Generalized pustular psoriasis (GPP) is a rare variant of psoriasis with severe clinical symptoms. However, the quality of life (QoL) of the patients is largely unknown. We conducted a nationwide cross‐sectional survey of Japanese GPP patients using the 36‐Item Short‐Form Health Survey version 2 (SF‐36v2) to elucidate patients’ QoL and how their QoL had changed over the last decade. We analyzed QoL data of 83 patients obtained from 2016 to 2019 (present group) and compared it with that of 105 patients collected in a previous survey conducted between 2003 and 2007 (past group). Although the QoL of the present patients was still largely impaired in comparison with the standard Japanese population, substantial improvement was found in some SF‐36v2 subscales including “general health”, “vitality”, “social functioning” and “mental health” as compared with that of the past group. Advances in treatment may contribute to this QoL improvement. Generalized pustular psoriasis (GPP) is a rare variant of psoriasis, which represent 2% of psoriatic diseases.Because of the small number of GPP patients in each facility, little is known about their QoL. Although no studies investigating the QoL of GPP patients were retrieved from the PubMed database, a cross‐sectional QoL survey on Japanese patients with GPP using the Medical Outcomes Study 36‐Item Short‐Form Health Survey version 2 (SF‐36v2) was carried out by a group from Okayama University between 2003 and 2007.The purpose of this study was to elucidate the QoL of present GPP patients by conducting a cross‐sectional survey using SF‐36v2 and to examine how the QoL of the patients has changed over the last decade by comparing past (2003–2007) and present (2016–2019) data.A questionnaire‐based study was performed by sending questionnaires to the 668 hospitals/facilities providing dermatological training under the certification of the Japanese Dermatological Association. The propriety of the participation in this research and the patient number were verified by the first questionnaire. The second questionnaire was sent to the participating institutions to collect the data of patients who were diagnosed with GPP based on the diagnostic criteria of Japanese guidelines.This study was approved by the ethics committee of Nihon University Itabashi Hospital (RK‐151110‐3). The SF‐36v2 license for this study was obtained from i‐Hope International.P < 0.05 is considered statistically significant. The Z‐test was performed for comparison with the standard population. Differences between the two groups were analyzed using the Mann–Whitney U‐test. Fisher’s exact test was employed to examine differences in patient backgrounds.Statistical analyses were performed using GraphPad Prism version 8 , in which A total of 83 patients’ data  from 33 institutions were collected for analyses as the present group. The past group consisted of 105 patients . Most of the patients were classified as von Zumbusch type, 99 (94.3%) in the past group and 80 (96.4%) in the present group based on the Japanese guidelines.Treatment backgrounds of the patients are also summarized in Table Each SF‐36v2 element from the national standard population in 2007 and 2017 was adjusted to the average of 50 points with 10 points SD. Then, patients’ data of the individual elements from past and present populations were converted accordingly into T‐scores for comparison. All SF‐36v2 subscales of the past group showed significantly lower values than the 2007 national standard Fig. . WhereasWe next examined how patients’ QoL changed over the last decade and calculated T‐scores on the basis of the 2007 national standard for both past and present arms. It was found that the T‐scores of the present group were statistically significantly higher in general health, vitality, social functioning and mental health Table . InteresThis is the first QoL study exclusively focused on GPP patients. In the data of the past group, all T‐scores of the subscales were significantly lower than the average of standard Japanese people. During the last decade, half of the subscales  were statistically significantly improved. Intact statuses of vitality, social functioning and mental health subscales only in the present patients may also support QoL improvement. In reference, comparison using standard populations in 2007 for past and 2017 for present patients, all subscales but bodily pain were statistically significantly improved. Although this is just a reference calculation approach, it suggests the possibility that wider ranges of QoL elements may have improved.One possible explanation for this QoL improvement is recent advances in treatment. New treatments such as biologics and GMA were first approved for GPP in 2010 and 2012, respectively, in Japan. Indeed, some treatments were reported to improve QoL of GPP patients.Our study has some limitations. First, there were some differences in patient backgrounds between the past and present populations. There was a substantial difference in sex ratio between the past and present groups for an unknown reason. Second, we could not compare the disease severity data between past and present arms, because Japanese GPP guidelines revised the severity criteria in 2014.In summary, this is the first study showing that GPP patients have impaired QoL compared with controls, even with recent advances in the treatment. We also demonstrated for the first time that QoL of GPP patients significantly improved during the last decade. Further researches are required to elucidate the contribution of new treatments such as biologics to patients’ QoL.K. H. reports grants, personal fees and non‐financial support from AbbVie; grants and personal fees from Eisai; personal fees from Janssen Pharmaceutical; grants and personal fees from Kaken Pharmaceutical; grants and personal fees from Kyorin; grants and personal fees from Maruho; grants and personal fees from Mitubishi‐Tanabe; grants from Nihon Pharmaceutical; grants, personal fees and non‐financial support from Novartis; grants and personal fees from Sanofi; grants from Sun Pharma; grants and personal fees from Taiho; and grants from Kyowa‐Kirin, outside the submitted work. H. F. reports grants and personal fees from AbbVie; grants and personal fees from Eisai; personal fees from Janssen Pharmaceutical; grants from Kaken Pharmaceutical; grants from Kyorin; grants and personal fees from Maruho; grants and personal fees from Mitubishi‐Tanabe; grants from Nihon Pharmaceutical; grants and personal fees from Novartis; grants and personal fees from Sanofi; grants from Sun Pharma; grants and personal fees from Taiho; personal fees from Eli Lilly; grants and personal fees from Kyowa‐Kirin; personal fees from UCB; and personal fees from Boehringer Ingelheim, outside the submitted work. K. I. reports personal fees from Minophagen; personal fees from NAOS JAPAN; personal fees from GSK; personal fees from Kyowa‐Kirin; personal fees from Torii Pharmaceutical; and personal fees from Mitsubishi‐Tanabe, outside the submitted work. T. T. reports grants and personal fees from AbbVie; grants and personal fees from Eisai; personal fees from Janssen Pharmaceutical; grants from Kaken Pharmaceutical and Kyorin; grants and personal fees from Maruho and Mitubishi‐Tanabe; grants from Nihon Pharmaceutical; grants and personal fees from Novartis; grants from Sanofi; grants from Sun Pharma; grants and personal fees from Taiho; personal fees from Eli Lilly; grants and personal fees from Kyowa‐Kirin; and personal fees from Boehringer Ingelheim, outside the submitted work.Table S1. Comparison of T‐scores of 36‐Item Short‐Form Health Survey version 2 (SF‐36v2) subscales calculated from respective coeval Japanese standards between past and present patientsClick here for additional data file.


Spaceborne radars offer a unique three‐dimensional view of the atmospheric components of the Earth's hydrological cycle. Existing and planned spaceborne radar missions provide cloud and precipitation information over the oceans and land difficult to access in remote areas. A careful look into their measurement capabilities indicates considerable gaps that hinder our ability to detect and probe key cloud and precipitation processes. The international community is currently debating how the next generation of spaceborne radars shall enhance current capabilities and address remaining gaps. Part of the discussion is focused on how to best take advantage of recent advancements in radar and space platform technologies while addressing outstanding limitations. First, the observing capabilities and measurement highlights of existing and planned spaceborne radar missions including TRMM, CloudSat, GPM, RainCube, and EarthCARE are reviewed. Then, the limitations of current spaceborne observing systems, with respect to observations of low‐level clouds, midlatitude and high‐latitude precipitation, and convective motions, are thoroughly analyzed. Finally, the review proposes potential solutions and future research avenues to be explored. Promising paths forward include collecting observations across a gamut of frequency bands tailored to specific scientific objectives, collecting observations using mixtures of pulse lengths to overcome trade‐offs in sensitivity and resolution, and flying constellations of miniaturized radars to capture rapidly evolving weather phenomena. This work aims to increase the awareness about existing limitations and gaps in spaceborne radar measurements and to increase the level of engagement of the international community in the discussions for the next generation of spaceborne radar systems. Current spaceborne radars offer a unique three‐dimensional view of the atmospheric component of the Earth's hydrological cycleCurrent spaceborne radar have limitations with respect to observations of low‐level clouds, midlatitude/high‐latitude precipitation, and convectionRecent advances in radar technology will enable filling current science gaps Three (out of seven) of the grand challenges posed by the World Climate Research Program  are in fact centered around this theme: (1) Clouds, Circulation and Climate Sensitivity, (2) Understanding and Predicting Weather and Climate Extremes, and (3) Water for the Food Baskets of the World. These challenges require improving our skill in observing and ultimately predicting when, where, and why clouds form, whether they precipitate or not, and, if they do, how much precipitation they generate in the current climate and how this might evolve in a warming climate; this is not an easy task as specific hurdles exist in all these areas.The Clouds play a critical role in the Earth's radiative budget through the reflection, absorption and emission of radiation, and through the vertical release of latent heat Figure . Clouds 2 for each 1 mm/day of liquid precipitation  as well as the thermal radiation emitted by the Earth's atmosphere . However, such measurements provide limited information about the vertical distribution of hydrometeors in the atmospheric column.Active sensors in the microwave spectrum were deployed to meet this need since, contrary to infrared and visible, microwave radiation can penetrate clouds and precipitation and detail their vertical structure. The development of microwave radars for the study of clouds and precipitation started almost 70 years ago. Early efforts focused on the development of centimeter‐wavelength radars (3–10 cm) capable of probing large areas with precipitation while experiencing limited attenuation. Since then, a large body of theoretical and experimental work has been accomplished to the point that most of the measurable properties of radar signals—amplitude, phase, polarization, and frequency—can be interpreted in terms of the sizes, shapes, motions, or thermodynamic phase of the precipitation particles Atlas, . Furtherλ4. Today, millimeter‐wavelength radars along with lidar systems are the principal tools for the study of clouds , a smaller but energetic research community focused in the development of radar operating at millimeter wavelengths (8.6 and 3.2 mm) often called “cloud radars.” Their sensitivity to cloud droplets and small ice crystals arises from their short wavelength and the fact that in the Rayleigh scattering regime the hydrometeor cross section depends on the 1/One pivotal moment on the use of centimeter‐ and millimeter‐wavelength radars for cloud and precipitation studies was the launch of the CloudSat Cloud Profiling Radar (CPR) mission in 2006 which featured the first 94 GHz radar in space. From the first moment the CPR transmitted in space  for the first ever four‐frequency airborne data set of multifrequency radar data with frequencies ranging from X to W band on board the NASA ER‐2  of Japan, paved the way toward the design of the first spaceborne rain radar  and by an increase of 9 W/m2 in the up‐welling longwave flux. The surplus of 4 W/m2 of radiative flux into the surface of the new budget is mostly compensated by an increase of the latent heat flux. Since the annual global mean evaporation is balanced by the annual global precipitation amount, the increase in the latent heat flux of 4 W/m2 corresponds to an increase of precipitation of 0.14 mm/day . Again, CloudSat measurements hinted in this direction by pinpointing at underestimation of light precipitation in the midlatitudes and a significative contribution (up to 4 W/m2) from snowfall at high latitudes. An overall increase in global mean precipitation by 5–8% have been now reported but not yet published by GEWEX.The deployment of such system in space to cover global scale did not start until the late 1990s. Space operating requirements and the cost associated with developing space‐qualified components with high technology readiness level (TRL) explain some of the latency in developing the first spaceborne missions and the slow rate at which subsequent missions have been being launched. The launches and the extended missions of the first two radars, the Tropical Rainfall Measuring Mission (TRMM) precipitation radar and the CloudSat cloud profiling radar  satellite, launched in November 1997 was a joint mission by the National Aeronautics and Space Administration (NASA) and the Japanese Aerospace Exploration Agency (JAXA) successfully operated from 1997 to 2015, was the first weather radar in space Okamoto, . The TRM2.1.1Maps of Precipitation in the Tropical Regions. TRMM provided the first global characterization of tropical rainfall. The rain maps in Figure Three‐Dimensional Views of Storm Systems. The ranging capability of the PR combined with the cross‐track scanning strategy has enabled TRMM to resolve the three‐dimensional structure of storms at an unprecedented vertical resolution of 250 m. In pulsed radar systems the vertical resolution, Δr, is related to the pulse length, τp, via Δr = cτp/2. The received power is typically oversampled, for example, for GPM power samples are collected at 1.2 MHz corresponding to a 125 m sampling. Figure Characterization of Storms. This new capability led to the retrieval of the latent heat release in the atmosphere  mission aims at further understanding global precipitation and its spatio‐temporal variability as a core component of the Earth's weather, climate, and hydrological systems , the GPM‐CO expands the TRMM measurements to higher latitudes and more overland regions. For the first time the 3‐D structure of precipitating systems, including moderate to intense snow events and extratropical cyclones, can be observed globally in the 35–65° latitudinal band.The DPR is the first ever dual‐frequency atmospheric radar in space with increased potential compared to its TRMM‐PR predecessor in narrowing down uncertainties in rainfall estimates and in providing insight in rain and ice microphysics.The GPM‐CO acts as the reference calibrator of a constellation of passive microwave radiometers  spacecraft  while JAXA's GPM products can be obtained from https://gportal.jaxa.jp/gpr/ or http://sharaku.eorc.jaxa.jp/.All GPM data are freely available at PPS  and the mean mass‐weighted raindrop size (Dm) with respect to the rain type and precipitation efficiency index . Compared with stratiform precipitation, convective systems tend to produce larger mean raindrop sizes (>2 mm) for precipitating clouds with the same precipitation efficiency index, and larger Nw for the same Dm, indicating different rain processes below and/or different ice microphysics above the melting layer.DFR has also potential to obtain microphysical properties associated with ice. Based on thresholds in Z and DFR, Iguchi et al.  introducAs well as providing valuable contributions to science, GPM near real time products, IMERG in primis, are now used to provide applications like hazard assessment for floods, landslides and droughts and to shed light upon societal issues like agricultural productivity, famine, and public health  launched the first satellite‐borne (CloudSat) W band (94 GHz) cloud profiling radar .The CloudSat data products, together with their descriptions and data product levels, are currently available from the CloudSat Data Processing Center , which is obtained from the MODIS level 2 MYD06 cloud product. The statistics derived in this manner are shown in Figures 2.4When attempting to improve the temporal sampling frequency to time scales of minutes or tens of minutes, a single‐radar in LEO solution is insufficient. One possible solution that has been explored is that of deploying a radar in GEO. Such solution is ideal for systematic monitoring of low latitude regions of particular interest , but it cannot be extended to truly global sampling and it does require significant resources in terms of size, mass and power because of the large distance from Earth. The alternative to deploying precipitation radars in GEO is to deploy several radars in LEO (as a convoy or constellation). This has not been realistically affordable for decades until the arrival of the smallsat and CubeSat platforms. At this point the challenge has moved to simultaneously miniaturizing, reducing costs and preserving fundamental performance requirements for this type of radar. Following these aims, a novel architecture compatible with the 6U class (or larger) has been developed at the NASA Jet Propulsion Laboratory (JPL). The Radar in a CubeSat (RainCube) architecture reduces the number of components, power consumption and mass by over one order of magnitude with respect to existing spaceborne radars. The RainCube mission  are shown in Figure Furthermore, direct application of deconvolution approaches has demonstrated potential to improve the along‐track resolution from the native 8 to 4 km , as part of its Earth Explorer Core mission, selected the Earth, Clouds, Aerosols, and Radiation Explorer (EarthCARE) mission with a spaceborne 94 GHz radar and this is intended for launch in 2022  have not been used yet but offer an attractive solution for dual‐wavelength measurements at small particle sizes and for water vapor profiling.The CloudSat and EarthCARE CPRs achieve high sensitivity and high horizontal resolution by using high‐power Extended Interaction Klystron (EIK) and nadir‐only views of cloud systems.Cross‐track scanning is only possible using active‐element phased‐array systems, and mechanical scanning is not practical due to the fast platform motion.Vertical resolution of 250 and 500 m has been implemented; however, the surface echo severely limits our ability to detect the lowest kilometer in the atmosphere.The EarthCARE CPR is the only Dopplerized radar but is expected to have limited performance in deep convective cloud systems due to strong hydrometeor attenuation.RainCube offers several technological breakthroughs  that should be considered in future spaceborne radar missions.The aforementioned existing or planned spaceborne radar missions have and will continue to enhance our ability to monitor and study cloud and precipitation processes on a global scale. Different frequencies, antenna types and transceiver technologies have been used in these systems Table . Some no3The existing and planned spaceborne radar systems described in section 3.1The aforementioned efforts to increase our spaceborne radar capabilities aims at a thorough understanding of aerosol‐cloud‐precipitation interactions by shedding light on the “processes” operating within the atmosphere which produce cloud and precipitation systems. Such “processes” include both “microphysical processes” like nucleation and growth mechanisms controlling the evolution of embryonic cloud droplets and ice crystals to precipitation sized particles and involving one  or multiple phases  of the water substance and “dynamical processes” linking 3‐D air motion and cloud structure. These mechanisms should be valid no matter what changes the Earth's circulation will undergo. For instance, accurate measurements of PSDs are fundamental for understanding the processes governing cloud microphysics and improving liquid precipitation representation in numerical models. Especially at small scales, microphysical processes such as condensation of water vapor, collision and coalescence between the droplets, evaporation in unsaturated air, and droplet breakup all contribute to the precipitation that falls at the ground  to 25 km today. Current global operational weather forecasts are performed at or near 5 km, thus approaching convection‐permitting scales. The understanding of these processes is also beneficial for remote sensing retrieval techniques since a better insight of the cloud and precipitation microphysics will automatically better constrain the “atmospheric states” and therefore reduce the uncertainties in the retrieved parameters.High‐latitude/midlatitude precipitation,including snowfall ;Convective clouds (convective transport and detrainment);Boundary layer clouds (autoconversion and accretion);Mixed phase clouds (Wegener‐Bergeron‐Findeisen process and phase transition);Water vapor in ice clouds and in the column (sublimation and ice nucleation).It is important to acknowledge that making progress in our understanding is not straightforward and requires symbiotic use of theory, models and observations and ability to disentangle the role of large scale meteorology and aerosols in cloud‐scale properties and processes. Here, we are concerned only with the advancement needed in spaceborne radar observations to maximize our ability to make progress. There are several areas (processes) of interest for the science community where radars are expected to provide a significant contribution:In addition to the aforementioned areas where improved measurements are desirable, it is important to state that capturing the diurnal cycle of clouds, convection and precipitation is also a very important issue. The low inclination of the TRMM and GPM missions, combined with their wide swath and their integration with existing passive spaceborne radiometers have allowed the sampling of the diurnal cycle of tropical and midlatitudes convection. On the other hand, CloudSat and EarthCARE follow a sun‐synchronous orbit. Future missions will have to consider architectures that address the need for advanced measurements while providing near‐global coverage and sampling the diurnal cycle in the tropics and midlatitudes. One possible solution of address this requirement is the use of constellations of CubeSats and SmallSats on different orbits. In light of this novel approach we now review some of the gaps in the current cloud and precipitation observing system that could be filled by the new cutting‐edge multifrequency radar systems.3.2−2) between global average ice water paths of different climate models  and habits which add complexities to the retrieval problem . For inRemote sensors also generally struggle to detect tenuous clouds  Ka band ARM Zenith Radar (KAZR) located at the Eastern North Atlantic (ENA) facility on the island of Graciosa  with an accuracy of 2 m s−1 from a platform that moves at about 7,600 m s−1 is a daunting task . In stronger convection, as for the case depicted in Figure −1) and the uncertainty of the Doppler velocity measurements (about 1–2 m s−1) that will make the retrieval of the original Doppler velocity field  has been shown to be a particularly useful quantity tied to cloud and precipitation formation  and Aerosols Cloud Convection and Precipitation  Earth Science Decadal Survey observing system concepts have been achieved in the last two decades. These advancements were enabled by various NASA technology investments and airborne field campaign activities and leveraged substantially on the rapid general progression of digital and small platform technologies. Overall, these mission concepts provided the necessary focus for technological advances specifically targeting the observation of clouds, convection and precipitation. Remarkable advances in component and subsystem technologies that are directly relevant to spaceborne cloud and precipitation radars have occurred in the last decade and continue to progress. At the core of new capabilities such as RainCube shown in Figure 07 and AeSince the launches of TRMM's Ku band PR in 1997 and CloudSat's W band CPR in 2004, two main avenues of advancement have been pursued to meet the stated or perceived needs of the science community: improved performance and reduced SWaP  /data rate, thus ultimately mission cost. Along the first, the DPR was developed by pairing slotted waveguide Ku band and Ka band electronic scanning, launched in 2014 and has been successfully operating in orbit since then. Also, the Cloud Profiling Radar , four specific additional needs with respect to the CloudSat baseline became the primary drivers of new radar concepts: combination of W band with one or more lower frequencies, introduction of at least a limited scanning capability, introduction of Doppler capability, and achievement of higher quality data sets . The first possible solution to meet such needs was the Radar for the ACE mission (ACERAD) technology development where the CloudSat‐class technology was augmented to obtain additional Ka band measurements over a limited swath of 30 km. The key technology developments implemented to enable this concept were the Dragonian antenna design , the Dual‐Frequency Dual‐Polarization Quasi‐Optical transmission line, the Ka/W band frequency selective surface, and the signal generation and processing strategy  and Three‐band (Ku/Ka/W band) Cloud and Precipitation Radar (3CPR). Both include use of active electronically scanning linear arrays (AESLA) illuminating a singly‐curved parabolic reflector (SCPR) to increase the radar cross‐track scanning capabilities without incurring the challenges and costs associated with large 2‐D active arrays. Both concepts adopt advanced signal generation and processing schemes to achieve the desired radar sensitivities, resolutions and Doppler accuracies. In WiSCR  and state‐of‐the‐art digital technologies. These include the design of radars composed where possible of commercial off‐the‐shelf electronic parts, and advanced waveforms. Among these, one radar that transitioned from early concept to launch and successful mission completion in less than 7 years is the Ka band RainCube, launched in 2018 and still operational at the time of writing  has already been integrated in the Multi‐Application Small‐satellite Tri‐band Radar whose airborne prototype is currently under development. In essence, this instrument concept unifies the 3CPR front end technologies described earlier  with the RainCube signal architecture to deliver an instrument that can address both the cloud and precipitation measurements as well as innovative altimetric measurements focusing on sea ice freeboard and the thickness of the snowpack above it, snowpack over ground, or, if installed in a spinning scanning platform, scatterometric measurements for ocean surface winds. Because of the miniaturized nature of each subsystem, and the modular scalability of the Active Line Array Feeds, this instrument concept can be scaled to antenna sizes ranging from 0.3 to 3 m, making it suitable for a variety of accommodations according to specific instrument performance and SWaP allocations , and including any or all of the three bands.−1 accuracy and +5 and ‐20 dBZ radar sensitivity at Ka and W band, respectively. More generally, the RainCube architecture enables a number of possibilities for small platforms, at a number of frequency bands spanning from X to G band. Several other compact radar concepts have recently been formulated or are under early development stages. They target primarily the evolving needs of the ACCP observing system concept. Among them, some target lower frequencies (such as X or Ku band) for improved penetration capability in deep convection and heavy precipitation and to leverage on mature electronics and large deployable antenna technologies. The general viability of this approach is well represented by examples such as the DARPA's Radio Frequency Risk Reduction Deployment Demonstration (R3D2) satellite which was launched with a less than 2 year development time using commercial parts and low cost  with similar nonscanning W band and G band channels. It also integrates the capability to adopt either a single antenna or a pair of antennas  with resampling times in the order of minutes and small platform velocity (relative to Earth's surface) to facilitate Doppler measurements. Because of the significant distance from Earth, the required technological advancement is the large size (about 30 m in diameter for Ka band) antenna which has been subject of technology development efforts in the first decade of the millennium  frequencies more suitable to observe clouds (precipitation) because of their better sensitivity (reduced attenuation). For instance the CloudSat W band radar is capable of detecting the vast majority the high clouds above 10 km and the regions of light precipitation  (black rectangles in the top panel) which are completely undetected by the Ku and Ka band radars. On the other hand, the Ku and Ka can profile precipitation in the most intense part of the precipitation (black rectangles in the center and bottom panels) where the W band is fully attenuated . Cloud radar observations allow to characterize vertical profiles of the microphysical properties  with the measured signals being the result of the complex interplay between non‐Rayleigh, attenuation and higher order effects  with emphasis on the quality of the observations ;Precipitation/cloud “mapping” observations with wide swath scanning modes focused at reducing revisiting time and sampling errors and at capturing diurnal cycle variability  and, secondarily, the internal structure of aggregate crystals are additional factors affecting the triple‐frequency radar signature of a population of ice particles. Therefore, even triple‐frequency observations may not be enough to disentangle all the complexity of ice particles: Specific ice particles can be unambiguously identified only in a minority of cases, for example, for fluffy aggregates when the characteristic hook signature is observed , making the interpretation of single‐frequency radar observations extremely challenging. Dual‐frequency first  above 750 m : The leading edge of the pulse has a rapid cut off at a factor of 1 time the pulse length while the trailing edge has a longer taper extending off to 3 times the pulse length. Forward simulation results suggest that the new pulse shape design would successfully allow for the detection of a larger fraction around 750 m above ground that being said, even with all its radar architecture modifications, the EarthCARE‐CPR would not be able to detect rain to the point of being able to determine if it will reach the surface or evaporate  is the main source of uncertainty in the Doppler velocity measurements ), the signal‐to‐noise ratio (SNR) and the number M of processed samples per estimate , and thus, the uncertainty in their Doppler velocity estimates is negligible. In spaceborne radars, σN is independent of the radar wavelength and is given by C is a nondimensional constant, Vsat is the platform motion in m s−1, PRF is the Pulse Repetition Frequency in Hz and D is the antenna size (m). The σN values for two different antenna sizes (2.5 and 4.0 m) and for different PRF values are shown in Figure The importance of knowing the vertical transports of water vapor and condensate by atmospheric moist convection cannot be overstated  between these two PRFs. It is important to state that these PRF values are the maximum allowed for a spacecraft operating at an altitude of 400 km if we want to avoid having more than one pulse in the tropospheric data window . Using higher PRF values is technologically possible but will require more than one operating PRF to remove the second trip echoes. The use of higher PRF values and of multi‐operating modes will drive up the power requirements for such a radar system. The use of a larger antenna (4.0 m) indicates that we can achieve low Doppler velocity uncertainties without the need to increase the PRF above 7,400 Hz.The EarthCARE CPR operates with a PRF between 6,200 and 7,400 Hz and has a 2.5 m antenna. There is significant reduction in the uncertainty (from 1.39 to 0.55 m s−1/(dB km−1) corresponding to a linear, along track radar reflectivity gradient is given by .Cloud and precipitation inhomogeneity within the radar beam sampling volume (NUBF) is another source of biases on mean Doppler velocity estimates from spaceborne Doppler radars. The NUBF effect can introduce biases that can reach several meters per second, especially at the cloud and precipitation field edges, and in areas with large variability in reflectivity and velocity  and a very high PRF that will violate the range‐Doppler dilemma resulting to second trip echoes within the troposphere. Large solid surfaces have the advantage that can be a shared resource for more than one frequency  trains of pulses with different pulse length and PRF schemes. A low PRF train of pulses can be used to map the hydrometeor locations in the troposphere while 2 or more high PRF trains of pulses can be used to provide higher quality Doppler but with second trip echoes in particular vertical layers in the atmosphere. In the end, data from all the different trains of pulses are combined to generate an artifact‐free mosaic of hydrometeor location and Doppler velocities in the troposphere. In addition to differences in their PRF, the different bursts of pulses can have different pulse lengths, thus addressing some of the shortcomings in detecting hydrometeors close to Earth's surface.Despite their added complexity, these techniques (PD and interleave pulse schemes) are technologically possible in future missions. One additional drawback that needs to be considered is the power requirement for such a high duty cycle transmitting schemes. Combining these schemes with a low‐power system that uses chirp could help to alleviate some of the concerns regarding the power requirements.The first concept is based on the recent successful spaceborne demonstration of a miniaturized, low‐cost CubeSat precipitation radar  to the second pulse (R2) due to the platform motion (Vsat). Thus, the target has an apparent Doppler velocity Vtarget≠0 that broadens (decorrelates) the radar signal and leads to increased uncertainty. In a possible DPCA dual‐antenna spaceborne radar configuration, the first pulse is transmitted by the forward antenna when at distance R1 from the target and the second pulse is transmitted from the trailing antenna when at the same location where the first antenna transmitted the first pulse. In this case, the second pulse travels the same distance as the first pulse (which requires matching the PRT with the product of the platform velocity and the antenna baseline); thus, there is no apparent Doppler velocity. This is one of the ways of implementing the DPCA technique and can lead to high quality Doppler measurements from a fast moving platform because it practically eliminates the platform motion effect and, as a result, the uncertainties discussed in Figure The second concept is the Displaced Phased Antenna Concept (DPCA), where the idea is to make the antenna appear stationary even though the platform is moving Figure . The estOver the last few years, two different technological approaches to address the need for spaceborne Doppler velocity measurements in deep convection have been developed and are briefly mentioned here Figure . The fi4.72O rotational absorption line to perform active sounding of humidity profiles and column water vapor. Because the radar measurement signal‐to‐noise increases with increasing cloud content, the DAR method is highly complementary to DIAL, which cannot perform the differential absorption measurement inside of clouds due to the confounding effects of multiple scattering. From a TCWV standpoint, DAR is an attractive potential spaceborne method because it uses the strong returns from the surface to perform the column water vapor measurement over all surface types, in cloudy and clear skies, and at all times of day.Recently, a new water vapor measurement technique has emerged led by efforts at JPL to fill the important observational gap of measuring humidity from space in the presence of clouds and precipitation. This technique, called differential absorption radar (DAR), is inspired by the well‐established differential absorption lidar (DIAL) measurement method −κv(f1). Subsequently, the first in‐cloud humidity profile retrievals with uncertainty estimation were presented  water vapor DIAL  accurate quantification of precipitation (particularly extreme precipitation in the tropics and light/solid precipitation over the midlatitude and high‐latitude regions) and of precipitation microphysics, (ii) detection of shallow clouds, (iii) Doppler in convective clouds, and (iv) in‐cloud water vapor sounding measurements. Mapping the diurnal convective clouds cycle is also a considerable gap. This is primarily a sampling issue that can be addressed only with the use of low‐cost constellation of CubeSats and SmallSats at different orbital planes. Thus, it is beyond the scope of this review that is primarily concern with improvements in the sensor level that can address the aforementioned gaps.Progress in radar technologies facilitate novel research avenues thanks to improved radar performances , unprecedented capabilities  and most cost effective solutions that can revolutionize the field of space‐based observations via the use of constellations of Cube/Small satellites. Here we suggest some critical directions that need to be expanded in the upcoming years.4.8.1Unique mapping capabilities. Because of their cloud‐penetrating range‐resolved profiling capabilities radars remain the only instruments capable of providing the vertical distributions of clouds and precipitation. The scientific community strives for a continuous long‐time records of such measurements. , which, as recently highlighted by Protat et al.  from airborne . This could help in better assessing the relevance of different a‐priori assumptions , the validity of the scattering tables utilized in the retrieval, the uncertainties introduced by using different single scattering properties  must be properly quantified. Also the impact and added value of additional information like Doppler velocities and colocated brightness temperatures (like for CloudSat) and/or PIA must be better understood  and present spaceborne based radar missions  but important gaps still remain for a thorough understanding of the water cycle and its evolution in a warming climate. Spaceborne radars are and will remain the pillars of the cloud and precipitation remote sensing observing system; however, apart from the long‐waited EarthCARE radar, the next generation of cloud and precipitation radar systems has not been defined yet and no such instrument/mission is currently in the funded pipeline of any of the National Space Agencies. The current preparatory studies for the NASA Aerosol, Cloud, Convection and Precipitation concept provide a unique opportunity for the whole cloud and precipitation science community to come together and contribute in identifying the key scientific questions, in defining their associated science requirements, in elaborating the technical and cost‐effective solutions to address them, and in seeking support by coordinating funding at the national and international level. With a grim future of climate emergency in sight, this review calls for renewed efforts in these directions.


