and polarization on degree scales

Planck 2018 results. VII. Isotropy and Statistics of the CMB

Analysis of the Planck 2018 data set indicates that the statistical properties of the cosmic microwave background (CMB) temperature anisotropies are in excellent agreement with previous studies using the 2013 and 2015 data releases. In particular, they are consistent with the Gaussian predictions of the $\Lambda$CDM cosmological model, yet also confirm the presence of several so-called "anomalies" on large angular scales. The novelty of the current study, however, lies in being a first attempt at a comprehensive analysis of the statistics of the polarization signal over all angular scales, using either maps of the Stokes parameters, $Q$ and $U$, or the $E$-mode signal derived from these using a new methodology (which we describe in an appendix). Although remarkable progress has been made in reducing the systematic effects that contaminated the 2015 polarization maps on large angular scales, it is still the case that residual systematics (and our ability to simulate them) can limit some tests of non-Gaussianity and isotropy. However, a detailed set of null tests applied to the maps indicates that these issues do not dominate the analysis on intermediate and large angular scales (i.e., $\ell \lesssim 400$). In this regime, no unambiguous detections of cosmological non-Gaussianity, or of anomalies corresponding to those seen in temperature, are claimed. Notably, the stacking of CMB polarization signals centred on the positions of temperature hot and cold spots exhibits excellent agreement with the $\Lambda$CDM cosmological model, and also gives a clear indication of how Planck provides state-of-the-art measurements of CMB temperature and polarization on degree scales

Exploring Cosmic Origins with CORE: Survey requirements and mission design

Future observations of cosmic microwave background (CMB) polarisation havethe potential to answer some of the most fundamental questions of modernphysics and cosmology. In this paper, we list the requirements for a future CMBpolarisation survey addressing these scientific objectives, and discuss thedesign drivers of the CORE space mission proposed to ESA in answer to the "M5"call for a medium-sized mission. The rationale and options, and themethodologies used to assess the mission's performance, are of interest toother future CMB mission design studies. CORE is designed as a near-ultimateCMB polarisation mission which, for optimal complementarity with ground-basedobservations, will perform the observations that are known to be essential toCMB polarisation scienceand cannot be obtained by any other means than adedicated space mission

The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses

Brendon J Coventry, Martin L AshdownDiscipline of Surgery, University of Adelaide, Royal Adelaide Hospital and Faculty of Medicine, University of Melbourne, AustraliaBackground: This year marks the twentieth anniversary of the approval by the US Food and Drug Administration of interleukin-2 (IL2) for use in cancer therapy, initially for renal cell carcinoma and later for melanoma. IL2 therapy for cancer has stood the test of time, with continued widespread use in Europe, parts of Asia, and the US. Clinical complete responses are variably reported at 5%&amp;ndash;20% for advanced malignant melanoma and renal cell carcinoma, with strong durable responses and sustained long-term 5&amp;ndash;10-year survival being typical if complete responses are generated.Methods: The literature was reviewed for the actions and clinical effects of IL2 on subsets of T cells. The influence of IL2 on clinical efficacy was also sought.Results: The review revealed that IL2 is capable of stimulating different populations of T cells in humans to induce either T effector or T regulatory responses. This apparent &amp;quot;functional paradox&amp;quot; has confounded a clear understanding of the mechanisms behind the clinical effects that are observed during and following administration of IL2 therapy. An average complete response rate of around 7% in small and large clinical trials using IL2 for advanced renal cell carcinoma and malignant melanoma has been shown from a recent review of the literature.Conclusion: This review considers the published literature concerning the actions and emerging clinical effects of IL2 therapy, spanning its 20-year period in clinical use. It further details some of the recently described &amp;quot;bimodal&amp;quot; effects of IL2 to explain the apparent functional paradox, and how IL2 might be harnessed to emerge rapidly as a much more effective and predictable clinical agent in the near future.Keywords: interleukin-2, cancer therapy, immunotherapy, immune response, translational research, cytokines, regulatory T cells, immune modulation, complete responses, bimodal rol

Complete clinical responses to cancer therapy caused by multiple divergent approaches: a repeating theme lost in translation

