Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

In this study, we compare equilibrium-line altitudes (ELAs) calculated using the area–altitude balance ratio (AABR) and the accumulation–area ratio (AAR) methods, with measured ELAs derived from direct field observations. We utilise a GIS toolbox to calculate the ELA for 64 extant glaciers by applying the AABR and AAR methods to DEMs and polygons of their geometry. The calculated ELAs (c-ELAs) are then compared to measured zero-net balance ELAs (znb-ELAs) obtained from mass-balance time series held by the WGMS for the same glaciers. The correlation between znb-ELAs and AABR (1.56)/AAR (0.58) c-ELAs is very strong, with an r2 = 0.99. The smallest median difference between znb-ELAs and c-ELAs (i.e. 65.5 m) is obtained when a globally representative AABR of 1.56 is used. When applied to palaeoglacier-climate applications, this difference translates to ~0.42°C, well within the uncertainty of palaeotemperature proxies used to determine mean summer temperature at the ELA. The more widely used mean AABR of 1.75 is shown to be statistically invalid due to the skewness of the dataset. On this basis, when calculating glacier ELAs, we recommend the use of a global AABR value of 1.56.

The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.

This work investigated the photophysical pathways for light absorption, charge generation, and charge separation in donor–acceptor nanoparticle blends of poly(3-hexylthiophene) and indene-C60-bisadduct. Optical modeling combined with steady-state and time-resolved optoelectronic characterization revealed that the nanoparticle blends experience a photocurrent limited to 60% of a bulk solution mixture. This discrepancy resulted from imperfect free charge generation inside the nanoparticles. High-resolution transmission electron microscopy and chemically resolved X-ray mapping showed that enhanced miscibility of materials did improve the donor–acceptor blending at the center of the nanoparticles; however, a residual shell of almost pure donor still restricted energy generation from these nanoparticles.

We describe system verification tests and early science results from the pulsar processor (PTUSE) developed for the newly commissioned 64-dish SARAO MeerKAT radio telescope in South Africa. MeerKAT is a high-gain (${\sim}2.8\,\mbox{K Jy}^{-1}$) low-system temperature (${\sim}18\,\mbox{K at }20\,\mbox{cm}$) radio array that currently operates at 580–1 670 MHz and can produce tied-array beams suitable for pulsar observations. This paper presents results from the MeerTime Large Survey Project and commissioning tests with PTUSE. Highlights include observations of the double pulsar $\mbox{J}0737{-}3039\mbox{A}$, pulse profiles from 34 millisecond pulsars (MSPs) from a single 2.5-h observation of the Globular cluster Terzan 5, the rotation measure of Ter5O, a 420-sigma giant pulse from the Large Magellanic Cloud pulsar PSR $\mbox{J}0540{-}6919$, and nulling identified in the slow pulsar PSR J0633–2015. One of the key design specifications for MeerKAT was absolute timing errors of less than 5 ns using their novel precise time system. Our timing of two bright MSPs confirm that MeerKAT delivers exceptional timing. PSR $\mbox{J}2241{-}5236$ exhibits a jitter limit of $<4\,\mbox{ns h}^{-1}$ whilst timing of PSR $\mbox{J}1909{-}3744$ over almost 11 months yields an rms residual of 66 ns with only 4 min integrations. Our results confirm that the MeerKAT is an exceptional pulsar telescope. The array can be split into four separate sub-arrays to time over 1 000 pulsars per day and the future deployment of S-band (1 750–3 500 MHz) receivers will further enhance its capabilities.

An Eclipse is an astronomical event that convenes a large audience. Few days before it, most of the community is aware of the event and the press is activated fully on it. The alignment recovers our most intrinsic human aspects, the curiosity, and enthusiasm for a natural phenomenon. This work is focused to enjoy and perceive it in three different ways: visually, listening, and in an artistic expression.

We focused on the construction of more than one hundred LightSound devices, which the main purpose is to record the light intensity and transform it into different tones. Besides, we created an artistic representation of the Eclipse motivated by the ancestral culture of the people residing in the totality zone. This music adds a sensorial joy to the eclipse event.

The Lembo clay deposit occurs on orthogneiss, but it also comprises clays with litho-relicts of volcanic rocks. In this study, ten samples from two sites were investigated. The mineralogical compositions consisted of kaolinite + halloysite + illite + quartz + hematite + anatase ± rutile ± orthoclase ± sanidine ± magnetite ± maghemite ± goethite ± Ba-Al-Fe-phosphates ± carbonates ± sulphates. Kaolinite-halloysite and quartz are the prevailing minerals. Some volcanicderived clays contain Fe-rich kaolinite-halloysite (9.6–14.1 wt.% Fe2O3). The chemical compositions, colours and specific surface area (SSA) measurements reveal two groups of clays: one with a positive whiteness index (IB), small SSA and small Fe content, and the other showing a large SSA, negative IB and relatively large Fe contents. The compositions of the first group are close to those of clays from the Mayouom deposit (Cameroon), and from some European commercial kaolins used in ceramics. Relatively Fe-rich clay materials may conform to most formulations of earthen bricks. As a whole, the Lembo clay deposit comprises various compositions of kaolinitic clays, which may yield the opportunity for extensive application in ceramics.

The Molonglo Observatory Synthesis Telescope (MOST) is an 18000 m2 radio telescope located 40 km from Canberra, Australia. Its operating band (820–851 MHz) is partly allocated to telecommunications, making radio astronomy challenging. We describe how the deployment of new digital receivers, Field Programmable Gate Array-based filterbanks, and server-class computers equipped with 43 Graphics Processing Units, has transformed the telescope into a versatile new instrument (UTMOST) for studying the radio sky on millisecond timescales. UTMOST has 10 times the bandwidth and double the field of view compared to the MOST, and voltage record and playback capability has facilitated rapid implementaton of many new observing modes, most of which operate commensally. UTMOST can simultaneously excise interference, make maps, coherently dedisperse pulsars, and perform real-time searches of coherent fan-beams for dispersed single pulses. UTMOST operates as a robotic facility, deciding how to efficiently target pulsars and how long to stay on source via real-time pulsar folding, while searching for single pulse events. Regular timing of over 300 pulsars has yielded seven pulsar glitches and three Fast Radio Bursts during commissioning. UTMOST demonstrates that if sufficient signal processing is applied to voltage streams, innovative science remains possible even in hostile radio frequency environments.

Photogrammetric processing of archival stereo imagery offers the opportunity to reconstruct glacier volume changes for regions where no such data exist, and to better constrain the contribution to sea-level rise from small glaciers and ice caps. The ability to derive digital elevation model (DEM) measurements of glacier volume from photogrammetry relies on good-quality, well-distributed ground reference data, which may be difficult to acquire. This study shows that ground-control points (GCPs) can be identified and extracted from point-cloud airborne lidar data and used to control photogrammetric glacier models. The technique is applied to midtre Lovénbreen, a small valley glacier in northwest Svalbard. We show that the amount of ground control measured and the elevation accuracy of GCP coordinates (based on known and theoretical error considerations) has a significant effect on photogrammetric model statistics, DEM accuracy and the subsequent geodetic measurement of glacier volume change. Models controlled with fewer than 20 lidar control points or GCPs from sub-optimal areas within the swath footprint overestimated volume change by 14–53% over a 2 year period. DEMs derived from models utilizing 20–25 or more GCPs, however, gave volume change estimates within ∼4% of those from repeat lidar data (−0.51 m a− 1 between 2003 and 2005). Our results have important implications for the measurement of glacier volume change from archival stereo-imagery sources.

The linearly polarized component of a pulsar signal at different radio frequencies can help to constrain the parallel component of the magnetic field along the line of sight. In this work we measured the polarimetric properties of the pulsars in the globular cluster 47 Tucanae and we report the Rotation Measure (RM) for 13 of them. A gradient in the RM values of the pulsars across the cluster is detected suggesting the presence of significant variations in the magnetic field across the very small angular scales associated with the lines of sight to the pulsars in 47 Tucanae. Both magnetic fields located in the globular cluster or in the Galactic disk in the direction of the cluster are taken into consideration. However, more detailed modelling of the dynamics of the cluster and deeper observations with the MeerKAT and/or the SKA1 radio telescopes are necessary to discriminate among the models.

The class of radio transients called Fast Radio Bursts (FRBs) encompasses enigmatic single pulses, each unique in its own way, hindering a consensus for their origin. The key to demystifying FRBs lies in discovering many of them in order to identity commonalities – and in real time, in order to find potential counterparts at other wavelengths. The recently upgraded UTMOST in Australia, is undergoing a backend transformation to rise as a fast transient detection machine. The first interferometric detections of FRBs with UTMOST, place their origin beyond the near-field region of the telescope thus ruling out local sources of interference as a possible origin. We have localised these bursts to much better than the ones discovered at the Parkes radio telescope and have plans to upgrade UTMOST to be capable of much better localisation still.