A major problem in quantifying symptoms of schizophrenia is establishing a reliable distinction between enduring and dynamic aspects of psychopathology. This is critical for accurate diagnosis, monitoring and evaluating treatment effects in both clinical practice and trials.We applied Generalizability Theory, a robust novel method to distinguish between dynamic and stable aspects of schizophrenia symptoms in the widely used Positive and Negative Symptom Scale (PANSS) using a longitudinal measurement design. The sample included 107 patients with chronic schizophrenia assessed using the PANSS at five time points over a 24‐week period during a multi‐site clinical trial of N‐Acetylcysteine as an add‐on to maintenance medication for the treatment of chronic schizophrenia.The original PANSS and its three subscales demonstrated good reliability and generalizability of scores (G = 0.77‐0.93) across sample population and occasions making them suitable for assessment of psychosis risks and long‐lasting change following a treatment, while subscales of the five‐factor models appeared less reliable. The most enduring symptoms represented by the PANSS were poor attention, delusions, blunted affect and poor rapport. More dynamic symptoms with 40%‐50% of variance explained by patient transient state including grandiosity, preoccupation, somatic concerns, guilt feeling and hallucinatory behaviour.Identified dynamic symptoms are more amendable to change and should be the primary target of interventions aiming at effectively treating schizophrenia. Separating out the dynamic symptoms would increase assay sensitivity in trials, reduce the signal to noise ratio and increase the potential to detect the effects of novel therapies in clinical trials. For example, some treatment studies select either the negative or positive subscale to identify changes in the symptoms of interest.Establishing the true reliability of a measure requires a distinction between stable and dynamic symptom patterns, which is only possible using repeated measures.The test‐retest reliability coefficient is commonly used to evaluate consistency in scoring on psychological measures over two occasions. Test‐retest reliability does not account for multiple sources of error that may affect the observed score on a testing occasion, such as interactions between person, item and occasion.Generalizability or G Theory is a sound method for evaluating specific sources of measurement error in clinical trials.Applying G Theory involves two stages: G‐study and the D‐study. The G‐study involves a factorial ANOVA corrected for the type of sampling involved  and estimates a G‐coefficient reflecting generalizability of the test scores across persons and situations. Bloch and Norman (p. 968)Only a few studies have applied G Theory to investigate the psychometric properties of the PANSS, and none distinguished between dynamic and stable symptom patterns using a longitudinal (repeated measures) design. Vangeneugden et al22.1P‐value cut‐off point of .05 . Patients were required to have residual symptoms, as defined by a baseline PANSS Total score of ≥55 or at least two of the positive and/or negative items being ≥3 despite maintenance treatment with atypical antipsychotic medications. The inclusion criteria were selected so that participants had current symptoms (mildly ill +) based on the literature of trials.P > .05), and these groups were therefore combined for the present analysis.Participants were 107 patients with a longstanding diagnosis of schizophrenia  aged between 18 and 65 years, and randomized to N‐acetyl cysteine  or placebo (n = 53) in a controlled trial that was reported by Berk et al2.2The PANSS2.3Generalizability analyses were conducted following the guidelines described elsewhere  and employed EduG 6.1‐e software.2, ϖ2 only considers variance directly related to the object of measurement. The absolute G‐coefficient (Ga) is equivalent to Phi (Φ) and accounts for other variance sources (eg item x occasion interaction) that may influence an absolute measure indirectly.Variance components for each facet and their interactions were computed based on traditional ANOVA estimates using equations introduced by Brennan.3Descriptive statistics were computed for the five separate PANSS assessments with the current sample and are presented in Table 3.1Results of the G‐Study analysis of the PANSS total scale, 3‐ and 5‐factor models subscales are presented in Table 3.2The D‐study aimed to identify the PANAS items that are sensitive to dynamic changes. Table 4The present study applied G Theory to evaluate reliability and quantify differences between dynamic and enduring symptom patterns in the PANSS within the context of a clinical trial involving a cohort of patients diagnosed with schizophrenia. Overall, the PANSS total scale demonstrated acceptable reliability and was superior in performance when compared to the individual subscales. The total PANSS score reflected enduring symptoms to a greater, and dynamic symptoms to a lesser, extent and was not affected by any other measurement error. The three individual PANSS subscales Positive Symptoms, Negative Symptoms and General Symptoms showed acceptable reliability and generalizability of scores across occasions and population of the sample. However, evaluation of the five‐factor structure of the PANSSThe current study distinguished between stable and more dynamic symptoms of schizophrenia using G Theory. The symptoms operationalized by the PANSS were overall more enduring, and the most stable symptoms included symptoms located on the general scale such as poor attention and mannerisms and posturing; symptoms on the positive scale of delusions; and symptoms on the negative scale of blunted affect and poor rapport. However, the most dynamic symptoms on the positive scale were identified such as hallucinatory behaviour and grandiosity as well as symptoms on the general scale including guilt feeling, somatic concern, preoccupation, disturbance of volition, motor retardation, uncooperativeness and lack of judgement and insight.It is notable that both the placebo and NAC groups exhibited significant baseline‐week 8 reductions in PANSS Total, Positive, General scores, but neither group exhibited significant reductions in PANSS Negative scores. While negative symptoms were generally stable, if symptoms at the subscale level were solely reported, then important dynamic changes occurring would be overlooked. For example, some symptoms on the negative subscale were dynamic, as were negative symptoms located on the general subscale (Motor retardation and Disturbance of volition). While the PANSS and its subscale scores can be used to evaluate the overall symptomatic change, individual item scores may be more useful than the scale and subscales scores to monitor more dynamic or enduring symptoms as evaluated in Table Although G Theory has previously been applied to the PANSS,There are a number of potential limitations to the present study. Although combining placebo and treatment groups may confound interpretation of stable vs dynamic features in the context of treatment, the inclusion of a variety of symptom levels was advantageous. Of note, baseline to week eight change for all PANSS measures did not differ significantly between groups, and the present analysis does identify stable vs dynamic symptom domains within the context of a clinical trial. Second, patients in this study were treated with an atypical antipsychotic medication, which may differentially modify PANSS symptoms. N‐acetyl cysteine is particularly likely to affect glutamate receptors and may be expected to have a greater effect on reality distortion and thought disorder symptoms. Therefore, assessment of medication‐naive subjects, either at the initial onset of psychosis or subjects at ultra‐high risk for developing schizophrenia, would represent an important extension of G theory and enable further exploration of stable and dynamic symptoms longitudinally. We also excluded 33 participants with missing data from the study sample that could potentially represent a selection bias. However, missing data were completely at random suggesting random selection of participants for the study was assumed and there was no evidence that the reduced sample was statistically different from the full sample.The results of this study inform future studies to develop an instrument for distinct and reliable measurement of dynamic and enduring schizophrenia symptoms. The current investigation of the PANSS provides a methodological pathway for the development of such instruments that would enhance clinical care by permitting accurate monitoring of patients symptoms over time using two mechanisms: first, by applying a dynamic symptoms scale to evaluate individual symptom change, and second, by assessing the overall psychopathology level by simultaneously applying an enduring symptoms measure. This is particularly useful with adolescent populations for differential diagnosis between schizophrenia and the paranoid and dissociative symptoms associated with borderline personality disorder,5The present study highlights the value of G Theory for quantifying stable and dynamic symptoms using the PANSS within the context of a clinical trial. The majority of symptoms represented by the PANSS were stable with the most enduring being poor attention, delusions, blunted affect and poor rapport. However, there are also more dynamic symptoms with 40%‐50% of variance explained by the patients’ transient state including grandiosity, preoccupation, somatic concerns, guilt feeling and hallucinatory behaviour. These dynamic symptoms are more amendable, which makes them the primary target of interventions aiming to effectively treat schizophrenia.The PANSS and its three subscales demonstrated acceptable reliability and generalizability in measuring stable and dynamic symptoms of schizophrenia. The use of subscales within the 5‐factors model of PANSS was not supported in this study and should be treated cautiously in other clinical trial contexts. Additional G Theory analyses of the PANSS are warranted using prodromal and medication‐naive patients in a naturalistic setting to identify stable vs dynamic features associated with the progression of schizophrenia.