Brendon J Coventry, Martin L AshdownDiscipline of Surgery, University of Adelaide, Royal Adelaide Hospital and Faculty of Medicine, University of Melbourne, AustraliaAbstract: Over 50 years of cancer therapy history reveals complete clinical responses (CRs) from remarkably divergent forms of therapies (eg, chemotherapy, radiotherapy, surgery, vaccines, autologous cell transfers, cytokines, monoclonal antibodies) for advanced solid malignancies occur with an approximately similar frequency of 5%&amp;ndash;10%. This has remained frustratingly almost static. However, CRs usually underpin strong durable 5-year patient survival. How can this apparent paradox be explained?Over some 20 years, realization that (1) chronic inflammation is intricately associated with cancer, and (2) the immune system is delicately balanced between responsiveness and tolerance of cancer, provides a greatly significant insight into ways cancer might be more effectively treated. In this review, divergent aspects from the largely segmented literature and recent conferences are drawn together to provide observations revealing some emerging reasoning, in terms of &amp;quot;final common pathways&amp;quot; of cancer cell damage, immune stimulation, and auto-vaccination events, ultimately leading to cancer cell destruction. Created from this is a unifying overarching concept to explain why multiple approaches to cancer therapy can provide complete responses at almost equivalent rates. This &amp;quot;missing&amp;quot; aspect provides a reasoned explanation for what has, and is being, increasingly reported in the mainstream literature &amp;ndash; that inflammatory and immune responses appear intricately associated with, if not causative of, complete responses induced by divergent forms of cancer therapy. Curiously, whether by chemotherapy, radiation, surgery, or other means, therapy-induced cell injury results, leaving inflammation and immune system stimulation as a final common denominator across all of these mechanisms of cancer therapy. This aspect has been somewhat obscured and has been &amp;quot;lost in translation&amp;quot; to date.Keywords: chemotherapy, immunotherapy, immune response, common pathways, translational research, oscillation, regulatory T-cells, immune modulation, complete response

Comparison of Sunyaev-Zel’dovich measurements from Planck and from the Arcminute Microkelvin Imager for 99 galaxy clusters

We present observations and analysis of a sample of 123 galaxy clusters from the 2013 Planck catalogue of Sunyaev-Zel’dovich sources with the Arcminute Microkelvin Imager (AMI), a ground-based radio interferometer. AMI provides an independent measurement with higher angular resolution, 3 arcmin compared to the Planck beams of 5–10 arcmin. The AMI observations thus provide validation of the cluster detections, improved positional estimates, and a consistency check on the fitted ‘size’ (θ_s) and ‘flux’ (Y_tot) parameters in the Generalised Navarro, Frenk and White (GNFW) model. We detect 99 of the clusters. We use the AMI positional estimates to check the positional estimates and error-bars produced by the Planck algorithms PowellSnakes and MMF3. We find that Y_tot values as measured by AMI are biased downwards with respect to the Planck constraints, especially for high Planck-SNR clusters. We perform simulations to show that this can be explained by deviation from the ‘universal’ pressure profile shape used to model the clusters. We show that AMI data can constrain the α and β parameters describing the shape of the profile in the GNFW model for individual clusters provided careful attention is paid to the degeneracies between parameters, but one requires information on a wider range of angular scales than are present in AMI data alone to correctly constrain all parameters simultaneously.The AMI telescope is supported by Cambridge University. YCP and CR acknowledge support from CCT/Cavendish Laboratory and STFC studentships, respectively. YCP and MO acknowledge support from Research Fellowships from Trinity College and Sidney Sussex College, Cambridge, respectively. This work was partially undertaken on the COSMOS Shared Memory system at DAMTP, University of Cambridge operated on behalf of the STFC DiRAC HPC Facility. This equipment is funded by BIS National E-infrastructure capital grant ST/J005673/1 and STFC grants ST/H008586/1, ST/K00333X/1. CM acknowledges her KICC Fellowship grant funding for the procurement of the cluster used for computational work. In addition, we would like to thank the IOA computing support team for maintaining the cluster.This is the final version of the article. It first appeared from the European Southern Observatory (ESO) via http://dx.doi.org/10.1051/0004-6361/20142418

Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY)

Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher "immunogenic potential". This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential