Showing papers by "University of Toronto published in 2018"

PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation

Abstract: Scoping reviews, a type of knowledge synthesis, follow a systematic approach to map evidence on a topic and identify main concepts, theories, sources, and knowledge gaps. Although more scoping reviews are being done, their methodological and reporting quality need improvement. This document presents the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist and explanation. The checklist was developed by a 24-member expert panel and 2 research leads following published guidance from the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network. The final checklist contains 20 essential reporting items and 2 optional items. The authors provide a rationale and an example of good reporting for each item. The intent of the PRISMA-ScR is to help readers (including researchers, publishers, commissioners, policymakers, health care providers, guideline developers, and patients or consumers) develop a greater understanding of relevant terminology, core concepts, and key items to report for scoping reviews.

Minimal information for studies of extracellular vesicles 2018 (MISEV2018) : a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

Abstract: The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Abstract: Background In a single-center phase 1–2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) Methods We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry The rates of event-f

Planck 2018 results. VI. Cosmological parameters

Abstract: We present cosmological parameter results from the final full-mission Planck measurements of the CMB anisotropies. We find good consistency with the standard spatially-flat 6-parameter $\Lambda$CDM cosmology having a power-law spectrum of adiabatic scalar perturbations (denoted "base $\Lambda$CDM" in this paper), from polarization, temperature, and lensing, separately and in combination. A combined analysis gives dark matter density $\Omega_c h^2 = 0.120\pm 0.001$, baryon density $\Omega_b h^2 = 0.0224\pm 0.0001$, scalar spectral index $n_s = 0.965\pm 0.004$, and optical depth $\tau = 0.054\pm 0.007$ (in this abstract we quote $68\,\%$ confidence regions on measured parameters and $95\,\%$ on upper limits). The angular acoustic scale is measured to $0.03\,\%$ precision, with $100\theta_*=1.0411\pm 0.0003$. These results are only weakly dependent on the cosmological model and remain stable, with somewhat increased errors, in many commonly considered extensions. Assuming the base-$\Lambda$CDM cosmology, the inferred late-Universe parameters are: Hubble constant $H_0 = (67.4\pm 0.5)$km/s/Mpc; matter density parameter $\Omega_m = 0.315\pm 0.007$; and matter fluctuation amplitude $\sigma_8 = 0.811\pm 0.006$. We find no compelling evidence for extensions to the base-$\Lambda$CDM model. Combining with BAO we constrain the effective extra relativistic degrees of freedom to be $N_{\rm eff} = 2.99\pm 0.17$, and the neutrino mass is tightly constrained to $\sum m_ u< 0.12$eV. The CMB spectra continue to prefer higher lensing amplitudes than predicted in base -$\Lambda$CDM at over $2\,\sigma$, which pulls some parameters that affect the lensing amplitude away from the base-$\Lambda$CDM model; however, this is not supported by the lensing reconstruction or (in models that also change the background geometry) BAO data. (Abridged)

Perovskite light-emitting diodes with external quantum efficiency exceeding 20 per cent

Abstract: Metal halide perovskite materials are an emerging class of solution-processable semiconductors with considerable potential for use in optoelectronic devices1–3. For example, light-emitting diodes (LEDs) based on these materials could see application in flat-panel displays and solid-state lighting, owing to their potential to be made at low cost via facile solution processing, and could provide tunable colours and narrow emission line widths at high photoluminescence quantum yields4–8. However, the highest reported external quantum efficiencies of green- and red-light-emitting perovskite LEDs are around 14 per cent7,9 and 12 per cent8, respectively—still well behind the performance of organic LEDs10–12 and inorganic quantum dot LEDs13. Here we describe visible-light-emitting perovskite LEDs that surpass the quantum efficiency milestone of 20 per cent. This achievement stems from a new strategy for managing the compositional distribution in the device—an approach that simultaneously provides high luminescence and balanced charge injection. Specifically, we mixed a presynthesized CsPbBr3 perovskite with a MABr additive (where MA is CH3NH3), the differing solubilities of which yield sequential crystallization into a CsPbBr3/MABr quasi-core/shell structure. The MABr shell passivates the nonradiative defects that would otherwise be present in CsPbBr3 crystals, boosting the photoluminescence quantum efficiency, while the MABr capping layer enables balanced charge injection. The resulting 20.3 per cent external quantum efficiency represents a substantial step towards the practical application of perovskite LEDs in lighting and display. A strategy for managing the compositional distribution in metal halide perovskite light-emitting diodes enables them to surpass 20% external quantum efficiency—a step towards their practical application in lighting and displays.

Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU

Abstract: Objective:To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU.Design:Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups g

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

Abstract: Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Automatic Chemical Design Using a Data-Driven Continuous Representation of Molecules

Abstract: We report a method to convert discrete representations of molecules to and from a multidimensional continuous representation. This model allows us to generate new molecules for efficient exploration and optimization through open-ended spaces of chemical compounds. A deep neural network was trained on hundreds of thousands of existing chemical structures to construct three coupled functions: an encoder, a decoder, and a predictor. The encoder converts the discrete representation of a molecule into a real-valued continuous vector, and the decoder converts these continuous vectors back to discrete molecular representations. The predictor estimates chemical properties from the latent continuous vector representation of the molecule. Continuous representations of molecules allow us to automatically generate novel chemical structures by performing simple operations in the latent space, such as decoding random vectors, perturbing known chemical structures, or interpolating between molecules. Continuous represent...

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Abstract: Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

DNA methylation-based classification of central nervous system tumours

Abstract: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

GW170817: Measurements of Neutron Star Radii and Equation of State.

Abstract: On 17 August 2017, the LIGO and Virgo observatories made the first direct detection of gravitational waves from the coalescence of a neutron star binary system. The detection of this gravitational-wave signal, GW170817, offers a novel opportunity to directly probe the properties of matter at the extreme conditions found in the interior of these stars. The initial, minimal-assumption analysis of the LIGO and Virgo data placed constraints on the tidal effects of the coalescing bodies, which were then translated to constraints on neutron star radii. Here, we expand upon previous analyses by working under the hypothesis that both bodies were neutron stars that are described by the same equation of state and have spins within the range observed in Galactic binary neutron stars. Our analysis employs two methods: the use of equation-of-state-insensitive relations between various macroscopic properties of the neutron stars and the use of an efficient parametrization of the defining function pðρÞ of the equation of state itself. From the LIGO and Virgo data alone and the first method, we measure the two neutron star radii as R1 ¼ 10.8 þ2.0 −1.7 km for the heavier star and R2 ¼ 10.7 þ2.1 −1.5 km for the lighter star at the 90% credible level. If we additionally require that the equation of state supports neutron stars with masses larger than 1.97 M⊙ as required from electromagnetic observations and employ the equation-of-state parametrization, we further constrain R1 ¼ 11.9 þ1.4 −1.4 km and R2 ¼ 11.9 þ1.4 −1.4 km at the 90% credible level. Finally, we obtain constraints on pðρÞ at supranuclear densities, with pressure at twice nuclear saturation density measured at 3.5 þ2.7 −1.7 × 1034 dyn cm−2 at the 90% level.

Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer

Abstract: Background Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the o...

Opportunities and obstacles for deep learning in biology and medicine.

Abstract: Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems-patient classification, fundamental biological processes and treatment of patients-and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we find that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a specific neural network's prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labelled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine.

Nanopore sequencing and assembly of a human genome with ultra-long reads

Abstract: We report the sequencing and assembly of a reference genome for the human GM12878 Utah/Ceph cell line using the MinION (Oxford Nanopore Technologies) nanopore sequencer. 91.2 Gb of sequence data, representing ∼30× theoretical coverage, were produced. Reference-based alignment enabled detection of large structural variants and epigenetic modifications. De novo assembly of nanopore reads alone yielded a contiguous assembly (NG50 ∼3 Mb). We developed a protocol to generate ultra-long reads (N50 > 100 kb, read lengths up to 882 kb). Incorporating an additional 5× coverage of these ultra-long reads more than doubled the assembly contiguity (NG50 ∼6.4 Mb). The final assembled genome was 2,867 million bases in size, covering 85.8% of the reference. Assembly accuracy, after incorporating complementary short-read sequencing data, exceeded 99.8%. Ultra-long reads enabled assembly and phasing of the 4-Mb major histocompatibility complex (MHC) locus in its entirety, measurement of telomere repeat length, and closure of gaps in the reference human genome assembly GRCh38.

Analysis of shared heritability in common disorders of the brain

Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

CO2 electroreduction to ethylene via hydroxide-mediated copper catalysis at an abrupt interface

Abstract: Carbon dioxide (CO 2 ) electroreduction could provide a useful source of ethylene, but low conversion efficiency, low production rates, and low catalyst stability limit current systems. Here we report that a copper electrocatalyst at an abrupt reaction interface in an alkaline electrolyte reduces CO 2 to ethylene with 70% faradaic efficiency at a potential of −0.55 volts versus a reversible hydrogen electrode (RHE). Hydroxide ions on or near the copper surface lower the CO 2 reduction and carbon monoxide (CO)–CO coupling activation energy barriers; as a result, onset of ethylene evolution at −0.165 volts versus an RHE in 10 molar potassium hydroxide occurs almost simultaneously with CO production. Operational stability was enhanced via the introduction of a polymer-based gas diffusion layer that sandwiches the reaction interface between separate hydrophobic and conductive supports, providing constant ethylene selectivity for an initial 150 operating hours.