Physical activity (PA) is a recognized contributor to healthy aging. However, the majority of studies exploring its associations with adverse outcomes in cohorts of older adults use single‐time PA estimates, which do not consider its dynamic nature. The aim of the present study is to explore the presence of different PA trajectories in the Toledo Study of Healthy Aging and their association with adverse outcomes. Our hypothesis is that prospectively maintaining or increasing PA is associated with a reduced risk of adverse outcomes.We used data from 1679 participants enrolled in the Toledo Study of Healthy Aging. Trajectories based on the Physical Activity Scale for the Elderly were identified using group‐based trajectory modelling. Cox and logistic regression were used to investigate associations between PA trajectories and mortality and hospitalization, and incident and worsening disability, respectively. Mortality was ascertained by linkage to the Spanish National Death Index; disability was evaluated through the Katz Index; and hospitalization was defined as the first admission to Toledo Hospital. Models were adjusted by age, sex, smoking, Charlson Index, education, cognitive impairment, polypharmacy, and Katz Index at Wave 2.n = 566), moderate PA‐mildly decreasing (n = 392), low PA‐increasing (n = 237), moderate PA‐consistent (n = 191), and low PA‐decreasing (n = 293). Belonging to the high PA‐consistent trajectory group was associated with reduced risks of mortality as compared with the low PA‐decreasing group  and hospitalization compared with the low PA‐increasing and low PA‐decreasing trajectory groups  and with lower rates of incident  and worsening disability  in relation to the low PA‐decreasing trajectory group and at follow‐up. Increasing PA during late life (low PA‐increasing group) was associated with lower incident disability rates  compared with decreasing PA (low PA‐decreasing group), despite similar baseline PA.We found four PA‐decreasing and one PA‐increasing trajectories: high PA‐consistent (Our results suggest that sustaining higher PA levels during aging might lead to healthy aging, characterized by a reduction in adverse outcomes. Our study supports the need for enhancing PA participation among older populations, with the goal of reducing personal and economic burden in a worldwide aging population. Lifelong physical activity (PA) promotes a wide range of health benefits and has long been recognized as an important protective factor for chronic diseases.The salutary effects of PA might extend to late life, as it is known to delay the onset of disabilityThe World Health Organization defines ‘healthy aging’ as the process of developing and maintaining the functional ability that enables well‐being in older age.Some studies have recently addressed this shortcoming and used prospective PA level evolution as the exposure variable. Most of these studies employed categorical analyses with clinical or empirical cut‐points for identifying groups with different PA progression patterns.Data‐driven approaches such as group‐based trajectory modelling (GBTM) have emerged as an informative and interesting analytical method that allows grouping of subjects presenting with similar baseline values and longitudinal patterns of change, in terms of their direction and magnitude, along follow‐up for a given variable within a population.The main aim of this study is to investigate the existence of different PA trajectories within the Toledo Study of Healthy Aging (TSHA) sample, a Spanish longitudinal population‐based study, and to evaluate their associations with adverse outcomes . Our hypothesis is that chronically active subjects and those maintaining PA over time will have a lower likelihood of experiencing adverse outcomes compared with consistently inactive subjects or those reducing PA levels during follow‐up and that increasing PA even at older ages promotes healthy aging, as characterized by reduced mortality, disability onset/worsening, and hospitalization rates.Data were taken from the TSHA study, the details of which have been reported elsewhere.The Clinical Research Ethics Committee of Toledo Hospital, Spain, approved the study protocol, and participants signed an informed consent prior to their inclusion in the study.Physical activity levels were estimated using the Physical Activity Scale for the Elderly (PASE). This questionnaire was designed to assess PA in epidemiologic studies of older people over a 1 week period. It ascertains the duration, intensity, and frequency of several activities and consists of 10 items that focus on three domains: leisure (five components), household (four), and work (one) activities. Participation in leisurely activities is recorded by frequency  and duration ; paid or unpaid work is recorded by total hours of work per week; and household activities and care for others are recorded with yes or no answers. Total PASE score is calculated by multiplying activity participation (yes/no) or the amount of time spent on each activity (hours/week) by empirically derived item weights, which are summed.Vital status was ascertained through the information provided by the Spanish National Death Index . Participants were followed up to death or June 2018, whichever came first. The average follow‐up for mortality was 5.92 years (range 0.01–7.5 years).Hospitalization was ascertained by review of the Toledo Hospital Complex records and was defined as the occurrence of a first admission to the hospital during follow‐up, up to December 2016. Median follow‐up for hospitalization was 4.08 years (range 0.01–5.24 years).The Katz Index was used to assess the functional ability in basic activities of daily living (BADLs).−2). Cognitive status was assessed by using the Mini‐Mental State Examination (MMSE).We selected covariates based on the literature and the biological plausibility for confounding the main associations of interest. Age, sex, education , and smoking status (yes/past/never) were registered during study visits. Presence of co‐morbidities was ascertained by self‐report and by checking the medical history to compute the Charlson Index score.t‐test or analysis of variance for continuous variables and the χ2 test for categorical variables.All analyses were performed using the R statistical environment for Windows. Mean (standard deviation) and frequency (percentage) are provided for continuous and categorical variables, respectively. Descriptive variables were compared between included and excluded subjects and between trajectories with an independent Student's ex ante. In GBTM, each group is conceptually thought of a collection of individuals who follow approximately the same developmental trajectory, where population variability is captured by differences across groups in the shape and direction of their trajectories.Bayesian statistics to choose between two or more alternative models, given the data. In our study, two times the change in the BIC between models greater than 10 was used as indicative of better fit in order to compare more complex—with a greater number of trajectories—vs. more parsimonious—with a lower number of trajectories—models.We used a GBTM approach to identify PA trajectories within our population. This type of finite mixture model provides an empirical means of identifying clusters of individuals defined by their developmental courses for a variable over time (trajectories) within a population. Briefly, this method assumes that the general population is composed of literally distinct subpopulations that are not identifiable based on measured characteristics Cox proportional hazards regression was used to investigate the associations between the GBTM‐derived PA trajectories and the adverse outcomes for which we had the date of occurrence . Logistic regression analysis was used for disability onset and disability worsening (that were registered during study visits). Multivariate trajectory models were adjusted for age and sex (Model 1), plus Charlson Index (Model 2), and additionally for baseline Katz Index, level of education, polypharmacy, cognitive status (MMSE), and smoking status (Model 3).TableBaseline characteristics of the subjects within each trajectory are presented in n = 566; 33.7%), (ii) moderate PA‐mildly decreasing , (iii) low PA‐increasing , (iv) moderate PA‐consistent , and (v) low PA‐decreasing   high PA‐consistent  across all models  and low PA‐decreasing  trajectory groups showed a significant increase in the likelihood of hospitalization when compared with subjects in the high PA‐consistent group, across all models  3.14; 95% CI = 1.59–6.19 (Model 3)].TableFigureThe low PA‐decreasing trajectory group showed significant increased risk of worsening disability when compared with subjects classified into the high PA‐consistent group ; P = 0.001), to be older , and to have difficulties in one or more BADLs at baseline .We additionally sought to compare groups with similar baseline PA (similar starting risk) but divergent PA trends along time (low PA‐increasing vs. low PA‐decreasing trajectory groups). Subjects in the low PA‐decreasing trajectory group were more likely to be women  for the group they were classified into did not meaningfully change the associations.Sensitivity analyses excluding subjects with posterior probabilities <0.5 , independently of important confounding factors. Subjects showing higher PA levels at baseline and sustaining them along time (high PA‐consistent trajectory) had lower odds of all adverse outcomes compared with those presenting with low baseline PA levels and an important decline along time (low PA‐decreasing trajectory) and lower risk for hospitalization than those with a low initial PASE score even when PA increased over time (low PA‐increasing trajectory). These findings support the need to promote effective intervention strategies aiming to maintain or increase PA among older adults, as a key factor for healthy aging.We identified five longitudinal trajectories within our population. Of these, four showed a prospective reduction in PA at old age, which agrees with previous observations of a majority of older adults reducing PA along time.Regarding the GBTM algorithm classification quality, the identified trajectory groups showed mean posterior probabilities of membership that were close to 0.8. As values of 0.7–0.8 are deemed indicative of an aggrupation that sufficiently discriminates between individuals with dissimilar patterns of change in a behaviour over time,In relation to the association of prospective PA changes and mortality, our results showing an increased risk for the low PA‐decreasing in relation to high PA‐consistent trajectory groups are consistent with the general notion that increased levels of PA lead to greater longevity in both men and women. These findings were also observed when using cross‐sectional PA