With the changing distribution of infectious diseases, and an increase in the burden of non-communicable diseases, low- and middle-income countries, including those in Africa, will need to expand their health care capacities to effectively respond to these epidemiological transitions. The interrelated risk factors for chronic infectious and non-communicable diseases and the need for long-term disease management, argue for combined strategies to understand their underlying causes and to design strategies for effective prevention and long-term care. Through multidisciplinary research and implementation partnerships, we advocate an integrated approach for research and healthcare for chronic diseases in Africa.

Depression is one of the most prevalent mental illnesses worldwide and a leading cause of disability, especially in the setting of treatment resistance. In recent years, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative strategy for treatment-resistant depression and its clinical efficacy has been investigated intensively across the world. However, the underlying neurobiological mechanisms of the antidepressant effect of rTMS are still not fully understood. This review aims to systematically synthesize the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996–2014), Embase (1980–2014) and PsycINFO (1806–2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1647 articles identified, 66 studies met both inclusion and exclusion criteria. rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limits the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggest that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. More research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

40Ar/39Ar in situ UV laser ablation of white mica, Rb–Sr mineral isochrons and zircon fission track dating were applied to determine ages of very low- to low-grade metamorphic processes at 3.5±0.4 kbar, 280±30°C in the Avalonian Mira terrane of SE Cape Breton Island (Nova Scotia). The Mira terrane comprises Neoproterozoic volcanic-arc rocks overlain by Cambrian sedimentary rocks. Crystallization of metamorphic white mica was dated in six metavolcanic samples by 40Ar/39Ar spot age peaks between 396±3 and 363±14 Ma. Rb–Sr systematics of minerals and mineral aggregates yielded two isochrons at 389±7 Ma and 365±8 Ma, corroborating equilibrium conditions during very low- to low-grade metamorphism. The dated white mica is oriented parallel to foliations produced by sinistral strike-slip faulting and/or folding related to the Middle–Late Devonian transpressive assembly of Avalonian terranes during convergence and emplacement of the neighbouring Meguma terrane. Exhumation occurred earlier in the NW Mira terrane than in the SE. Transpression was related to the closure of the Rheic Ocean between Gondwana and Laurussia by NW-directed convergence. The 40Ar/39Ar spot age spectra also display relict age peaks at 477–465 Ma, 439 Ma and 420–428 Ma attributed to deformation and fluid access, possibly related to the collision of Avalonia with composite Laurentia or to earlier Ordovician–Silurian rifting. Fission track ages of zircon from Mira terrane samples range between 242±18 and 225±21 Ma and reflect late Palaeozoic reburial and reheating close to previous peak metamorphic temperatures under fluid-absent conditions during rifting prior to opening of the Central Atlantic Ocean.

Reproductive effects from phthalate exposure have been documented mostly in animal studies. This study explored the association between prenatal exposure to phthalate metabolites, anogenital distance and penile measurements in male newborns in Toluca, State of Mexico. A total of 174 pregnant women provided urine samples for phthalate analysis during their last prenatal visit, and the 73 who gave birth to male infants were included in the study. The 73 male newborns were weighed and measured using standardized methods after delivery. After adjusting for creatinine and supine length at birth, significant inverse associations were observed between an index of prenatal exposure to total phthalate exposure and the distance from the anus to anterior base of the penis (β = −0.191 mm per 1 μg/l, P = 0.037), penile width (β = −0.0414, P = 0.050) and stretched length (β = −0.2137, P = 0.034); prenatal exposure to mono-2-ethylhexyl phthalate exposure was associated with a reduction in the stretched length of the penis (β = −0.2604, P = 0.050). Human exposure to phthalates is a public health concern, and the system most vulnerable to its potential effects seems to be the immature male reproductive tract.

The OVV blazar 3C 446 was monitored over seven months in 1997 with ground based telescopes and instruments on ESA's Infrared Space Observatory (ISO). The aim was to try to detect variations in the IR and see if these were correlated with optical variations. The object varied in the optical and near-IR during this period, but did not vary in the far-IR. Despite being a factor of ten weaker than in 1983, the optical-IR SED exhibited the same slope. The new far-IR observations from ISO allow us to determine the location of the turnover in the spectrum, caused by synchrotron self-absorption. It occurs just longwards of 100 μm.