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

Abstract: Background The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. Methods We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). Results Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free surv...

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter

Abstract: Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma

Abstract: Background Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell–like [ABC], germinal-center B-cell–like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. Methods We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. Results We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B muta...

Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial

Abstract: Importance Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months. Intervention Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects. Main Outcomes and Measures Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)–positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration. Results Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1–positive and PD-L1–negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment. Conclusions and Relevance Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1–positive and PD-L1–negative tumors. Further study of pembrolizumab for this group of patients is warranted. Trial Registration clinicaltrials.gov Identifier: NCT02335411

Efficient and stable emission of warm-white light from lead-free halide double perovskites

Abstract: Lighting accounts for one-fifth of global electricity consumption1. Single materials with efficient and stable white-light emission are ideal for lighting applications, but photon emission covering the entire visible spectrum is difficult to achieve using a single material. Metal halide perovskites have outstanding emission properties2,3; however, the best-performing materials of this type contain lead and have unsatisfactory stability. Here we report a lead-free double perovskite that exhibits efficient and stable white-light emission via self-trapped excitons that originate from the Jahn–Teller distortion of the AgCl6 octahedron in the excited state. By alloying sodium cations into Cs2AgInCl6, we break the dark transition (the inversion-symmetry-induced parity-forbidden transition) by manipulating the parity of the wavefunction of the self-trapped exciton and reduce the electronic dimensionality of the semiconductor4. This leads to an increase in photoluminescence efficiency by three orders of magnitude compared to pure Cs2AgInCl6. The optimally alloyed Cs2(Ag0.60Na0.40)InCl6 with 0.04 per cent bismuth doping emits warm-white light with 86 ± 5 per cent quantum efficiency and works for over 1,000 hours. We anticipate that these results will stimulate research on single-emitter-based white-light-emitting phosphors and diodes for next-generation lighting and display technologies. After alloying with metal cations, a lead-free halide double perovskite shows stable performance and remarkably efficient white-light emission, with possible applications in lighting and display technologies.

Challenges for commercializing perovskite solar cells.

Abstract: BACKGROUND Perovskite solar cells (PSCs) have attracted intensive attention because of their ever-increasing power conversion effi­ciency (PCE), low-cost materials constituents, and simple solution fabrication process. Initi­ated in 2009 with an efficiency of 3.8%, PSCs have now achieved a lab-scale power conversion efficiency of 23.3%, rivaling the performance of commercial multicrystalline silicon solar cells, as well as copper indium gallium selenide (CIGS) and cadmium telluride (CdTe) thin-film solar cells. Thousands of articles re­lated to PSCs have been published each year since 2015, highlighting PSCs as a topic of in­tense interest in photovoltaics (PV) research. With high efficiencies achieved in lab devices, stability and remaining challenges in upscal­ing the manufacture of PSCs are two critical concerns that must be addressed on the path to PSC commercialization. ADVANCES We review recent progress in PSCs and discuss the remaining challenges along the pathway to their commercialization. Device configurations of PSCs (see the figure) include mesoscopic formal (n-i-p) and inverted (p-i-n) structures, planar formal and inverted struc­tures, and the printable triple mesoscopic structures. PCEs of devices that use these structures have advanced rapidly in the case of small-area devices (~0.1 cm 2 ). PSCs are also attracting attention as top cells for the construction of tandem solar cells with existing mature PV technologies to increase efficiency beyond the Shockley-Queisser limit of single-junction devices. The stability of PSCs has attracted much well-deserved attention of late, and notable progress has been made in the past few years. PSCs have recently achieved exhibited life­times of 10,000 hours under 1 sun (1 kW/m 2 ) illumina­tion with an ultraviolet filter at a stabilized temperature of 55°C and at short-circuit conditions for a printable triple mesoscopic PSCs. This irradiation is equivalent to the total irradiation of 10 years of outdoor use in most of Europe. However, within the PSC community, standard testing protocols require further development. In addition, transpar­ency in reporting standards on stability tests needs to be improved; this can be achieved by providing both initial photovoltaic performance and normalization parameters. The upscaling of PSCs has also progressed steadily, leading to PSC mini-modules, standard-sized modules, and power systems. PV companies have set out to manufacture large-area PSC modules (see the figure), and a 110-m 2 perovskite PV system with screen-printed triple mesoscopic PSC modules was recently debuted. Studies of these increased-area modules and systems will promote the development of PSCs toward commercializa­tion. PSC research is expanding to cover fundamental topics on materials and lab-sized cells, as well as to address issues of in­dustrial-scale manufacturing and deployment. OUTLOOK The PV market has been continu­ously expanding in recent years, bringing op­portunities for new PV technologies of which PSCs are promising candidates. It is impera­tive to achieve a low cost per watt, which means that both efficiency and lifetime need improve­ment relative to current parameters. The efficiency gap between lab cells and industrial modules has seen impressive reduc­tions in crystalline silicon; PSCs must simi­larly enlarge module areas to the panel level and need to achieve lifetimes comparable to those of legacy PV technologies. Other improvements will need to include industry-scale electronic-grade films, recycling methods to address concerns regarding lead toxicity, and the adoption of standardized testing protocols to predict the operation lifetime of PSCs. Modules will need to endure light-induced degradation, potential-induced degradation, partial-shade stress, and mechanical shock. The field can benefit from lessons learned during the development of mature PV technologies as it strives to de­fine, and overcome, the hurdles to PSC com­mercial impact.

Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016

Abstract: Summary Background Lower respiratory infections are a leading cause of morbidity and mortality around the world The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study 2016, provides an up-to-date analysis of the burden of lower respiratory infections in 195 countries This study assesses cases, deaths, and aetiologies spanning the past 26 years and shows how the burden of lower respiratory infection has changed in people of all ages Methods We used three separate modelling strategies for lower respiratory infections in GBD 2016: a Bayesian hierarchical ensemble modelling platform (Cause of Death Ensemble model), which uses vital registration, verbal autopsy data, and surveillance system data to predict mortality due to lower respiratory infections; a compartmental meta-regression tool (DisMod-MR), which uses scientific literature, population representative surveys, and health-care data to predict incidence, prevalence, and mortality; and modelling of counterfactual estimates of the population attributable fraction of lower respiratory infection episodes due to Streptococcus pneumoniae, Haemophilus influenzae type b, influenza, and respiratory syncytial virus We calculated each modelled estimate for each age, sex, year, and location We modelled the exposure level in a population for a given risk factor using DisMod-MR and a spatio-temporal Gaussian process regression, and assessed the effectiveness of targeted interventions for each risk factor in children younger than 5 years We also did a decomposition analysis of the change in LRI deaths from 2000–16 using the risk factors associated with LRI in GBD 2016 Findings In 2016, lower respiratory infections caused 652 572 deaths (95% uncertainty interval [UI] 586 475–720 612) in children younger than 5 years (under-5s), 1 080 958 deaths (943 749–1 170 638) in adults older than 70 years, and 2 377 697 deaths (2 145 584–2 512 809) in people of all ages, worldwide Streptococcus pneumoniae was the leading cause of lower respiratory infection morbidity and mortality globally, contributing to more deaths than all other aetiologies combined in 2016 (1 189 937 deaths, 95% UI 690 445–1 770 660) Childhood wasting remains the leading risk factor for lower respiratory infection mortality among children younger than 5 years, responsible for 61·4% of lower respiratory infection deaths in 2016 (95% UI 45·7–69·6) Interventions to improve wasting, household air pollution, ambient particulate matter pollution, and expanded antibiotic use could avert one under-5 death due to lower respiratory infection for every 4000 children treated in the countries with the highest lower respiratory infection burden Interpretation Our findings show substantial progress in the reduction of lower respiratory infection burden, but this progress has not been equal across locations, has been driven by decreases in several primary risk factors, and might require more effort among elderly adults By highlighting regions and populations with the highest burden, and the risk factors that could have the greatest effect, funders, policy makers, and programme implementers can more effectively reduce lower respiratory infections among the world's most susceptible populations Funding Bill & Melinda Gates Foundation

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.

Abstract: Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 ( HER2/chromosome enumeration probe 17 [CEP17] ratio ≥ 2.0; average HER2 copy number < 4.0 signals per cell), ISH group 3 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 6.0 signals per cell), and ISH group 4 ( HER2/CEP17 ratio < 2.0; average HER2 copy number ≥ 4.0 and < 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays. The Expert Panel recommends that laboratories using single-probe ISH assays include concomitant IHC review as part of the interpretation of all single-probe ISH assay results. Find additional information at www.asco.org/breast-cancer-guidelines .