estimates,Importantly, the mortality‐sparing benefits of late‐life PA might only be slightly affected by pre‐cohort PA behaviour,Because PA is a powerful countermeasureagainst the development and progression of chronic conditions, it is assumed toconstitute a means to reduce healthcare system utilization With regard to the association between PA and disability onset, our results support previous work reporting an inverse association,et al. sought to explore associations between PA trajectories and functionality in a Taiwanese older adult cohort of 3186 subjects  using a growth mixture model along 11 years follow‐up.Yu et al. performed a meta‐analysis of four studies that reported associations between PA and BADL disability progression.Regarding the associations between PA levels and disability worsening, the limited evidence points to a negative association between higher activity levels (measured in diverse ways) and the odds of showing lower functionality at follow‐up. In this line, Tak The low PA‐increasing trajectory group showed an increased risk of hospitalization, but not disability, when compared with the high PA‐consistent group. We hypothesize that the strong association between increasing activity and functionality during late life might arise as the result of actual improvements in the physical domain of intrinsic capacity resulting from PA. Tellingly, associations between PA and functionality tend to be stronger in the case of motor activities of daily living,ad hoc, ex ante classification rules. By doing so, we accounted for the factual dynamic nature of PA, overcoming bias of previous research. Although GBTM might remain unfamiliar for most of clinical focused researchers, it presents some compelling features that might be quite useful to study longitudinal data. The characterization of groups of subjects following different evolutions for a variable has commonly relied on subjective categorization based on clinical or empirical thresholds . Although reasonable, these assignment rules present with some pitfalls. First, the existence of different groups is assumed a priori, and this point cannot be tested objectively. Second, they do not allow for assessing the precision of individual classifications to the various groups, and hence, uncertainty about individual group membership might emerge. In our case, an important strength of GBTM is that it allows for a data‐based in‐depth study of the features of potential healthy aging phenotypes (PA‐maintainers/increasers), which in turn could help clinicians to identify strategies for maintaining PA engagement among the elderly. To estimate PA levels, we used a well‐validated tool specific for older adults, whose advantages include its brevity, easy scoring process, the inclusion of activities other than exercise, and the inclusion of activities common to older ensuring a comprehensive assessment of overall PA. While objective PA measures are more reliable and overcome PA questionnaires' limitations, they might be impractical in large cohorts, as in ours. This work is one of the first to our knowledge trying to explore the presence of different PA trajectories within a cohort of older adults and their associations with important adverse outcomes in an older adult cohort.Our study has several strengths including the large sample size, excellent ascertainment of adverse outcomes, and the inclusion of relevant variables that could confound the associations. The TSHA is a representative population of community‐dwelling and institutionalized men and women with a wide range of ages and both. Furthermore, we used the novel GBTM, a powerful statistical tool to group subjects into qualitatively distinct developmental progressions that differ not only at baseline but also in the direction and magnitude of the change and that are not readily identifiable using Our study, nevertheless, has important limitations. First, self‐reported PA tools are poorly correlated with objectively measured PA, and their use is subject to the inclusion of recall errors and social desirability leading to bias, especially among older adults. Additionally, over‐reporting of PA levels, if present, would lead to an underestimation of the actual effect of PA on adverse outcomes.Although GBTM is increasingly been used for identifying trajectories for both exposures and outcomes in observational and experimental research, it is inherently limited in capturing individual variability and may lead to over‐grouping.Reverse causality cannot be excluded in our study, due to its observational nature. PA participation might be conditioned by health status and vice versa. Nevertheless, the associations remained significant after adjustment for important risk factors, co‐morbidities, and functional status.We acknowledge the potential absence of unrecognized or uncontrolled covariates that could affect our observations. Of note is the absence of a measure of sedentary behaviour as a competing exposure. Sedentary behaviour has recently been postulated as a key health factor, independent of PA patterns, and is associated with mortality,Our study contributes to expand the notion of PA as a powerful modifiable factor that promotes healthy aging by means of preventing important adverse outcomes including mortality, disability, and hospitalization. It does so from a new perspective, by using a novel approach that allows to empirically identify different PA‐related aging phenotypes, that as our results suggest, are associated with relevant outcomes for older people. The prevention of BADL disability is especially relevant, because it is associated with receiving home care services and an increased risk of long‐term nursing home admission and health care costs.In summary, we confirmed our hypotheses in our older adult cohort that consistent high PA levels provide protection against important adverse outcomes when compared with low PA baseline levels and decreasing PA. Importantly, increasing PA levels during late life might entail a lower risk of disability in comparison with prospectively reducing activity.The authors declare that they have no conflict of interest.Journal of Cachexia, Sarcopenia and Muscle.The study protocol was approved by the Clinical Research Ethics Committee of the Toledo Hospital, Spain. This work was performed according to the ethical standards laid down in the 1964 Declaration of Helsinki and later amendments. Participants signed informed consent forms prior to their inclusion in the cohort. The authors certify that they comply with the ethical guidelines for authorship and publishing of the Table S1. Baseline characteristics of included vs. not‐included subjectsClick here for additional data file.


Ortner syndrome or cardiovocal syndrome is hoarseness of voice due to left recurrent laryngeal nerve palsy as a result of cardiovascular abnormality. It is not known that pneumothorax has any association with Ortner syndrome. A 56‐year‐old gentleman, with previous history of 20 pack‐year smoking and 1‐year history of hypertension, presented to us with cough for two weeks with intermittent haemoptysis, as well as hoarseness of voice for the past one year. Direct laryngoscopy confirmed that he had left vocal cord palsy. Clinical and radiological investigations suggested that he had left pneumothorax. Left chest tube thoracostomy was performed and computed tomography of chest revealed aortic isthmus aneurysm with dissection extending to distal left common iliac artery and residual left hydropneumothorax. The patient was then referred to the vascular team and cardiothoracic team for further management. This study describes pneumothorax with Ortner syndrome, which is an unusual presentation of aortic dissection. There are few published articles showing that patients with aortic dissection may present with Ortner syndrome. However, to date, there is no published article regarding Ortner syndrome association with aortic aneurysm and pneumothorax. Clinical presentation of aortic aneurysm and pneumothorax can be both variable, ranging from non‐specific symptoms to cardiorespiratory collapse. Both diseases are potentially life‐threatening and require immediate medical attention. This case reports a man who presented with a first episode of spontaneous left pneumothorax with incidental finding of aortic dissection on computed tomography (CT) of the chest. We were able to both identify the life‐threatening medical condition and manage the patient accordingly.A 56‐year‐old gentleman was referred to our centre from a nearby district hospital with cough for two weeks associated with intermittent haemoptysis. He denied chest pain or dyspnoea. He did not report any constitutional symptoms. He also complained of hoarseness of voice for the past one year. He has a background history of hypertension diagnosed a year back. He is an ex‐smoker with 20 pack‐year smoking history. His family history was unremarkable. Chest radiograph at the district hospital showed a left‐sided pneumothorax; therefore, he was subsequently transferred to our centre.2) was 96% under room air. He was not in respiratory distress. Chest auscultation revealed reduced air entry over the left lung. His trachea was not deviated. He had no signs to suggest Marfan syndrome. Chest radiograph revealed a left pneumothorax  was 169/106 mmHg, heart rate 91 beats per min, and his peripheral capillary oxygen saturation (SpOCT of the chest was performed in view of unexplained hoarseness of voice with spontaneous pneumothorax. Surprisingly, it showed residual left hydropneumothorax as well as an aortic dissection, distal to the origin of the left subclavian artery complicated with haematoma within the mediastinum and an aneurysm inferior to the arch of aorta Fig. . A full There are few published articles regarding patients with aortic dissection presenting with Ortner syndrome , 2. Our With the new‐onset of left‐sided pneumothorax, this patient might be having two different pathologies occurring concurrently or an aortic dissection as a result of his pneumothorax.On further literature search, we have found two published case reports regarding type A aortic dissections occurring following tension pneumothorax , 4 and aIn conclusion, although it is a rare entity, aortic dissection may be associated with pneumothorax and should be considered especially if the patient's condition does not improve even after decompression of the pneumothorax. Clinicians also need to have high degree of clinical suspicious when symptoms are not explainable with the apparent clinical diagnosis.Appropriate written informed consent was obtained for publication of this case report and accompanying images.Lo Shan Min designed the work and interpreted the data. Hema Yamini Ramarmuty revised the manuscript critically for important content. Kunji Kannan is responsible for the final approval of the version to be published.


Millions worldwide suffer from arthritis of the hips, and total hip replacement is a clinically successful treatment for end‐stage arthritis patients. Typical hip implants incorporate a cobalt alloy (Co–Cr–Mo) femoral head fixed on a titanium alloy (Ti‐6Al‐4V) femoral stem via a Morse taper junction. However, fretting and corrosion at this junction can cause release of wear particles and metal ions from the metallic implant, leading to local and systemic toxicity in patients. This study is a multiscale structural‐chemical investigation, ranging from the micrometer down to the atomic scale, of the underlying mechanisms leading to metal ion release from such taper junctions. Correlative transmission electron microscopy and atom probe tomography reveals microstructural and compositional alterations in the subsurface of the titanium alloy subjected to in vitro gross‐slip fretting against the cobalt alloy. Even though the cobalt alloy is comparatively more wear‐resistant, changes in the titanium alloy promote tribocorrosion and subsequent degradation of the cobalt alloy. These observations regarding the concurrent occurrence of electrochemical and tribological phenomena are vital to further improve the design and performance of taper junctions in similar environments. Corrosion and wear at taper junctions in metallic implants can release toxic metal ions into the body. Although biomedical cobalt alloys have a higher hardness than titanium alloys, this study finds that changes on the titanium alloy during fretting can promote tribocorrosion in the cobalt alloy. Such insights can be used to improve material design in taper junctions and implants. In the United States alone, 52.5 million adults were affected by arthritis in 2010 and 78.4 million adults will be affected by 2040.6+ ions are carcinogenic.In order to ease surgery as well as facilitate revision without removing a well‐fixed stem from the femoral bone,Cases of ALTRs due to fretting cobalt–titanium alloy taper junctions have been reported in MoMCobalt and titanium alloys are known to be highly corrosion‐resistant due to the formation of passive oxide layers on the surface.m H2O2. This scenario reflects loading conditions of hip joint taper junctions in an inflammatory periprosthetic environment. For this purpose, we employ the correlative transmission electron microscopy (TEM) and atom probe tomography (APT) method, which is a novel high resolution technique to investigate nano‐ and atomic‐scale phenomena involving both structural and chemical features.To summarize, the wear and corrosion mechanisms as well as associated ion release pathways occurring during fretting of cobalt–titanium alloy couples in taper junctions are to date unclear. Recognizing that changes in the subsurface play a role during fretting, we investigate here the nano‐scale structure and near‐atomic scale 3D elemental distribution of the subsurfaces of a cobalt‐titanium alloy couple that was subjected to in‐vitro gross‐slip fretting in bovine calf serum with 3 m22.1FigureThe microstructural analysis of the titanium and cobalt alloys (before the fretting tests) is shown in Electron channeling contrast imaging (ECCI) of the mechanically polished surface of the cobalt alloy  prior to fretting reveals the typical microstructure of a wrought processed Co–Cr–Mo alloy without carbides Figure .50 Equiam H2O2, as schematically illustrated in Figure To elucidate the mechanisms of fretting corrosion, a curved cobalt alloy pin was fretted against a titanium alloy cylinder in a medium consisting of bovine calf serum and 3 m2.22.2.1FigureThe microstructure of the titanium alloy after fretting is shown in 2.2.2The TEM bright field image (BF) of the cross‐section of a shelf is given in Figure 2.2.3FigureFigureFor further investigating the laminate features in zone 1, an APT specimen was lifted from this zone  matrix is defined by a sharp (≈5 nm thick) boundary.The surface oxide (ROI 1), which shares a boundary with the β‐rich titanium matrix, is compositionally near to TiO , as seen in Figure The composition profile across a subsurface oxide (ROI 2) is given in Figure Titanium‐rich fragmented particles (82 at% Ti isosurfaces) are distributed inside the β‐rich matrix phase Figure . Figure 2.32.3.1FigureSince the constituent elements of the cobalt alloy appear inside the subsurface of the titanium alloy Figure , it is o2.3.2A STEM‐BF image of the subsurface of a groove on the cobalt alloy is given in Figure 2.3.3In order to preserve surface features during sample preparation, the correlative STEM‐APT specimen was covered by a platinum protective layer. Excluding the upper platinum layer on the APT specimen, the 1D composition profile of the subsurface Figure  appears 2.4TableTribomaterial is formed during fretting due to wear particles that are not ejected from the system because they agglomerate and mix with denatured proteins .The higher amount of titanium detected in the tribomaterial compared to the serum indicates that titanium wear particles generated during the fretting remain in the tribomaterial and are not transported into the serum. The higher chromium content compared to cobalt in the tribomaterial  indicates the presence of chromium oxides. In contrast, the chromium and cobalt concentration in the serum is at a ratio of 0.28, closer to that of the cobalt alloy composition of 0.41, suggesting that corrosion of the cobalt alloy takes place releasing cobalt, chromium and molybdenum into the serum.3The goal of this study was to pinpoint the origin of metal ion release from titanium–cobalt alloy taper junctions in hip implants during fretting in a proteinaceous environment as well as reveal how the titanium alloy is able to wear the harder cobalt alloy. Since wear and corrosion phenomena take place simultaneously in this tribosystem, we realized that it is necessary to probe not only the wear surfaces, but also deploy a multiscale probing approach capable of identifying both chemical and structural changes in the subsurface of the material.FigureAfter the fretting tests, the cobalt alloy has shallow grooves on the surface and slight plastic deformation in the subsurface region. The titanium alloy surface has raised shelves, separated by troughs filled with grainy debris. The subsurface of the shelves is comprised of fragmented α‐crystals, oxide bands, the refined matrix and intermixed zones, all laminated together. Our observations are consistent with one of the few subsurface studies on a Co–Cr–Mo alloy neck/Ti‐12Mo‐6Zr‐2Fe alloy stem couple from an implant retrieval where grain refinement and oxides in the titanium subsurface were observed alongside loss of nanocrystallinity on the cobalt alloy side.3.12 is 6–10 GPa.The initial state of the tribosystem prior to fretting has been schematically illustrated in Figure 3.2When abraded by the titanium oxide debris, we hypothesize that the material of the titanium alloy is shifted in front of the groove, generating chips on the surface of the titanium alloy similar those observed in the case of microcutting Figure .573.3However, these chips are not torn‐off and emitted as wear particles but instead pile up on each other. On successive fretting strokes, this pile‐up of chips lifts the subsurface to form the raised shelves found on the titanium alloy wear surface Figure . This hy3.42O2 which was added to the interfacial medium), which are present in highly inflamed synovial fluid, are known to increase the corrosion potential of the cobalt alloy making it more susceptible to corrosion.The thus generated shelves on the titanium alloy surface as well as the grainy debris microplough the cobalt alloy surface, as is evident from the grooved features on the cobalt alloy wear surface Figure . The det2O3 and amorphous TiO2 in the tissues surrounding corroded dual taper Co–Cr–Mo/Ti‐12Mo‐6Zr‐2Fe junctionsOur observation of the incorporation of (formerly surface) titanium and chromium oxides in the subsurface of the titanium alloy is consistent with the recent discovery of Cr4Although implant failure in the body is a complex, multifactorial process, the chosen contact conditions and interfacial medium in these in vitro tests have allowed us to evaluate the origin of metal ion release during fretting corrosion in implants with cobalt‐titanium alloy taper junctions at the near‐atomic scale. A folding mechanism taking place during the fretting generates raised shelves on the titanium surface. These shelves on the titanium alloy microplough the cobalt alloy and hence promote tribocorrosion in the cobalt alloy. As a result, the constituent elements of the cobalt alloy can be found on the titanium subsurface and metal ions are released into the surrounding fluid. This conclusion provides a mechanistic explanation why Ti‐6Al‐4V and Co‐29Cr‐6Mo should not be paired in hip implant taper junctions in the presence of a corrosive medium when micromotion between both materials cannot be ruled out. Better understanding of this failure sequence is relevant to develop new titanium alloys for the taper junction that do not form shelves during fretting or explore alternative alloys that are less susceptible to tribocorrosion under conditions where the taper junction is not fully locked.5m H2O2, at a pH value = 7.6 (average pH in the body) and held at a constant temperature of 37 °C (average body temperature). H2O2 has been proposed to be among the reactive oxidizing species generated by cells when there is a strong inflammatory reaction or infection and has been known to increase the corrosion susceptibility of both cobalt and titanium alloys.2O2 has been mostly used in corrosion studies,A custom built testing rig attached with a potentiostat was used for this study. A cobalt (Co‐29Cr‐6Mo) alloy pin, mechanically polished to a near‐flat convex surface (radius = 8–10 m) and a titanium (Ti‐6Al‐4V) alloy cylinder of diameter = 13 mm were used. The titanium cylinder was held by a sample adapter such that the long axis stays vertical and the polished surfaces of two cobalt alloy pins  touched the curved surface of the titanium alloy cylinder from opposite sides, as schematically illustrated in Figure A protocol developed at MPIE, Düsseldorf was implemented for correlative TEM/APT analysis.The authors declare no conflict of interest.


Breast cancer metastasis to the stomach is rare; invasive lobular carcinoma has a predilection to spread to the gastrointestinal system and is morphologically similar to primary diffuse gastric carcinoma. This case highlights heterogeneous metastatic progression and that documentation of heterogeneity is important for informing future treatment strategies and prognostication. Breast cancer metastasis to the stomach is rare; invasive lobular carcinoma has a predilection to spread to the gastrointestinal system and is morphologically similar to primary diffuse gastric carcinoma. This case highlights heterogeneous metastatic progression and that documentation of heterogeneity is important for informing future treatment strategies and prognostication. For patients whose tumor has metastasized, however, the outcome remains dismal with 5‐year survival rates of ~27%.To illustrate this, we present a case of invasive carcinoma of no special type (IC‐NST) from a patient who developed a local recurrence and widespread metastatic disease of the gastrointestinal tract with a range of histological patterns and immunophenotypes. Different tumor components were studied using comparative genomic hybridization (CGH) to detect DNA copy number changes in an attempt to understand clonal relationships as well as to highlight the challenges that this can create for the pathologists and oncologists in their routine practice.2A 52‐year‐old female patient underwent a wide local excision of a 13‐mm left breast lesion in 2002. A histological grade 2 invasive carcinoma of no special type (IC‐NST) with clear margins was diagnosed. The tumor was positive for estrogen (ER) and progesterone (PgR) receptors and negative for HER2. Adjuvant therapy consisted of radiotherapy (61.1 Gy in 30 fractions over 6 weeks) followed by Tamoxifen, which was changed to Arimidex due to endometrial thickening. Hormonal therapy ceased in 2007. In 2009, a 6 mm recurrence of histological grade 2 IC‐NST was detected at the site of the 2002 surgery; mastectomy and axillary clearance were carried out and followed by four cycles of Docetaxel/Cyclophosphamide. In the same year, a biopsy of the stomach identified a malignancy and a subsequent subtotal gastrectomy was performed revealing infiltrating adenocarcinoma of the distal stomach resection and omentum but not of the large bowel or regional lymph nodes. The diffuse growth pattern of the carcinoma observed on surgical resection slides indicated a poorly cohesive gastric carcinoma or a metastasis arising from an undiagnosed primary invasive lobular breast cancer. This diagnosis was followed by chemotherapy, which consisted of three cycles of Doxorubicin and Cyclophosphamide. The patient died in 2010.2.1The original classification and description of tumor morphology was reassessed and confirmed for all of the specimens. An associated intermediate‐grade DCIS component was also noted in the 2002 primary tumor. In the 2009 local recurrence, an IC‐NST with an associated component of intermediate‐grade and high‐grade DCIS was confirmed. The tumor in the stomach and omentum from 2009 showed a diffuse carcinoma infiltrating the whole thickness of the gastric wall as sheets of single cells and single files of cells, indicative of a metastatic lobular carcinoma of the breast or a poorly cohesive gastric carcinoma.2.2Immunohistochemistry data are summarised in Table 2.3Comparative genomic hybridization was employed  or metastatic lobular breast cancer. Cancer genomics can clarify differential diagnoses such as this by defining relationships between the lesions in question. Ideally, high‐resolution genomics technologies would be applied; however, in this case, low‐resolution chromosomal‐based CGH analysis was employed due to the small and intricate nature of the lesions being examined, and the necessity for laser‐capture microdissection and DNA amplification. Nevertheless, this molecular analysis was sufficient to clearly indicate that all lesions examined were clonally related with a close degree of overlap in copy number aberrations. Thus, the 2009 breast lesion, encompassing DCIS and IC‐NST, appeared to be a recurrence of the original breast tumor, and the stomach tumor is a metastasis derived from one of the two previously diagnosed breast tumors, notwithstanding the clonal expansion of the phenotypical divergence to an invasive lobular‐like pattern of growth.The current case illustrates the concept of intratumoral heterogeneity and clonal evolution during progression, where a switch in immunophenotype was observed. The primary breast tumors were both classified as grade 2 IC‐NST, and the stomach/omentum metastatic deposits were characteristically of invasive lobular carcinoma type. We hypothesize that a small population (subclone) of ‘lobular‐like’ neoplastic cells within the primary tumor that went undetected , disseminated, and seeded the metastases. The evolution of this infiltrative lobular growth pattern coincided with dysfunction of E‐cadherin‐catenin cell adhesion complex, which is observed by complete absence of the E‐cadherin, β‐catenin, and cytoplasmic p‐120‐catenin in the metastasis. We have previously shown that a lobular‐like phenotype can arise via a ductal‐like pathway of tumorigenesis, as exemplified by the mixed ductal‐lobular histological subtype,The immunophenotype of breast cancer is crucial for the selection of targeted therapy. The expression of ER and PgR is dynamically controlled and so are also prone to being downregulated during progression.The gastrointestinal tract is not a common metastatic site for breast cancer  and The Royal Brisbane and Women's Hospital (2005/022) approved the study. The patient gave written consent for this work to be done.


A mediastinal mass in patients with a history of asbestos exposure should raise the suspicion of malignant mesothelioma. A mediastinal mass in patients with a history of asbestos exposure should raise the suspicion of malignant mesothelioma. A 73‐year‐old man was admitted to our hospital having progressive difficulty in swallowing solid foods and persistent cough. He was not a smoker and had no past medical history of cancer or infectious disease. However, the patient reported weight loss and a long‐term exposure to asbestos as a worker in a steel‐making industry. Oesophagogastroscopy showed a narrowing of the distal oesophagus Fig.  due to eAppropriate written informed consent was obtained for publication of this case report and accompanying images.


The establishment of the trophectoderm (TE) and the inner cell mass (ICM) is the first cell lineage segregation that occurs in mammalian preimplantation development. TE will contribute to the placenta while ICM cells give rise to the epiblast (EPI) and primitive endoderm (PrE). There are two historical models for TE/ICM segregation: the positional (inside‐outside) model and the polarity model, but both models alone cannot explain the mechanism of TE/ICM segregation.This article discusses a current possible model based on recent studies including the finding through live‐cell imaging of the expression patterns of caudal type homeobox 2 (Cdx2), a key transcription factor of TE differentiation in the mouse embryo.It was observed that a part of outer Cdx2‐expressing blastomeres was internalized at the around 20‐ to 30‐cell stage, downregulates Cdx2, ceases TE differentiation, and participates in ICM lineages.The early blastomere, which starts differentiation toward the TE cell fate, still has plasticity and can change its fate. Differentiation potency of all blastomeres until approximately the 32‐cell stage is presumably not irreversibly restricted even if they show heterogeneity in their epigenetic modifications or gene expression patterns. Early blastomere which starts differentiation toward the TE cell fate still have has plasticity and can change its fate to ICM lineages depending on their positional changes. The establishment of the trophectoderm (TE) and the inner cell mass (ICM) is the first cell lineage segregation that occurs during mammalian preimplantation development. TE is an epithelium‐like structure that is formed by trophoblast cells, as it appears on the surface of the embryo to contribute to the placenta, while ICM cells, which arise from the cell clump that is surrounded by the TE layer, give rise to the epiblast (EPI) and primitive endoderm (PrE) approximately one day after the appearance of the TE. For lineage segregation of TE/ICM, mouse preimplantation embryo is known to hold great plasticity at even the 32‐cell stage, while several reports suggest heterogeneity among 2‐ or 4‐cell blastomeres, which subsequently affect cell fate decisions.22.12+ ions from the embryo incubation media, which prevents E‐cadherin hemophilic binding, ablates compaction.2+ phospholipid‐dependent protein kinase C (PKC) by treating 4‐cell embryos with chemicals leads to premature compaction via an E‐cadherin‐based pathway.During mouse preimplantation development, a fertilized egg undergoes cleavage and increases its cell number. At the 8‐cell stage, embryos undergo compaction—the first major morphogenetic event in which the cell‐cell contact area is at its maximum, the cell shape flattens, and the embryo forms a tightly packed cell mass with a spherical outer surface Figure . The mos2.22 hydrolysis was also demonstrated to induce accumulation of actomyosin at the apical cortex of the blastomere via activation of PKC, and consequently RhoA. This is a prerequisite for the second phase, in which the PAR3‐PAR6‐aPKC complex accumulates to the apical domain, which excludes actomyosin and forms a mature apical domain.Concurrent with compaction, polarization occurs at the 8‐cell stage. Each blastomere of an 8‐cell embryo acquires apical‐basal polarity, which is accompanied by the apical localization of microvilli 2.3At approximately the 32‐cell stage, the segregation of the following first two cell lineages occurs: the trophectoderm (TE) and the inner cell mass (ICM), which appear during the blastocyst stage at outside and inside positions of the embryo, respectively Figure . TE will2.4Cavitation is the second major morphogenetic event that occurs in concurrence with the formation of an outer‐inner configuration. Moreover, multiple small cavities have been found to appear in the intercellular spaces of the embryo2.5Following TE/ICM formation, the second cell lineage segregation occurs, as ICM cells differentiate into the epiblast (EPI) and primitive endoderm —since their full developmental potential and extraembryonic parts were experimentally confirmed, as previously described—several lineage‐tracing studies reveal that some blastomeres in the 2‐ and 4‐cell embryos were biased toward certain cell lineages and did not contribute equally to all cell lineages.5For the cell fate segregation of TE and ICM, two models have been suggested: the positional (inside‐outside) model originally proposed by TarkowskiThe polarity model suggests that the differences among the blastomeres in their inheritance of this apical (polarized) surface at cell division, that is, the angle of cell division, determine the developmental fate.6Cdx2‐expressing cells in living embryos  were eventually internalized,Thus we propose a “tentative state” in which a blastomere that is progressing in the differentiation pathway begins to change morphology or express lineage marker genes, which does not irreversibly determine their cell fate. Given TE cell specification, it is presumed that first cell polarity promotes differentiation pathway toward the TE cell fate in outer polarized blastomeres, and blastomeres that possess apical domain abundantly flatten their cell shape early and dominantly occupied the surface of the embryo. A part of the outer blastomeres that include a part of the apolar blastomeres covered by early‐flattened blastomeres, lose their outer surface, and are consequently internalized. Internalized blastomeres until around the 16‐cell stage  hardly express Cdx2 and are presumed to become ICM cells. After around the 32‐cell stage, positional information becomes dominant and governs polarity. Internalized blastomeres, which stay outside after around 20‐cell stage and then are internalized , are presumed to express a considerable amount of Cdx2, but downregulate Cdx2 expression after internalization, cease to proceed trophoblast differentiation, and change their fate to ICM , primitive endoderm cells that mainly form embryonic membranes (PrE cells), and trophoblast cells that form the TE layer (TE cells). The preimplantation development of both human and mouse blastocysts is nearly identical, but some differences do exist; for instance, the timing of the zygotic genome activation (ZGA), at which the activation of embryonic transcription begins, is different between mice and humans. The major wave of ZGA occurs at the late 2‐cell stage in the mouse, while at the 8‐cell stage in human embryos.It is generally known that stem cell lines, the embryonic stem cells (ESCs), trophoblast stem cells (TSCs), and extraembryonic endoderm stem cells (XENCs) can be established from these three cell types in mouse preimplantation embryos and have distinct features and are based on different signaling pathways. ESCs are a pluripotent immortal cell line that is derived by the culture of the ICM cells—originally in the media that contain the cytokine leukemia inhibitory factor (LIF). They express pluripotent markers—such as Oct4 or Nanog—and can contribute to all tissues in the chimeric mouse. The signaling pathway in which LIF inhibits differentiation and promotes the self‐renewal of ESC is well studied. Further, LIF signaling is transduced via the heterodimer of LIF receptor (LIFR) and the common subunit gp130.Attempts to establish human TSC using the human trophoblast have been performed by several researches without success. In recent years, Okae et al reported the derivation of human TSC from human blastocyst and early placenta.8For TE specification, there are two traditional models—the positional model and the polarity model. These models are not exclusive and instead can be complementary, and their hierarchical relationship is being resolved. In this article, we proposed a “tentative state,” in which a blastomere proceeds to undergo TE cell differentiation (in terms of changes in morphology and expression of marker genes) but is not irreversibly restricted and can change its cell fate to ICM. All blastomeres until approximately the 16‐cell stage are supposed to be in the “tentative state,” even if they show heterogeneity in their epigenetic modifications or gene expression patterns. Considering TE specification with this concept, first cell polarity initiates differentiation toward the TE cell fate, and later, when positional information becomes dominant, all outer cells start to express Cdx2. A part of outer cells is internalized, downregulates Cdx2, ceases to proceed along the TE differentiation pathway, and participates in ICM formation. Further, we introduced human TSC, which is a material that is expected to be useful for both basic and medical research. Observation of mouse embryos and studies that use mouse and human TSC or TSC‐like cells will allow a further understanding on TE development before and after implantation.Conflict of interest: The author declares no conflict of interest. Human rights statements and informed consent: This article does not contain any studies with human participants. Animal study: All the animal experiments in this article were approved by the Ethical Committee for Animal Experiment of NIBB.